Apo-Pramipexole Special Precautions

Carcinogenesis and Mutagenesis: For animal data, see Pharmacology: Toxicology under Actions.
Two-year carcinogenicity studies have been conducted with pramipexole in mice and rats. In rats, pramipexole was administered in the diet, at doses of 0.3, 2 and 8 mg/kg/day. The highest dose corresponded to 12.5 times the highest recommended clinical dose (1.5 mg t.i.d.) based on comparative AUC values. No significant increases in tumors occurred.
Testicular Leydig cell adenomas were found in male rats as follows: 13 of 50 control group A males, 9 of 60 control group B males, 17 of 50 males given 0.3 mg/kg/day, 22 of 50 males given 2 mg/kg/day, and 22 of 50 males given 8 mg/kg/day. Leydig cell hyperplasia and increased numbers of adenomas are attributed to pramipexole-induced decreases in serum prolactin levels, causing a down-regulation of Leydig cell luteinizing hormone (LH) receptors and a compensatory elevation of LH secretion by the pituitary gland. The endocrine mechanisms believed to be involved in rats are not relevant to humans.
In mice, pramipexole was administered in the diet, at doses of 0.3, 2 and 10 mg/kg/day. The highest dose corresponded to 11 times the highest recommended clinical dose on an mg/m² basis. No significant increases in tumours occurred.
Pramipexole was not mutagenic in a battery of in vitro and in vivo assays including the Ames assay and the in vivo mouse micronucleus assay.
Cardiovascular: Hypotension: In case of severe cardiovascular disease, care should be taken. Dopamine agonists appear to impair the systemic regulation of blood pressure with resulting postural (orthostatic) hypotension, especially during dose escalation. Postural (orthostatic) hypotension has been observed in patients treated with pramipexole dihydrochloride monohydrate. Therefore, patients should be carefully monitored for signs and symptoms of orthostatic hypotension especially during dose escalation (see Dosage & Administration) and should be informed of this risk.
In clinical trials of pramipexole dihydrochloride monohydrate, however, and despite clear orthostatic effects in normal volunteers, the reported incidence of clinically significant orthostatic hypotension was not greater among those assigned to pramipexole dihydrochloride monohydrate than among those assigned to placebo. This result is clearly unexpected in light of the previous experience with the risks of dopamine agonist therapy.
While this finding could reflect a unique property of pramipexole dihydrochloride monohydrate, it might also be explained by the conditions of the study and the nature of the population enrolled in the clinical trials. Patients were very carefully titrated, and patients with active cardiovascular disease or significant orthostatic hypotension at baseline were excluded.
Connective Tissue: Fibrotic Complications: Although not reported with pramipexole in the clinical development program, cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.
Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, non-ergot derived dopamine agonists can cause them is unknown.
A small number of reports have been received of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis, in the post-marketing experience for pramipexole dihydrochloride monohydrate. While the evidence is not sufficient to establish a causal relationship between pramipexole dihydrochloride monohydrate and these fibrotic complications, a contribution of pramipexole dihydrochloride monohydrate cannot be completely ruled out in rare cases.
Dependence/Tolerance: Pramipexole dihydrochloride monohydrate has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. However, in a rat model on cocaine self-administration, pramipexole dihydrochloride monohydrate had little or no effect.
Neurologic: Dyskinesia: APO-PRAMIPEXOLE (pramipexole dihydrochloride monohydrate) may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate pre-existing dyskinesia. Decreasing the dose of levodopa may ameliorate this side effect.
Neuroleptic Malignant Syndrome: A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in anti-Parkinsonian therapy, including pramipexole dihydrochloride monohydrate (see Dosage & Administration for dose tapering).
Ophthalmologic: Retinal Pathology in Albino Rats: Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-year carcinogenicity study with pramipexole. These findings were first observed during week 76 and were dose-dependent in animals receiving 2 mg/kg/day (25/50 male rats, 10/50 female rats) and 8 mg/kg/day (44/50 male rats, 37/50 female rats). Plasma AUCs at these doses were 2.5 and 12.5 times the AUC seen in humans at the maximal recommended dose of 4.5 mg per day. Similar findings were not present in either control rats, or in rats receiving 0.3 mg/kg/day of pramipexole (0.3 times the AUC seen in humans at the 4.5 mg per day dose).
Studies demonstrated that pramipexole at very high dose (25 mg/kg/day) reduced the rate of disk shedding from the photoreceptor rod cells of the retina in albino rats; this reduction was associated with enhanced sensitivity to the damaging effects of light. In a comparative study, degeneration and loss of photoreceptor cells occurred in albino rats after 13 weeks of treatment with 25 mg/kg/day of pramipexole (54 times the highest clinical dose on a mg/m basis) and constant light (100 lux) but not in Brown-Norway rats exposed to the same dose and higher light intensities (500 lux).
The albino rats seem to be more susceptible than pigmented rats to the damaging effect of pramipexole and light. While the potential significance of this effect on humans has not been established, it cannot be excluded that human albinos (or people who suffer from albinismus oculi) might have an increased susceptibility to pramipexole compared to normally pigmented people. Therefore, such patients should take APO-PRAMIPEXOLE only under ophthalmological monitoring.
