Mylan-Pramipexole Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Adults

Mylan-Pramipexole (pramipexole dihydrochloride monohydrate) is indicated for:

• treatment of the signs and symptoms of idiopathic Parkinson’s disease. Mylan-Pramipexole may be used both as early therapy, without concomitant levodopa, and as an adjunct to levodopa.

Geriatrics (> 65 years of age): The majority of pramipexole (88%) is cleared via renal secretion. Due to age-related reduction in renal function, the elderly have a slower clearance of pramipexole (approximately 25-30% lower). The efficacy and safety appear to be unaffected, except the relative risk of hallucination is higher. (See WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).

Pediatrics: The safety and efficacy of pramipexole dihydrochloride monohydrate have not been established in children less than 18 years of age, therefore Mylan-Pramipexole is not recommended in this patient population.

CONTRAINDICATIONS

• Mylan-Pramipexole (pramipexole dihydrochloride monohydrate) is contraindicated in patients who have demonstrated hypersensitivity to pramipexole or the excipients of the drug product (see DOSAGE FORMS, COMPOSITION AND PACKAGING).

WARNINGS AND PRECAUTIONS

The following Warnings and Precautions are listed in alphabetical order.

Carcinogenesis and Mutagenesis

For animal data, see Part II: TOXICOLOGY.

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 tumours 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 AND ADMINISTRATION) and should be informed of this risk (see INFORMATION FOR THE PATIENT).

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 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, nonergot 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 postmarketing 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

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 AND 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-dependant 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 an 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 pramipexole dihydrochloride monohydrate 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 pramipexole dihydrochloride monohydrate to patients with renal insufficiency (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics and DOSAGE AND 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 above, 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

No studies on the effect on human fertility have been conducted.

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.

Special Populations

Pregnant Women: There are no studies of pramipexole dihydrochloride monohydrate in pregnant women. Because animal reproduction studies are not always predictive of human response, pramipexole dihydrochloride monohydrate should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Nursing Women: 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.

Geriatrics (> 65 years of age): 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 Pharmacokinetics).

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.

Pediatrics: The safety and efficacy of pramipexole dihydrochloride monohydrate in children under 18 years of age have not been established.

Monitoring and Laboratory Tests

There are no specific laboratory tests recommended for the management of patients receiving pramipexole dihydrochloride monohydrate.

ADVERSE REACTIONS

PARKINSON’S DISEASE

Adverse Drug Reaction Overview

During the premarketing development of pramipexole dihydrochloride monohydrate, patients enrolled in clinical trials had either early or advanced Parkinson’s disease. Apart from the severity and duration of their disease, the two populations differed in their use of concomitant levodopa therapy. Namely, patients with early disease did not receive concomitant levodopa therapy during treatment with pramipexole dihydrochloride monohydrate, while those with advanced Parkinson’s disease did.

Because these two populations may have differential risk for various adverse events, adverse event data will be presented for both populations.

All controlled clinical trials performed during premarketing development (except one fixed dose study) used a titration design. Consequently, it was impossible to adequately evaluate the effects of a given dose on the incidence of adverse events.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adverse Reactions Leading to Discontinuation of Treatment

Early Parkinson’s disease

Approximately 12% of 388 patients treated with pramipexole dihydrochloride monohydrate and 11% of 235 patients treated with placebo discontinued treatment due to adverse events. The events most commonly causing discontinuation of treatment were related to the nervous system, namely hallucinations (3.1% on pramipexole dihydrochloride monohydrate vs. 0.4% on placebo), dizziness (2.1% on pramipexole dihydrochloride monohydrate vs. 1.0% on placebo), somnolence (1.6% on pramipexole dihydrochloride monohydrate vs. 0% on placebo), headache and confusion (1.3% and 1.0%, respectively, on pramipexole dihydrochloride monohydrate vs. 0% on placebo), and to the gastrointestinal system (nausea 12.1% on pramipexole dihydrochloride monohydrate vs. 0.4% on placebo).

Advanced Parkinson’s disease

Approximately 12% of 260 patients treated with pramipexole dihydrochloride monohydrate and 16% of 264 patients treated with placebo discontinued treatment due to adverse events. The events most commonly causing discontinuation of treatment were related to the nervous system, namely hallucinations (2.7% on pramipexole dihydrochloride monohydrate vs 0.4% on placebo), dyskinesia (1.9% on pramipexole dihydrochloride monohydrate vs 0.8% on placebo), dizziness (1.2% on pramipexole dihydrochloride monohydrate vs 1.5% on placebo), confusion (1.2% on pramipexole dihydrochloride monohydrate vs 2.3% on placebo, and to the cardiovascular system (postural [orthostatic] hypotension (2.3% on pramipexole dihydrochloride monohydrate vs 1.1% on placebo).

Most Frequent Adverse Events

Adverse events occurring with an incidence of greater than, or equal to, 10% and listed in decreasing order of frequency, were as follows:

Early Parkinson’s disease: nausea, dizziness, somnolence, insomnia, asthenia and constipation.

Advanced Parkinson’s disease: postural [orthostatic] hypotension, dyskinesia, insomnia, dizziness, hallucinations, accidental injury, dream abnormalities, constipation and confusion.

Incidence of Adverse Events in Placebo Controlled Trials

Table 1, lists treatment-emergent adverse events that were reported in the double-blind, placebo- controlled studies by ≥1% of patients treated with pramipexole dihydrochloride monohydrate and were numerically more frequent than in the placebo group. Adverse events were usually mild or moderate in intensity.

Table 1 – Adverse Events From Placebo-Controlled Early and Adjunct Therapy Studies (Incidence of Events ≥ 1% in Patients Treated with Pramipexole Dihydrochloride Monohydrate and Numerically More Frequent than in patients treated with Placebo).

^† Patients received concomitant levodopa

* Patients may have reported multiple adverse experiences during the study or at discontinuation, thus, patients may be included in more than one category.

Other Clinical Trial Adverse Drug Reactions (≥ 1%)

Other events reported by 1% or more of patients treated with pramipexole dihydrochloride monohydrate but reported equally or more frequently in the placebo group were as follows:

Early Parkinson’s Disease

Infection, accidental injury, headache, pain, tremor, back pain, syncope, postural hypotension, hypertonia, diarrhoea, rash, ataxia, dry mouth, leg cramps, twitching, pharyngitis, sinusitis, sweating, rhinitis, urinary tract infection, vasodilation, flu syndrome, increased saliva, tooth disease, dyspnoea, increased cough, gait abnormalities, urinary frequency, vomiting, allergic reaction, hypertension, pruritis, hypokinesia, increased creatine PK, nervousness, dream abnormalities, chest pain, neck pain, paresthesia, tachycardia, vertigo, voice alteration, conjunctivitis, paralysis, accommodation abnormalities, tinnitus, diplopia, and taste perversions.

