Symptoms
The most likely adverse reactions would be those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hypotension, involuntary movements, hallucinations, confusion, convulsions and other signs of central dopaminergic stimulation.
Management
There is no known antidote for overdose of dopamine agonists. In case of suspected overdose, removal of the patch(es) should be considered because after removal of the patch(es) the active substance input is stopped and the plasma concentration of rotigotine decreases rapidly. The patient should be monitored closely, including heart rate, heart rhythm and blood pressure.
Treatment of overdose may require general supportive measures to maintain the vital signs. Dialysis would not be expected to be beneficial as rotigotine is not eliminated by dialysis.
If it is necessary to discontinue rotigotine, this should be done gradually to prevent neuroleptic malignant syndrome.
Magnetic resonance imaging or cardioversion.
Not applicable.
Summary of the safety profile
Based on the analysis of pooled placebo-controlled clinical trials comprising a total of 748 Leganto- and 214 placebo-treated patients, 65.5% of the patients on Leganto and 33.2% of patients on placebo reported at least one adverse reaction.
At the beginning of therapy dopaminergic adverse reactions such as nausea and vomiting may occur. These are usually mild or moderate in intensity and transient even if treatment is continued.
Adverse drug reactions (ADRs) reported in more than 10% of patients treated with Leganto are nausea, application site reactions, asthenic conditions and headache.
In trials where the application sites were rotated as reflected in the instructions provided in the SmPC and package leaflet, 34.2% of 748 patients using Leganto, experienced application site reactions. The majority of application site reactions were mild or moderate in intensity, limited to the application areas and resulted in discontinuation of Leganto in 7.2% of subjects.
Discontinuation rate
The discontinuation rate was studied in 3 clinical trials ranging up to 3 years in duration. The percentage of subjects discontinuing was 25-38% over the first year, 10% in the second year, and 11% in the third year. Periodic assessment of efficacy should be performed, along with evaluation of safety, including augmentation.
Tabulated list of adverse reactions
The following table covers adverse drug reactions from the pooled studies mentioned above in patients with Restless Legs Syndrome. Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
| System/organ classes acc. to MedDRA | Very common
| Common
| Uncommon
| Rare | Not known |
| Immune system disorders | Hypersensitivity, which may include angioedema, tongue oedema and lip oedema | ||||
| Psychiatric disorders | Sleep attacks/sudden onset of sleep, sexual desire disordersa (incl. hypersexuality, libido increased), insomnia, sleep disorder, abnormal dreams, impulse-control disordersa,d (incl. pathological gambling, stereotypy/ punding, binge eating/eating disorderb, compulsive shoppingc) | Obsessive-compulsive disorder, agitationd | Aggressive behaviour/ aggressionb, disorientationd | Dopamine dysregulation syndromec, perception disturbancese (incl. hallucination, hallucination visual, hallucination auditory, illusion), nightmaree, paranoiae, confusional statee, psychotic disordere, delusione, deliriume | |
| Nervous system disorders | Headache | Somnolence | Dizzinesse, disturbances in consciousness NECe (incl. syncope, syncope vasovagal, loss of consciousness), dyskinesiae, dizziness posturale, lethargye, convulsione | ||
| Eye disorders | Vision blurrede, visual impairmente, photopsiae | ||||
| Ear and labyrinth disorders | Vertigoe | ||||
| Cardiac disorders | Palpitationse, atrial fibrillatione, supraventricular tachycardiae | ||||
| Vascular disorders | Hypertension | Orthostatic hypotension | Hypotensione | ||
| Respiratory, thoracic and mediastinal disorders | Hiccupse | ||||
| Gastrointestinal disorders | Nausea | Vomiting, dyspepsia | Constipatione, dry mouthe, abdominal paine, diarrhoeac | ||
| Skin and subcutaneous tissue disorders | Pruritus | Erythemae, hyperhidrosise, pruritus generalisede, skin irritatione, dermatitis contacte, rash generalisede | |||
| Reproductive system and breast disorder | Erectile dysfunctione | ||||
| General disorders and administration site conditions | Application and instillation site reactionsa (incl. erythema, pruritus, irritation, rash, dermatitis, vesicles, pain, eczema, inflammation, swelling, discolouration, papules, exfoliation, urticaria, hypersensitivity), asthenic conditionsa (incl. fatigue, asthenia, malaise) | Irritability, oedema peripheral | |||
| Investigations | Weight decreasede, hepatic enzyme increasede (incl. AST, ALT, GGT), weight increasede, heart rate increasede, CPK increasedd,e (see Special populations) | ||||
| Injury, poisoning and procedural complications | Falle |
a High Level Term
b Observed in open-label studies
c Observed during post-marketing
d Observed in 2011 data pool of double-blind placebo-controlled studies
e Observed in studies performed in patients with Parkinson's disease
Description of selected adverse reactions
Sudden onset of sleep and somnolence
Rotigotine has been associated with somnolence including excessive daytime somnolence and sudden sleep onset episodes.7).
