ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
SIFROL 0.088 mg tablets
2.
Each tablet contains 0.125 mg pramipexole dihydrochloride monohydrate equivalent to 0.088 mg
pramipexole.
Please note:
Pramipexole doses as published in the literature refer to the salt form.
Therefore, doses will be expressed in terms of both pramipexole base and pramipexole salt (in
brackets).
For a full list of excipients, see section 6.1.
3.
Tablet.
The tablets are white, flat, of round shape, and have a code embossed (one side with the code P6, and
one side with the Boehringer Ingelheim company symbol).
4.
SIFROL is indicated in adults for treatment of the signs and symptoms of idiopathic Parkinson’s
disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease,
through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations
of the therapeutic effect occur (end of dose or “on off” fluctuations).
SIFROL is indicated in adults for symptomatic treatment of moderate to severe idiopathic Restless
Legs Syndrome in doses up to 0.54 mg of base (0.75 mg of salt) (see section 4.2).
Posology
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 0.264 mg of base (0.375 mg of salt) 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
(mg of base)
Total Daily Dose
(mg of base)
Dose
(mg of salt)
Total Daily Dose
(mg of salt)
1
3 x 0.088
0.264
3 x 0.125
0.375
2
3 x 0.18
0.54
3 x 0.25
0.75
3
3 x 0.35
1.1
3 x 0.5
1.50
2
If a further dose increase is necessary the daily dose should be increased by 0.54 mg of base (0.75 mg
of salt) at weekly intervals up to a maximum dose of 3.3 mg of base (4.5 mg of salt) 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 0.264 mg of base (0.375 mg of salt) to a
maximum of 3.3 mg of base (4.5 mg of salt) per day. During dose escalation in pivotal studies,
efficacy was observed starting at a daily dose of 1.1 mg of base (1.5 mg of salt). 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 1.1 mg of base (1.5 mg of
salt). In advanced Parkinson’s disease, pramipexole doses higher than 1.1 mg of base (1.5 mg of salt)
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. Pramipexole should be tapered off at a rate of 0.54 mg of base (0.75 mg of salt)
per day until the daily dose has been reduced to 0.54 mg of base (0.75 mg of salt). Thereafter the dose
should be reduced by 0.264 mg of base (0.375 mg of salt) per day (see section 4.4).
Dosing in patients with 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 0.088 mg of base (0.125 mg of salt) twice a
day (0.176 mg of base/0.25 mg of salt daily). A maximum daily dose of 1.57 mg pramipexole base
(2.25 mg of salt) should not be exceeded.
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 0.088 mg of base (0.125 mg of salt) daily. A maximum daily
dose of 1.1 mg pramipexole base (1.5 mg of salt) 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.
Dosing in patients with 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.
3
Restless Legs Syndrome
The recommended starting dose of SIFROL is 0.088 mg of base (0.125 mg of salt) 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 0.54 mg of base (0.75 mg of salt) per day (as shown in the
table below).
Dose Schedule of SIFROL
Titration Step Once Daily Evening Dose
(mg of base)
Once Daily Evening Dose
(mg of salt)
1
0.088
0.125
2*
0.18
0.25
3*
0.35
0.50
4*
0.54
0.75
* 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 0.54 mg of base
(0.75 mg of salt) 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.
Dosing in patients with 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.
Dosing in patients with hepatic impairment
Dose adjustment in patients with hepatic failure is not required, as approx. 90% of absorbed active
substance is excreted through the kidneys.
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.
Hypersensitivity to the active substance or to any of the excipients.
4
When prescribing SIFROL in a patient with Parkinson’s disease with renal impairment a reduced dose
is suggested in line with section 4.2.
Hallucinations
Hallucinations are known as a side effect of treatment with dopamine agonists and levodopa. Patients
should be informed that (mostly visual) hallucinations can occur.
Dyskinesia
In advanced Parkinson’s disease, in combination treatment with levodopa, dyskinesia can occur during
the initial titration of SIFROL. If they occur, the dose of levodopa should be decreased.
Sudden onset of sleep and somnolence
Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in
patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without
awareness or warning signs, has been reported uncommonly. Patients must be informed of this and
advised to exercise caution while driving or operating machines during treatment with SIFROL.
Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from
driving or operating machines. Furthermore a reduction of the dose or termination of therapy may be
considered. Because of possible additive effects, caution should be advised when patients are taking
other sedating medicinal products or alcohol in combination with pramipexole (see sections 4.5, 4.7
and section 4.8).
Impulse control disorders and compulsive behaviours
Pathological gambling, increased libido and hypersexuality have been reported in patients treated with
dopamine agonists for Parkinson’s disease, including SIFROL. Furthermore, patients and caregivers
should be aware of the fact that other behavioural symptoms of impulse control disorders and
compulsions such as binge eating and compulsive shopping can occur. Dose reduction/tapered
discontinuation should be considered.
Patients with psychotic disorders
Patients with psychotic disorders should only be treated with dopamine agonists if the potential
benefits outweigh the risks. Co-administration of antipsychotic medicinal products with pramipexole
should be avoided (see section 4.5).
Ophthalmologic monitoring
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
Severe cardiovascular disease
In case of severe cardiovascular disease, care should be taken. It is recommended to monitor blood
pressure, especially at the beginning of treatment, due to the general risk of postural hypotension
associated with dopaminergic therapy.
Neuroleptic malignant syndrome
Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal
of dopaminergic therapy (see section 4.2).
Augmentation
Reports in the literature indicate that treatment of Restless Legs Syndrome with dopaminergic
medicinal products can result in augmentation. Augmentation refers to the earlier onset of symptoms
in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other
extremities. Augmentation was specifically investigated in a controlled clinical trial over 26 weeks.
Augmentation was observed in 11.8% of patients in the pramipexole group (N = 152) and 9.4% of
patients in the placebo group (N = 149). Kaplan-Meier analysis of time to augmentation showed no
significant difference between pramipexole and placebo groups.
5
Plasma protein binding
Pramipexole is bound to plasma proteins to a very low (< 20%) extent, and little biotransformation is
seen in man. Therefore, interactions with other medicinal products affecting plasma protein binding or
elimination by biotransformation are unlikely. As anticholinergics are mainly eliminated by
biotransformation, the potential for an interaction is limited, although an interaction with
anticholinergics has not been investigated. There is no pharmacokinetic interaction with selegiline and
levodopa.
Inhibitors/competitors of active renal elimination pathway
Cimetidine reduced the renal clearance of pramipexole by approximately 34%, presumably by
inhibition of the cationic secretory transport system of the renal tubules. Therefore, medicinal products
that are inhibitors of this active renal elimination pathway or are eliminated by this pathway, such as
cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine, and procainamide, may interact
with pramipexole resulting in reduced clearance of pramipexole. Reduction of the pramipexole dose
should be considered when these medicinal products are administered concomitantly with SIFROL.
Combination with levodopa
When SIFROL is given in combination with levodopa, it is recommended that the dose of levodopa is
reduced and the dose of other anti-parkinsonian medicinal products is kept constant while increasing
the dose of SIFROL.
Because of possible additive effects, caution should be advised when patients are taking other sedating
medicinal products or alcohol in combination with pramipexole (see section 4.4, 4.7 and 4.8).
Antipsychotic medicinal products
Co-administration of antipsychotic medicinal products with pramipexole should be avoided (see
section 4.4), e.g. if antagonistic effects can be expected.
Pregnancy
The effect on pregnancy and lactation has not been investigated in humans. Pramipexole was not
teratogenic in rats and rabbits, but was embryotoxic in the rat at maternotoxic doses (see section 5.3).
SIFROL should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit
justifies the potential risk to the foetus.
Breast-feeding
As pramipexole treatment inhibits secretion of prolactin in humans, inhibition of lactation is expected.
The excretion of pramipexole into breast milk has not been studied in women. In rats, the
concentration of active substance-related radioactivity was higher in breast milk than in plasma.
In the absence of human data, SIFROL should not be used during breast-feeding. However, if its use is
unavoidable, breast-feeding should be discontinued.
Fertility
No studies on the effect on human fertility have been conducted. In animal studies, pramipexole
affected oestrous cycles and reduced female fertility as expected for a dopamine agonist. However,
these studies did not indicate direct or indirect harmful effects with respect to male fertility.
6
SIFROL can have a major influence on the ability to drive and use machines.
Hallucinations or somnolence can occur.
Patients being treated with SIFROL and presenting with somnolence and/or sudden sleep episodes
must be informed to refrain from driving or engaging in activities where impaired alertness may put
themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent
episodes and somnolence have resolved (see also sections 4.4, 4.5 and 4.8).