Advanced Parkinson’s Disease

Nausea, pain, infection, headache, depression, tremor, hypokinesia, anorexia, back pain, dyspepsia, flatulence, ataxia, flu syndrome, sinusitis, diarrhoea, myalgia, abdominal pain, anxiety, rash, paresthesia, hypertension, increased saliva, tooth disorder, apathy, hypotension, sweating, vasodilation, vomiting, increased cough, nervousness, pruritus, hyperesthesia, neck pain, syncope, arthralgia, dysphagia, palpitations, pharyngitis, vertigo, leg cramps, conjunctivitis, and lacrimation.

Adverse Events: Relationship to Age, Gender, and Race

Among the treatment-emergent adverse events in patients treated with pramipexole dihydrochloride monohydrate, hallucinations appeared to exhibit a positive relationship to age. No gender-related differences were observed. Only a small percentage (4%) of patients enrolled were non-Caucasian, therefore, an evaluation of adverse events related to race is not possible.

Other Adverse Events Observed During all Phase 2 and 3 Clinical Trials

Pramipexole dihydrochloride monohydrate has been administered to 1,715 subjects during the premarketing development program, 782 of who participated in double-blind, controlled studies. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. These categories are used in the listing below.

The events listed below occurred in less than 1% of the 1,715 subjects exposed to pramipexole dihydrochloride monohydrate. All reported events, except those already listed above, are included, without regard to determination of a causal relationship to pramipexole dihydrochloride monohydrate.

Events are listed within body-system categories in order of decreasing frequency.

Body as a whole: fever, enlarged abdomen, rigid neck, no drug effect.

Cardiovascular system: palpitations, angina pectoris, atrial arrhythmia, peripheral vascular disease.

Digestive system: tongue discoloration, GI hemorrhage, fecal incontinence.

Endocrine system: diabetes mellitus.

Hemic & lymphatic system: ecchymosis.

Metabolic & nutritional system: gout.

Musculoskeletal system: bursitis, myasthenia.

Nervous system: apathy, libido decrease, paranoid reaction, akinesia, coordination abnormalities, speech disorder, hyperkinesia, neuralgia.

Respiratory system: voice alteration, asthma, hemoptysis.

Skin & appendages: skin disorder, herpes simplex.

Special senses: tinnitus, taste perversion, otitis media, dry eye, ear disorder, hemianopia.

Urogenital system: urinary incontinence, dysuria, prostate disorder, kidney calculus.

In individual patients, hypotension may occur at the beginning of treatment, especially if pramipexole dihydrochloride monohydrate is titrated too rapidly.

Post-Market Adverse Drug Reactions

In addition to the adverse events reported during clinical trials, the following adverse reactions have been identified (essentially in Parkinson’s disease patients) during post-approval use of pramipexole dihydrochloride monohydrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Sudden Onset on Sleep

Patients treated with pramipexole dihydrochloride monohydrate have rarely reported suddenly falling asleep while engaged in activities of daily living; including operation of motor vehicles which has sometimes resulted in accidents (see WARNINGS).

Abnormal Behaviour

Post marketing experience suggests pramipexole dihydrochloride monohydrate may be associated with increase or decrease of libido and hypersexuality.

Pathological (compulsive) gambling has been described in the literature for some dopamine agonists used in the treatment of Parkinson’s disease. Cases of pathological (compulsive) gambling have been reported in patients treated with pramipexole dihydrochloride monohydrate, especially at high doses. Pathological gambling, increased libido and hypersexuality were generally reversible upon dose reduction or treatment discontinuation.

Abnormal behaviour (reflecting symptoms of impulse control disorders and compulsions), paranoia, increased eating (binge eating, hyperphagia), compulsive shopping, restlessness have been observed.

As a result of pooled clinical trial data analysis and review of post-marketing experience hiccups and visual impairment (including diplopia) have been reported.

Based on post-marketing experience inappropriate antidiuretic hormone secretion has been reported. One of the diagnostic criteria of inappropriate antidiuretic hormone secretion is hyponatremia. Signs and symptoms of hyponatremia include headache, nausea, malaise, lethargy, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.

In clinical studies and post-marketing experience cardiac failure has been reported in patients with pramipexole. In a pharmacoepidemiological study pramipexole use was associated with an increased risk of cardiac failure compared with non-use of pramipexole. A causal relationship between pramipexole and cardiac failure has not been demonstrated.

DRUG INTERACTIONS

Drug-Drug Interactions

The drugs listed in table 2 are based on information collected in clinical studies, interaction case reports, or pharmacological properties of the drug that may be used. See ACTION AND CLINICAL PHARMACOLOGY, Drug-Drug Interactions for more information.

Pramipexole dihydrochloride monohydrate is bound to plasma proteins to a very low extent (<20%) and little biotransformation is seen in humans. Therefore, interactions with other medication affecting plasma protein binding or elimination by biotransformation are unlikely. Medications that inhibit the active renal tubular secretion of basic (cationic) drugs or are themselves eliminated by active renal tubular secretion may interact with pramipexole dihydrochloride monohydrate resulting in reduced clearance of either or both medications.

Table 2 - Established or Potential Pharmacokinetic Interactions

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

There are no known interactions between pramipexole dihydrochloride monohydrate and laboratory tests.

DOSAGE AND ADMINISTRATION

Parkinson’s Disease

Mylan-Pramipexole (pramipexole dihydrochloride monohydrate) should be taken orally, three times daily. The tablets can be taken with or without food.

Missed Dose

Patients should be advised that if a dose is missed, they should not take a double dose, but continue with the regular treatment schedule.

Dosing Considerations

Adults

In all clinical studies, dosage was initiated at a subtherapeutic level to avoid orthostatic hypotension and severe adverse effects. Mylan-Pramipexole should be titrated gradually in all patients. The dosage should be increased to achieve maximal therapeutic effect, balanced against the principal adverse reactions of dyskinesia, nausea, dizziness and hallucinations.

Initial treatment

Dosages should be increased gradually from a starting dose of 0.375 mg/day given in three divided doses and should not be increased more frequently than every 5 to 7 days. A suggested ascending dosage schedule that was used in clinical studies is shown in the following table:

Table 3: ASCENDING-DOSE SCHEDULE OF PRAMIPEXOLE

Maintenance treatment

Pramipexole dihydrochloride monohydrate was effective and well-tolerated over a dosage range of 1.5 to 4.5 mg/day, administered in equally divided doses three times per day, as monotherapy or in combination with levodopa (approximately 800 mg/day). In a fixed-dose study in patients with early Parkinson’s disease, pramipexole dihydrochloride monohydrate at doses of 3, 4.5 and 6 mg/day was not shown to provide any significant benefit beyond that achieved at a daily dose of 1.5 mg/day. For individual patients who have not achieved efficacy at 1.5 mg/day, higher doses can result in additional therapeutic benefit.

