NEUPRO SIDE EFFECTS
SIDE EFFECTS
The following serious adverse reactions are discussed below and elsewhere in the labeling:
- Sulfite Sensitivity
- Falling Asleep During Activities of Daily Living and Somnolence
- Hallucinations/Psychosis
- Symptomatic Hypotension
- Syncope
- Impulse Control/Compulsive Behaviors
- Elevation of Blood Pressure and Heart Rate
- Weight Gain and Fluid Retention
- Dyskinesia
- Application Site Reactions
- Augmentation and Rebound in RLS
- Hyperpyrexia and Confusion
- Withdrawal Symptoms
- Fibrotic Complications
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction associated with treatment/total number of patients treated) observed in the clinical trials of a drug cannot be directly compared to incidence of adverse reactions in the clinical trials of another drug and may not reflect the incidence of adverse reactions observed in practice.
Adverse Reactions In Early-Stage Parkinson’s Disease
The safety of NEUPRO was evaluated in a total of 649 early-stage Parkinson’s disease patients who participated in three double-blind, placebo-controlled studies with durations of 3 to 9 months. Additional safety information was collected in short-term studies and two open-label extension studies in patients with early-stage Parkinson’s disease.
In the double-blind, placebo-controlled, dose-response study in patients with early-stage Parkinson’s disease, the most common adverse reactions (at least 5% greater than placebo) for the maximum recommended dose of NEUPRO (6 mg/24 hours) were nausea, vomiting, somnolence, application site reactions, dizziness, anorexia, disturbances in initiating and maintaining sleep, hyperhidrosis, and visual disturbance.
In this trial, 12% of patients treated with the maximum recommended NEUPRO dose (6 mg/24 hours) discontinued treatment because of adverse reactions, compared with 6% of patients who received placebo.
Table 1 summarizes the adverse reactions that occurred in greater than 2% of NEUPRO-treated patients and more frequent than in placebo-treated patients in a double-blind, placebo-controlled, fixed-dose trial in patients with early-stage Parkinson’s disease. Incidences for the non-recommended 8 mg/24 hours dose are also shown.
Table 1 : Adverse Reactions in a Placebo-Controlled, Fixed-Dose Trial in Patients with Early-Stage Parkinson’s Disease
| Adverse Reaction | Placebo N=64 % |
NEUPRO Dose | |||
| 2 mg/24h N=67 % |
4 mg/24h N=63 % |
6 mg/24h N=65 % |
8 mg/24h N=70 % |
||
| Nausea | 13 | 34 | 38 | 48 | 41 |
| Vomiting | 3 | 10 | 16 | 20 | 11 |
| Somnolence | 3 | 12 | 14 | 19 | 20 |
| Application and instillation site reactions | 19 | 21 | 19 | 32 | 43 |
| Dizziness | 11 | 21 | 14 | 22 | 20 |
| Anorexia | 0 | 2 | 2 | 9 | 4 |
| Disturbances in initiating and maintaining sleep | 6 | 6 | 11 | 14 | 11 |
| Hyperhidrosis | 3 | 3 | 3 | 11 | 3 |
| Visual disturbance | 0 | 0 | 0 | 5 | 3 |
| Abnormal dreams | 0 | 2 | 5 | 3 | 7 |
| Abnormal El ectrocardi ogram T wave | 0 | 0 | 2 | 3 | 0 |
| Balance disorder | 0 | 0 | 2 | 3 | 0 |
| Dyspepsia | 0 | 2 | 2 | 3 | 0 |
| Fatigue | 3 | 8 | 18 | 6 | 13 |
| Tinnitus | 0 | 0 | 2 | 3 | 0 |
| Constipation | 3 | 2 | 3 | 5 | 6 |
| Erythema | 3 | 3 | 6 | 5 | 6 |
| Hallucinations | 2 | 0 | 2 | 3 | 3 |
| Muscle spasms | 2 | 3 | 2 | 3 | 4 |
| Paresthesia | 2 | 3 | 3 | 3 | 0 |
| Peripheral edema | 2 | 2 | 3 | 3 | 4 |
| White blood cells urine positive | 2 | 3 | 3 | 3 | 1 |
The incidence of certain adverse reactions with NEUPRO was notably increased compared to placebo treatment (i.e., at least 5% greater than placebo) in either the titration or maintenance phases of the dose-response trial. During the titration phase, this increased incidence of a treatment difference was observed for nausea, somnolence, vomiting, application site reactions (ASRs), dizziness, sweating increased, anorexia, and visual disturbance. During the maintenance phase, an increased incidence was observed for nausea and ASRs. Some adverse reactions developing in the titration phase persisted (at least 7 days) into the maintenance phase. These “persistent” adverse reactions included ASRs, anorexia, somnolence, and nausea.
