Leganto - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Leganto 1 mg/24 h transdermal patch

Each patch releases 1 mg of rotigotine per 24 hours. Each patch of 5 cm2 contains 2.25 mg of rotigotine.

Leganto 3 mg/24 h transdermal patch

Each patch releases 3 mg of rotigotine per 24 hours. Each patch of 15 cm2 contains 6. rotigotine.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Transdermal patch.

Thin, matrix-type, square-shaped with rounded edges, consisting

Leganto 1 mg/24 h transdermal patch

The outside of the backing layer is tan-coloured and i ted with ‘Leganto 1 mg/24 h’.

Leganto 3 mg/24 h transdermal patch

The outside of the backing layer is tan-coloured and imprinted with ‘Leganto 3 mg/24 h’.

4.1 Therapeutic indications

4.1 Therapeutic indications

Leganto is indicated for the symptomatic treatment of moderate to severe idiopathic Restless Legs

4.2 Posology

4.2 Posology

ommendations 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.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Magnetic resonance imaging or cardioversion (see section 4.4).

ggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal inergic therapy. Therefore, it is recommended to taper treatment (see section 4.2).

Dopamine agonist withdrawal syndrome

Symptoms suggestive of dopamine agonist withdrawal syndrome (for example, pain, fatigue, depression, sweating, and anxiety) have been reported with abrupt withdrawal of dopaminergic therapy, therefore, it is recommended to taper treatment (see section 4.2).

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

Neuroleptics given as antiemetic should not be given to patients taking dopamine agonists section 4.5).

Ophthalmologic monitoring

Ophthalmologic monitoring is recommended at regular intervals or if vision a

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

tion 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 (see section 5.1).

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.

4.5 Interaction with other medicinal products and other forms of interaction

Because rotigotine is a dopamine agonist, it is assumed that dopamine antagonists, such as neuroleptics (e.g. phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of Leganto, and co-administration should be avoided. Because of possible additive effects, caution should be advised when patients are taking sedating medicinal products or other CNS (central nervous system) depressants (e.g. benzodiazepines, antipsychotics, antidepressants) or alcohol in combination with rotigotine.

Co-administration of L-dopa and carbidopa with rotigotine had no effect on the pharmacokinetics of rotigotine, and rotigotine had no effect on the pharmacokinetics of L-dopa and carbidopa.

Co-administration of domperidone with rotigotine had no effect on the pharmacokinetics o

Co-administration of omeprazole (inhibitor of CYP2C19), in doses of 40 mg/day, had pharmacokinetics and metabolism of rotigotine in healthy volunteers.

Co-administration of rotigotine (3 mg/24 h) did not affect the pharmacodynami pharmacokinetics of oral contraceptives (0.03 mg ethinylestradiol, 0.15 mg l rel).

Interactions with other forms of hormonal contraception have not been investigated.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential, contraception in females

Women of childbearing potential should use effective treatment with rotigotine.

Pregnancy

There are no adequate data from the use o gotine in pregnant women. Animal studies do not indicate any teratogenic effects in rats and its, but embryo-toxicity was observed in rats and mice at materno-toxic doses (see section 5.3). The potential risk for humans is unknown. Rotigotine should not be used during pregnancy.

Breast-feeding

Because rotigotine decreases prolactin secretion in humans, inhibition of lactation is expected. Studies in rats have shown that rotigotine and/or its metabolite(s) are excreted in breast milk. In the absence of human data, breast-feeding should be discontinued.

Fertility ation on fertility studies, please see section 5.3.

4.7 Effects on ability to drive and use machines

Rotigotine may have major influence on the ability to drive and use machines.

Patients being treated with rotigotine and presenting with somnolence and/or sudden sleep episodes must be informed not to drive or engage in activities (e.g. operating machines) where impaired alertness may put themselves or others at risk of serious injury or death until such recurrent episodes and somnolence have resolved (see also sections 4.4 and 4.5).