Impulse control disorders
Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists, including rotigotine.
Special populations
Adverse reactions of increased creatine phosphokinase (CPK) were observed with rotigotine in clinical studies conducted in Japan. These occurred in 3.4% of Japanese subjects on rotigotine compared to 1.9% on placebo in double-blind Parkinson's disease and RLS studies. The majority of the adverse reactions of increased CPK observed in all double-blind and open-label studies resolved and were considered mild in severity. CPK levels have not been routinely measured in other populations.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
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In repeated dose and long-term toxicity studies, the major effects were associated with the dopamine agonist related pharmacodynamic effects and the consequent decrease of prolactin secretion.
After a single dose of rotigotine, binding to melanin-containing tissues (i.e., eyes) in the pigmented rat and monkey was evident, but was slowly cleared over the 14-day observation period.
Retinal degeneration was observed by transmission microscopy at a dose equivalent to 2.8 times the maximum recommended human dose on a mg/m² basis in a 3-month study in albino rats. The effects were more pronounced in female rats. Additional studies to further evaluate the specific pathology have not been performed. Retinal degeneration was not observed during the routine histopathological evaluation of the eyes in any of the toxicology studies in any species used. The relevance of these findings to humans is not known.
In a carcinogenicity study, male rats developed Leydig cell tumours and hyperplasia. Malignant tumours were noted predominantly in the uterus of mid- and high-dose females. These changes are well-known effects of dopamine agonists in rats after life-long therapy and assessed as not relevant to man.
The effects of rotigotine on reproduction have been investigated in rats, rabbits and mice. Rotigotine was not teratogenic in all three species, but was embryotoxic in rats and mice at materno-toxic doses. Rotigotine did not influence male fertility in rats, but clearly reduced female fertility in rats and mice, because of the effects on prolactin levels which are particularly significant in rodents.
Rotigotine did not induce gene mutations in the Ames test, but did show effects in the in vitro Mouse Lymphoma Assay with metabolic activation and weaker effects without metabolic activation. This mutagenic effect could be attributed to a clastogenic effect of rotigotine. This effect was not confirmed in vivo in the Mouse Micronucleus Test in the rat Unscheduled DNA Synthesis (UDS) test. Since it ran more or less parallel with a decreased relative total growth of the cells, it may be related to a cytotoxic effect of the compound. Therefore, the relevance of the one positive in vitro mutagenicity test is not known.
Leganto is indicated for the symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome (RLS) in adults.
Pharmacotherapeutic group: Anti-parkinson drugs, dopamine agonists; ATC code: N04BC09
Rotigotine is a non-ergolinic dopamine agonist for the treatment of signs and symptoms of Parkinson's disease and Restless Legs Syndrome.
Mechanism of action
Rotigotine is believed to elicit its beneficial effect on Parkinson's disease by activation of the D3, D2 and D1 receptors of the caudate-putamen in the brain.
The precise mechanism of action of rotigotine as a treatment of RLS is unknown. It is thought that rotigotine may exert its activity mainly via dopamine receptors.
Pharmacodynamic effects
Regarding the functional activity at the various receptor subtypes and their distribution in the brain, rotigotine is a D2 and D3 receptor agonist acting also on D1, D4 and D5 receptors. With non-dopaminergic receptors, rotigotine showed antagonism at alpha2B and agonism at 5HT1A receptors, but no activity on the 5HT2B receptor.
Clinical efficacy
The efficacy of rotigotine was evaluated in 5 placebo-controlled trials with more than 1,400 patients with idiopathic Restless Legs Syndrome (RLS). Efficacy was demonstrated in controlled trials in patients treated for up to 29 weeks. The effect was maintained over a 6 months period.
The changes from baseline in the International RLS Rating Scale (IRLS) and CGI-item 1 (severity of illness) were primary efficacy parameters. For both primary endpoints statistically significant differences have been observed for the doses 1 mg/24 h, 2 mg/24 h and 3 mg/24 h in comparison to placebo. After 6 months of maintenance treatment in patients with moderate to severe RLS, the baseline IRLS score improved from 30.7 to 20.7 for placebo and from 30.2 to 13.8 for rotigotine. The adjusted mean difference was -6.5 points (CI95% -8.7; -4.4, p <0.0001). CGI-I responder rates (much improved, very much improved) were 43.0% and 67.5% for placebo and rotigotine respectively (difference 24.5% CI 95%: 14.2%; 34.8%, p<0.0001).
In a placebo-controlled, 7-week trial polysomnographic parameters were investigated. Rotigotine significantly reduced the periodic limb movement index (PLMI) from 50.9 to 7.7 versus 37.4 to 32.7 for placebo (p<0.0001).
