Renal impairment: When prescribing SIFROL tablets in a patient with renal impairment a reduced dose is suggested in line with Dosage & Administration.
Hallucinations: Hallucinations and confusion are known side effects of treatment with dopamine agonists and levodopa in Parkinson's disease patients. Hallucinations were more frequent when SIFROL was given in combination with levodopa in Parkinson's disease patients with advanced disease than in monotherapy in Parkinson's disease patients with early disease. Within the RLS clinical development program for registration, one case of hallucinations has been reported. Patients should be informed that (mostly visual) hallucinations can occur.
Patients should be aware of the fact that hallucinations can occur and may adversely affect their ability to drive.
Abnormal Behaviour: Patients and caregivers should be made aware of the fact that abnormal behaviour (reflecting symptoms of impulse control disorders and compulsive behaviours) such as binge eating, compulsive shopping, hypersexuality and pathological gambling have been reported in patients treated with dopaminergic drugs. Dose reduction/tapered discontinuation should be considered.
Retinal changes in albino rats: Ophthalmological monitoring is recommended at regular interval or if vision abnormalities occur. Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-years carcinogenicity study. Evaluation of the retinas of albino mice, pigmented rats, monkeys, and minipigs did not reveal similar changes. The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e. disk shedding) may be involved.
Postural hypotension: 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.
Dystonia: Patients with Parkinson's disease may present with axial dystonia such as antecollis, camptocormia or pleurothotonus (Pisa Syndrome). Dystonia has occasionally been reported following initiation of dopamine agonists including pramipexole, although a clear causal relationship has not been established. Dystonia may also occur several months following medication initiation or adjustment. If dystonia occurs, the dopaminergic medication regimen should be reviewed and an adjustment considered.
Treatment discontinuation in Parkinson's disease: Symptoms suggestive of a neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy (see Dosage & Administration).
Drug withdrawal syndrome: A drug withdrawal syndrome has been reported during or after discontinuation of dopamine agonists including pramipexole. Risk factors may include high cumulative dopaminergic exposure. Withdrawal symptoms do not respond to levodopa, and may include apathy, anxiety, depression, fatigue, sweating and pain. Prior to discontinuation, patients should be informed about potential withdrawal symptoms, and closely monitored during and after discontinuation. In case of severe withdrawal symptoms, temporary re-administration of a dopamine agonist at the lowest effective dose may be considered.
Melanoma: Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.
For the reasons stated as previously mentioned, patients and providers are advised to monitor for melanoma when using pramipexole or other dopaminergic drugs.
Patients with psychotic disorder: Patient with psychotic disorders should only be treated with dopamine agonists if the potential benefits outweigh the risk. Co-administration of antipsychotic medications with SIFROL is not recommended, e.g. if dopamine-antagonistic effects can be expected.
Augmentation in RLS: Reports in the literature indicate that treatment of RLS with dopaminergic medications 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. Kaplan-Meier analysis of time to augmentation showed no significant difference between pramipexole (N=152) and placebo groups (N=149).
Remnants in stool: Some patients have reported the occurrence of remnants in faeces which may resemble intact SIFROL prolonged-release tablets. If patients report such an observation, the physician should reassess patient's response to therapy.
Sudden onset of sleep and somnolence: Falling Asleep During Activities of Daily Living: Patients treated with Pramipexole have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles which sometimes resulted in accidents. Although many of these patients reported somnolence while on Pramipexole, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported as late as one year after the initiation of treatment.
Somnolence is a common occurrence in patients receiving Pramipexole at doses above 1.5 mg/day. Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
Before initiating treatment with Pramipexole, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with Pramipexole such as concomitant sedating medications, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine - see previous text, Interactions). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), Pramipexole should ordinarily be discontinued. If a decision is made to continue Pramipexole, patients should be advised to not drive and to avoid other potentially dangerous activities. While dose reduction clearly reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
Driving and Using Machines: Patients should be aware of the fact that hallucinations can occur and may adversely affect their ability to drive.
Patients should be alerted to the potential sedating effects associated with SIFROL, including somnolence and the possibility of falling asleep while engaged in activities of daily living. (See previous text.)