Adverse Reactions In Advanced-Stage Parkinson’s Disease
The safety evaluation of NEUPRO was based on a total of 672 NEUPRO-treated patients with advanced-stage Parkinson’s disease who participated in three double-blind, placebo-controlled studies (two fixed-dose trials and one flexible-dose trial) with durations of 3 to 7 months. Patients received concomitant levodopa in these studies. Additional safety information was collected in earlier short-term studies and two open-label extension studies in patients with advanced-stage Parkinson’s disease.
In the dose-response, placebo-controlled trial for advanced-stage Parkinson’s disease, the most common adverse reactions (at least 5% greater than placebo) for the maximum recommended dose of NEUPRO (8 mg/24 hours) were application site reactions, nausea, peripheral edema, dizziness, and dyskinesia.
In this trial, approximately 15% of patients treated with the maximum recommended NEUPRO dose (8 mg/24 hours) discontinued treatment because of adverse reactions, compared with 9% of patients who received placebo.
Table 2 summarizes the adverse reactions that occurred in greater than 2% of NEUPRO-treated patients and more frequent than in placebo-treated patients in a double-blind, placebo-controlled, fixed-dose trial in patients with advanced-stage Parkinson’s disease. Incidences for the non-recommended 12 mg/24 hours dose are also shown.
Table 2 : Adverse Reactions in a Placebo-Controlled, Fixed-Dose Trial in Patients with Advanced-Stage Parkinson’s Disease
| Adverse Reaction | Placebo N=120 % |
NEUPRO Dose | |
| 8 mg/24h N=118 % |
12 mg/24h N=111 % |
||
| Application and instillation site reactions | 13 | 36 | 46 |
| Nausea | 19 | 28 | 22 |
| Peripheral edema | 1 | 9 | 14 |
| Dizziness | 15 | 23 | 14 |
| Dyskinesia | 7 | 14 | 17 |
| Somnolence | 28 | 32 | 32 |
| Vomiting | 6 | 10 | 8 |
| Arthralgia | 7 | 11 | 8 |
| Hallucinations | 3 | 7 | 13 |
| Hyperhidrosis | 0 | 3 | 1 |
| Sinus congestion | 0 | 3 | 2 |
| Constipation | 6 | 9 | 5 |
| Disturbances in initiating and maintaining sleep | 6 | 9 | 14 |
| First degree atrioventricular block | 0 | 3 | 0 |
| Herpes simplex | 0 | 3 | 0 |
| Hypertension | 0 | 3 | 5 |
| Influenza | 0 | 3 | 1 |
| Nasal congestion | 0 | 3 | 3 |
| Headache | 8 | 10 | 8 |
| Diarrhea | 5 | 7 | 5 |
| Basal cell carcinoma | 1 | 3 | 0 |
| Cough | 1 | 3 | 3 |
| Dyspepsia | 2 | 3 | 0 |
| Erythema | 1 | 3 | 2 |
| Hot flush | 1 | 3 | 0 |
| Paresthesias | 3 | 4 | 3 |
| Tremor | 3 | 4 | 3 |
| Hypoaesthesia | 2 | 3 | 3 |
| Nightmare | 2 | 3 | 5 |
The incidence of certain adverse reactions with NEUPRO was notably increased compared to placebo treatment (i.e., at least 5% greater than placebo) in either the titration or maintenance phases of the dose-response trial. During the titration phase, an increased incidence was observed for application site reactions (ASRs), nausea, hallucinations, constipation, dyskinesia, and dizziness. During the maintenance phase, an increased incidence was observed for ASRs and peripheral edema. Some adverse reactions developing in the titration phase persisted (at least 7 days) into the maintenance phase. A notably “persistent” adverse reaction was ASRs.