4.8 Undesirable effects

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 i and package leaflet, 34.2% of 748 patients using Leganto, experienced application site re majority of application site reactions were mild or moderate in intensity, limited to the ap 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 and from post-marketing experience. 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 disorders3 (incl. hypersexuality, libido increased), insomnia, sleep disorder, abnormal	Obsessivecompulsive disorder, agitationd	Aggressive behaviour/ aggressionb, disorientationd	Dopamine dysregulation syndromec, perception disturbancese (incl. hallucination, hallucination visual, hallucination auditory,

		dreams, impulsecontrol disordersa,d (incl. pathological gambling, stereotypy/ punding, binge eating/eating disorderb, compulsive shopping0)			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	F				Hiccupse
Gastrointestinal disorders	Nausea	Vomiting, dyspepsia			Constipatione, dry mouthe, abdominal paine, diarrhoea0
Skin and subcutaneous tissue disorders		Pruritus			Erythemae, hyperhidrosise, pruritus generalisede, skin irritatione, dermatitis contacte, rash generalisede

Reproductive system and breast disorder					Erectile dysfunction6
General disorders and administration site conditions	Application and instillation site reactions3(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		zo.			Weight decreased6, hepatic enzyme increasede (incl. AST, ALT, GGT), weight increasede, heart rate increasede, CPK increasedd,e
Injury, poisoning and procedural complications	J				Falle
Musculoskeletal and connective tissue disorders *					Rhabdomyolysis6

a High Lev b Observed c Observed

d 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. In isolated cases “sudden onset of sleep” occurred while driving and resulted in motor vehicle accidents (see also sections 4.4 and 4.7).

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 (see section 4.4).

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 the national reporting system listed in

4.9 Overdose

4.9 Overdose

Symptoms

The most likely adverse reactions would be those related to the pharmacodyn dopamine agonist, including nausea, vomiting, hypotension, involuntary mov confusion, convulsions and other signs of central dopaminergic stimulati

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.

5.1 Pharmacodyna

rties

up: 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.

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 compariso 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 rotigotin e 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 res (difference 24.5% CI 95%: 14.2%; 34.8%, p<0.0001).

In a placebo-controlled, 7-week trial polysomnographic parameters were inve significantly reduced the periodic limb movement index (PLMI) from 50.9 to 7. for placebo (p<0.0001).

Augmentation

In two 6-month, double-blind, placebo-controlled studies, clini elevant augmentation was observed in 1.5% of rotigotine-treated patients versus 0.5% of o treated patients. In two openlabel, 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.

5.2 Pharmacokinetic properties

Absorption

rotigotine is continuously released from the transdermal patch and absorbed y-state concentrations are reached after one to two days of patch application stable level by once daily application in which the patch is worn for 24 hours. concentrations increase dose-proportionally over a dose range of 1 mg/24 h to

ately 45% of the active substance within the patch is released to the skin in 24 hours. The

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.

5.3 Prec

afety dataafety data

In repeated dose and long-term toxicity studies, the major effects were associated with the dopamine

lated 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.

6.1

List of excipients

Transparent fluoropolymer coated polyester film.

6.2 Incompatibilitie

6.2 Incompati­bilitie

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

6.5 Nature and contents of container

Peel off sachet in a plastic box: One side is composed of an ethylene copolymer (innermost layer), an aluminium foil, low density polyethylene film and paper; the other side is composed of polyethylene (innermost layer), aluminium, ethylene copolymer and paper.

The box contains 7, 28, 30 or 84 (multipack containing 3 packs of 28) transdermal patches, individually sealed in sachets.

Not all pack sizes may be marketed.

6.6 Special precaution for disposal

6.6 Special precaution for disposal

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.

7. MARKETING AUTHORISATION HOLDER

UCB Pharma S.A.

Allée de la Recherche 60

B-1070 Bruxelles

Belgium

8. MARKETING AUTHORISATION NUMBER(S)

8. MARKETING AUTHORISATION NUMBER(S)

Leganto 1 mg/24 h transdermal patch

EU/1/11/695/001

EU/1/11/695/003

EU/1/11/695/004

EU/1/11/695/007

Leganto 3 mg/24 h transdermal patch

EU/1/11/695/019

EU/1/11/695/021

EU/1/11/695/022

EU/1/11/695/025

Date of first authorisat

Date of latest renewal:

10.