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APO-PRAMIPEXOLE
(Pramipexole Dihydrochloride Monohydrate) Tablets, 0.25 mg, 0.5 mg, 1.0 mg, 1.5 mg Antiparkinsonian Agent / Dopamine Agonist
Control No. 105379
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 9 DRUG INTERACTIONS 14 DOSAGE AND ADMINISTRATION 17 OVERDOSAGE 17 ACTION AND CLINICAL PHARMACOLOGY. 19 STORAGE AND STABILITY 22 DOSAGE FORMS, COMPOSITION AND PACKAGING 22
PHARMACEUTICAL INFORMATION 24 CLINICAL TRIALS 24 DETAILED PHARMACOLOGY 28 TOXICOLOGY 30 REFERENCES 41
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APO-PRAMIPEXOLE
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Tablets 0.25 mg, 0.5 mg, 1.0 mg, 1.5 mg | None For a complete listing see Dosage Forms, Composition and Packaging section. |
Adults
APO-PRAMIPEXOLE (pramipexole dihydrochloride monohydrate) is indicated for treatment of the signs and symptoms of idiopathic Parkinson's disease. APO-PRAMIPEXOLE may be used both as early therapy, without concomitant levodopa, and as an adjunct to levodopa.
Geriatrics (> 65 years of age): WARNINGS AND PRECAUTIONSSpecial Population, Geriatrics
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
,
)
Pediatrics:
The safety and efficacy of pramipexole dihydrochloride has not been established in children under 18 years of age, therefore APO-PRAMIPEXOLE is not recommended in this patient population.
APO-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).
Sudden Onset of Sleep
Patients receiving treatment with pramipexole dihydrochloride and other dopaminergic agents have reported suddenly falling asleep while engaged in activities of daily living, including operating a motor vehicle, which sometimes resulted in accidents. Although some of the patients reported somnolence while on pramipexole dihydrochloride, others perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Physicians should alert patients of the reported cases of sudden onset of sleep, bearing in mind that these events are NOT limited to initiation of therapy. Patients should also be advised that sudden onset of sleep has occurred without warning signs. If drowsiness or sudden onset of sleep should occur, patients should immediately contact their physician. Until further information is available on the management of this unpredictable and serious adverse event, patients should be warned not to drive or engage in other activities where impaired alertness could put themselves and others at risk of serious injury or death (e.g., operating machines). Substituting other dopamine agonists may not alleviate these symptoms, as episodes of falling asleep while engaged in activities of daily living have also been reported in patients taking these products. While dose reduction clearly reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. Presently, the precise cause of this event is unknown. It is known that many Parkinson's disease patients experience alterations in sleep architecture, which results in excessive daytime sleepiness or spontaneous dozing, and that dopaminergic agents can also induce sleepiness.
The following Warnings and Precautions are listed in alphabetical order.
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 tumors occurred. Testicular Leydig cell adenomas were found in male rats as follows: 13 of 50 control group A males, 9 of 60 control group B males, 17 of 50 males given 0.3 mg/kg/day, 22 of 50 males given 2 mg/kg/day, and 22 of 50 males given 8 mg/kg/day. Leydig cell hyperplasia and increased numbers of adenomas are attributed to pramipexole-induced decreases in serum prolactin levels, causing a down-regulation of Leydig cell luteinizing hormone (LH) receptors and a compensatory elevation of LH secretion by the pituitary gland. The endocrine mechanisms believed to be involved in rats are not relevant to humans. In mice, pramipexole was administered in the diet, at doses of 0.3, 2 and 10 mg/kg/day. The highest dose corresponded to 11 times the highest recommended clinical dose on a mg/m2 basis. No significant increases in tumors 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.
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. 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, however, and despite clear orthostatic effects in normal volunteers, the reported incidence of clinically significant orthostatic hvpotension was not greater among those assigned to pramipexole dihydrochloride 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, 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.
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. While the evidence is not sufficient to establish a causal relationship between pramipexole dihydrochloride and these fibrotic complications, a contribution of pramipexole dihydrochloride cannot be completely ruled out in rare cases.
Pramipexole dihydrochloride 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 had little or no effect.