When pramipexole dihydrochloride monohydrate is used in combination with levodopa, a reduction of the levodopa dosage should be considered. In the controlled study in advanced Parkinson’s disease, the dosage of levodopa was reduced by an average of 27% from baseline.

Discontinuation of Treatment

Pramipexole dihydrochloride monohydrate tablets should be tapered off at a rate of 0.75 mg per day until the daily dose has been reduced to 0.75 mg. Thereafter the dose should be reduced by 0.375 mg per day.

Recommended Dose and Dosage Adjustment

The maximal recommended dose of pramipexole dihydrochloride monohydrate is 4.5 mg per day. Pramipexole dihydrochloride monohydrate is not recommended at the 6 mg per day dose since the incidence of some adverse reactions is higher.

Dosing in patients with concomitant levodopa therapy

In patients with concomitant levodopa therapy it is recommended that the dosage of levodopa is reduced during both dose escalation and maintenance treatment with Mylan-Pramipexole. This may be necessary in order to avoid excessive dopaminergic stimulation.

Patients with renal impairment

Since the clearance of pramipexole is reduced in patients with renal impairment (see Pharmacokinetics), the following dosage recommendation should be considered:

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 30 and 50 ml/min, the initial daily dose of Mylan-Pramipexole should be administered in two divided doses, starting at 0.125 mg twice a day (0.25 mg daily). A maximum daily dose of 2.25 mg pramipexole should not be exceeded.

In patients with a creatinine clearance between 15 and 30 ml/min, the daily dose of Mylan-Pramipexole should be administered in a single dose, starting at 0.125 mg daily. A maximum daily dose of 1.5 mg pramipexole should not be exceeded.

Pramipexole has not been adequately studied in patients with very severe renal impairment (creatinine Cl < 15 mL/min and haemodialysis patients) and its administration to patients with end stage renal disease is not recommended.

If renal function declines during maintenance therapy reduce Mylan-Pramipexole daily dose by same percentage as decline in creatinine clearance, i.e. if creatinine clearance declines by 30%, then reduce Mylan-Pramipexole daily dose 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.

Patients with hepatic impairment

Dose reduction not considered necessary.

Dosing in children and adolescents:

Safety and efficacy of pramipexole dihydrochloride monohydrate have not been established in children and adolescents up to 18 years of age.

OVERDOSAGE

Signs and Symptoms

There is no clinical experience with massive overdosage. The expected adverse events are those related to the pharmacodynamic profile of a dopamine agonist including nausea, vomiting, hyperkinesia, hallucinations, agitation and hypotension.

One patient with a 10-year history of schizophrenia (who participated in a schizophrenia study) took 11 mg/day of pramipexole dihydrochloride monohydrate for two days; this was two to three times the daily dose recommended in the protocol. No adverse events were reported related to the increased dose. The blood pressure remained stable although pulse rates increased to between 100 and 120 beats/minute. The patient withdrew from the study at the end of week 2 due to lack of efficacy.

Recommended Management

There is no known antidote for overdosage of a dopamine agonist. If signs of central nervous system stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdosage has not been assessed. Management of the overdose may require general supportive measures along with gastric lavage, intravenous fluids, and electrocardiogram monitoring. Haemodialysis has not been shown to be helpful.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Pramipexole dihydrochloride monohydrate is a non ergot dopamine agonist with high in vitro specificity at the D₂ subfamily of dopamine receptors. Pramipexole is a full agonist and exhibits higher affinity to the D₃ receptor subtypes (which are in prominent distribution within the mesolimbic area) than to D₂ or D₄ receptor subtypes. While pramipexole dihydrochloride monohydrate exhibits high affinity for the dopamine D₂ receptor subfamily, it has low affinity for α₂ adrenergic receptors and negligible or undetectable affinity for other dopaminergic, adrenergic, histaminergic, adenosine and benzodiazepine receptors.

The ability of pramipexole to alleviate the signs and symptoms of Parkinson’s disease is believed to be related to its ability to stimulate dopamine receptors in the striatum. This assumption is supported by a dose-dependent antagonism of Parkinsonian symptoms in rhesus monkeys pre-treated with the neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which destroys dopamine cell bodies in the substantia nigra.

In human volunteers a dose-dependent decrease in prolactin was observed.

Pharmacokinetics

Absorption: Following oral administration, pramipexole is rapidly absorbed reaching peak concentrations between 1 and 3 hours. The absolute bioavailability of pramipexole is greater than 90%. Pramipexole can be administered with or without food. A high-fat meal did not affect the extent of pramipexole absorption (AUC and C_max) in healthy volunteers, although the time to maximal plasma concentration ₍T_max) was increased by about 1 hour.

Pramipexole displays linear pharmacokinetics over the range of doses that are recommended for patients with Parkinson’s disease.

Distribution: Pramipexole is extensively distributed, having a volume of distribution of about 500 L. Protein binding is less than 20% in plasma; with albumin accounting for most of the protein binding in human serum. Pramipexole distributes into red blood cells as indicated by an erythrocyte to plasma ratio of approximately 2.0 and a blood to plasma ratio of approximately 1.5. Consistent with the large volume of distribution in humans, whole body autoradiography and brain tissue levels in rats indicated that pramipexole was widely distributed throughout the body, including the brain.

Metabolism and Excretion: Urinary excretion is the major route of pramipexole elimination. Approximately 88% of a ¹⁴C -labelled dose was recovered in the urine and less than 2% in the faeces following single intravenous and oral doses in healthy volunteers. The terminal elimination half-life was about 8.5 hours in young volunteers (mean age 30 years) and about 12 hours in elderly volunteers (mean age 70 years). Approximately 90% of the recovered ¹⁴C- labelled dose was unchanged drug; with no specific metabolites having been identified in the remaining 10% of the recovered radio-labelled dose. Pramipexole is the levorotational (-) enantiomer, and no measurable chiral inversion or racemization occurs in vivo.

The renal clearance of pramipexole is approximately 400 mL/min, approximately three times higher than the glomerular filtration rate. Thus, pramipexole is secreted by the renal tubules, probably by the organic cation transport system.

Special Populations and Conditions

Because therapy with pramipexole is initiated at a subtherapeutic dose and gradually titrated according to clinical tolerability to obtain optimal therapeutic effect, adjustment of the initial dose based on gender, weight, or age is not necessary. However, renal insufficiency, which can cause a large decrease in the ability to eliminate pramipexole, may necessitate dosage adjustment.

Early vs. advanced Parkinson’s disease patients: The pharmacokinetics of pramipexole was comparable between early and advanced Parkinson’s disease patients.

Healthy Volunteers: In a clinical trial with healthy volunteers, where pramipexole extended release tablets were titrated faster than recommended (every 3 days) up to 4.5 mg per day, an increase in blood pressure and heart rate was observed. Such effect was not observed in patient studies.

Pediatrics: The pharmacokinetics of pramipexole in the pediatric population has not been evaluated.