Augmentation
In two 6-month, double-blind, placebo-controlled studies, clinically relevant augmentation was observed in 1.5% of rotigotine-treated patients versus 0.5% of placebo treated patients. In two open-label, follow-up studies over a subsequent 12 months, the rate of clinically relevant augmentation was 2.9%. None of these patients discontinued therapy because of augmentation. In a 5-year open-label treatment study, augmentation occurred in 11.9% of patients treated with the approved dosages for RLS (1-3 mg/24 h), and 5.1% were considered clinically significant. In this study, the majority of augmentation episodes occurred in the first and second years of treatment. Furthermore, in this study a higher dose of 4 mg/24 h that is unapproved in RLS was also used and led to higher rates of augmentation.
Skin adhesion
In a multicenter, double-blind, randomized, 2-way, crossover study in 52 outpatients, the skin adhesion of the improved room temperature patch formulation was compared to the cold storage formulation, using the 8 mg/24 h rotigotine patch. Skin adhesion was measured on 2 consecutive days of 24 hours patch application. The improved room temperature patch formulation showed better skin adhesion than the cold storage formulation with >90% of patches showing sufficient adhesion (i.e. >70% of the patch area adhering) compared to <83%. Comparable skin tolerability was reported for both formulations. The majority of erythema observed was mild and none severe.
Absorption
Following application, rotigotine is continuously released from the transdermal patch and absorbed through the skin. Steady-state concentrations are reached after one to two days of patch application and are maintained at a stable level by once daily application in which the patch is worn for 24 hours. Rotigotine plasma concentrations increase dose-proportionally over a dose range of 1 mg/24 h to 24 mg/24 h.
Approximately 45% of the active substance within the patch is released to the skin in 24 hours. The absolute bioavailability after transdermal application is approximately 37%.
Rotating the site of patch application may result in day-to-day differences in plasma levels. Differences in bioavailability of rotigotine ranged from 2% (upper arm versus flank) to 46% (shoulder versus thigh). However, there is no indication of a relevant impact on the clinical outcome.
Distribution
The in vitro binding of rotigotine to plasma proteins is approximately 92%.
The apparent volume of distribution in humans is approximately 84 l/kg.
Biotransformation
Rotigotine is metabolised to a great extent. Rotigotine is metabolised by N-dealkylation as well as direct and secondary conjugation. In vitro results indicate that different CYP isoforms are able to catalyse the N-dealkylation of rotigotine. Main metabolites are sulfates and glucuronide conjugates of the parent compound as well as N-desalkyl-metabolites, which are biologically inactive.
The information on metabolites is incomplete.
Elimination
Approximately 71% of the rotigotine dose is excreted in urine and a smaller part of about 23% is excreted in faeces.
The clearance of rotigotine after transdermal administration is approximately 10 l/min and its overall elimination half-life is 5 to 7 hours. The pharmacokinetic profile shows a biphasic elimination with an initial half-life of about 2 to 3 hours.
Because the patch is administered transdermally, no effect of food and gastrointestinal conditions is expected.
Special patient groups
Because therapy with Leganto is initiated at a low dose and gradually titrated according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the dose based on gender, weight, or age is not necessary.
Hepatic and renal impairment
In subjects with moderate hepatic impairment or mild to severe renal impairment, no relevant increases of rotigotine plasma levels were observed. Leganto was not investigated in patients with severe hepatic impairment.
Plasma levels of conjugates of rotigotine and its desalkyl metabolites increase with impaired renal function. However, a contribution of these metabolites to clinical effects is unlikely.
Paediatric population
Limited pharmacokinetic data obtained in adolescent patients with RLS (13-17 years, n=24) following treatment with multiple doses of 0.5 to 3mg/24h showed that systemic exposure to rotigotine was similar to that observed in adults.).
Magnetic resonance imaging and cardioversion
The backing layer of Leganto contains aluminium. To avoid skin burns, Leganto should be removed if the patient has to undergo magnetic resonance imaging (MRI) or cardioversion.
Orthostatic hypotension
Dopamine agonists are known to impair the systemic regulation of the blood pressure resulting in postural/orthostatic hypotension. These events have also been observed during treatment with rotigotine, but the incidence was similar to that observed in placebo-treated patients.
It is recommended to monitor blood pressure, especially at the beginning of treatment, due to the general risk of orthostatic hypotension associated with dopaminergic therapy.
Syncope
In clinical studies with rotigotine, syncope has been observed at a rate that was similar to that observed in patients treated with placebo. Because patients with clinically relevant cardiovascular disease were excluded in these studies, patients with severe cardiovascular disease should be asked about symptoms of syncope and pre-syncope.