Expected adverse reactions
The following adverse reactions are expected under the use of SIFROL: abnormal dreams, amnesia,
behavioural symptoms of impulse control disorders and compulsions such as binge eating, compulsive
shopping, hypersexuality and pathological gambling; confusion, constipation, delusion, dizziness,
dyskinesia, dyspnoea, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia,
hypotension, insomnia, libido disorders, nausea, paranoia, peripheral oedema, pneumonia, pruritus,
rash and other hypersensitivity; restlessness, somnolence, sudden onset of sleep, syncope, visual
impairment including diplopia, vision blurred and visual acuity reduced, vomiting, weight decrease
including decreased appetite, weight increase.
Based on the analysis of pooled placebo-controlled trials, comprising a total of 1,923 patients on
pramipexole and 1,354 patients on placebo, adverse drug reactions were frequently reported for both
groups. 63% of patients on pramipexole and 52% of patients on placebo reported at least one adverse
drug reaction.
Tables 1 and 2 display the frequency of adverse drug reactions from placebo-controlled clinical trials
in Parkinson’s disease and Restless Legs Syndrome. The adverse drug reactions reported in these
tables are those events that occurred in 0.1% or more of patients treated with pramipexole and were
reported significantly more often in patients taking pramipexole than placebo, or where the event was
considered clinically relevant. The majority of adverse drug reactions were mild to moderate, they
usually start early in therapy and most tended to disappear even as therapy was continued.
Within the system organ classes, adverse reactions are listed under headings of frequency (number of
patients expected to experience the reaction), using the following categories: very common (≥ 1/10);
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very
rare (< 1/10,000); not known (cannot be estimated from the available data).
Parkinson’s disease, most common adverse reactions
The most commonly (≥ 5%) reported adverse drug reactions in patients with Parkinson’s disease more
frequent with pramipexole treatment than with placebo were nausea, dyskinesia, hypotension,
dizziness, somnolence, insomnia, constipation, hallucination, headache and fatigue. The incidence of
somnolence is increased at doses higher than 1.5 mg pramipexole salt per day (see section 4.2). A
more frequent adverse drug reaction in combination with levodopa was dyskinesia. Hypotension may
occur at the beginning of treatment, especially if pramipexole is titrated too fast.
7
Table 1: Parkinson’s disease
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
Common
abnormal dreams, behavioural symptoms of impulse control
disorders and compulsions, confusion, hallucinations, insomnia
Uncommon
binge eating, compulsive shopping, delusion, hyperphagia,
hypersexuality, libido disorder, paranoia, pathological gambling,
restlessness
Nervous system disorders
Very common
dizziness, dyskinesia, somnolence
Common
headache
Uncommon
amnesia, hyperkinesia, sudden onset of sleep, syncope
Eye disorders
Common
visual impairment including diplopia, vision blurred and visual
acuity reduced
Vascular disorders
Common hypotension
Respiratory, thoracic, and mediastinal disorders
Uncommon
dyspnoea, hiccups
Gastrointestinal disorders
Very common nausea
Common constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common
fatigue, peripheral oedema
Investigations
Common
weight decrease including decreased appetite
Uncommon
weight increase
Restless Legs Syndrome, most common adverse reactions
The most commonly (≥ 5%) reported adverse drug reactions in patients with Restless Legs Syndrome
treated with pramipexole were nausea, headache, dizziness and fatigue. Nausea and fatigue were more
often reported in female patients treated with SIFROL (20.8% and 10.5%, respectively) compared to
males (6.7% and 7.3%, respectively).
8
Table 2: Restless Legs Syndrome
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
Common
abnormal dreams, insomnia
Uncommon
behavioural symptoms of impulse control disorders and
compulsions such as binge eating, compulsive shopping,
hypersexuality, and pathological gambling; confusion, delusion,
hallucinations, hyperphagia, libido disorder, paranoia,
restlessness
Nervous system disorders
Common
dizziness, headache, somnolence
Uncommon
amnesia, dyskinesia, hyperkinesia, sudden onset of sleep, syncope
Eye disorders
Uncommon
visual impairment including diplopia, vision blurred and visual
acuity reduced
Vascular disorders
Uncommon hypotension
Respiratory, thoracic, and mediastinal disorders
Uncommon
dyspnoea, hiccups
Gastrointestinal disorders
Very common nausea
Common constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common
fatigue
Uncommon
peripheral oedema
Investigations
Uncommon
weight decrease including decreased appetite, weight increase
Somnolence
Pramipexole is commonly associated with somnolence and has been associated uncommonly with
excessive daytime somnolence and sudden sleep onset episodes (see also section 4.4).
Libido disorders
Pramipexole may uncommonly be associated with libido disorders (increased or decreased).
Impulse control disorders and compulsive behaviours
Patients treated with dopamine agonists for Parkinson’s disease, including SIFROL, especially at high
doses, have been reported as exhibiting signs of pathological gambling, increased libido and
hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation (see also
section 4.4).
In a cross-sectional, retrospective screening and case-control study including 3,090 Parkinson’s
disease patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic treatment had
symptoms of an impulse control disorder during the past six months. Manifestations observed include
pathological gambling, compulsive shopping, binge eating, and compulsive sexual behaviour
(hypersexuality). Possible independent risk factors for impulse control disorders included
dopaminergic treatments and higher doses of dopaminergic treatment, younger age ( ≤ 65 years), not
being married and self-reported family history of gambling behaviours.
9
There is no clinical experience with massive overdose. The expected adverse reactions would be those
related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting,
hyperkinesia, hallucinations, agitation and hypotension. There is no established antidote for overdose
of a dopamine agonist. If signs of central nervous system stimulation are present, a neuroleptic agent
may be indicated. Management of the overdose may require general supportive measures, along with
gastric lavage, intravenous fluids, administration of activated charcoal and electrocardiogram
monitoring.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-Parkinson drugs, dopamine agonists, ATC code: N04BC05.
Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 subfamily
of dopamine receptors of which it has a preferential affinity to D3 receptors, and has full intrinsic
activity.
Pramipexole alleviates parkinsonian motor deficits by stimulation of dopamine receptors in the
striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release, and
turnover.
The mechanism of action of pramipexole as treatment for Restless Legs Syndrome is unknown.
Neuropharmacological evidence suggests primary dopaminergic system involvement.
In human volunteers, a dose-dependent decrease in prolactin was observed. In a clinical trial with
healthy volunteers, where SIFROL prolonged-release tablets were titrated faster (every 3 days) than
recommended up to 3.15 mg pramipexole base (4.5 mg of salt) per day, an increase in blood pressure
and heart rate was observed. Such effect was not observed in patient studies.
Clinical trials in Parkinson’s disease
In patients pramipexole alleviates signs and symptoms of idiopathic Parkinson’s disease. Placebo-
controlled clinical trials included approximately 1,800 patients of Hoehn and Yahr stages I – V treated
with pramipexole. Out of these, approximately 1,000 were in more advanced stages, received
concomitant levodopa therapy, and suffered from motor complications.
In early and advanced Parkinson’s disease, efficacy of pramipexole in controlled clinical trials was
maintained for approximately six months. In open continuation trials lasting for more than three years
there were no signs of decreasing efficacy.
In a controlled double blind clinical trial of 2 year duration, initial treatment with pramipexole
significantly delayed the onset of motor complications, and reduced their occurrence compared to
initial treatment with levodopa. This delay in motor complications with pramipexole should be
balanced against a greater improvement in motor function with levodopa (as measured by the mean
change in UPDRS-score). The overall incidence of hallucinations and somnolence was generally
higher in the escalation phase with the pramipexole group. However, there was no significant
difference during the maintenance phase. These points should be considered when initiating
pramipexole treatment in patients with Parkinson’s disease.
The European Medicines Agency has waived the obligation to submit the results of studies with
SIFROL in all subsets of the paediatric population in Parkinson’s Disease (see section 4.2 for
information on paediatric use).
10
Clinical trials in Restless Legs Syndrome
The efficacy of pramipexole was evaluated in four placebo-controlled clinical trials in approximately
1,000 patients with moderate to very severe idiopathic Restless Legs Syndrome.
The mean change from baseline in the Restless Legs Syndrome Rating Scale (IRLS) and the Clinical
Global Impression-Improvement (CGI-I) were the primary efficacy outcome measures. For both
primary endpoints statistically significant differences have been observed for the pramipexole dose
groups 0.25 mg, 0.5 mg and 0.75 mg pramipexole salt in comparison to placebo. After 12 weeks of
treatment the baseline IRLS score improved from 23.5 to 14.1 points for placebo and from 23.4 to 9.4
points for pramipexole (doses combined). The adjusted mean difference was -4.3 points (CI 95% -6.4;
-2.1 points, p-value <0.0001). CGI-I responder rates (improved, very much improved) were 51.2% and
72.0% for placebo and pramipexole, respectively (difference 20% CI 95%: 8.1%; 31.8%, p<0.0005).
Efficacy was observed with 0.088 mg of base (0.125 mg of salt) per day after the first week of
treatment.