Geriatrics: Renal function declines with age. Since pramipexole clearance is correlated with renal function, the drug’s total oral clearance was approximately 25% to 30% lower in elderly (aged 65 years or older) compared with young healthy volunteers (aged less than 40 years). The decline in clearance resulted in an increase in elimination half-life from approximately 8.5 hours in young volunteers (mean age 30 years) to 12 hours in elderly volunteers (mean age 70 years).

Gender: Pramipexole renal clearance is about 30% lower in women than in men, most of this difference can be accounted for by differences in body weight. The reduced clearance resulted in a 16 to 42% increase in AUC and a 2 to 10% increase in C_max. The differences remained constant over the age range of 20 to 80 years. The difference in pramipexole half-life between males and females was less than 10%.

Race: A retrospective population pharmacokinetic analysis on data from patients with Parkinson’s disease receiving immediate-release pramipexole suggests that oral clearance of pramipexole is 17% higher in black male patients compared to white male patients.

Hepatic Insufficiency: The potential influence of hepatic insufficiency on pramipexole pharmacokinetics has not been evaluated; however, it is considered to be small. Since approximately 90% of the recovered ¹⁴C-labelled dose was excreted in the urine as unchanged drug, hepatic impairment would not be expected to have a significant effect on pramipexole elimination.

Renal Insufficiency: The clearance of pramipexole was about 75% lower in patients with severe renal impairment (creatinine clearance approximately 20 mL/min) and about 60% lower in patients with moderate impairment (creatinine clearance approximately 40 mL/min) compared with healthy volunteers. A lower starting and maintenance dose is recommended in patients with renal impairment (see DOSAGE AND ADMINISTRATION). In patients with varying degrees of renal impairment, pramipexole clearance correlates well with creatinine clearance. Therefore, creatinine clearance can be used as a predictor of the extent of decrease in pramipexole clearance. As pramipexole clearance is reduced even more in dialysis patients (N=7), than in patients with severe renal impairment, the administration of pramipexole to patients with end stage renal disease is not recommended.

Drug-Drug Interactions

Anticholinergics

As anticholinergics are mainly eliminated by hepatic metabolism, pharmacokinetic drug-drug interactions with pramipexole are rather unlikely.

Antiparkinsonian drugs

In volunteers (N = 11), selegiline did not influence the pharmacokinetics of pramipexole. Population pharmacokinetic analysis suggests that amantadine may alter the oral clearance of pramipexole (N = 54). Levodopa/carbidopa did not influence the pharmacokinetics of pramipexole in volunteers (N = 10). Pramipexole did not alter the extent of absorption (AUC) or elimination of levodopa/carbidopa, although it increased levodopa C_max by about 40%, and decreased T_max from 2.5 to 0.5 hours.

While increasing the dose of pramipexole dihydrochloride monohydrate in Parkinson’s disease patients it is recommended that the dosage of levodopa is reduced and the dosage of other antiparkinsonian medication is kept constant.

Cimetidine

Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, increased pramipexole dihydrochloride monohydrate AUC by 50% and increased its half-life by 40% in volunteers (N = 12).

Probenecid

Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transport system, did not influence the pharmacokinetics of pramipexole dihydrochloride monohydrate in volunteers (N = 12).

Other drugs eliminated via renal secretion

Concomitant therapy with drugs secreted by the renal cationic transport system (e.g., amantadine, cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine), may decrease the oral clearance of pramipexole dihydrochloride monohydrate and thus, may necessitate an adjustment in the dosage of pramipexole dihydrochloride monohydrate. In case of concomitant treatment with these kinds of drugs (incl. amantadine) attention should be paid to signs of dopamine overstimulation, such as dyskinesias, agitation or hallucinations. In such cases a dose reduction is necessary. Concomitant therapy with drugs secreted by the renal anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide and chlorpropamide) are not likely to have any effect on the oral clearance of pramipexole dihydrochloride monohydrate.

CYP interactions

Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole dihydrochloride monohydrate elimination because pramipexole dihydrochloride monohydrate is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole dihydrochloride monohydrate does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 μM, suggesting that pramipexole dihydrochloride monohydrate will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid).

Dopamine antagonists

Since pramipexole dihydrochloride monohydrate is a dopamine agonist, dopamine antagonists such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines) or metoclopramide may diminish the effectiveness of pramipexole dihydrochloride monohydrate and should ordinarily not be administered concurrently.

Miscellaneous

Because of possible additive effects, caution should be advised when patients are taking other sedating medication or alcohol in combination with pramipexole dihydrochloride monohydrate and when taking concomitant medication that increase plasma levels of pramipexole (e.g. cimetidine).

STORAGE AND STABILITY

Store at controlled room temperature of 15 °C to 30 °C. Protect from light and moisture. Tablets should be kept in original container until ready for use.

SPECIAL HANDLING INSTRUCTIONS

The product should be dispensed in the original container.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms:

Mylan-Pramipexole tablets are available in 4 strengths:

0.25 mg: A white to off white, biconvex, oval shaped tablet debossed with ‘PX2’ on one side and ‘M’ on one side of breakline on the other side.

0.5 mg: A white to off white, biconvex, oval shaped tablet debossed with ‘PX3’ on one side and ‘M’ on one side of breakline on the other side.

1.0 mg: A white to off white, biconvex oval shaped tablet debossed with ‘M over PX4’ on one side and plain with breakline on other side.

1.5 mg: A white to off white, biconvex oval shaped tablet debossed with ‘M over PX5’ on one side and plain with breakline on other side.

Composition:

Each tablet contains 0.25 mg, 0.5 mg, 1.0 mg, or 1.5 mg of pramipexole dihydrochloride monohydrate as the medicinal (active) ingredient.

In addition, Mylan-Pramipexole tablets also contain the following non-medicinal ingredients:

crospovidone, hydroxy propyl cellulose, magnesium stearate, mannitol, pregelatinized starch, silica colloidal anhydrous and sodium citrate.

Packaging:

Mylan-Pramipexole tablets are available in HDPE bottles of 90's.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance: Pramipexole dihydrochloride monohydrate

Proper name: Pramipexole (INN/USAN)

Chemical name: 1. (S)-2-Amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole dihydrochloride monohydrate

1. 2. (S)-4,5,6,7-tetrahydro-N⁶-propyl-2,6-benthiazolediamine dihydrochloride monohydrate

Molecular formula and molecular mass: C₁₀H₂₁Cl₂N₃OS (302.27 g/mol)

Structural formula:

Physicochemical properties: Pramipexole dihydrochloride is a white to off-white crystalline powder.

Pramipexole is soluble in water, methanol and ethanol, practically insoluble in N,N-dimethylformamide, chloroform and dichloromethane.

It has a melting range between 280 - 290°C with decomposition.

It has a pH between 3.0 and 4.0.

