Mirapex

Interactions with herbal products have not been established.

Interactions with food have not been established.

There are no known interactions between MIRAPEX and laboratory tests.

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

Some patients may find optimal relief at 0.75 mg per day, albeit with a higher rate of adverse reactions. Intermediate doses (such as 0.375 mg or 0.625 mg per day) may be used. Patients should be re-assessed periodically, and the dose adjusted accordingly.

It is recommended that MIRAPEX be discontinued over a period of one week.

Due to the chronic and fluctuating nature of RLS, continuous treatment may not be necessary. If discontinuation is desirable, tapering in 4-7 day intervals is recommended whenever possible.

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

In all clinical studies, dosage was initiated at a subtherapeutic level to avoid orthostatic hypotension and severe adverse effects. MIRAPEX 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.

Dose reduction is not considered necessary in patients with hepatic impairment, as approx. 90% of absorbed drug is excreted through the kidneys.

Patients with a creatinine clearance above 50 mL/min require no reduction in daily dose.

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

The duration between up titration steps should be increased to 14 days in RLS patients with severe and moderately severe renal impairment (creatinine clearance 20-60 mL/min). (See Action and Clinical Pharmacology, Renal Insufficiency).

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

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

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

MIRAPEX 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, MIRAPEX 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 MIRAPEX 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.

Dose reduction not considered necessary.

conjunctivitis, dry eye, eye irritation, eyelid edema, vision blurred, visual acuity reduced, visual disturbance.

goiter, hypothyroidism.

Dose Related Adverse Events in a 12-Week Double-Blind, Placebo-Controlled Fixed Dose Study in Restless Legs Syndrome (occurring in ≥5% of all patients in the treatment phase)

congenital atrial septal defect.

tongue discoloration, GI hemorrhage, fecal incontinence.

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

Post marketing experience suggests MIRAPEX 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 MIRAPEX, 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), abnormal dreams, amnesia, delusion, hyperkinesias, paranoia, increased eating (binge eating, hyperphagia), compulsive shopping, restlessness, visual disturbance including vision blurred and visual acuity reduced, vomiting, weight decrease, and weight increase have been observed.

Insomnia and peripheral edema have been reported.

asthma, chronic obstructive airways disease (including exacerbation), cough, dyspnoea, exertional dyspnoea, epistaxis, nasal congestion, nasal septum deviation, pharyngolaryngeal pain, respiratory tract infection, sinus congestion, snoring.

balance disorder, carpal tunnel syndrome, cerebral ischemia, cervicobrachial syndrome, disturbance in attention, dizziness postural, dysgeusia, hypoesthesia, memory impairment, migraine, nerve compression, paraesthesia, Restless Legs Syndrome, sciatica, sedation, sinus headache, sudden onset of sleep, syncope, tension headache, transient ischemic attack, tremor.

skin disorder, herpes simplex.

fever, enlarged abdomen, rigid neck, no drug effect.

acne, eczema, erythema, hyperhidrosis, night sweats, photosensitivity allergic reaction, pruritus, rash, rosacea, seborrheic dermatitis.

hysterectomy.

arthralgia, bursitis, cervical spinal stenosis, intervertebral disc protrusion, intervertebral discitis, joint stiffness, localized osteoarthritis, lumbar spinal stenosis, muscle cramps, musculoskeletal stiffness, neck pain, myalgia, osteoporosis, sensation of heaviness, spinal osteoarthritis, tendonitis, toe deformity.

Borrelia infection, bronchitis, cystitis, ear infection, fungal infection, gastroenteritis, herpes simplex, herpes zoster, hordeolum, laryngitis, localized infection, onychomycosis, otitis (externa and media), paronychia, pharyngitis, pneumonia, rhinitis, sinusitis, tonsillitis, tooth infection, urinary tract infection, vaginitis, viral infection.

palpitations, angina pectoris, atrial arrhythmia, peripheral vascular disease.

MIRAPEX Tablets have been administered to 889 individuals in RLS clinical trials. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing; similar types of events were grouped into a smaller number of standardized categories using MedDRA dictionary terminology. These categories are used in the listing below. The events listed below occurred on at least two occasions (on one occasion if the event was serious) within the 889 individuals exposed to MIRAPEX. All reported events, except those already listed above, are included, without regard to determination of a causal relationship to MIRAPEX.

diabetes mellitus.

flushing, haematoma, hypertension, hypotension, orthostatic hypotension.

lung cancer metastatic, metastases to lung, ovarian cancer, prostatic adenoma, renal neoplasm, squamous cell carcinoma.

alanine aminotransferase increased, aspartate aminotransferase increased, blood glucose increased, blood pressure increased, blood triglycerides increased, gammaglutamyltransferase increased, heart rate increased, heart rate irregular, weight decreased, weight increased.

anaemia.

abnormal dreams, agitation, anxiety, confusional state, depression, irritability, libido decreased, mood altered, nervousness, nightmare, restlessness, sleep disorder, stress symptoms.

abdominal discomfort, abdominal distension, abdominal pain, dyspepsia, enteritis, flatulence, gastroesophageal reflux disease, gastritis, haemorrhoids, inguinal hernia, irritable bowel syndrome, loose stools, toothache, umbilical hernia.