In a placebo-controlled polysomnography study over 3 weeks SIFROL significantly reduced the
number of periodic limb movements during time in bed.
Longer term efficacy was evaluated in a placebo-controlled clinical trial. After 26 weeks of treatment,
there was an adjusted mean reduction in IRLS total score of 13.7 and 11.1 points in the pramipexole
and placebo group, respectively, with a statistically significant (p = 0.008) mean treatment difference
of -2.6. CGI-I responder rates (much improved, very much improved) were 50.3% (80/159) and 68.5%
(111/162) for placebo and pramipexole, respectively (p = 0.001), corresponding to a number needed to
treat (NNT) of 6 patients (95%CI: 3.5, 13.4).
The European Medicines Agency has deferred the obligation to submit the results of studies with
SIFROL in one or more subsets of the paediatric population in Restless Legs Syndrome (see section
4.2 for information on paediatric use).
Clinical trial in Tourette Disorder
The efficacy of pramipexole (0.0625-0.5 mg/day) with paediatric patients aged 6-17 years with
Tourette Disorder was evaluated in a 6-week, double-blind, randomised, placebo-controlled flexible
dose study. A total of 63 patients were randomised (43 on pramipexole, 20 on placebo). The primary
endpoint was change from baseline on the Total Tic Score (TTS) of the Yale Global Tic Severity
Scale (YGTSS). No difference was observed for pramipexole as compared to placebo for either the
primary endpoint or for any of the secondary efficacy endpoints including YGTSS total score, Patient
Global Impression of Improvement (PGI-I), Clinical Global Impression of Improvement (CGI-I), or
Clinical Global Impressions of Severity of Illness (CGI-S). Adverse events occurring in at least 5% of
patients in the pramipexole group and more common in the pramipexole-treated patients than in
patients on placebo were: headache (27.9%, placebo 25.0%), somnolence (7.0%, placebo 5.0%),
nausea (18.6%, placebo 10.0%), vomiting (11.6%, placebo 0.0%), upper abdominal pain (7.0%,
placebo 5.0%), orthostatic hypotension (9.3%, placebo 5.0%), myalgia (9.3%, placebo 5.0%), sleep
disorder (7.0%, placebo 0.0%), dyspnoea (7.0%, placebo 0.0%) and upper respiratory tract infection
(7.0%, placebo 5.0%). Other significant adverse events leading to discontinuation of study medication
for patients receiving pramipexole were confusional state, speech disorder and aggravated condition
(see section 4.2).
5.2 Pharmacokinetic properties
Pramipexole is rapidly and completely absorbed following oral administration. The absolute
bioavailability is greater than 90% and the maximum plasma concentrations occur between 1 and 3
hours. Concomitant administration with food did not reduce the extent of pramipexole absorption, but
the rate of absorption was reduced. Pramipexole shows linear kinetics and a small inter-patient
variation of plasma levels. In humans, the protein binding of pramipexole is very low (< 20%) and the
11
volume of distribution is large (400 l). High brain tissue concentrations were observed in the rat
(approx. 8-fold compared to plasma).
Pramipexole is metabolised in man only to a small extent.
Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of
14C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The total
clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately
400 ml/min. The elimination half-life (t½) varies from 8 hours in the young to 12 hours in the elderly.
5.3 Preclinical safety data
Repeated dose toxicity studies showed that pramipexole exerted functional effects, mainly involving
the CNS and female reproductive system, and probably resulting from an exaggerated
pharmacodynamic effect of pramipexole.
Decreases in diastolic and systolic pressure and heart rate were noted in the minipig, and a tendency to
a hypotensive effect was discerned in the monkey.
The potential effects of pramipexole on reproductive function have been investigated in rats and
rabbits. Pramipexole was not teratogenic in rats and rabbits but was embryotoxic in the rat at
maternally toxic doses. Due to the selection of animal species and the limited parameters investigated,
the adverse effects of pramipexole on pregnancy and male fertility have not been fully elucidated.
A delay in sexual development (i.e., preputial separation and vaginal opening) was observed in rats.
The relevance for humans is unknown.
Pramipexole was not genotoxic. In a carcinogenicity study, male rats developed Leydig cell
hyperplasia and adenomas, explained by the prolactin-inhibiting effect of pramipexole. This finding is
not clinically relevant to man. The same study also showed that, at doses of 2 mg/kg (of salt) and
higher, pramipexole was associated with retinal degeneration in albino rats. The latter finding was not
observed in pigmented rats, nor in a 2-year albino mouse carcinogenicity study or in any other species
investigated.
6.
6.1 List of excipients
Mannitol
maize starch
anhydrous colloidal silica
povidone K 25
magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from light.
12
6.5 Nature and contents of container
OPA/aluminium/PVC-aluminium blisters.
Each blister strip contains 10 tablets.
Cartons containing 3 or 10 blister strips (30 or 100 tablets).
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
8.
EU/1/97/050/001-002
9.
Date of first authorisation: 14 October 1997
Date of latest renewal: 14 October 2007
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu.
13
1.
SIFROL 0.18 mg tablets
2.
Each tablet contains 0.25 mg pramipexole dihydrochloride monohydrate equivalent to 0.18 mg
pramipexole.
Please note:
Pramipexole doses as published in the literature refer to the salt form.
Therefore, doses will be expressed in terms of both pramipexole base and pramipexole salt (in
brackets).
For a full list of excipients, see section 6.1.
3.
Tablet.
The tablets are white, flat, of oval shape, scored on both sides, and have a code embossed (one side
with the code P7, and one side with the Boehringer Ingelheim company symbol).
Tablets can be divided into equal halves.
4.
SIFROL is indicated in adults for treatment of the signs and symptoms of idiopathic Parkinson’s
disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease,
through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations
of the therapeutic effect occur (end of dose or “on off” fluctuations).
SIFROL is indicated in adults for symptomatic treatment of moderate to severe idiopathic Restless
Legs Syndrome in doses up to 0.54 mg of base (0.75 mg of salt) (see section 4.2).
Posology
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 0.264 mg of base (0.375 mg of salt) 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
(mg of base)
Total Daily Dose
(mg of base)
Dose
(mg of salt)
Total Daily Dose
(mg of salt)
1
3 x 0.088
0.264
3 x 0.125
0.375
2
3 x 0.18
0.54
3 x 0.25
0.75
3
3 x 0.35
1.1
3 x 0.5
1.50
14
If a further dose increase is necessary the daily dose should be increased by 0.54 mg of base (0.75 mg
of salt) at weekly intervals up to a maximum dose of 3.3 mg of base (4.5 mg of salt) 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 0.264 mg of base (0.375 mg of salt) to a
maximum of 3.3 mg of base (4.5 mg of salt) per day. During dose escalation in pivotal studies,
efficacy was observed starting at a daily dose of 1.1 mg of base (1.5 mg of salt). 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 1.1 mg of base (1.5 mg of
salt). In advanced Parkinson’s disease, pramipexole doses higher than 1.1 mg of base (1.5 mg of salt)
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. Pramipexole should be tapered off at a rate of 0.54 mg of base (0.75 mg of salt)
per day until the daily dose has been reduced to 0.54 mg of base (0.75 mg of salt). Thereafter the dose
should be reduced by 0.264 mg of base (0.375 mg of salt) per day (see section 4.4).
Dosing in patients with 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 0.088 mg of base (0.125 mg of salt) twice a
day (0.176 mg of base/0.25 mg of salt daily). A maximum daily dose of 1.57 mg pramipexole base
(2.25 mg of salt) should not be exceeded.
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 0.088 mg of base (0.125 mg of salt) daily. A maximum daily
dose of 1.1 mg pramipexole base (1.5 mg of salt) 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.
Dosing in patients with 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.
15
Restless Legs Syndrome
The recommended starting dose of SIFROL is 0.088 mg of base (0.125 mg of salt) 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 0.54 mg of base (0.75 mg of salt) per day (as shown in the
table below).
Dose Schedule of SIFROL
Titration Step Once Daily Evening Dose
(mg of base)
Once Daily Evening Dose
(mg of salt)
1
0.088
0.125
2*
0.18
0.25
3*
0.35
0.50
4*
0.54
0.75
* 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 0.54 mg of base
(0.75 mg of salt) 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.
Dosing in patients with 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.
Dosing in patients with hepatic impairment
Dose adjustment in patients with hepatic failure is not required, as approx. 90% of absorbed active
substance is excreted through the kidneys.
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.
Hypersensitivity to the active substance or to any of the excipients.
16
When prescribing SIFROL in a patient with Parkinson’s disease with renal impairment a reduced dose
is suggested in line with section 4.2.
Hallucinations
Hallucinations are known as a side effect of treatment with dopamine agonists and levodopa. Patients
should be informed that (mostly visual) hallucinations can occur.
Dyskinesia
In advanced Parkinson’s disease, in combination treatment with levodopa, dyskinesia can occur during
the initial titration of SIFROL. If they occur, the dose of levodopa should be decreased.