The dissociation constants are pKa1 = 5.0 and pKa2 = 9.6

Optical rotation between -64° and -68°

The partition coefficient is log D = 0.87

CLINICAL TRIALS

Comparative Bioavailability Studies

One comparative bioequivalence study was conducted on Mylan-Pramipexole (Pramipexole Dihydrochloride Tablets) against Mirapex® as follows:

Fasting study: Study #: BA09101129-01: A single-dose, blinded, randomized, two-period, two-treatment, cross-over bioequivalence study under fasting conditions was conducted comparing Mylan-Pramipexole 0.25 mg tablets (Mylan Pharmaceuticals ULC) to Mirapex® 0.25 mg tablets (Boehringer Ingelheim Canada Ltd.) in twenty healthy male subjects. The results are presented below.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* Mylan-Pramipexole 0.25 mg tablets (Mylan Pharmaceuticals ULC)

^†Mirapex^® 0.25 mg tablets (Boehringer Ingelheim Canada Ltd.) were purchased in Canada

^§ Expressed as the median (range)

^€ Expressed as the arithmetic mean (CV %)

Parkinson’s Disease

Study demographics and trial design

Up to February 29, 1996, 1715 patients have been exposed to pramipexole dihydrochloride monohydrate, with 669 patients being exposed for over one year and 222 patients being exposed for over two years.

The effectiveness of pramipexole dihydrochloride monohydrate in the treatment of Parkinson’s disease was evaluated in a multinational drug development program consisting of seven randomized controlled trials. Three were conducted in patients with early Parkinson’s disease who were not receiving concomitant levodopa, and four were conducted in patients with advanced Parkinson’s disease who were receiving concomitant levodopa. Among these seven studies, three Phase 3 studies provide the most persuasive evidence of pramipexole dihydrochloride monohydrate’s effectiveness in the management of patients with Parkinson’s disease who were or were not receiving concomitant levodopa. Two of the trials enrolled patients with early Parkinson’s disease (not receiving levodopa), and one enrolled patients with advanced Parkinson’s disease who were receiving maximally tolerated doses of levodopa.

Study results

In all studies, the Unified Parkinson’s Disease Rating Scale (UPDRS), or one or more of its subscales, served as the primary outcome assessment measure.

Studies in patients with early Parkinson’s disease

Patients in the two studies with early Parkinson’s disease had mean disease duration of 2 years, limited or no prior exposure to levodopa, and were not experiencing the “on-off” phenomenon and dyskinesia characteristics of later stages of the disease.

One of the trials was a double-blind, placebo-controlled, parallel study in which patients were randomized to pramipexole dihydrochloride monohydrate (N = 164) or placebo (N = 171). The trial consisted of a 7-week dose escalation period and a 6-month maintenance period. Patients could be on selegiline and/or anticholinergics but not on levodopa products. Patients treated with pramipexole dihydrochloride monohydrate had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day, administered in three divided doses. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS Part II (activities of daily living [ADL] subscale) score was 1.9 in the pramipexole dihydrochloride monohydrate group and -0.4 in the placebo group. The mean improvement from baseline on the UPDRS part III (motor subscale) was 5.0 in the pramipexole dihydrochloride monohydrate group and -0.8 in the placebo group. Both differences were statistically significant. The mean daily dose of pramipexole dihydrochloride monohydrate during the maintenance period was 3.8 mg/day.

The difference in mean daily dose between males and females was less than 10%. Patients >75 years (N = 26) received the same mean daily dose as younger patients.

The second early Parkinson’s disease study was a double-blind, placebo-controlled parallel trial which evaluated dose-response relationships. It consisted of a 6-week dose escalation period and a 4-week maintenance period. A total of 264 patients were enrolled. Patients could be on selegiline, anticholinergics, amantadine, or any combination of these, but not on levodopa products. Patients were randomized to 1 of 4 fixed doses of pramipexole dihydrochloride monohydrate (1.5 mg, 3.0 mg, 4.5 mg, or 6.0 mg per day) or placebo. No dose-response relationship was demonstrated. The between treatment differences on both parts of the UPDRS were statistically significant in favour of pramipexole dihydrochloride monohydrate at all doses.

In both studies in early Parkinson’s disease patients, no differences in effectiveness were detected based upon age or gender. Patients receiving selegiline or anticholinergics had responses similar to patients not receiving these drugs.

To date, results comparing pramipexole dihydrochloride monohydrate to levodopa are not available.

Studies in patients with advanced Parkinson’s disease

In the advanced Parkinson’s disease study, the primary assessments were the UPDRS and daily diaries that quantified amounts of “on” and “off” times.

Patients (N = 181 on pramipexole dihydrochloride monohydrate, N = 179 on placebo) had a mean disease duration of 9 years, had been exposed to levodopa for a mean of 8 years, received concomitant levodopa during the trial and had “on-off” periods. Patients could additionally be on selegiline, anticholinergics, amantadine, or any combination of these. The study consisted of a 7-week dose-escalation period and a 6-month maintenance period. Patients treated with pramipexole dihydrochloride monohydrate had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose but no higher than 4.5 mg/day, administered in three divided doses. At the end of the 6-months maintenance period, the mean improvement from baseline on the UPDRS part II (ADL) score was 2.7 in the pramipexole dihydrochloride monohydrate group and 0.5 in the placebo group. The mean improvement from baseline on the UPDRS part III (motor) score was 5.6 in the pramipexole dihydrochloride monohydrate group and 2.8 in the placebo group. Both differences were statistically significant. The mean daily dose of pramipexole dihydrochloride monohydrate during the maintenance period was 3.5 mg/day. The dose of levodopa could be reduced if dyskinesia or hallucinations developed. Levodopa dose reduction occurred in 76% and 54% of pramipexole dihydrochloride monohydrate and placebo- treated patients, respectively. On average, the percent decrease was 27% in the pramipexole dihydrochloride monohydrate group and 5% in the placebo group.

In females the mean daily dose was approximately 10% lower than in male patients. Patients aged over 75 years (N = 24) had approximately a 10% lower dose than younger patients.

The mean number of “off” hours per day during baseline was approximately 6 hours for both groups. Throughout the trial, patients treated with pramipexole dihydrochloride monohydrate had a mean “off” period of approximately 4 hours, while the duration of “off” periods remained essentially unchanged in the placebo-treated subjects.

No differences in effectiveness were detected based upon age or gender.

DETAILED PHARMACOLOGY

Receptor binding studies

Preclinical studies, which compared the relative pharmacological activities and receptor binding affinities (displacement of [³H]spiroperidol) of the pramipexole racemate and its optical isomers, showed the levorotational (-) enantiomer to be more potent.