Sudden onset of sleep and somnolence
Rotigotine has been associated with somnolence and episodes of sudden sleep onset. Sudden onset of sleep during daily activities, in some cases without awareness of any warning signs, has been reported. Prescribers should continually reassess patients for drowsiness or sleepiness, as patients may not acknowledge drowsiness or sleepiness until directly questioned. A reduction of dosage or termination of therapy should be carefully considered.
Impulse control disorders
Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathologic gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists, including rotigotine. Dose reduction/tapered discontinuation should be considered if such symptoms develop.
Neuroleptic malignant syndrome
Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy. Therefore, it is recommended to taper treatment.
Abnormal thinking and behaviour
Abnormal thinking and behaviour have been reported and can consist of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behaviour, disorientation, aggressive behaviour, agitation, and delirium.
Fibrotic complications
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 treatment is discontinued, complete resolution does not always occur.
Although these adverse reactions are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived dopamine agonists can cause them is unknown.
Neuroleptics
Ophthalmologic monitoring
Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.
Heat application
External heat (excessive sunlight, heating pads and other sources of heat such as sauna, hot bath) should not be applied to the area of the patch.
Application site reactions
Application site skin reactions may occur and are usually mild or moderate in intensity. It is recommended that the application site should be rotated on a daily basis (e.g. from the right side to the left side and from the upper body to the lower body). The same site should not be used within 14 days. If application site reactions occur which last for more than a few days or are persistent, if there is an increase in severity, or if the skin reaction spreads outside the application site, an assessment of the risk/benefit balance for the individual patient should be conducted.
If there is a skin rash or irritation from the transdermal system, direct sunlight on the area should be avoided until the skin heals, as exposure could lead to changes in the skin color.
If a generalised skin reaction (e.g. allergic rash, including erythematous, macular, papular rash or pruritus) associated with the use of Leganto is observed, Leganto should be discontinued.
Peripheral oedema
Peripheral oedema has been observed in clinical trials conducted in patients with RLS.
Augmentation
Augmentation may occur. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in severity of symptoms, and spread of symptoms to involve other body parts. In long-term clinical studies with rotigotine, the majority of augmentation episodes were seen in the first and second years of treatment. Doses higher than the approved dose range for RLS should be avoided as this may lead to higher rates of augmentation.
Sulphite sensitivity
Leganto contains sodium metabisulphite, a sulphite that may cause allergic-type reactions including anaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptible people.
Rotigotine may have major influence on the ability to drive and use machines.
5).Posology
The dose recommendations made are in nominal dose.
A single daily dose should be initiated at 1 mg/24 h. Depending on the individual patient response, the dose may be increased in weekly increments of 1 mg/24 h to a maximum dose of 3 mg/24 h. The need for treatment continuation should be reconsidered every 6 months.
Leganto is applied once a day. The patch should be applied at approximately the same time every day. The patch remains on the skin for 24 hours and will then be replaced by a new one at a different site of application.
If the patient forgets to apply the patch at the usual time of the day or if the patch becomes detached, another patch should be applied for the remainder of the day.
Treatment discontinuation
Leganto should be discontinued gradually. The daily dose should be reduced in steps of 1 mg/24 h with a dose reduction preferably every other day, until complete withdrawal of Leganto. Following this procedure, rebound (worsening of symptoms beyond initial intensity after discontinuation of treatment) has not been observed.
Special populations
Hepatic impairment
Adjustment of the dose is not necessary in patients with mild to moderate hepatic impairment. Caution is advised when treating patients with severe hepatic impairment, which may result in lower rotigotine clearance. Rotigotine has not been investigated in this patient group. A dose reduction might be needed in case of worsening of the hepatic impairment.
Renal impairment
Adjustment of the dose is not necessary in patients with mild to severe renal impairment, including those requiring dialysis. Unexpected accumulation of rotigotine levels may also occur at acute worsening of renal function.
Paediatric population
The safety and efficacy of rotigotine in children and adolescents have not yet been established.
Method of administration
Leganto is for transdermal use.
The patch should be applied to clean, dry, intact healthy skin on the abdomen, thigh, hip, flank, shoulder, or upper arm. Reapplication to the same site within 14 days should be avoided. Leganto should not be placed on skin that is red, irritated or damaged.
Use and handling
Each patch is packed in a sachet and should be applied directly after the sachet has been opened. One half of the release liner should be removed and the sticky side should be applied and pressed firmly to the skin. Then, the patch is fold back and the second part of the release liner is removed. The sticky side of the patch should not be touched. The patch should be pressed down firmly with the palm of the hand for about 30 seconds, so that it sticks well.
The patch should not be cut into pieces.
After use the patch still contains active substance. After removal, the used patch should be folded in half, adhesive side inwards so that the matrix layer is not exposed, placed in the original sachet and then discarded. Any used or unused patches should be disposed of in accordance with local requirements or returned to the pharmacy.