Sudden onset of sleep and somnolence
Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in
patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without
awareness or warning signs, has been reported uncommonly. Patients must be informed of this and
advised to exercise caution while driving or operating machines during treatment with SIFROL.
Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from
driving or operating machines. Furthermore a reduction of the dose or termination of therapy may be
considered. Because of possible additive effects, caution should be advised when patients are taking
other sedating medicinal products or alcohol in combination with pramipexole (see sections 4.5, 4.7
and section 4.8).
Impulse control disorders and compulsive behaviours
Pathological gambling, increased libido and hypersexuality have been reported in patients treated with
dopamine agonists for Parkinson’s disease, including SIFROL. Furthermore, patients and caregivers
should be aware of the fact that other behavioural symptoms of impulse control disorders and
compulsions such as binge eating and compulsive shopping can occur. Dose reduction/tapered
discontinuation should be considered.
Patients with psychotic disorders
Patients with psychotic disorders should only be treated with dopamine agonists if the potential
benefits outweigh the risks. Co-administration of antipsychotic medicinal products with pramipexole
should be avoided (see section 4.5).
Ophthalmologic monitoring
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
Severe cardiovascular disease
In case of severe cardiovascular disease, care should be taken. It is recommended to monitor blood
pressure, especially at the beginning of treatment, due to the general risk of postural hypotension
associated with dopaminergic therapy.
Neuroleptic malignant syndrome
Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal
of dopaminergic therapy (see section 4.2).
Augmentation
Reports in the literature indicate that treatment of Restless Legs Syndrome with dopaminergic
medicinal products can result in augmentation. Augmentation refers to the earlier onset of symptoms
in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other
extremities. Augmentation was specifically investigated in a controlled clinical trial over 26 weeks.
Augmentation was observed in 11.8% of patients in the pramipexole group (N = 152) and 9.4% of
patients in the placebo group (N = 149). Kaplan-Meier analysis of time to augmentation showed no
significant difference between pramipexole and placebo groups.
17
Plasma protein binding
Pramipexole is bound to plasma proteins to a very low (< 20%) extent, and little biotransformation is
seen in man. Therefore, interactions with other medicinal products affecting plasma protein binding or
elimination by biotransformation are unlikely. As anticholinergics are mainly eliminated by
biotransformation, the potential for an interaction is limited, although an interaction with
anticholinergics has not been investigated. There is no pharmacokinetic interaction with selegiline and
levodopa.
Inhibitors/competitors of active renal elimination pathway
Cimetidine reduced the renal clearance of pramipexole by approximately 34%, presumably by
inhibition of the cationic secretory transport system of the renal tubules. Therefore, medicinal products
that are inhibitors of this active renal elimination pathway or are eliminated by this pathway, such as
cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine, and procainamide, may interact
with pramipexole resulting in reduced clearance of pramipexole. Reduction of the pramipexole dose
should be considered when these medicinal products are administered concomitantly with SIFROL.
Combination with levodopa
When SIFROL is given in combination with levodopa, it is recommended that the dose of levodopa is
reduced and the dose of other anti-parkinsonian medicinal products is kept constant while increasing
the dose of SIFROL.
Because of possible additive effects, caution should be advised when patients are taking other sedating
medicinal products or alcohol in combination with pramipexole (see section 4.4, 4.7 and 4.8).
Antipsychotic medicinal products
Co-administration of antipsychotic medicinal products with pramipexole should be avoided (see
section 4.4), e.g. if antagonistic effects can be expected.
Pregnancy
The effect on pregnancy and lactation has not been investigated in humans. Pramipexole was not
teratogenic in rats and rabbits, but was embryotoxic in the rat at maternotoxic doses (see section 5.3).
SIFROL should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit
justifies the potential risk to the foetus.
Breast-feeding
As pramipexole treatment inhibits secretion of prolactin in humans, inhibition of lactation is expected.
The excretion of pramipexole into breast milk has not been studied in women. In rats, the
concentration of active substance-related radioactivity was higher in breast milk than in plasma.
In the absence of human data, SIFROL should not be used during breast-feeding. However, if its use is
unavoidable, breast-feeding should be discontinued.
Fertility
No studies on the effect on human fertility have been conducted. In animal studies, pramipexole
affected oestrous cycles and reduced female fertility as expected for a dopamine agonist. However,
these studies did not indicate direct or indirect harmful effects with respect to male fertility.
18
SIFROL can have a major influence on the ability to drive and use machines.
Hallucinations or somnolence can occur.
Patients being treated with SIFROL and presenting with somnolence and/or sudden sleep episodes
must be informed to refrain from driving or engaging in activities where impaired alertness may put
themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent
episodes and somnolence have resolved (see also sections 4.4, 4.5 and 4.8).
Expected adverse reactions
The following adverse reactions are expected under the use of SIFROL: abnormal dreams, amnesia,
behavioural symptoms of impulse control disorders and compulsions such as binge eating, compulsive
shopping, hypersexuality and pathological gambling; confusion, constipation, delusion, dizziness,
dyskinesia, dyspnoea, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia,
hypotension, insomnia, libido disorders, nausea, paranoia, peripheral oedema, pneumonia, pruritus,
rash and other hypersensitivity; restlessness, somnolence, sudden onset of sleep, syncope, visual
impairment including diplopia, vision blurred and visual acuity reduced, vomiting, weight decrease
including decreased appetite, weight increase.
Based on the analysis of pooled placebo-controlled trials, comprising a total of 1,923 patients on
pramipexole and 1,354 patients on placebo, adverse drug reactions were frequently reported for both
groups. 63% of patients on pramipexole and 52% of patients on placebo reported at least one adverse
drug reaction.
Tables 1 and 2 display the frequency of adverse drug reactions from placebo-controlled clinical trials
in Parkinson’s disease and Restless Legs Syndrome. The adverse drug reactions reported in these
tables are those events that occurred in 0.1% or more of patients treated with pramipexole and were
reported significantly more often in patients taking pramipexole than placebo, or where the event was
considered clinically relevant. The majority of adverse drug reactions were mild to moderate, they
usually start early in therapy and most tended to disappear even as therapy was continued.
Within the system organ classes, adverse reactions are listed under headings of frequency (number of
patients expected to experience the reaction), using the following categories: very common (≥ 1/10);
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very
rare (< 1/10,000); not known (cannot be estimated from the available data).
Parkinson’s disease, most common adverse reactions
The most commonly (≥ 5%) reported adverse drug reactions in patients with Parkinson’s disease more
frequent with pramipexole treatment than with placebo were nausea, dyskinesia, hypotension,
dizziness, somnolence, insomnia, constipation, hallucination, headache and fatigue. The incidence of
somnolence is increased at doses higher than 1.5 mg pramipexole salt per day (see section 4.2). A
more frequent adverse drug reaction in combination with levodopa was dyskinesia. Hypotension may
occur at the beginning of treatment, especially if pramipexole is titrated too fast.
19
Table 1: Parkinson’s disease
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
Common
abnormal dreams, behavioural symptoms of impulse control
disorders and compulsions, confusion, hallucinations, insomnia
Uncommon
binge eating, compulsive shopping, delusion, hyperphagia,
hypersexuality, libido disorder, paranoia, pathological gambling,
restlessness
Nervous system disorders
Very common
dizziness, dyskinesia, somnolence
Common
headache
Uncommon
amnesia, hyperkinesia, sudden onset of sleep, syncope
Eye disorders
Common
visual impairment including diplopia,vision blurred and visual
acuity reduced
Vascular disorders
Common hypotension
Respiratory, thoracic, and mediastinal disorders
Uncommon
dyspnoea, hiccups
Gastrointestinal disorders
Very common nausea
Common constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common
fatigue, peripheral oedema
Investigations
Common
weight decrease including decreased appetite
Uncommon
weight increase
Restless Legs Syndrome, most common adverse reactions
The most commonly (≥ 5%) reported adverse drug reactions in patients with Restless Legs Syndrome
treated with pramipexole were nausea, headache, dizziness and fatigue. Nausea and fatigue were more
often reported in female patients treated with SIFROL (20.8% and 10.5%, respectively) compared to
males (6.7% and 7.3%, respectively).
20
Table 2: Restless Legs Syndrome
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
Common
abnormal dreams, insomnia
Uncommon
behavioural symptoms of impulse control disorders and
compulsions such as binge eating, compulsive shopping,
hypersexuality, and pathological gambling; confusion, delusion,
hallucinations, hyperphagia, libido disorder, paranoia,
restlessness
Nervous system disorders
Common
dizziness, headache, somnolence
Uncommon
amnesia, dyskinesia, hyperkinesia, sudden onset of sleep, syncope
Eye disorders
Uncommon
visual impairment including diplopia,vision blurred and visual
acuity reduced
Vascular disorders
Uncommon hypotension
Respiratory, thoracic, and mediastinal disorders
Uncommon
dyspnoea, hiccups
Gastrointestinal disorders
Very common nausea
Common constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common
fatigue
Uncommon
peripheral oedema
Investigations
Uncommon
weight decrease including decreased appetite, weight increase
Somnolence
Pramipexole is commonly associated with somnolence and has been associated uncommonly with
excessive daytime somnolence and sudden sleep onset episodes (see also section 4.4).
