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ROPILYNZ XL 4 MG PROLONGED-RELEASE TABLETS

Active substance(s): ROPINIROLE HYDROCHLORIDE / ROPINIROLE HYDROCHLORIDE / ROPINIROLE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Ropilynz XL 4 mg prolonged-release tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 4 mg ropinirole (as ropinirole hydrochloride).
Excipients with known effect:
Each 4 mg prolonged-release tablet contains 0.8100 mg of sunset yellow
(E110).
For full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Prolonged-release tablet.
Light brown, oval biconvex tablets 12.6 x 6.6 ± 0.1 mm in diameter and 4.7 ±
0.2mm in thickness.

4
4.1

4.2

CLINICAL PARTICULARS
Therapeutic indications
Treatment of Parkinson's disease under the following conditions:
• Initial treatment as monotherapy, in order to delay the introduction of
levodopa
• In combination with levodopa, over the course of the disease, when the
effect of levodopa wears off or becomes inconsistent and fluctuations
in the therapeutic effect occur (“end of dose” or “on-off” type
fluctuations).
Posology and method of administration
Posology
Adults

Individual dose titration against efficacy and tolerability is recommended.
Initial titration

The starting dose of ropinirole prolonged-release tablets is 2 mg once daily for
the first week; this should be increased to 4 mg once daily from the second
week of treatment. A therapeutic response may be seen at a dose of 4 mg once
daily of ropinirole prolonged-release tablets.

Patients who initiate treatment with a dose of 2 mg/day of ropinirole
prolonged-release tablets and who experience undesirable effects that they
cannot tolerate, may benefit from switching to treatment with ropinirole
immediate-release tablets at a lower daily dose, divided into three equal doses.
Therapeutic regimen
Patients should be maintained on the lowest dose of ropinirole prolongedrelease tablets that achieves symptomatic control.
If sufficient symptomatic control is not achieved or maintained at a dose of 4
mg once daily of ropinirole prolonged-release tablets, the daily dose may be
increased by 2 mg at weekly or longer intervals up to a dose of 8 mg once
daily of ropinirole prolonged-release tablets.
If sufficient symptomatic control is still not achieved or maintained at a dose
of 8 mg once daily of ropinirole prolonged-release tablets, the daily dose may
be increased by 2 mg to 4 mg at two weekly or longer intervals. The maximum
daily dose of ropinirole prolonged-release tablets is 24 mg.
It is recommended that patients are prescribed the minimum number of
ropinirole prolonged-release tablets that are necessary to achieve the required
dose by utilising the highest available strengths of ropinirole prolonged-release
tablets.
If treatment is interrupted for one day or more, re-initiation by dose titration
should be considered (see above).
When Ropilynz XL prolonged-release tablets are administered as adjunct
therapy to levodopa, it may be possible to reduce gradually the levodopa dose,
depending on the clinical response. In clinical trials, the levodopa dose was
reduced gradually by approximately 30% in patients receiving ropinirole
prolonged-release tablets concurrently. In patients with advanced Parkinson's
disease, receiving Ropilynz XL prolonged-release tablets in combination with
levodopa, dyskinesias can occur during the initial titration of Ropilynz XL
prolonged-release tablets. In clinical trials it was shown that a reduction of the
levodopa dose may ameliorate dyskinesia (see section 4.8).
When switching treatment from another dopamine agonist to ropinirole, the
marketing authorisation holder’s guidance on discontinuation should be
followed before initiating ropinirole.
As with other dopamine agonists, it is necessary to discontinue ropinirole
treatment gradually by reducing the daily dose over the period of one week
(see section 4.4).
Switching from ropinirole film-coated (immediate release) tablets to Ropilynz
XL prolonged-release tablets
Patients may be switched overnight from ropinirole film-coated (immediaterelease) tablets to ropinirole prolonged-release tablets. The dose of ropinirole
prolonged-release tablets should be based on the total daily dose of ropinirole
film-coated (immediate- release) tablets that the patient was taking. The table
below shows the recommended dose of Ropilynz XL prolonged-release tablets
for patients switching from ropinirole film-coated (immediate-release) tablets:
Switching from ropinirole film-coated (immediate-release) tablets to Ropilynz
XL prolonged-release tablets
Ropinirole film-coated (immediaterelease) tablets
Total daily dose (mg)

