Mirapex (pramipexole dihydrochloride) is a dopamine agonist developed by Boehringer Ingelheim for the treatment of Parkinson’s disease (PD) symptoms and restless legs syndrome (RLS). The drug is available in immediate and prolonged-release doses.
Mirapex in immediate-release formulation was approved by the US Food and Drug Administration (FDA) in June 1997 and by the European Union (EU) in March 1998 under the name Mirapexin in combination with levodopa for unlimited period for the treatment of PD symptoms.
In 2006, the FDA and EU approved the drug for the treatment of restless legs syndrome (RLS), a neurological disorder.
In October 2009, Mirapexin® as prolonged-release tablets was approved in Europe for the treatment of the signs and symptoms of idiopathic PD, alone (without levodopa) or in combination with levodopa. In February 2010, the FDA approved Mirapex ER® (pramipexole dihydrochloride) extended-release tablets for early PD and later for the treatment of both early and advanced PD in March 2010. Mirapex ER is not indicated for RLS treatment.
Pramipexole-containing medicines are now marketed as Mirapexin in Greece, Italy, Spain, and the UK, and as Sifrol® in Denmark, Finland, Germany, the Netherlands, and Sweden.
Parkinson’s disease details and symptoms
Parkinson’s disease is a chronic neurological disorder and is estimated to affect around 2% of the US population aged older than 65 years. PD is estimated to be the second most common neurological illness in older patients, after Alzheimer’s disease. The disease can affect any person aged older than 40 years, with the risk of the disease increasing for people aged 80 years and older.
The disease occurs when there is a progressive loss of neurons or brain cells in the substantia nigra, the part of the brain that controls movement. The substantia nigra produces the chemical neurotransmitter dopamine. When the neurons die, the amount of dopamine transported to the striatum decreases, causing problems with mobility.
PD is characterised by both motor and non-motor symptoms, which worsen over time. Motor symptoms include tremors, muscle cramps, slowed motion or bradykinaesia, and poor balance. Non-motor symptoms include depression, anxiety, cognitive impairment, and sleep disorders. These symptoms, however, can vary from one patient to another.
There is currently no cure available for treating PD, although medications to treat the symptoms of the disease are accessible.
Details and symptoms of restless legs syndrome
RLS, also known as Willis-Ekbom disease, is a neurological disorder that causes a persistent need to move the legs, usually because of an uncomfortable sensation.
Symptoms occur mainly at night and the primary symptom is an urge to move the legs. Other indications of RLS include sensations that begin while resting, as well as relief with movements such as creeping, itching, pulling, crawling, tugging, throbbing, scorching, or gnawing feelings.
Mirapex’s mechanism of action
Pramipexole is a non-ergot agonist of the dopamine receptor, which has greater levels of affinity and selectivity towards D2 and D3 receptors.
In Parkinson’s disease patients, the cells that release dopamine begin to die and the amount of dopamine in the brain drops. Pramipexole has the ability to stimulate dopamine receptors in the striatum of the brain in the same way as dopamine, allowing patients to control their movement and mitigate their Parkinson’s symptoms.
The exact mechanism through which pramipexole acts in RLS is not known, but the condition is thought to be caused by issues with how dopamine functions in the brain, which can be treated with pramipexole.
Parkinson’s disease is a chronic neurological disorder.
Clinical trials on Mirapex
Clinical data from a single randomised, double-blind, placebo-controlled multi-centre clinical study supported the FDA’s approval of Mirapex for early PD. A second study focused on switching patients from Mirapex to Mirapex ER overnight.
The first trial compared Mirapex ER with a placebo in patients with early PD and showed substantial clinical differences between the two.
The clinical study involved more than 400 patients with early PD. They were treated with varied dosages of Mirapex ER, Mirapex or a placebo and evaluated after nine weeks and 18 weeks. When compared to placebo, patients treated with Mirapex ER showed clinically substantial improvement in symptoms, indicated by mean change from baseline in Unified Parkinson’s Disease Rating Scale (UPDRS). UPDRS was developed to follow the longitudinal course of PD-related disability and impairment.
The UPDRS II+III score was used as the primary efficacy endpoint in clinical trials for treatment of PD, which was achieved in the study.
A second trial evaluated the efficacy of switching from Mirapex to Mirapex ER overnight. In the trial, 85% (87 of 104) of patients who completed the first trial were successfully switched to Mirapex ER, while some patients required dosage modifications.
In both trials, the safety and tolerability profile of Mirapex ER in patients with early PD was similar to that of Mirapex when compared with placebo.
Adverse effects of Mirapex in the clinical trials included nausea, dizziness, sleepiness, difficulty falling asleep, weakness, and constipation. Adverse effects related to Mirapex ER included sleepiness, nausea and vomiting, constipation, dizziness, fatigue, hallucinations, dry mouth, muscle spasms, and oedema.
The FDA’s approval of Mirapex ER for advanced PD patients was based on efficacy results from a single randomised, double-blind, placebo-controlled, three-parallel group clinical trial.
The clinical trial programme enrolled 517 people with advanced PD. The adjusted mean changes from baseline in the UPDRS Parts II+III score was the primary efficacy outcome. Mirapex ER exceeded placebo on both primary and vital secondary efficacy endpoints.
The most common side effects associated with the drug in the clinical trial include dyskinaesia, nausea, constipation, hallucinations, headache, and anorexia.
The EU’s approval for both immediate-release and prolonged-release tablets was based on five major trials for the immediate-release tablets, in which the drug was compared with placebo in four studies. One study was conducted in 360 people with advanced disease, while the remaining three studies were conducted in 886 patients with early disease who were not taking levodopa. The trials’ primary measure of efficacy was the reduction in the severity of PD.
The fifth trial compared Mirapexin with levodopa in 300 patients with early disease and evaluated the number of patients who showed movement symptoms. In the trial, Mirapexin’s immediate-release and prolonged-release tablets produced the same levels of the active substance in the body, according to studies comparing the two tablets in early and advanced PD and focusing on switching patients from immediate- to prolonged-released tablets. Mirapexin was also more effective than levodopa at improving movement symptoms in early disease.
Mirapexin immediate-release tablets were evaluated in two major clinical trials for RLS. The first compared Mirapexin with placebo in 344 people and looked at symptom improvement. The second study included 150 Mirapexin-treated patients and investigated the effects of continuing Mirapexin against switching to placebo. The key measure of efficiency was the time taken for symptoms to worsen.
The results of the second study were insufficient to prove the long-term effectiveness of Mirapexin. Adverse reactions reported in patients with RLS included nausea, headache, dizziness and fatigue.