Libido disorders
Pramipexole may uncommonly be associated with libido disorders (increased or decreased).
Impulse control disorders and compulsive behaviours
Patients treated with dopamine agonists for Parkinson’s disease, including SIFROL, especially at high
doses, have been reported as exhibiting signs of pathological gambling, increased libido and
hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation (see also
section 4.4).
In a cross-sectional, retrospective screening and case-control study including 3,090 Parkinson’s
disease patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic treatment had
symptoms of an impulse control disorder during the past six months. Manifestations observed include
pathological gambling, compulsive shopping, binge eating, and compulsive sexual behaviour
(hypersexuality). Possible independent risk factors for impulse control disorders included
dopaminergic treatments and higher doses of dopaminergic treatment, younger age ( ≤ 65 years), not
being married and self-reported family history of gambling behaviours.
21
There is no clinical experience with massive overdose. The expected adverse reactions would be those
related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting,
hyperkinesia, hallucinations, agitation and hypotension. There is no established antidote for overdose
of a dopamine agonist. If signs of central nervous system stimulation are present, a neuroleptic agent
may be indicated. Management of the overdose may require general supportive measures, along with
gastric lavage, intravenous fluids, administration of activated charcoal and electrocardiogram
monitoring.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-Parkinson drugs, dopamine agonists, ATC code: N04BC05.
Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 subfamily
of dopamine receptors of which it has a preferential affinity to D3 receptors, and has full intrinsic
activity.
Pramipexole alleviates parkinsonian motor deficits by stimulation of dopamine receptors in the
striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release, and
turnover.
The mechanism of action of pramipexole as treatment for Restless Legs Syndrome is unknown.
Neuropharmacological evidence suggests primary dopaminergic system involvement.
In human volunteers, a dose-dependent decrease in prolactin was observed. In a clinical trial with
healthy volunteers, where SIFROL prolonged-release tablets were titrated faster (every 3 days) than
recommended up to 3.15 mg pramipexole base (4.5 mg of salt) per day, an increase in blood pressure
and heart rate was observed. Such effect was not observed in patient studies.
Clinical trials in Parkinson’s disease
In patients pramipexole alleviates signs and symptoms of idiopathic Parkinson’s disease. Placebo-
controlled clinical trials included approximately 1,800 patients of Hoehn and Yahr stages I – V treated
with pramipexole. Out of these, approximately 1,000 were in more advanced stages, received
concomitant levodopa therapy, and suffered from motor complications.
In early and advanced Parkinson’s disease, efficacy of pramipexole in controlled clinical trials was
maintained for approximately six months. In open continuation trials lasting for more than three years
there were no signs of decreasing efficacy.
In a controlled double blind clinical trial of 2 year duration, initial treatment with pramipexole
significantly delayed the onset of motor complications, and reduced their occurrence compared to
initial treatment with levodopa. This delay in motor complications with pramipexole should be
balanced against a greater improvement in motor function with levodopa (as measured by the mean
change in UPDRS-score). The overall incidence of hallucinations and somnolence was generally
higher in the escalation phase with the pramipexole group. However, there was no significant
difference during the maintenance phase. These points should be considered when initiating
pramipexole treatment in patients with Parkinson’s disease.
The European Medicines Agency has waived the obligation to submit the results of studies with
SIFROL in all subsets of the paediatric population in Parkinson’s Disease (see section 4.2 for
information on paediatric use).
22
Clinical trials in Restless Legs Syndrome
The efficacy of pramipexole was evaluated in four placebo-controlled clinical trials in approximately
1,000 patients with moderate to very severe idiopathic Restless Legs Syndrome.
The mean change from baseline in the Restless Legs Syndrome Rating Scale (IRLS) and the Clinical
Global Impression-Improvement (CGI-I) were the primary efficacy outcome measures. For both
primary endpoints statistically significant differences have been observed for the pramipexole dose
groups 0.25 mg, 0.5 mg and 0.75 mg pramipexole salt in comparison to placebo. After 12 weeks of
treatment the baseline IRLS score improved from 23.5 to 14.1 points for placebo and from 23.4 to 9.4
points for pramipexole (doses combined). The adjusted mean difference was -4.3 points (CI 95% -6.4;
-2.1 points, p-value <0.0001). CGI-I responder rates (improved, very much improved) were 51.2% and
72.0% for placebo and pramipexole, respectively (difference 20% CI 95%: 8.1%; 31.8%, p<0.0005).
Efficacy was observed with 0.088 mg of base (0.125 mg of salt) per day after the first week of
treatment.
In a placebo-controlled polysomnography study over 3 weeks SIFROL significantly reduced the
number of periodic limb movements during time in bed.
Longer term efficacy was evaluated in a placebo-controlled clinical trial. After 26 weeks of treatment,
there was an adjusted mean reduction in IRLS total score of 13.7 and 11.1 points in the pramipexole
and placebo group, respectively, with a statistically significant (p = 0.008) mean treatment difference
of -2.6. CGI-I responder rates (much improved, very much improved) were 50.3% (80/159) and 68.5%
(111/162) for placebo and pramipexole, respectively (p = 0.001), corresponding to a number needed to
treat (NNT) of 6 patients (95%CI: 3.5, 13.4).
The European Medicines Agency has deferred the obligation to submit the results of studies with
SIFROL in one or more subsets of the paediatric population in Restless Legs Syndrome (see section
4.2 for information on paediatric use).
Clinical trial in Tourette Disorder
The efficacy of pramipexole (0.0625-0.5 mg/day) with paediatric patients aged 6-17 years with
Tourette Disorder was evaluated in a 6-week, double-blind, randomised, placebo-controlled flexible
dose study. A total of 63 patients were randomised (43 on pramipexole, 20 on placebo). The primary
endpoint was change from baseline on the Total Tic Score (TTS) of the Yale Global Tic Severity
Scale (YGTSS). No difference was observed for pramipexole as compared to placebo for either the
primary endpoint or for any of the secondary efficacy endpoints including YGTSS total score, Patient
Global Impression of Improvement (PGI-I), Clinical Global Impression of Improvement (CGI-I), or
Clinical Global Impressions of Severity of Illness (CGI-S). Adverse events occurring in at least 5% of
patients in the pramipexole group and more common in the pramipexole-treated patients than in
patients on placebo were: headache (27.9%, placebo 25.0%), somnolence (7.0%, placebo 5.0%),
nausea (18.6%, placebo 10.0%), vomiting (11.6%, placebo 0.0%), upper abdominal pain (7.0%,
placebo 5.0%), orthostatic hypotension (9.3%, placebo 5.0%), myalgia (9.3%, placebo 5.0%), sleep
disorder (7.0%, placebo 0.0%), dyspnoea (7.0%, placebo 0.0%) and upper respiratory tract infection
(7.0%, placebo 5.0%). Other significant adverse events leading to discontinuation of study medication
for patients receiving pramipexole were confusional state, speech disorder and aggravated condition
(see section 4.2).
5.2 Pharmacokinetic properties
Pramipexole is rapidly and completely absorbed following oral administration. The absolute
bioavailability is greater than 90% and the maximum plasma concentrations occur between 1 and 3
hours. Concomitant administration with food did not reduce the extent of pramipexole absorption, but
the rate of absorption was reduced. Pramipexole shows linear kinetics and a small inter-patient
variation of plasma levels. In humans, the protein binding of pramipexole is very low (< 20%) and the
23
volume of distribution is large (400 l). High brain tissue concentrations were observed in the rat
(approx. 8-fold compared to plasma).
Pramipexole is metabolised in man only to a small extent.
Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of
14C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The total
clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately
400 ml/min. The elimination half-life (t½) varies from 8 hours in the young to 12 hours in the elderly.
5.3 Preclinical safety data
Repeated dose toxicity studies showed that pramipexole exerted functional effects, mainly involving
the CNS and female reproductive system, and probably resulting from an exaggerated
pharmacodynamic effect of pramipexole.
Decreases in diastolic and systolic pressure and heart rate were noted in the minipig, and a tendency to
a hypotensive effect was discerned in the monkey.
The potential effects of pramipexole on reproductive function have been investigated in rats and
rabbits. Pramipexole was not teratogenic in rats and rabbits but was embryotoxic in the rat at
maternally toxic doses. Due to the selection of animal species and the limited parameters investigated,
the adverse effects of pramipexole on pregnancy and male fertility have not been fully elucidated.
A delay in sexual development (i.e., preputial separation and vaginal opening) was observed in rats.