Adverse Reactions In Restless Legs Syndrome
The safety evaluation of NEUPRO was based on 745 NEUPRO-treated patients with Restless Legs Syndrome who participated in two double-blind, placebo-controlled studies with maintenance durations of 6 months. Additional safety information was collected in earlier short-term studies and three open-label extension studies in patients with RLS.
In the two double-blind, placebo-controlled, fixed-dose trials for RLS, the most common adverse reactions (at least 5% greater than placebo) for the maximum recommended dose of NEUPRO (3 mg/24 hours) were application site reactions, nausea, disturbances in initiating and maintaining sleep, somnolence, and headache.
In the two fixed-dose, placebo-controlled trials, 24% of patients treated with the maximum recommended NEUPRO dose (3 mg/24 hours) discontinued treatment because of adverse reactions, compared with 3% of patients who received placebo.
Table 3 summarizes the adverse reactions that occurred in at least 2% of NEUPRO-treated patients and more frequent than in placebo-treated patients in two double-blind, placebo-controlled, fixed-dose trials in patients with Restless Legs Syndrome.
Table 3 : Adverse Reactions in Pooled Placebo-Controlled, Fixed-Dose Trials of Patients with Restless Legs Syndrome
| Adverse Reaction | Placebo N=217 % |
NEUPRO Dose | |||
| 0.5 mg/24h N=99 % |
1 mg/24h N=215 % |
2 mg/24h N=211 % |
3 mg/24h N=220 % |
||
| Application and instillation site reactions | 4 | 23 | 27 | 38 | 43 |
| Nausea | 10 | 18 | 15 | 23 | 21 |
| Disturbances in initiating and maintaining sleep | 3 | 2 | 4 | 3 | 10 |
| Headache | 11 | 21 | 15 | 18 | 16 |
| Asthenic conditions* | 8 | 11 | 7 | 14 | 12 |
| Somnolence | 4 | 8 | 5 | 8 | 10 |
| Hypertension | 0 | 3 | 1 | 1 | 4 |
| Pruritus | 3 | 9 | 4 | 3 | 7 |
| Dry mouth | 4 | 3 | 3 | 3 | 7 |
| Vomiting | 1 | 2 | 2 | 4 | 4 |
| Dizziness | 6 | 7 | 5 | 9 | 6 |
| Hyperhidrosis | 2 | 1 | 3 | 5 | 3 |
| Abnormal dreams | 0 | 2 | 1 | 2 | 3 |
| Irritability | 0 | 0 | 1 | 3 | 1 |
| Muscle spasms | 1 | 3 | 1 | 4 | 1 |
| Dyspepsia | 1 | 2 | 1 | 2 | 3 |
| Hot flush | 1 | 4 | 1 | 3 | 0 |
| Menstrual disorder | 0 | 0 | 0 | 2 | 1 |
| Sleep disorder | 1 | 0 | 2 | 3 | 3 |
| Viral gastroenteritis | 0 | 1 | 1 | 2 | 1 |
| Sleep attacks | 0 | 0 | 1 | 0 | 2 |
| Sexual desire disorder | 3 | 6 | 4 | 4 | 5 |
| Depression | 1 | 3 | 1 | 2 | 1 |
| Decreased serum ferritin | 1 | 2 | 1 | 1 | 2 |
| Vertigo | 1 | 0 | 4 | 3 | 1 |
| Constipation | 3 | 6 | 3 | 2 | 5 |
| Erythema | 1 | 1 | 1 | 0 | 2 |
| Sinusitis | 1 | 2 | 1 | 2 | 3 |
| Diarrhea | 4 | 6 | 4 | 5 | 4 |
| Increased weight | 1 | 3 | 1 | 1 | 2 |
| Nasopharyngitis | 7 | 5 | 10 | 7 | 8 |
| *Asthenic conditions is a high-level term for the following preferred terms: asthenia, malaise, and fatigue. | |||||
The incidence of certain adverse reactions with NEUPRO treatment was increased compared to placebo (i.e., at least 5% greater than placebo) in either the titration or maintenance phases of the dose-response trials. During the titration phase, an increased incidence was observed for application site reactions (ASRs), nausea, headache, asthenic conditions, and disturbances in initiating and maintaining sleep. During the maintenance phase, an increased incidence was observed for ASRs. Some adverse reactions developing in the titration phase persisted (at least 7 days) into the maintenance phase. These “persistent” adverse reactions were ASRs, nausea, and disturbances in initiating and maintaining sleep.