Ropinirole prolonged-release
tablets (Ropilynz XL)
Total daily dose (mg)

0.75 - 2.25

2

3 - 4.5

4

6

6

7.5 - 9

8

12

12

15 - 18

16

21

20

24

24

After switching to Ropilynz XL prolonged-release tablets, the dose may be
adjusted depending on the therapeutic response (see “Initial titration” and
“Therapeutic regimen” above).
Paediatric population
Ropilynz XL prolonged-release tablets are not recommended for use in
children below 18 years of age due to a lack of data on safety and efficacy.
Elderly
The clearance of ropinirole is decreased by approximately 15% in patients 65
years of age or above. Although a dose adjustment is not required, ropinirole
dose should be individually titrated, with careful monitoring of tolerability, to
the optimal clinical response. In patients aged 75 years and above, slower
titration during treatment initiation may be considered.
Renal impairment
In patients with mild to moderate renal impairment (creatinine clearance
between 30 and 50 ml/min) no change in the clearance of ropinirole was
observed, indicating that no dosage adjustment is necessary in this population.
A study into the use of ropinirole in patients with end stage renal disease
(patients on haemodialysis) has shown that a dose adjustment in these patients
is required as follows: the recommended initial dose of Ropilynz XL is 2 mg
once daily. Further dose escalations should be based on tolerability and
efficacy. The recommended maximum dose of Ropilynz XL is 18 mg/day in
patients receiving regular haemodialysis.
Supplemental doses after haemodialysis are not required (see section 5.2).
The use of ropinirole in patients with severe renal impairment (creatinine
clearance less than 30 ml/min) without regular haemodialysis has not been
studied.
Method of administration
For oral use
Ropilynz XL prolonged-release tablets should be taken once a day, at a similar
time each day. The prolonged-release tablets may be taken with or without
food (see section 5.2).
Ropilynz XL prolonged-release tablets must be swallowed whole and must not
be chewed, crushed or divided.

4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed
in section 6.1.
Severe renal impairment (creatinine clearance < 30 ml/min) without
regular haemodialysis.
Hepatic impairment.

4.4

Special warnings and precautions for use
Ropinirole has been associated with somnolence and episodes of sudden sleep
onset, particularly in patients with Parkinson's disease. Sudden onset of sleep
during daily activities, in some cases without awareness or warning signs, has
been reported uncommonly. Patients must be informed of this and advised to
exercise caution while driving or operating machines during treatment with
ropinirole. Patients who have experienced somnolence and/or an episode of
sudden sleep onset must refrain from driving or operating machines. A
reduction of dosage or termination of therapy may be considered.
Patients with major psychiatric or psychotic disorders, or a history of these
disorders, should not be treated with dopamine agonists unless the potential
benefits outweigh the risks.
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 pathological gambling,
increased libido, hypersexuality, compulsive spending or buying, binge eating
and compulsive eating can occur in patients treated with dopamine agonists,
including ropinirole. Dose reduction/tapered discontinuation should be
considered if such symptoms develop.
Ropilynz XL tablets are designed to release medication over a 24hr period. If
rapid gastrointestinal transit occurs, there may be risk of incomplete release of
medication, and of medication residue being passed in the stool.
Due to the risk of hypotension, blood pressure monitoring is recommended,
particularly at the start of treatment, in patients with severe cardiovascular
disease (in particular coronary insufficiency).
Dopamine agonist withdrawal syndrome
To discontinue treatment in patients with Parkinson’s disease, ropinirole
should be tapered off (see section 4.2). Non-motor adverse effects may occur
when tapering or discontinuing dopamine agonists including ropinirole.
Symptoms include apathy, anxiety, depression, fatigue, sweating and pain
which may be severe. Patients should be informed about this before tapering
the dopamine agonist, and monitored regularly thereafter. In case of persistent

symptoms, it may be necessary to increase the ropinirole dose temporarily (see
section 4.8).
Hallucinations:
Hallucinations are known as a side effect of treatment with dopamine agonists
and levodopa. Patients should be informed that hallucinations can occur.
Ropilynz XL 2mg
Ropilynz XL contains lactose. Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption should not take this medicine.
4.5