The relevance for humans is unknown.
Pramipexole was not genotoxic. In a carcinogenicity study, male rats developed Leydig cell
hyperplasia and adenomas, explained by the prolactin-inhibiting effect of pramipexole. This finding is
not clinically relevant to man. The same study also showed that, at doses of 2 mg/kg (of salt) and
higher, pramipexole was associated with retinal degeneration in albino rats. The latter finding was not
observed in pigmented rats, nor in a 2-year albino mouse carcinogenicity study or in any other species
investigated.
6.
6.1 List of excipients
Mannitol
maize starch
anhydrous colloidal silica
povidone K 25
magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from light.
24
6.5 Nature and contents of container
OPA/aluminium/PVC-aluminium blisters.
Each blister strip contains 10 tablets.
Cartons containing 3 or 10 blister strips (30 or 100 tablets).
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
8.
EU/1/97/050/003-004
9.
Date of first authorisation: 14 October 1997
Date of latest renewal: 14 October 2007
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu.
25
1.
SIFROL 0.35 mg tablets
2.
Each tablet contains 0.5 mg pramipexole dihydrochloride monohydrate equivalent to 0.35 mg
pramipexole.
Please note:
Pramipexole doses as published in the literature refer to the salt form.
Therefore, doses will be expressed in terms of both pramipexole base and pramipexole salt (in
brackets).
For a full list of excipients, see section 6.1.
3.
Tablet.
The tablets are white, flat, of oval shape, scored on both sides, and have a code embossed (one side
with the code P8, and one side with the Boehringer Ingelheim company symbol).
Tablets can be divided into equal halves.
4.
SIFROL is indicated in adults for treatment of the signs and symptoms of idiopathic Parkinson’s
disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease,
through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations
of the therapeutic effect occur (end of dose or “on off” fluctuations).
SIFROL is indicated in adults for symptomatic treatment of moderate to severe idiopathic Restless
Legs Syndrome in doses up to 0.54 mg of base (0.75 mg of salt) (see section 4.2).
Posology
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 0.264 mg of base (0.375 mg of salt) 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
(mg of base)
Total Daily Dose
(mg of base)
Dose
(mg of salt)
Total Daily Dose
(mg of salt)
1
3 x 0.088
0.264
3 x 0.125
0.375
2
3 x 0.18
0.54
3 x 0.25
0.75
3
3 x 0.35
1.1
3 x 0.5
1.50
26
If a further dose increase is necessary the daily dose should be increased by 0.54 mg of base (0.75 mg
of salt) at weekly intervals up to a maximum dose of 3.3 mg of base (4.5 mg of salt) 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 0.264 mg of base (0.375 mg of salt) to a
maximum of 3.3 mg of base (4.5 mg of salt) per day. During dose escalation in pivotal studies,
efficacy was observed starting at a daily dose of 1.1 mg of base (1.5 mg of salt). 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 1.1 mg of base (1.5 mg of
salt). In advanced Parkinson’s disease, pramipexole doses higher than 1.1 mg of base (1.5 mg of salt)
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. Pramipexole should be tapered off at a rate of 0.54 mg of base (0.75 mg of salt)
per day until the daily dose has been reduced to 0.54 mg of base (0.75 mg of salt). Thereafter the dose
should be reduced by 0.264 mg of base (0.375 mg of salt) per day (see section 4.4).
Dosing in patients with 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 0.088 mg of base (0.125 mg of salt) twice a
day (0.176 mg of base/0.25 mg of salt daily). A maximum daily dose of 1.57 mg pramipexole base
(2.25 mg of salt) should not be exceeded.
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 0.088 mg of base (0.125 mg of salt) daily. A maximum daily
dose of 1.1 mg pramipexole base (1.5 mg of salt) 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.
Dosing in patients with 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.
27
Restless Legs Syndrome
The recommended starting dose of SIFROL is 0.088 mg of base (0.125 mg of salt) 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 0.54 mg of base (0.75 mg of salt) per day (as shown in the
table below).
Dose Schedule of SIFROL
Titration Step Once Daily Evening Dose
(mg of base)
Once Daily Evening Dose
(mg of salt)
1
0.088
0.125
2*
0.18
0.25
3*
0.35
0.50
4*
0.54
0.75
* 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 0.54 mg of base
(0.75 mg of salt) 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.
Dosing in patients with 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.
Dosing in patients with hepatic impairment
Dose adjustment in patients with hepatic failure is not required, as approx. 90% of absorbed active
substance is excreted through the kidneys.
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.
Hypersensitivity to the active substance or to any of the excipients.
28
When prescribing SIFROL in a patient with Parkinson’s disease with renal impairment a reduced dose
is suggested in line with section 4.2.
Hallucinations
Hallucinations are known as a side effect of treatment with dopamine agonists and levodopa. Patients
should be informed that (mostly visual) hallucinations can occur.
Dyskinesia
In advanced Parkinson’s disease, in combination treatment with levodopa, dyskinesia can occur during
the initial titration of SIFROL. If they occur, the dose of levodopa should be decreased.
Sudden onset of sleep and somnolence
Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in
patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without
awareness or warning signs, has been reported uncommonly. Patients must be informed of this and
advised to exercise caution while driving or operating machines during treatment with SIFROL.
Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from
driving or operating machines. Furthermore a reduction of the dose or termination of therapy may be
considered. Because of possible additive effects, caution should be advised when patients are taking
other sedating medicinal products or alcohol in combination with pramipexole (see sections 4.5, 4.7
and section 4.8).
Impulse control disorders and compulsive behaviours
Pathological gambling, increased libido and hypersexuality have been reported in patients treated with
dopamine agonists for Parkinson’s disease, including SIFROL. Furthermore, patients and caregivers
should be aware of the fact that other behavioural symptoms of impulse control disorders and
compulsions such as binge eating and compulsive shopping can occur. Dose reduction/tapered
discontinuation should be considered.
Patients with psychotic disorders
Patients with psychotic disorders should only be treated with dopamine agonists if the potential
benefits outweigh the risks. Co-administration of antipsychotic medicinal products with pramipexole
should be avoided (see section 4.5).
Ophthalmologic monitoring
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
Severe cardiovascular disease
In case of severe cardiovascular disease, care should be taken. It is recommended to monitor blood
pressure, especially at the beginning of treatment, due to the general risk of postural hypotension
associated with dopaminergic therapy.
Neuroleptic malignant syndrome
Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal
of dopaminergic therapy (see section 4.2).
Augmentation
Reports in the literature indicate that treatment of Restless Legs Syndrome with dopaminergic
medicinal products can result in augmentation. Augmentation refers to the earlier onset of symptoms
in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other
extremities. Augmentation was specifically investigated in a controlled clinical trial over 26 weeks.
Augmentation was observed in 11.8% of patients in the pramipexole group (N = 152) and 9.4% of
patients in the placebo group (N = 149). Kaplan-Meier analysis of time to augmentation showed no
significant difference between pramipexole and placebo groups.
29
Plasma protein binding
Pramipexole is bound to plasma proteins to a very low (< 20%) extent, and little biotransformation is
seen in man. Therefore, interactions with other medicinal products affecting plasma protein binding or
elimination by biotransformation are unlikely. As anticholinergics are mainly eliminated by
biotransformation, the potential for an interaction is limited, although an interaction with
anticholinergics has not been investigated. There is no pharmacokinetic interaction with selegiline and
levodopa.
Inhibitors/competitors of active renal elimination pathway
Cimetidine reduced the renal clearance of pramipexole by approximately 34%, presumably by
inhibition of the cationic secretory transport system of the renal tubules. Therefore, medicinal products
that are inhibitors of this active renal elimination pathway or are eliminated by this pathway, such as
cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine, and procainamide, may interact
with pramipexole resulting in reduced clearance of pramipexole. Reduction of the pramipexole dose
should be considered when these medicinal products are administered concomitantly with SIFROL.
Combination with levodopa
When SIFROL is given in combination with levodopa, it is recommended that the dose of levodopa is
reduced and the dose of other anti-parkinsonian medicinal products is kept constant while increasing
the dose of SIFROL.
Because of possible additive effects, caution should be advised when patients are taking other sedating
medicinal products or alcohol in combination with pramipexole (see section 4.4, 4.7 and 4.8).
Antipsychotic medicinal products
Co-administration of antipsychotic medicinal products with pramipexole should be avoided (see
section 4.4), e.g. if antagonistic effects can be expected.
Pregnancy
The effect on pregnancy and lactation has not been investigated in humans. Pramipexole was not
teratogenic in rats and rabbits, but was embryotoxic in the rat at maternotoxic doses (see section 5.3).
SIFROL should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit
justifies the potential risk to the foetus.
Breast-feeding
As pramipexole treatment inhibits secretion of prolactin in humans, inhibition of lactation is expected.