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.

MIRAPEX 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 MIRAPEX. All reported events, except those already listed above, are included, without regard to determination of a causal relationship to MIRAPEX.

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

dysmenorrhoea, menopausal symptoms, sexual dysfunction.

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 MIRAPEX. 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.

anorexia, decreased appetite, hypercholesterolemia, hyperlipidemia, hypocalcaemia, increased appetite.

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.

alcohol interaction, asthenia, chest pain, peripheral edema, feeling cold, feeling hot, inflammation localized, influenza-like illness, malaise, pain, pitting edema, pyrexia, thirst.

gout.

arrhythmia, coronary artery disease, myocardial infarction, myocardial ischemia, palpitations, tachycardia.

MIRAPEX (pramipexole dihydrochloride monohydrate) Tablets for treatment of RLS has been evaluated for safety in 889 patients, including 427 treated for over six months and 75 for over one year. The overall safety assessment focuses on the results of three double-blind, placebo-controlled trials, in which 575 patients with RLS were treated with MIRAPEX for 3-12 weeks. The most commonly observed adverse events with MIRAPEX in the treatment of RLS (observed in >5% of pramipexole treated patients and at a rate at least twice that observed in placebo-treated patients) were nausea and somnolence. Occurrences of nausea and somnolence in clinical trials were generally mild and transient.

Approximately 7% of 575 patients treated with MIRAPEX during the double-blind periods of three placebo-controlled trials discontinued treatment due to adverse events compared to 5% of 223 patients who received placebo. The adverse event most commonly causing discontinuation of treatment was nausea (1%).

tinnitus, vertigo.

bursitis, myasthenia.

nocturia, pollakiuria, polyuria, renal colic.

contusion, epicondylitis, failure of implant, fall, foot fracture, fractured sacrum, hip fracture, joint injury, joint sprain, limb injury, muscle strain, open fracture, radius fracture, sunburn, tendon rupture, thermal burn, wound, wrist fracture.

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.

biliary colic, cholecystitis, cholelithiasis.

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

urinary incontinence, dysuria, prostate disorder, kidney calculus.

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

During the premarketing development of MIRAPEX (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 MIRAPEX, 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.

voice alteration, asthma, hemoptysis.

Patients treated with MIRAPEX 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 and Precautions).

hypersensitivity, seasonal allergy.

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.

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

ecchymosis.

Although no gender-related differences were observed in Parkinson’s disease patients, nausea and fatigue, both generally transient, were more frequently reported by female than male RLS patients. Less than 4% of patients enrolled were non-Caucasian, therefore, an evaluation of adverse events related to race in not possible.

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 (>65 years of age).)

The safety and efficacy of MIRAPEX have not been established in children less than 18 years of age, therefore MIRAPEX is not recommended in this patient population.

MIRAPEX (pramipexole dihydrochloride monohydrate) is indicated for:

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

  
  

• symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome. The effectiveness of MIRAPEX used for longer than 12 weeks has not been systematically evaluated in controlled trials for Restless Legs Syndrome. The physician who elects to prescribe MIRAPEX for an extended time should periodically re-evaluate the long-term usefulness for the individual patient.

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.

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 MIRAPEX (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.

Each white, round tablet, both faces flat with beveled edges, one side has a deep break score and is imprinted with the symbol P9 on either side of the score, the other side is also scored and imprinted with the Boehringer Ingelheim company symbol on either side of the score, contains: pramipexole dihydrochloride monohydrate 1 mg. Nonmedicinal ingredients: colloidal silicon dioxide, cornstarch, magnesium stearate, mannitol and povidone. Bottles of 90.

Each white, oval tablet, both faces flat with beveled edges, one side has a deep break score and is imprinted with the symbol P8 on either side of the score, the other side is also scored and imprinted with the Boehringer Ingelheim company symbol on either side of the score, contains: pramipexole dihydrochloride monohydrate 0.5 mg. Nonmedicinal ingredients: colloidal silicon dioxide, cornstarch, magnesium stearate, mannitol and povidone. Bottles of 90.