Interaction with other medicinal products and other forms of interaction
There is no pharmacokinetic interaction between ropinirole and L-dopa or
domperidone which would necessitate dosage adjustment of these medicinal
products.
Neuroleptics and other centrally active dopamine antagonists, such as sulpiride
or metoclopramide, may diminish the effectiveness of ropinirole and therefore,
concomitant use of these medicinal products should be avoided.
Increased plasma concentrations of ropinirole have been observed in patients
treated with high doses of oestrogens. In patients already receiving hormone
replacement therapy (HRT), ropinirole treatment may be initiated in the
normal manner. However, it may be necessary to adjust the ropinirole dose, in
accordance with clinical response, if HRT is stopped or introduced during
treatment with ropinirole.
Ropinirole is principally metabolised by the cytochrome P450 isoenzyme
CYP1A2. A pharmacokinetic study (with a ropinirole film-coated (immediaterelease) tablet dose of 2 mg, three times a day) in Parkinson’s disease patients,
revealed that ciprofloxacin increased the Cmax and AUC of ropinirole by 60%
and 84% respectively, with a potential risk of adverse events. Hence, in
patients already receiving ropinirole, the dose of ropinirole may need to be
adjusted when medicinal products known to inhibit CYP1A2, e.g.
ciprofloxacin, enoxacin or fluvoxamine, are introduced or withdrawn.
A pharmacokinetic interaction study in patients with Parkinson’s disease
between ropinirole (with a ropinirole film-coated (immediate-release) tablet
dose of 2 mg, three times a day) and theophylline, a substrate of CYP1A2,
revealed no change in the pharmacokinetics of either ropinirole or
theophylline.
Smoking is known to induce CYP1A2 metabolism, therefore if patients stop or
start smoking during treatment with ropinirole, adjustment of dose may be
required.
Smoking is known to induce CYP1A2 metabolism, therefore if patients stop or
start smoking during treatment with ropinirole, adjustment of dose may be
required.
In patients receiving the combination of vitamin K antagonists and ropinirole,
cases of unbalanced INR have been reported. Increased clinical and biological
surveillance (INR) is warranted.

4.6

Fertility, pregnancy and lactation
Pregnancy
There are no adequate data from the use of ropinirole in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). As the
potential risk for humans is unknown, it is recommended that ropinirole is not
used during pregnancy unless the potential benefit to the patient outweighs the
potential risk to the foetus.
Breastfeeding
Ropinirole should not be used in breast-feeding mothers as it may inhibit
lactation.
Fertility
No human fertility data is available.

4.7

Effects on ability to drive and use machines
Patients being treated with ropinirole and presenting with somnolence and/or
sudden sleep episodes must be informed to refrain from driving or engaging in
activities where impaired alertness may put themselves or others at risk of
serious injury or death (e.g. using machines) until such recurrent episodes and
somnolence have resolved (see section 4.4).

4.8

Undesirable effects

Undesirable effects reported are listed below by system organ class and frequency. It
is noted if these undesirable effects were reported in clinical trials as monotherapy or
adjunct therapy to levodopa.
Frequencies are defined as: 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.
The following adverse drug reactions have been reported in either Parkinson’s disease
clinical trials with ropinirole prolonged-release tablets at doses up to 24 mg/day, or
from post-marketing reports:

In monotherapy

In adjunct therapy

Immune system disorders
Not known

Hypersensitivity reactions (including urticaria, angioedema,
rash, pruritus).

Psychiatric disorders
Common

Hallucinations

Confusion
Uncommon

Psychotic reactions (other than hallucinations) including
delirium, delusion, paranoia.