Dyskinesia
APO-PRAMIPEXOLE (pramipexole dihydrochloride monohydrate) may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting 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 (see DOSAGE AND ADMINISTRATION for dose tapering).
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 a mg/m basis) and constant light (100 lux) but not in Brown-Norway rats exposed to the same dose and higher light intensities (500 lux). The albino rats seem to be more susceptible than pigmented rats to the damaging effect of pramipexole and light. While the potential significance of this effect on humans has not been established, it cannot be excluded that human albinos (or people who suffer from albinismus oculi) might have an increased susceptibility to pramipexole compared to normally pigmented people. Therefore, such patients should take APO-PRAMIPEXOLE only under ophthalmological control.
Behavioural changes
Patients and caregivers should be aware of the fact that behavioural changes can occur (e.g. pathological gambling, increased libido, binge eating). Dose reduction/taper 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 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, 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 and concomitant levodopa, hallucinations were observed in 16.5% (43 of 260) of patients receiving pramipexole dihydrochloride 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 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 patients than placebo patients <65 years old, and >65 years old, respectively.
Since pramipexole dihydrochloride is eliminated through the kidneys, caution should be exercised when prescribing APO-PRAMIPEXOLE to patients with renal insufficiency (see ACTION AND CLINICAL PHARMACOLOGY, pharmacokinetics and DOSAGE AND ADMINISTRATION).
Rhabdomyolysis
A single case of rhabdomyolysis occurred in a 49-year old male with advanced Parkinson's disease treated with pramipexole dihydrochloride. The patient was hospitalized with an elevated CPK (10.631 IU/L). The symptoms resolved with discontinuation of the medication.
Melanoma
Some epidemiologic studies have shown that patients with Parkinson's disease have a higher risk (perhaps 2- to 4-fold higher) of developing melanoma than the general population. Whether the observed increased risk was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, was unclear. Pramipexole dihydrochloride is one of the dopamine agonists used to treat Parkinson's disease. Although pramipexole dihydrochloride has not been associated with an increased risk of melanoma specifically, its potential role as a risk factor has not been systematically studied. Patients using pramipexole dihydrochloride for any indication should be made aware of these results and should undergo periodic dermatologic screening.
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.
There are no studies of pramipexole dihydrochloride in pregnant women. Because animal reproduction studies are not always predictive of human response, APO- PRAMIPEXOLE should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
The excretion of pramipexole into breast milk has not been studied in women. Since pramipexole dihydrochloride 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 dihydrochloride 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 was increased in the elderly.
The safety and efficacy of pramipexole dihydrochloride in children under 18 years of age has not been established.
There are no specific laboratory tests recommended for the management of patients receiving pramipexole dihydrochloride.
Adverse Drug Reaction Overview
During the premarketing development of pramipexole dihydrochloride, 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, 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 approximating rates.
Adverse Reactions Leading to Discontinuation of Treatment Early Parkinson's Disease Approximately 12% of 388 patients treated with pramipexole dihydrochloride 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 vs 0.4% on placebo), dizziness (2.1% on pramipexole dihydrochloride vs 1.0% on placebo), somnolence (1.6% on pramipexole dihydrochloride vs 0% on placebo), headache and confusion (1.3% and 1.0% respectively, on pramipexole dihydrochloride vs 0% on placebo), and to the gastrointestinal system (nausea 12.1% on pramipexole dihydrochloride vs 0.4% on placebo).