Each white, oval tablet, both faces flat with beveled edges, one side has a deep break score and is imprinted with the symbol P7 on either side of the score, the other side is also scored and imprinted with the Boehringer Ingelheim company symbol on either side of the score, contains: pramipexole dihydrochloride monohydrate 0.25 mg. Nonmedicinal ingredients: colloidal silicon dioxide, cornstarch, magnesium stearate, mannitol and povidone. Bottles of 90.

Each white, round tablet, both faces flat with bevelled edges, one side imprinted with the symbol P6, the other side imprinted with the Boehringer Ingelheim company symbol, contains: pramipexole dihydrochloride monohydrate 0.125 mg. Nonmedicinal ingredients: colloidal silicon dioxide, cornstarch, magnesium stearate, mannitol and povidone. Blister packs of 30.

Each white, round tablet, both faces flat with beveled edges, one side has a deep break score and is imprinted with the symbol P11 on either side of the score, the other side is also scored and imprinted with the Boehringer Ingelheim company symbol on either side of the score, contains: pramipexole dihydrochloride monohydrate 1.5 mg. Nonmedicinal ingredients: colloidal silicon dioxide, cornstarch, magnesium stearate, mannitol and povidone. Bottles of 90.

A single case of rhabdomyolysis occurred in a 49-year old male with advanced Parkinson’s disease treated with MIRAPEX. The patient was hospitalized with an elevated CPK (10.631 IU/L). The symptoms resolved with discontinuation of the medication.

Since MIRAPEX (pramipexole dihydrochloride monohydrate) is eliminated through the kidneys, caution should be exercised when prescribing MIRAPEX to patients with renal insufficiency (see Action and Clinical Pharmacology, Pharmacokinetics and Dosage and Administration).

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 MIRAPEX. While the evidence is not sufficient to establish a causal relationship between MIRAPEX and these fibrotic complications, a contribution of MIRAPEX cannot be completely ruled out in rare cases.

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 a 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.

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 MIRAPEX only under ophthalmological monitoring.

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 MIRAPEX (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 MIRAPEX, however, and despite clear orthostatic effects in normal volunteers, the reported incidence of clinically significant orthostatic hypotension was not greater among those assigned to MIRAPEX 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 MIRAPEX, 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.

MIRAPEX 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.

The safety and efficacy of MIRAPEX in children under 18 years of age have not been established.

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

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.

Reports in the literature indicate treatment of RLS with dopaminergic medications can result in a worsening of symptoms in the early morning hours, referred to as rebound. Reports in the literature also indicate 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. Spontaneous reports of augmentation were uncommon in the RLS development programme. The frequency of augmentation and/or rebound after longer use of MIRAPEX and the appropriate management of these events have not been evaluated in controlled clinical trials.

In RLS clinical trials, some patients have reported worsening of the RLS symptoms following abrupt discontinuation of MIRAPEX treatment. The worsening of symptoms was independent of the MIRAPEX dosage and generally resolved within one week. Tapering is recommended whenever possible if discontinuation is necessary.

MIRAPEX 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 Action and Clinical Pharmacology, 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 MIRAPEX was increased in the elderly.

MIRAPEX 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, MIRAPEX had little or no effect.

Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma that 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 MIRAPEX for any indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g. dermatologists).

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 MIRAPEX. (See Dosage and Administration for dose tapering.)

There are no specific laboratory tests recommended for the management of patients receiving MIRAPEX.

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.

Hallucinations and confusion are known side effects of treatment with dopamine agonist and levodopa. Hallucinations were more frequent when MIRAPEX 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 MIRAPEX, 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 MIRAPEX and concomitant levodopa, hallucinations were observed in 16.5% (43 of 260) of patients receiving MIRAPEX 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 MIRAPEX 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 MIRAPEX patients than placebo patients <65 years old, and >65 years old, respectively.

In the RLS clinical program, one pramipexole-treated patient (of 889) reported hallucinations; this patient discontinued treatment and the symptoms resolved.

The excretion of pramipexole into breast milk has not been studied in women. Since MIRAPEX 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.

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.

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

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.

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.

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%.

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

A cross-study comparison of data suggests that the pharmacokinetic profile of pramipexole administered once daily in RLS patients is generally consistent with the pharmacokinetic profile of pramipexole in healthy volunteers.

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

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

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).

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.

MIRAPEX (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 MIRAPEX 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.

The precise mechanism of action of MIRAPEX as a treatment for Restless Legs Syndrome is not known. Although the pathophysiology of Restless Legs Syndrome is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron emission tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of Restless Legs Syndrome.

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

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 MIRAPEX and thus, may necessitate an adjustment in the dosage of MIRAPEX. 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 MIRAPEX.

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.

The potential influence of race on pramipexole pharmacokinetics has not been evaluated.

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.

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

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

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

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