Not known

Pathological gambling, increased libido, hypersexuality,
compulsive spending or buying, binge eating and
compulsive eating can occur in patients treated with
dopamine agonists including [Invented name]. (see section
4.4. ‘Special warnings and precautions for use’).
Aggression*

Not known

Nervous system disorders
Very common

Somnolence

Somnolence**

Syncope

Dyskinesia***

Common

Dizziness (including vertigo)

Uncommon

Sudden onset of sleep, excessive daytime somnolence

Vascular disorders
Common
Uncommon

Postural hypotension,
hypotension
Postural hypotension,
hypotension

Gastrointestinal disorders
Very common

Nausea

Nausea****

Common

Constipation, heartburn
Vomiting, abdominal pain
Hepatobiliary disorders
Not known

Hepatic reactions, mainly increased liver enzymes

General disorders and administrative site conditions
Common
Frequency not
known

Oedema peripheral
Leg oedema
Dopamine agonist withdrawal syndrome including apathy,
anxiety, depression, fatigue, sweating and pain.

*Aggression has been associated with psychotic reactions as well as
compulsive symptoms.
** Somnolence has been reported very commonly in the adjunct therapy
immediate- release clinical trials, and commonly in the adjunct therapy
prolonged-release clinical trials.
*** In patients with advanced Parkinson’s disease, dyskinesias can occur during the
initial titration of ropinirole. In clinical trials it was shown that a reduction of the
levodopa dose may ameliorate dyskinesia (see section 4.2).

****Nausea has been reported very commonly in the adjunct therapy
immediate- release clinical trials, and commonly in the adjunct therapy
prolonged-release clinical trials.
Dopamine agonist withdrawal syndrome
Non-motor adverse effects may occur when tapering or discontinuing
dopamine agonists including ropinirole (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 Yellow Card Scheme
(www.mhra.gov.uk/yellowcard).

4.9

Overdose
The symptoms of ropinirole overdose are related to its dopaminergic activity.
These symptoms may be alleviated by appropriate treatment with dopamine
antagonists such as neuroleptics or metoclopramide.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Dopamine agonists, ATC code N04BC04
Mechanism of action
Ropinirole is a non-ergoline D2/D3 dopamine agonist which stimulates striatal
dopamine receptors.
Ropinirole alleviates the dopamine deficiency which characterises Parkinson's
disease by stimulating striatal dopamine receptors.
Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of
prolactin.
Clinical efficacy
A 36-week, double-blind, three-period crossover study, in monotherapy,
conducted in 161 patients with early phase Parkinson's disease demonstrated
that ropinirole prolonged-release tablets were non-inferior to immediaterelease film-coated tablets on the primary endpoint, the treatment difference in
change from baseline in the Unified Parkinson’s Disease Rating Scale
(UPDRS) motor score (a 3-point non-inferiority margin on the UPDRS motor
score was defined). The adjusted mean difference between ropinirole
prolonged-release tablets and immediate-release film-coated tablets at study
endpoint was -0.7 points (95% CI: [-1.51, 0.10], p=0.0842).
Following the overnight switch to a similar dose of the alternative tablet
formulation, there was no difference in the adverse event profile and less than
3% of patients required a dose adjustment (all dose adjustments were increases
by one dose level. No patients required a dose decrease).

A 24-week, double-blind, placebo-controlled, parallel group study of
ropinirole prolonged-release tablets in patients with Parkinson's disease who
were not optimally controlled on levodopa demonstrated that a clinically
relevant and statistically significant superiority over placebo on the primary
endpoint, change from baseline in awake time “off” (adjusted mean treatment
difference -1.7 hours, [95% CI: [-2.34, -1.09], p<0.0001). This was supported
by secondary efficacy parameters of change from baseline in total awake time
“on” (+1.7 hours (95% CI: [1.06, 2.33], p<0.0001) and total awake time “on”
without troublesome dyskinesias (+1.5 hours (95% CI: [0.85, 2.13],
p<0.0001). Importantly, there was no indication of an increase from baseline
in awake time “on” with troublesome dyskinesias, either from diary card data
or from the UPDRS items.
Study of the effect of ropinirole on cardiac repolarisation
A thorough QT study conducted in male and female healthy volunteers who
received doses of 0.5, 1, 2 and 4 mg of ropinirole immediate-release tablets
once daily showed a maximum increase of the QT interval duration at the
1 mg dose of 3.46 milliseconds (point estimate) as compared to placebo. The
upper bound of the one sided 95% confidence interval for the largest mean
effect was less than 7.5 milliseconds. The effect of ropinirole at higher doses
has not been systematically evaluated.
The available clinical data from a thorough QT study do not indicate a risk of
QT prolongation at doses of ropinirole up to 4 mg/day. A risk of QT
prolongation cannot be excluded as a thorough QT study at doses up to
24 mg/day has not been conducted.
5.2