Psychiatric: Behavioural changes: Patients and caregivers should be aware of the fact that abnormal behaviour (reflecting symptoms of impulse control disorders and compulsive behaviours) such as pathological gambling, increased libido, hypersexuality, binge eating or compulsive shopping have been reported in patients treated with dopaminergic drugs. Dose reduction/tapered discontinuation should be considered.
Hallucinations: Hallucinations and confusion are known side effects of treatment with dopamine agonist and levodopa. Hallucinations were more frequent when pramipexole dihydrochloride monohydrate was given in combination with levodopa in patients with advanced disease than in monotherapy in patients with early disease. Patients should be aware of the fact that hallucinations (mostly visual) can occur.
In the double-blind, placebo-controlled trials in early Parkinson's disease, hallucinations were observed in 9% (35 of 388) of patients receiving pramipexole dihydrochloride monohydrate, compared with 2.6% (6 of 235) of patients receiving placebo. In the double-blind, placebo-controlled trials in advanced Parkinson's disease, where patients received pramipexole dihydrochloride monohydrate and concomitant levodopa, hallucinations were observed in 16.5% (43 of 260) of patients receiving pramipexole dihydrochloride monohydrate compared with 3.8% (10 of 264) of patients receiving placebo. Hallucinations were of sufficient severity to cause discontinuation of treatment in 3.1% of the early Parkinson's disease patients and 2.7% of the advanced Parkinson's disease patients compared with about 0.4% of placebo patients in both populations.
Age appears to increase the risk of hallucinations. In patients with early Parkinson's disease, the risk of hallucinations was 1.9 times and 6.8 times greater in pramipexole dihydrochloride monohydrate patients than placebo patients <65 years old and >65 years old, respectively. In patients with advanced Parkinson's disease, the risk of hallucinations was 3.5 times and 5.2 times greater in pramipexole dihydrochloride monohydrate patients than placebo patients <65 years old and >65 years old, respectively.
Renal: Since pramipexole dihydrochloride monohydrate is eliminated through the kidneys, caution should be exercised when prescribing APO-PRAMIPEXOLE to patients with renal insufficiency (see Pharmacology: Pharmacokinetics under Actions; Dosage & Administration).
Skeletal Muscular: Rhabdomyolysis: A single case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson's disease treated with pramipexole dihydrochloride monohydrate. The patient was hospitalized with an elevated CPK (10.631 IU/L). The symptoms resolved with discontinuation of the medication.
Skin and Appendages: 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 previously, patients and health-care providers are advised to monitor for melanomas frequently and on a regular basis when using pramipexole dihydrochloride monohydrate for any indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g. dermatologists).
Sexual Function/Reproduction: In rat fertility studies, pramipexole at a dose of 2.5 mg/kg/day, prolonged the estrus cycle and inhibited implantation. These effects were associated with a reduction in serum levels of prolactin, a hormone necessary for implantation and maintenance of early pregnancy in rats.
Pramipexole, at a dose of 2.5 mg/kg/day inhibited implantation. Pramipexole, at a dose of 1.5 mg/kg/day (4.3 times the AUC observed in humans at the maximal recommended clinical dose of 1.5 mg t.i.d.) resulted in a high incidence of total resorption of embryos. This finding is thought to be due to the prolactin lowering effect of pramipexole. Prolactin is necessary for implantation and maintenance of early pregnancy in rats, but not in rabbits and humans. Because of pregnancy disruption and early embryonic loss, the teratogenic potential of pramipexole could not be assessed adequately. In pregnant rabbits which received doses up to 10 mg/kg/day during organogenesis (plasma AUC 71 times that seen in humans at the 1.5 mg t.i.d. dose), there was no evidence of adverse effects on embryo-fetal development. Postnatal growth was inhibited in the offspring of rats treated with a 0.5 mg/kg/day dose of pramipexole during the latter part of pregnancy and throughout lactation.
Monitoring and Laboratory Tests: There are no specific laboratory tests recommended for the management of patients receiving pramipexole dihydrochloride monohydrate.
Use in Pregnancy: There are no studies of pramipexole dihydrochloride monohydrate in pregnant women. Because animal reproduction studies are not always predictive of human response, APO-PRAMIPEXOLE should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Use in Lactation: The excretion of pramipexole into breast milk has not been studied in women. Since pramipexole dihydrochloride monohydrate suppresses lactation, it should not be administered to mothers who wish to breast-feed infants.
A single-dose, radio-labelled study showed that drug-related materials were excreted into the breast milk of lactating rats. Concentrations of radioactivity in milk were three to six times higher than concentrations in plasma at equivalent time points.
Use in the Elderly: Pramipexole dihydrochloride monohydrate total oral clearance was approximately 25 to 30% lower in the elderly (aged 65 years and older) as a result of a decline in pramipexole renal clearance due to an age-related reduction in renal function. This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours (see Pharmacology: Pharmacokinetics under Actions).
In clinical studies, 40.8% (699 of 1715) of patients were between the ages of 65 and 75 years, and 6.5% (112 of 1715) of patients were >75 years old. There were no apparent differences in efficacy or safety between older and younger patients, except that the relative risk of hallucination associated with the use of pramipexole dihydrochloride monohydrate was increased in the elderly.
Use in Children: The safety and efficacy of pramipexole dihydrochloride monohydrate in children under 18 years of age have not been established.