Studies with cloned human receptors, expressed in cultured Chinese hamster ovary (CHO) cells, indicate that, within the recently discovered D2 receptor subfamily, pramipexole binds with highest affinity to the D3 subtype (Ki = 0.5 nM). Pramipexole has approximately a 5- to 10-fold preferential affinity for the D3 receptor when compared to its affinities for the high affinity forms of the D2S, D2L and D4 subtypes (Ki values: 3.3, 3.9 and 5.1 nM, respectively). As is true for other dopamine agonists, exposure of the receptor to a non-hydrolyzable analog of GTP decreases the affinity of pramipexole for the cloned D3 receptor much less than it does for the cloned D2 or D4 subtypes. The small GTP-shift for agonists of the D3 receptor site is an indication of the weak coupling of this receptor to the G-protein second messenger system in CHO cells.

Besides binding to the dopamine-D2 receptor subfamily, pramipexole has a low affinity for α2 adrenoreceptors and a very low affinity for histamine H2 and serotonin 5-HT1A receptors. Its affinity for other dopaminergic, adrenergic, histaminergic, serotonergic, cholinergic, glutamatergic, adenosine and benzodiazepine receptors is negligible or undetectable.

Receptor binding autoradiography with [³H] pramipexole (5 nM, 62 Ci/mmole) was used to evaluate the distribution of pramipexole binding sites within the rat brain. The highest concentrations of [³H] pramipexole binding sites were found in the Islets of Calleja, previously reported to contain D3, but not D2 or D4 mRNA. [³H] Pramipexole binding was also high in other mesolimbic areas, such as the nucleus accumbens, olfactory tubercle, and amygdala. [³H]Pramipexole binding was also high in caudate, although slightly less than in mesolimbic areas. Striatal areas have higher D2:D3 mRNA ratios than do mesolimbic regions. Fewer [³H] pramipexole binding sites were found in VTA and substantia nigra, areas rich in cell bodies for dopamine neurons. Although it is likely that much of this [³H] pramipexole binding reflects D2 receptors, the relatively high mesolimbic binding could reflect the preferential affinity pramipexole has for the D3 receptor subtype.

Animal Studies

Antagonism of Reserpine-Induced Akinesia

Reserpine treatment leads to depletion of monoamines, including dopamine. Animals so treated are essentially akinetic, but can be activated by dopamine agonists.

Pramipexole, (30 μmole/kg = 9 mg/kg IP) stimulated locomotor activity in reserpinized mice. These data are consistent with a pramipexole-induced stimulation of postsynaptic dopamine receptors in the basal ganglia.

Antagonism of Haloperidol-Induced Catalepsy

The dopamine receptor antagonist haloperidol induces hypomotility, rigidity, and catalepsy in the rat. The cataleptic behaviour is regarded to be highly predictive of neuroleptic-induced Parkinson like extrapyramidal side effects.

In one study, rats were injected with haloperidol, 1 mg/kg. Rats were considered cataleptic if they maintained a position with their forepaws elevated on a 6 to 8 cm high rod for at least 30 seconds two hours after haloperidol. Pramipexole dose-dependently suppressed catalepsy, with an ED50 of 4.4 mg/kg SC.

In a second study, catalepsy, produced by 5 μmole/kg SC (=2 mg/kg) of haloperidol, was scored by measuring the time rats remained with their forepaws on a squared wooden cube. Pramipexole (50 μmole/kg = 15.1 mg/kg) readily blocked the catalepsy.

Rotational Behaviour in 6-Hydroxydopamine (6-OHDA) Lesioned Rats

When 6-OHDA is injected unilaterally into the medial forebrain bundle of rats, a selective degeneration of presynaptic dopaminergic neurons occurs; rendering the animals essentially hemi-Parkinsonian. The postsynaptic neurons at the site of the lesion become hypersensitive to dopamine agonists. When dopamine agonists are administered to lesioned rats, a contralateral rotational behaviour can be observed. The number of rotations is evaluated in a rotameter.

In an initial study, pramipexole and, for comparison, apomorphine was tested in doses of 0.01 to 0.1 mg/kg. The D1- and D2-selective dopamine antagonists, SCH 23390 and haloperidol, respectively, were used to determine the subfamily of receptors involved. All compounds were administered SC.

Both pramipexole (ED50 0.026 mg/kg, maximum effect 80 to 140 minutes after administration) and apomorphine (ED50 0.030 mg/kg, maximum effect 5 to 65 minutes after administration) induced contralateral turning behaviour in 6-OHDA-lesioned rats. Whereas the effect of apomorphine ceased after 80 minutes, pramipexole was effective throughout the recording period of 2 hours.

Pretreatment with 0.05 mg/kg of haloperidol markedly attenuated the effect of pramipexole (0.05 mg/kg). The very high dose of 2 mg/kg of SCH 23390 also inhibited the effect, albeit to a smaller extent.

A second study confirmed the potent and long-lasting effects of pramipexole in this animal model of Parkinson’s disease; maximal effects occurred with a dose of 0.3 μmoles/kg (=0.09 mg/kg) SC. Higher doses produced less effect.

MPTP-Induced Parkinsonian Symptoms in Rhesus Monkeys

MPTP (n-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine) is a highly selective neurotoxin which destroys the dopamine cell bodies in the zona compacta of the substantia nigra. The chronic dopamine depletion in the substantia nigra, results in a syndrome which resembles severe Parkinsonism, observed in patients. The effect of MPTP is irreversible. Due to chronic denervation, the postsynaptic dopamine D2 receptors become hypersensitive. A presynaptic action of a compound in the substantia nigra is excluded in this model because the presynaptic neurons have been destroyed.

Pramipexole (0.03 to 0.1 mg/kg IM) dose-dependently reversed the Parkinson-like symptoms in MPTP-treated rhesus monkeys. The dose which antagonized the symptoms in 50% of the animals (ED50) was 0.045 mg/kg IM. A dose of 0.06 mg/kg was effective in all animals. The animals’ locomotor activity, recorded with an electronic device mounted on their arm, returned to normal and did not exceed that of monkeys not pretreated with MPTP. Stereotyped movements, abnormal excitation, salivation, or sedation were not observed in the dose range tested. A dose of 0.1 mg/kg IM was effective for more than 5h.

In another study, oral doses of 0.05 to 0.1 mg/kg of pramipexole were evaluated in MPTP treated rhesus monkeys. At a dose of 0.075 mg/kg, the compound completely reversed the Parkinsonian symptoms. The duration of action varied between 5 and 24 hours.

TOXICOLOGY

Acute toxicity

The acute toxicity of pramipexole was studied in mice, rats, and dogs following oral and intravenous single doses. Administration of the pramipexole dose was followed by a 14 day observation period. Comparative lethality data are presented in the table below.

TABLE 4: SPECIES COMPARISON OF LD50

Clinical symptoms following acute dosing in rats and mice included ataxia, convulsions, dyspnoea, tachypnea, reduced motility, increased nervousness or hyperactivity. In dogs, oral and intravenous dosing resulted in frequent and prolonged vomiting.

Long-term toxicity

The effects of long-term administration of pramipexole were evaluated in the rat, minipig, and monkey. Definitive studies have been summarized in Table 5.