Laboratory Changes
Some clinical laboratory analytes were abnormal in patients treated with the maximum recommended NEUPRO dose in the fixed-dose, placebo-controlled, dose-response trials for patients with early-and advanced-stage Parkinson’s disease and with RLS.
Patients with early-stage Parkinson’s disease receiving NEUPRO had an increased risk for low hemoglobin below the normal reference range (NEUPRO 8% vs. placebo 2%) and for decreased hematocrit below the normal reference range (NEUPRO 8% vs. placebo 5%). Patients with advanced-stage Parkinson’s disease receiving NEUPRO had an increased risk for a low hemoglobin below the normal reference range (NEUPRO 15% vs. placebo 11%) and for decreased hematocrit below the normal reference range (NEUPRO 17% vs. placebo 14%). Patients with RLS receiving NEUPRO had an increased risk for a decreased hemoglobin below the normal reference range (NEUPRO 15% vs. placebo 12%). There was also an increased risk for markedly decreased hemoglobin and hematocrit (NEUPRO 2% vs. placebo 0%) in patients with advanced-stage Parkinson’s disease receiving NEUPRO and for markedly decreased hematocrit (NEUPRO 1% vs. placebo 0%) in patients with RLS receiving NEUPRO.
Patients with early-stage Parkinson’s disease receiving NEUPRO had an increased risk for elevated serum blood urea nitrogen (BUN) above the normal reference range (NEUPRO 11% vs. placebo 2%). There was also an increased risk for markedly elevated serum BUN (NEUPRO 3% vs. placebo 2%) in patients with advanced-stage Parkinson’s disease receiving NEUPRO.
There was an increased risk for low serum glucose below the normal reference range in patients with early-stage Parkinson’s disease receiving NEUPRO (NEUPRO 15% vs. placebo 6%) and in patients with advanced-stage Parkinson’s disease (NEUPRO 10% vs. placebo 7%). There was also an increased risk for markedly decreased serum glucose (NEUPRO 1% vs. placebo 0%) in patients with advanced-stage Parkinson’s disease receiving NEUPRO.
Serum creatine phosphokinase (CPK) was elevated in Japanese patients taking NEUPRO for early-or advanced-stage Parkinson’s disease in placebo-controlled, flexible-dose studies conducted in Japan. The frequency of CPK elevation observed in patients receiving NEUPRO for early-stage Parkinson’s disease was 40% (35/88) in the NEUPRO group compared to 17% (15/89) in the placebo group. The frequency of CPK elevation observed in patients receiving NEUPRO for advanced-stage Parkinson’s disease was 39% (99/253) in the NEUPRO group compared to 20% (34/171) in the placebo group using pooled data from two studies. Increased CPK occurred at any time during the respective studies, and in some instances increased CPK was observed at two or more consecutive visits. The total daily dose of NEUPRO taken by patients with early-and advanced-stage Parkinson’s disease ranged between 2 mg/24 hours to 16 mg/24 hours. Studies of NEUPRO conducted outside of Japan did not include assessments of serum CPK in patients treated for Parkinson’s disease. Increased CPK was also reported in postmarketing data.
Postmarketing Experience
The following adverse reaction has been identified during post-approval use of NEUPRO. 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.
General Disorders and Administration Site Conditions: withdrawal symptoms
Nervous System Disorders: Dropped head syndrome
Musculoskeletal and connective tissue disorders: Rhabdomyolysis
SRC: NLM .