The excretion of pramipexole into breast milk has not been studied in women. In rats, the
concentration of active substance-related radioactivity was higher in breast milk than in plasma.
In the absence of human data, SIFROL should not be used during breast-feeding. However, if its use is
unavoidable, breast-feeding should be discontinued.
Fertility
No studies on the effect on human fertility have been conducted. In animal studies, pramipexole
affected oestrous cycles and reduced female fertility as expected for a dopamine agonist. However,
these studies did not indicate direct or indirect harmful effects with respect to male fertility.
30
SIFROL can have a major influence on the ability to drive and use machines.
Hallucinations or somnolence can occur.
Patients being treated with SIFROL and presenting with somnolence and/or sudden sleep episodes
must be informed to refrain from driving or engaging in activities where impaired alertness may put
themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent
episodes and somnolence have resolved (see also sections 4.4, 4.5 and 4.8).
Expected adverse reactions
The following adverse reactions are expected under the use of SIFROL: abnormal dreams, amnesia,
behavioural symptoms of impulse control disorders and compulsions such as binge eating, compulsive
shopping, hypersexuality and pathological gambling; confusion, constipation, delusion, dizziness,
dyskinesia, dyspnoea, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia,
hypotension, insomnia, libido disorders, nausea, paranoia, peripheral oedema, pneumonia, pruritus,
rash and other hypersensitivity; restlessness, somnolence, sudden onset of sleep, syncope, visual
impairment including diplopia, vision blurred and visual acuity reduced, vomiting, weight decrease
including decreased appetite, weight increase.
Based on the analysis of pooled placebo-controlled trials, comprising a total of 1,923 patients on
pramipexole and 1,354 patients on placebo, adverse drug reactions were frequently reported for both
groups. 63% of patients on pramipexole and 52% of patients on placebo reported at least one adverse
drug reaction.
Tables 1 and 2 display the frequency of adverse drug reactions from placebo-controlled clinical trials
in Parkinson’s disease and Restless Legs Syndrome. The adverse drug reactions reported in these
tables are those events that occurred in 0.1% or more of patients treated with pramipexole and were
reported significantly more often in patients taking pramipexole than placebo, or where the event was
considered clinically relevant. The majority of adverse drug reactions were mild to moderate, they
usually start early in therapy and most tended to disappear even as therapy was continued.
Within the system organ classes, adverse reactions are listed under headings of frequency (number of
patients expected to experience the reaction), using the following categories: very common (≥ 1/10);
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very
rare (< 1/10,000); not known (cannot be estimated from the available data).
Parkinson’s disease, most common adverse reactions
The most commonly (≥ 5%) reported adverse drug reactions in patients with Parkinson’s disease more
frequent with pramipexole treatment than with placebo were nausea, dyskinesia, hypotension,
dizziness, somnolence, insomnia, constipation, hallucination, headache and fatigue. The incidence of
somnolence is increased at doses higher than 1.5 mg pramipexole salt per day (see section 4.2). A
more frequent adverse drug reaction in combination with levodopa was dyskinesia. Hypotension may
occur at the beginning of treatment, especially if pramipexole is titrated too fast.
31
Table 1: Parkinson’s disease
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
Common
abnormal dreams, behavioural symptoms of impulse control
disorders and compulsions, confusion, hallucinations, insomnia
Uncommon
binge eating, compulsive shopping, delusion, hyperphagia,
hypersexuality, libido disorder, paranoia, pathological gambling,
restlessness
Nervous system disorders
Very common
dizziness, dyskinesia, somnolence
Common
headache
Uncommon
amnesia, hyperkinesia, sudden onset of sleep, syncope
Eye disorders
Common
visual impairment including diplopia,vision blurred and visual
acuity reduced
Vascular disorders
Common hypotension
Respiratory, thoracic, and mediastinal disorders
Uncommon
dyspnoea, hiccups
Gastrointestinal disorders
Very common nausea
Common constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common
fatigue, peripheral oedema
Investigations
Common
weight decrease including decreased appetite
Uncommon
weight increase
Restless Legs Syndrome, most common adverse reactions
The most commonly (≥ 5%) reported adverse drug reactions in patients with Restless Legs Syndrome
treated with pramipexole were nausea, headache, dizziness and fatigue. Nausea and fatigue were more
often reported in female patients treated with SIFROL (20.8% and 10.5%, respectively) compared to
males (6.7% and 7.3%, respectively).
32
Table 2: Restless Legs Syndrome
System Organ Class
Adverse Drug Reaction
Infections and infestations
Uncommon
pneumonia
Psychiatric disorders
Common
abnormal dreams, insomnia
Uncommon
behavioural symptoms of impulse control disorders and
compulsions such as binge eating, compulsive shopping,
hypersexuality, and pathological gambling; confusion, delusion,
hallucinations, hyperphagia, libido disorder, paranoia,
restlessness
Nervous system disorders
Common
dizziness, headache, somnolence
Uncommon
amnesia, dyskinesia, hyperkinesia, sudden onset of sleep, syncope
Eye disorders
Uncommon
visual impairment including diplopia, vision blurred and visual
acuity reduced
Vascular disorders
Uncommon hypotension
Respiratory, thoracic, and mediastinal disorders
Uncommon
dyspnoea, hiccups
Gastrointestinal disorders
Very common nausea
Common constipation, vomiting
Skin and subcutaneous tissue disorders
Uncommon hypersensitivity, pruritus, rash
General disorders and administration site conditions
Common
fatigue
Uncommon
peripheral oedema
Investigations
Uncommon
weight decrease including decreased appetite, weight increase
Somnolence
Pramipexole is commonly associated with somnolence and has been associated uncommonly with
excessive daytime somnolence and sudden sleep onset episodes (see also section 4.4).
Libido disorders
Pramipexole may uncommonly be associated with libido disorders (increased or decreased).
Impulse control disorders and compulsive behaviours
Patients treated with dopamine agonists for Parkinson’s disease, including SIFROL, especially at high
doses, have been reported as exhibiting signs of pathological gambling, increased libido and
hypersexuality, generally reversible upon reduction of the dose or treatment discontinuation (see also
section 4.4).
In a cross-sectional, retrospective screening and case-control study including 3,090 Parkinson’s
disease patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic treatment had
symptoms of an impulse control disorder during the past six months. Manifestations observed include
pathological gambling, compulsive shopping, binge eating, and compulsive sexual behaviour
(hypersexuality). Possible independent risk factors for impulse control disorders included
dopaminergic treatments and higher doses of dopaminergic treatment, younger age ( ≤ 65 years), not
being married and self-reported family history of gambling behaviours.
33
There is no clinical experience with massive overdose. The expected adverse reactions would be those
related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting,
hyperkinesia, hallucinations, agitation and hypotension. There is no established antidote for overdose
of a dopamine agonist. If signs of central nervous system stimulation are present, a neuroleptic agent
may be indicated. Management of the overdose may require general supportive measures, along with
gastric lavage, intravenous fluids, administration of activated charcoal and electrocardiogram
monitoring.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-Parkinson drugs, dopamine agonists, ATC code: N04BC05.
Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 subfamily
of dopamine receptors of which it has a preferential affinity to D3 receptors, and has full intrinsic
activity.
Pramipexole alleviates parkinsonian motor deficits by stimulation of dopamine receptors in the
striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release, and
turnover.
The mechanism of action of pramipexole as treatment for Restless Legs Syndrome is unknown.
Neuropharmacological evidence suggests primary dopaminergic system involvement.
In human volunteers, a dose-dependent decrease in prolactin was observed. In a clinical trial with
healthy volunteers, where SIFROL prolonged-release tablets were titrated faster (every 3 days) than
recommended up to 3.15 mg pramipexole base (4.5 mg of salt) per day, an increase in blood pressure
and heart rate was observed. Such effect was not observed in patient studies.
Clinical trials in Parkinson’s disease
In patients pramipexole alleviates signs and symptoms of idiopathic Parkinson’s disease. Placebo-
controlled clinical trials included approximately 1,800 patients of Hoehn and Yahr stages I – V treated
with pramipexole. Out of these, approximately 1,000 were in more advanced stages, received
concomitant levodopa therapy, and suffered from motor complications.
In early and advanced Parkinson’s disease, efficacy of pramipexole in controlled clinical trials was
maintained for approximately six months. In open continuation trials lasting for more than three years
there were no signs of decreasing efficacy.
In a controlled double blind clinical trial of 2 year duration, initial treatment with pramipexole
significantly delayed the onset of motor complications, and reduced their occurrence compared to
initial treatment with levodopa. This delay in motor complications with pramipexole should be
balanced against a greater improvement in motor function with levodopa (as measured by the mean
change in UPDRS-score). The overall incidence of hallucinations and somnolence was generally
higher in the escalation phase with the pramipexole group. However, there was no significant
difference during the maintenance phase. These points should be considered when initiating
pramipexole treatment in patients with Parkinson’s disease.
