Apo-Pramipexole Adverse Reactions

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 l.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 9 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. (See Table 9.)

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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, pruritus, 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 as follows.
The events listed as follows occurred in less than 1% of the 1,715 subjects exposed to pramipexole dihydrochloride monohydrate. All reported events, except those already listed previously, 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 of 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), abnormal dreams, 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.