Advanced Parkinson's Disease
Approximately 12% of 260 patients treated with pramipexole dihydrochloride 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 vs 0.4% on placebo), dyskinesia (1.9 % on pramipexole dihydrochloride vs 0.8% on placebo), dizziness (1.2% on pramipexole dihydrochloride vs l.5% on placebo), confusion (1.2 % on pramipexole dihydrochloride vs 2.3% on placebo, and to the cardiovascular system (postural [orthostatic] hypotension (2.3% on pramipexole dihydrochloride 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 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 AND NUMERICALLY MORE FREQUENT THAN IN PATIENTS TREATED WITH PLACEBO)
| Body System / Adverse Event | Early Therapy | Advanced Therapy | ||
| Pramipexole dihydrochloride N = 388 % occurrence | Placebo N = 235 % occurrence | Pramipexole dihydrochloride+ N = 260 % occurrence | Placebo+ N = 264 % occurrence | |
| Body as a Whole | 14 | 12 | 10 | 8 |
| Asthenia | ||||
| General edema | 5 | 3 | 4 | 3 |
| Malaise | 2 | 1 | 3 | 2 |
| Reaction unevaluable | 2 | 1 | - | - |
| Fever | 1 | 0 | - | - |
| Chest pain | - | - | 3 | 2 |
| Accidental injury | - | - | 17 | 15 |
| Cardiovascular System Postural Hypotension | - | - | 53 | 48 |
| Digestive System | 28 14 4 2 - | 18 6 2 0 - | - 10 - - 7 | - 9 - - 3 |
| Nausea Constipation Anorexia Dysphagia Dry Mouth | ||||
| Metabolic & Nutritional | 5 | 4 | 2 | 1 |
| System | ||||
| Peripheral edema | ||||
| Decreased weight | 2 | 0 | - | - |
| Increased creatine PK | - | - | 1 | 0 |
| Musculoskeletal System | - | - | 3 | 1 |
| Arthritis | ||||
| Twitching | - | - | 2 | 0 |
| Bursitis | - | - | 2 | 0 |
| Myasthenia | - | - | 1 | 0 |
| Body System / Adverse Event | Early Therapy | Advanced Therapy | ||
| Pramipexole dihydrochloride N = 388 % occurrence | Placebo N = 235 % occurrence | Pramipexole dihydrochloride+ N = 260 % occurrence | Placebo+ N = 264 % occurrence | |
| Nervous System | 25 | 24 | 26 | 25 |
| Dizziness | ||||
| Somnolence | 22 | 9 | 9 | 6 |
| Insomnia | 17 | 12 | 27 | 22 |
| Hallucinations | 9 | 3 | 17 | 4 |
| Confusion | 4 | 1 | 10 | 7 |
| Amnesia | 4 | 2 | 6 | 4 |
| Hyperesthesia | 3 | 1 | - | - |
| Dystonia | 2 | 1 | 8 | 7 |
| Thinking abnormalities | 2 | 0 | 3 | 2 |
| Decreased libido | 1 | 0 | - | - |
| Myoclonus | 1 | 0 | - | - |
| Hypertonia | - | - | 7 | 6 |
| Paranoid reaction | - | - | 2 | 0 |
| Delusions | - | - | 1 | 0 |
| Sleep disorders | - | - | 1 | 0 |
| Dyskinesia | - | - | 47 | 31 |
| Gait abnormalities | - | - | 7 | 5 |
| Dream abnormalities | - | - | 11 | 10 |
| Respiratory System | - | - | 4 | 3 |
| Dyspnea | ||||
| Rhinitis | - | - | 3 | 1 |
| Pneumonia | - | - | 2 | 0 |
| Skin & Appendages Skin disorders | - | - | 2 | 1 |
| Special Senses | 3 - - | 0 - - | 3 4 1 | 1 2 0 |
| Vision Abnormalities Accommodation abnormalities Diplopia | ||||
| Urogenital System | 2 | 1 | - | - |
| Impotence | ||||
| Urinary frequency | - | - | 6 | 3 |
| Urinary tract infection | - | - | 4 | 3 |
| Urinary incontinence | - | - | 2 | 1 |
+ 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 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 hvpotension, hypertonia, diarrhea, rash, ataxia, dry mouth, leg cramps, twitching, pharyngitis, sinusitis, sweating, rhinitis, urinary tract infection, vasodilation, flu syndrome, increased saliva, tooth disease, dyspnea, 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, 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 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. All reported events, except those already listed above, are included, without regard to determination of a causal relationship to pramipexole dihydrochloride. 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: Metabolic & nutritional system: Musculoskeletal system:
ecchymosis.
gout.
bursitis, myasthenia.
Nervous system:
apathy, libido decrease, paranoid reaction, akinesia, coordination abnormalities, speech disorder, hyperkinesias, 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 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. 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 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 may be associated with increase or decrease of libido. 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, especially at high doses. This behaviour was generally reversible upon treatment discontinuation. Abnormal behaviour, abnormal dreams, delusion, hyperkinesias, increased eating (binge eating, hyperphagia), paranoia and weight increase have been observed. Insomnia and peripheral edema have been reported.