The European Medicines Agency has waived the obligation to submit the results of studies with
SIFROL in all subsets of the paediatric population in Parkinson’s Disease (see section 4.2 for
information on paediatric use).
34
Clinical trials in Restless Legs Syndrome
The efficacy of pramipexole was evaluated in four placebo-controlled clinical trials in approximately
1,000 patients with moderate to very severe idiopathic Restless Legs Syndrome.
The mean change from baseline in the Restless Legs Syndrome Rating Scale (IRLS) and the Clinical
Global Impression-Improvement (CGI-I) were the primary efficacy outcome measures. For both
primary endpoints statistically significant differences have been observed for the pramipexole dose
groups 0.25 mg, 0.5 mg and 0.75 mg pramipexole salt in comparison to placebo. After 12 weeks of
treatment the baseline IRLS score improved from 23.5 to 14.1 points for placebo and from 23.4 to 9.4
points for pramipexole (doses combined). The adjusted mean difference was -4.3 points (CI 95% -6.4;
-2.1 points, p-value <0.0001). CGI-I responder rates (improved, very much improved) were 51.2% and
72.0% for placebo and pramipexole, respectively (difference 20% CI 95%: 8.1%; 31.8%, p<0.0005).
Efficacy was observed with 0.088 mg of base (0.125 mg of salt) per day after the first week of
treatment.
In a placebo-controlled polysomnography study over 3 weeks SIFROL significantly reduced the
number of periodic limb movements during time in bed.
Longer term efficacy was evaluated in a placebo-controlled clinical trial. After 26 weeks of treatment,
there was an adjusted mean reduction in IRLS total score of 13.7 and 11.1 points in the pramipexole
and placebo group, respectively, with a statistically significant (p = 0.008) mean treatment difference
of -2.6. CGI-I responder rates (much improved, very much improved) were 50.3% (80/159) and 68.5%
(111/162) for placebo and pramipexole, respectively (p = 0.001), corresponding to a number needed to
treat (NNT) of 6 patients (95%CI: 3.5, 13.4).
The European Medicines Agency has deferred the obligation to submit the results of studies with
SIFROL in one or more subsets of the paediatric population in Restless Legs Syndrome (see section
4.2 for information on paediatric use).
Clinical trial in Tourette Disorder
The efficacy of pramipexole (0.0625-0.5 mg/day) with paediatric patients aged 6-17 years with
Tourette Disorder was evaluated in a 6-week, double-blind, randomised, placebo-controlled flexible
dose study. A total of 63 patients were randomised (43 on pramipexole, 20 on placebo). The primary
endpoint was change from baseline on the Total Tic Score (TTS) of the Yale Global Tic Severity
Scale (YGTSS). No difference was observed for pramipexole as compared to placebo for either the
primary endpoint or for any of the secondary efficacy endpoints including YGTSS total score, Patient
Global Impression of Improvement (PGI-I), Clinical Global Impression of Improvement (CGI-I), or
Clinical Global Impressions of Severity of Illness (CGI-S). Adverse events occurring in at least 5% of
patients in the pramipexole group and more common in the pramipexole-treated patients than in
patients on placebo were: headache (27.9%, placebo 25.0%), somnolence (7.0%, placebo 5.0%),
nausea (18.6%, placebo 10.0%), vomiting (11.6%, placebo 0.0%), upper abdominal pain (7.0%,
placebo 5.0%), orthostatic hypotension (9.3%, placebo 5.0%), myalgia (9.3%, placebo 5.0%), sleep
disorder (7.0%, placebo 0.0%), dyspnoea (7.0%, placebo 0.0%) and upper respiratory tract infection
(7.0%, placebo 5.0%). Other significant adverse events leading to discontinuation of study medication
for patients receiving pramipexole were confusional state, speech disorder and aggravated condition
(see section 4.2).
5.2 Pharmacokinetic properties
Pramipexole is rapidly and completely absorbed following oral administration. The absolute
bioavailability is greater than 90% and the maximum plasma concentrations occur between 1 and 3
hours. Concomitant administration with food did not reduce the extent of pramipexole absorption, but
the rate of absorption was reduced. Pramipexole shows linear kinetics and a small inter-patient
variation of plasma levels. In humans, the protein binding of pramipexole is very low (< 20%) and the
35
volume of distribution is large (400 l). High brain tissue concentrations were observed in the rat
(approx. 8-fold compared to plasma).
Pramipexole is metabolised in man only to a small extent.
Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of
14C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The total
clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately
400 ml/min. The elimination half-life (t½) varies from 8 hours in the young to 12 hours in the elderly.
5.3 Preclinical safety data
Repeated dose toxicity studies showed that pramipexole exerted functional effects, mainly involving
the CNS and female reproductive system, and probably resulting from an exaggerated
pharmacodynamic effect of pramipexole.
Decreases in diastolic and systolic pressure and heart rate were noted in the minipig, and a tendency to
a hypotensive effect was discerned in the monkey.
The potential effects of pramipexole on reproductive function have been investigated in rats and
rabbits. Pramipexole was not teratogenic in rats and rabbits but was embryotoxic in the rat at
maternally toxic doses. Due to the selection of animal species and the limited parameters investigated,
the adverse effects of pramipexole on pregnancy and male fertility have not been fully elucidated.
A delay in sexual development (i.e., preputial separation and vaginal opening) was observed in rats.
The relevance for humans is unknown.
Pramipexole was not genotoxic. In a carcinogenicity study, male rats developed Leydig cell
hyperplasia and adenomas, explained by the prolactin-inhibiting effect of pramipexole. This finding is
not clinically relevant to man. The same study also showed that, at doses of 2 mg/kg (of salt) and
higher, pramipexole was associated with retinal degeneration in albino rats. The latter finding was not
observed in pigmented rats, nor in a 2-year albino mouse carcinogenicity study or in any other species
investigated.
6.
6.1 List of excipients
Mannitol
maize starch
anhydrous colloidal silica
povidone K 25
magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from light.
36
6.5 Nature and contents of container
OPA/aluminium/PVC-aluminium blisters.
Each blister strip contains 10 tablets.
Cartons containing 3 or 10 blister strips (30 or 100 tablets).
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
8.
EU/1/97/050/011-012
9.
Date of first authorisation: 14 October 1997
Date of latest renewal: 14 October 2007
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu.
37
1.
FURTHER INFORMATION
What SIFROL contains
The active substance is pramipexole.
Each tablet contains 0.26 mg, 0.52 mg, 1.05 mg, 1.57 mg, 2.1 mg, 2.62 mg, or 3.15 mg pramipexole as
0.375 mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, or 4.5 mg pramipexole dihydrochloride
monohydrate, respectively.
The other ingredients are hypromellose 2208, maize starch, carbomer 941, colloidal anhydrous silica,
magnesium stearate.
186
What SIFROL looks like and contents of the pack
SIFROL 0.26 mg and 0.52 mg prolonged-release tablets are white to off-white, of round shape, and
have bevelled edges.
SIFROL 1.05 mg, 1.57 mg, 2.1 mg, 2.62 mg and 3.15 mg prolonged-release tablets are white to off-
white and of oval shape.
All tablets have the Boehringer Ingelheim company symbol embossed on one side and the codes P1,
P2, P3, P12, P4, P13, or P5 on the other side, representing the tablet strengths 0.26 mg, 0.52 mg,
1.05 mg, 1.57 mg, 2.1 mg, 2.62 mg and 3.15 mg, respectively.
All strengths of SIFROL are available in aluminium blister strips of 10 tablets per strip, in cartons
containing 1, 3 or 10 blister strips (10, 30 or 100 prolonged-release tablets). Not all pack sizes may be
marketed.
Marketing Authorisation Holder
Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany
Manufacturer
Boehringer Ingelheim Pharma GmbH & Co. KG
D-55216 Ingelheim am Rhein
Germany
187
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11
Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11
България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко КГ -
клон България
Тел: +359 2 958 79 98
Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel.: +36 1 299 8900
Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111
Malta
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88
Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889
Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900
Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00
Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 60 80 940
Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-0
Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Polska
Boehringer Ingelheim Sp.zo.o.
Tel.: +48 22 699 0 699
España
Boehringer Ingelheim España S.A.
Tel: +34 93 404 58 00
Portugal
Boehringer Ingelheim, Lda.
Tel: +351 21 313 53 00
France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33
România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucuresti
Tel: +40 21 302 2800
Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620
Slovenija
Boehringer Ingelheim RCV GmbH & Co KG,
Podružnica Ljubljana
Tel: +386 1 586 40 00
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG,
organizačná zložka
Tel: +421 2 5810 1211
Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1
Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800
188
Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00
Latvija
Boehringer Ingelheim Pharma GmbH
Pārstāvniecība Latvijā
Tel: +371 67 240 068
United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel.: +370 37 473922
This leaflet was last approved in {MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.
189
Source: European Medicines Agency
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