A delay in sexual development (i.e., preputial separation and vaginal opening) was observed in rats. The relevance for humans is unknown.

CARCINOGENICITY STUDIES

Mouse

Pramipexole was administered to Chbb: NMRI mice, 50/sex/group for two years at drug-in-diet-doses of 0.3, 2, or 10 mg/kg/day. Two control groups received only powdered feed.

Plasma concentrations of pramipexole rose with increasing doses in an almost linear, or more steeply than linear, manner. On average, females had higher plasma levels than males.

No distinct, drug-related clinical effects were noted at 0.3 mg/kg/day, although this group had a tendency to consume less feed than the control groups. In the 2 and 10 mg/kg groups, lower body weights and a tendency for increased food and water consumption were noted. Increased spontaneous activity was noted in females at 2 mg/kg, and in both sexes at 10 mg/kg.

The following non-neoplastic changes were noted: increased incidence of fibro-osseous proliferative lesions in the femurs of treated females, decreased incidence of tubular atrophy in the testes of treated males. Increased haemopoietic activity was noted in the femoral bone marrow of females at 2 and 10 mg/kg.

With the exception of a nonsignificant decrease in hepatocellular adenomas in males in all treated groups, and statistically significant decreases in adrenal cortical adenomas in males at 10 mg/kg and malignant lymphomas in females at 2 and 10 mg/kg, the incidence of neoplastic changes was similar in treated and control animals.

Therefore, under the conditions of the study, no carcinogenic effect of the test compound could be established.

Rat

Pramipexole was administered to Chbb:THOM rats, 50/sex/group, for two years by drug-in-diet, at doses of 0.3, 2, or 8 mg/kg/day. Two control groups received only vehicle (powdered feed).

Plasma concentrations of pramipexole increased almost proportionally with increasing dose.

The incidence of mortality (unscheduled deaths and sacrifices) was similar in the treated and two control groups.

Increased spontaneous activity was observed in females at 8 mg/kg. A dose-related, slight to marked decrease in body weight gain was observed in all treated groups, particularly in females. Food consumption was slightly decreased in males from all treated groups, but was moderately increased in females at 2 and 8 mg/kg.

An increased incidence of the following non-neoplastic changes was noted: Leydig cell hyperplasia in males at 2 and 8 mg/kg; large, prominent corpora lutea in females at 8 mg/kg; chronic suppurative inflammatory lesions and haemorrhages in the uteri of females at 2 and 8 mg/kg; change in normal glandular pattern in the mammary gland parenchyma in females at 2 and 8 mg/kg; retinal degeneration in males and females at 2 and 8 mg/kg; minimal to slight diffuse hepatocellular fatty change in females at 2 and 8 mg/kg. A treatment-related decrease in the incidence of focal/multifocal medullary hyperplasia of the adrenal gland and cystic changes of the mammary gland were observed in females at 2 and 8 mg/kg.

A statistically significant increase in the incidence of Leydig cell adenomas was noted in males at 2 and 8 mg/kg. The following neoplasms were significantly decreased in rats at 2 and 8 mg/kg: mammary gland neoplasia in females, pituitary adenomas in both sexes, total number of primary neoplasms in females. Additionally, a decrease in the incidence of benign adrenal medullary neoplasms was observed in female rats at 0.3, 2, and 8 mg/kg/day.

Although retinal degeneration was observed in albino rats given 2 or 8 mg/kg/day, no retinal degeneration was noted at the low dose of 0.3 mg/kg/day. No retinal degeneration was seen in the two year carcinogenicity study in mice at doses of 0.3, 2, or 10 mg/kg/day, in the one year drug-in-diet rat study at doses of 0.5, 3, or 15 mg/kg/day, or in any other study in any species. In investigative studies, the treatment of albino rats with pramipexole clearly reduced the rate of disk shedding from photoreceptor cells, suggesting a perturbation of the steady-state necessary for maintenance of membrane integrity. This change was associated with increased sensitivity of the retina of albino rats to the damaging effects of light. In contrast, pigmented rats exposed to the same levels of pramipexole and even higher intensities of light had absolutely no degeneration of any portion of the retina.

In conclusion, under the conditions of this study, apart from slight decreases in body weight gain, no drug-related adverse effects, including hyperplastic/neoplastic lesions, were recorded at the lowest dose of 0.3 mg/kg/day. Therefore, the NOAEL was 0.3 mg/kg/day.

Mutagenicity studies

In a standard battery of in vitro and in vivo studies, pramipexole was found to be non-mutagenic and nonclastogenic.

REPRODUCTION AND TERATOLOGY

Reproduction and general fertility

Groups of 24 male and 24 female Chbb:THOM rats were administered pramipexole in distilled water at doses of 0 (vehicle), 0.1, 0.5, or 2.5 mg/kg/day. Males were treated for 10 weeks prior to mating and throughout copulation; females were treated 2 weeks prior to mating during the mating period, and during the gestation and lactation periods.

No treatment-related effects were observed in adults in the 0.1 mg/kg/day group. Additionally, no treatment-related effects were observed in the offspring in this group.

Rats in the 0.5 mg/kg/day group (particularly females) showed clinical signs of CNS excitation (agitation and constant running lasting 6 to 7 hours). Food consumption, body weight, mating, and pregnancy parameters were not affected. A dose of 2.5 mg/kg/day caused moderate to severe agitation in adults, associated with temporary retardation of body weight and food consumption. Treatment-related irregularities in the estrous cycle and/or the severe agitation observed over the treatment period in the 2.5 mg/kg/day group may have been connected to the longer mating performance and the high percentage (61%) of females which failed to become pregnant in this group. The high percentage of non-pregnant females may also have been due to an inhibition of prolactin secretion by pramipexole since the maintenance of functional corpora lutea and successful implantation are dependent upon prolactin.

In the 0.5 mg/kg group, litter parameters of the Caesarean-section group were unchanged, but in the spontaneous delivery group pup body weight development was delayed. While it was not possible to evaluate litter parameters for the Caesarean-section group at 2.5 mg/kg (only one dam produced living progeny), the few pups from the 2.5 mg/kg spontaneous delivery group weighed less at birth and had an even smaller weight increase during the rearing than the 0.5 mg/kg group. In both groups, a slight delay in opening of the eyes was observed. Effects observed in pups in the 0.5 and 2.5 mg/kg/day groups were believed to result from maternal toxicity.

Under the conditions of this study, pramipexole produced maternal toxicity at doses of 0.5 mg/kg/day and greater. There was no indication of impaired male fertility. No teratogenic effects were seen. Apart from retarded weight gain and a retardation in the maturation parameter ‘opening of the eyes’ in the mid- and high-dose pups, the fertility test on the F1 generation showed no impairments. The maximum no-effect dose was 0.1 mg/kg/day.