The drugs listed in this table 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 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. Medication 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 resulting in reduced clearance of either or both medications.
Table 2 - Established or Potential Pharmacokinetic Interactions
| Pramipexole dihydrochloride | Effect | Clinical comment |
| Antiparkinsonian drugs | ||
| Levodopa/carbidopa | Pramipexole increases levodopa Cmax by about 40% and reduces Tmax from 2.5 to 0.5 hours. No change in total exposure (AUC) was observed. Levodopa/carbidopa has no effect on the pharmacokinetics of pramipexole in healthy volunteers. | The combined use of pramipexole and levodopa increases the frequency of hallucination. Dosage adjustment. Even discontinuation may be necessary. While increasing the dose of pramipexole dihydrochloride 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. |
| Selegiline | Selegiline has no effect on the pharmacokinetics of pramipexole in volunteers. | |
| Amantadine | Amantadine inhibits the renal cationic transport system. Amantadine might alter the clearance of pramipexole. | Dosage adjustment may be necessary. See below. |
| Anticholinergics | ||
| Anticholinergics | As anticholinergics are mainly eliminated by hepatic metabolism, pharmacokinetic drug-drug interactions with pramipexole are rather unlikely. | |
| Other drugs eliminated via renal secretion | ||
| Drugs eliminate via the renal cationic transport system Amantadine Cimetidine Ranitidine Diltiazem Triamterene | These drugs inhibit the renal tubular secretion of organic bases via the cationic transport system. They reduce the renal clearance of pramipexole to various degrees. | Dosage adjustment should be considered if concomitant treatment is necessary. Dosage reduction is necessary if adverse reactions, such as dyskinesia, agitation, or hallucination, are observed. |
| Pramipexole dihydrochloride | Effect | Clinical comment |
| Verapamil Quinidine Quinine | ||
| Drugs eliminate via the renal anionic transport system Probenecid Cephalosporins Penicillins Indomethacin Hydrochlorothiazide Chloropramide | These drugs inhibit the renal tubular secretion of organic bases via the anionic transport system. They are unlikely to reduce the renal clearance of pramipexole. | Dosage adjustment is not necessary. |
| Interactions mediated by CYP isoenzymes | ||
| Drugs metabolized by CYP isoenzymes | Inhibitors of CYP isoenzymes are not expected to affect the elimination of pramipexole. Pramipexole has no inhibitory action on CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4. Inhibition of CYP2D6 is observed with an apparent Ki of 30 uM, suggesting that pramipexole dihydrochloride will not inhibit CYP enzymes at plasma concentrations following the highest recommended clinical dose (1.5 mg tid). | |
| Dopamine antagonists | ||
| Neuroleptics, e.g. phenothiazines, butyrphenones, thioxanthines Metoclopramide | Pramipexole is a dopamine agonist. Dopamine antagonists reduce its therapeutic effects. | Concurrent use is not recommended. Pramipexole can exacerbate psychotic symptoms. |
| Miscellaneous | ||
| Sedating medications or alcohol | Possible additive effects. | Because of possible additive effects, caution should be advised when patients are taking other sedating medication or alcohol in combination with pramipexole dihydrochloride. |
Interactions with food have not been established.
Interactions with herbal products have not been established.
There are no known interactions between pramipexole dihydrochloride and laboratory tests.
APO-PRAMIPEXOLE (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.
In all clinical studies, dosage was initiated at a subtherapeutic level to avoid orthostatic hvpotension and severe adverse effects. APO-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:
| Week | Dosage (mg) | Total Daily Dose (mg) |
| 1 | 0.125 tid | 0.375 |
| 2 | 0.25 tid | 0.75 |
| 3 | 0.50 tid | 1.5 |
| 4 | 0.75 tid | 2.25 |
| 5 | 1.00 tid | 3.0 |
| 6 | 1.25 tid | 3.75 |
| 7 | 1.50 tid | 4.5 |
Maintenance treatment
Pramipexole dihydrochloride 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 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 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
It is recommended that pramipexole dihydrochloride be discontinued over a period of one week.
The maximal recommended dose of pramipexole dihydrochloride is 4.5 mg per day. Pramipexole dihydrochloride 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 pramipexole dihydrochloride. This may be necessary in order to avoid excessive dopaminergic stimulation.
Patients with Renal Impairment
Since the clearance of pramipexole dihydrochloride is reduced in patients with renal impairment (see Pharmacokinetics), the following dosage recommendation should be considered:
| Renal Status | Starting Dose (mg) | Maximum Dose (mg) |
| Mild Impairment (creatinine Cl > 60 mL/min) | 0.125 tid | 1.5 tid |
| Moderate Impairment (creatinine Cl = 35 to 59 mL/min) | 0.125 bid | 1.5 bid |
| Severe impairment (creatinine Cl =15 to 34 mL/min) | 0.125 qd | 1 .5 qd |
| Very Severe impairment (creatinine Cl <15 mL/min and hemodialysis patients) | Pramipexole dihydrochloride has not been adequately studied in this group and its administration to patients with end stage renal disease is not recommended. | |
Patients with a creatinine clearance above 50 ml/min require no reduction in daily dose. If renal function declines during maintenance therapy reduce APO-PRAMIPEXOLE daily dose by same percentage as decline in creatinine clearance, i.e. if creatinine clearance declines by 30%, then reduce APO-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 have not been established in children and adolescents up to 18 years of age.
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 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.
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.
APO-PRAMIPEXOLE (pramipexole dihydrochloride) 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 APO-PRAMIPEXOLE exhibits high affinity for the dopamine D2 receptor subfamily, it has low affinity for a2 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 pretreated 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.
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 Cmax) in healthy volunteers, although the time to maximal plasma concentration (Tmax) 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 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.
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.
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.
The pharmacokinetics of pramipexole was comparable between early and advanced Parkinson's disease patients.
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).
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 Cmax. 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%.
The potential influence of race on pramipexole pharmacokinetics has not been evaluated.
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.
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
). 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.
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 Ievodopa Cmax by about 40%, and decreased Tmax from 2.5 to 0.5 hours. While increasing the dose of pramipexole dihydrochloride 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 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 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 APO-PRAMIPEXOLE and thus, may necessitate an adjustment in the dosage of APO-PRAMIPEXOLE. 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 APO-PRAMIPEXOLE.
CYP interactions
Inhibitors of cytochrome P450 enzymes would not be expected to affect APO-PRAMIPEXOLE elimination because pramipexole dihydrochloride is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole dihydrochloride does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 uM, suggesting that pramipexole dihydrochloride will not inhibit CYP enzymes at plasma concentrations observed following the highest recommended clinical dose (1.5 mg tid).
Dopamine antagonists
Since APO-PRAMIPEXOLE is a dopamine agonist, dopamine antagonists such as the neuroleptics (phenothiazines, butyrophenones, thioxanthines) or metoclopramide may diminish the effectiveness of APO-PRAMIPEXOLE 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 APO-PRAMIPEXOLE and when taking concomitant medication that increase plasma levels of pramipexole (e.g. cimetidine).
Store at room temperature, 15-30degC (59-86degF).
The tablet formulations contain the following non-medicinal ingredients: magnesium stearate, microcrystalline cellulose and starch (corn).
Availability of Dosage Forms:
APO-PRAMIPEXOLE (pramipexole dihydrochloride monohydrate) tablets are available in bottles of 100 tablets.
White to off-white, oval, flat-faced, beveled edge tablet, scored and engraved "PR .25" on one side and "APO" on the other side containing 0.25 mg pramipexole dihydrochloride monohydrate.
White to off-white, oval, flat-faced, beveled edge tablet, scored and engraved "PR .5" on one side and "APO" on the other side containing 0.5 mg pramipexole dihydrochloride monohydrate.
White to off-white, round, flat-faced, beveled edge tablet, scored and engraved "PR" over "1" on one side and "APO" on the other side containing 1 mg pramipexole dihydrochloride monohydrate.
White to off-white, round, flat-faced, beveled edge tablet, scored and engraved "PR" over "1.5" on one side and "APO" on the other side containing 1.5 mg pramipexole dihydrochloride monohydrate.