Due to the lower conception rate in rats administered 2.5 mg/kg/day in the above study; a second Segment I study was conducted. Pramipexole in distilled water was administered to rats at oral doses of 0 (vehicle) or 2.5 mg/kg/day to groups of 24 males at least 9 weeks before mating and during the mating period, and to groups of 24 females at least 2 weeks before mating and during the mating and gestation period as follows: Group 0 (vehicle control): males and females treated with distilled water; Group 1 (positive control): males and females treated with 2.5 mg/kg/day pramipexole; Group 2: males treated with 2.5 mg/kg/day pramipexole, females with distilled water; and Group 3: males treated with distilled water, females with 2.5 mg/kg/day of pramipexole.

Slight toxic effects were noted in treated animals (temporary reduction in body weight gain in males, body weight loss in females at study initiation accompanied by decreased feed intake followed by overcompensation). Both sexes reacted with moderate to severe agitation, which lasted 8 hours or more after administration.

Although treated and untreated couples mated as expected, the number and percentage of pregnant dams were significantly reduced in treated females regardless of whether or not the male partners had been treated. The estrous cycle of about 50% of treated females was prolonged. Light microscopical examination of ovaries from treatment groups 1 and 3 showed an increase in the number of corpora lutea by 75% and 62.5%, respectively. A slight decrease in number of ovarian follicles (showing all stages of folliculogenesis) was noted. A significant (p < 0.001) decrease in prolactin levels in all treated males and in eight out of 10 treated females after the administration of 2.5 mg/kg per day was found. The prolonged estrous cycle, the inhibition of nidation, and the increased number of corpora lutea were regarded as a consequence of the marked reduction in prolactin levels. No evidence of embryo-/fetotoxicity or teratogenicity was noted.

Plasma levels taken two hours after the last administration showed concentrations of pramipexole in the range of 93 to 236 ng/mL (females) and 134 ng/mL (males).

In conclusion, under the conditions of this study, the effect of lowered fertility in females was clearly shown to be a consequence of female rather than male treatment with pramipexole.

Teratogenicity

Groups of 36 female Chbb:THOM rats were administered pramipexole in distilled water at oral doses of 0 (vehicle), 0.1, 0.5 or 1.5 mg/kg/day from days 7 to 16 of gestation.

Treatment-related CNS stimulation and a dose-dependent decrease in food intake was observed at 0.5 and 1.5 mg/kg/day. In the majority of high-dose (1.5 mg/kg/day) dams (approximately 78%), there were early resorptions of the entire litter. All surviving pups developed normally. The embryotoxicity (resorptions) seen in the high-dose group were associated with predominantly pharmacodynamically-induced CNS effects (agitation and increased spontaneous activity) in the dams. Although a dose of 0.5 mg/kg/day also produced CNS symptoms in the dams, it did not cause embryo toxic or fetotoxic effects in the offspring. No teratogenicity was observed up to and including the high dose of 1.5 mg/kg/day.

Under the conditions of this study, the NOAEL for maternal toxicity was 0.1 mg/kg/day, the NOAEL for embryo-fetal toxicity was 0.5 mg/kg/day, and the teratogenic NOAEL was 1.5 mg/kg/day.

Groups of 18 mated female Chbb:HM rabbits were administered pramipexole in distilled water at oral doses of 0 (vehicle), 0.1, 1, or 10 mg/kg/day from day 6 to 18 of gestation. Fetuses were delivered by C-section on day 29.

Reversible excitation and restlessness after 3 to 4 days of treatment were observed at 10 mg/kg/day. Maternal toxicity was observed at 10 mg/kg per day (temporary dose-dependent weight loss or retarded weight gains, one intercurrent death after the third dose of 10 mg/kg probably due to shock-like cardiovascular collapse). Embryo-/fetotoxicity or teratogenicity was not observed.

Under the conditions of this study, the NOAEL for maternal toxicity was 1 mg/kg/day and the embryo-/fetotoxic and teratogenic NOAEL was 10 mg/kg/day.

Peri-postnatal toxicity

Groups of 24 pregnant Chbb:THOM rats were administered pramipexole in distilled water at oral doses of 0 (vehicle), 0.1, 0.5, or 1.5 mg/kg/day from day 16 of gestation through day 21 of parturition.

The low dose of 0.1 mg/kg/day was well tolerated. Doses of 0.5 and 1.5 mg/kg/day caused considerable agitation and hyperactivity, particularly in lactating rats. Slight maternal toxicity

(decreased food consumption) was observed in the 1.5 mg/kg/day dose group. No effects on the duration of pregnancy were observed at any dose.

In the 3-week rearing phase, during which dams in the 0.5 and 1.5 mg/kg/day groups showed signs of great agitation, the body weight increase of pups in those groups was less than that of the controls, perhaps due to insufficient opportunity to suckle. There was no increase in pup mortality, and no fetotoxicity was observed.

The physiological behaviour of the pups during the rearing period and the marginal differences between a few behavioural and developmental parameters in the 0.5 and 1.5 mg/kg/day dose groups, show that despite the great state of excitement in the dams, the vast majority of pups developed normally. Only body weight, which was less (to a dose-dependent degree) than that of control animals, had not recuperated by the time the offspring reached sexual maturity). While the F1 females were lighter, there was no biologically relevant effect on mating and gestational parameters.

Under the conditions of this study the NOEL for maternal toxicity and fetal development was 0.1 mg/kg/day.

Local tolerance

Pramipexole at a single dose of 100 mg or repeated doses of 0.05% to 0.5% for three days was not irritating to rabbit eyes. Doses of 0.00625% to 0.5% administered to rabbits for four weeks caused mild to moderated increased conjunctival secretion and isolated mild reddening. There was no concentration-effect relationship and findings were fully reversible. No treatment-related histopathological changes of dose-related systemic reactions were observed.

Pramipexole at a single dose of 0.5 g applied occlusively and semi-occlusively to the intact skin of male rabbits was not irritating. Repeated doses of 0.1 g applied to the skin of male rabbits under occlusion for 24-hour periods for five consecutive days was not irritating to intact skin but caused mild, reversible irritation to abraded skin.

A 0.1% injectable solution of pramipexole injected paravenously into the jugular vein was conditionally tolerated by rats. Single intravenous injections of pramipexole 0.1% solution into the marginal vein of the ear were tolerated by rabbits. Single intraarterial injections of pramipexole into the central artery of the ear were tolerated by rabbits.

A skin sensitization (Maximization Test) study in guinea pigs with pramipexole base resulted in a mild sensitizing potential based on sensitization rates of 25% (first challenge) and 20% (rechallenge). A skin sensitization (Modification of Beuhler Test) study in guinea pigs with pramipexole base as a CPA-patch formulation did not reveal any sensitizing potential.

A 0.1% pramipexole solution for injection added to freshly drawn citrated human blood had no haemolytic effect.

RETINOPATHY IN ALBINO RATS

(See Part I: WARNINGS AND PRECAUTIONS)

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