Pharmacokinetic properties
Absorption
Bioavailability of ropinirole is approximately 50% (36–57%). Following oral
administration, of ropinirole prolonged-release tablets plasma concentrations
increase slowly, with a median time to Cmax generally achieved between 6 and
10 hours.
In a steady-state study in 25 Parkinson’s disease patients receiving 12 mg of
ropinirole prolonged release tablets once daily, a high fat meal increased the
systemic exposure to ropinirole as shown by an average 20% increase in AUC
and an average 44% increase in Cmax. Tmax was delayed by 3.0 hours.
However, these changes are unlikely to be clinically relevant (e.g. increased
incidence of adverse events).
The systemic exposure to ropinirole is comparable for ropinirole prolongedrelease tablets and ropinirole film-coated (immediate-release) tablets based on
the same daily dose.
Distribution
Plasma protein binding of ropinirole is low (10–40%). Consistent with its high
lipophilicity, ropinirole exhibits a large volume of distribution (approximately
7 L/kg).
Biotransformation
Ropinirole is primarily cleared by CYP1A2 metabolism and its metabolites are
mainly excreted in the urine. The major metabolite is at least 100-times less
potent than ropinirole in animal models of dopaminergic function.
Elimination

Ropinirole is cleared from the systemic circulation with an average
elimination half-life of about six hours. The increase in systemic exposure
(Cmax and AUC) to ropinirole is approximately proportional over the
therapeutic dose range. No change in the oral clearance of ropinirole is
observed following single and repeated oral administration. Wide interindividual variability in the pharmacokinetic parameters has been observed.
Following steady-state administration of Ropinirole prolonged-release tablets,
the inter-individual variability for Cmax was between 30% and 55% and for
AUC was between 40% and 70%.
Renal Impairment
There was no changed observed in the pharmacokinetics of ropinirole in
Parkinson’s disease patients with mild to moderate renal impairment.
In patients with end stage renal disease receiving regular haemodialysis, oral
clearance of ropinirole is reduced by approximately 30%. Oral clearance of the
metabolites SKF-104557 and SKF-89124 were also reduced by approximately
80% and 60%, respectively. Therefore, the recommended maximum dose is
limited to 18 mg/day in these patients with Parkinson’s disease (see section
4.2).
5.3

Preclinical safety data
Reproductive Toxicity
Administration of ropinirole to pregnant rats at maternally toxic doses resulted
in decreased foetal body weight at 60 mg/kg/day (approximately twice the
AUC at the maximum dose in humans), increased foetal death at 90 mg/kg/day
(approximately 3 times the AUC at the maximum dose in humans) and digit
malformations at 150 mg/kg/day (approximately 5 times the AUC at the
maximum dose in humans). There were no teratogenic effects in the rat at 120
mg/kg/day (approximately 4 times the AUC at the maximum dose in humans)
and no indication of an effect on development in the rabbit.
Toxicology
The toxicology profile is principally determined by the pharmacological
activity of ropinirole: behavioural changes, hypoprolactinaemia, decrease in
blood pressure and heart rate, ptosis and salivation. In the albino rat only,
retinal degeneration was observed in a long term study at the highest dose (50
mg/kg/day), and was probably associated with an increased exposure to light.
Genotoxicity
Genotoxicity was not observed in the usual battery of in vitro and in vivo tests.
Carcinogenicity
From two-year studies conducted in the mouse and rat at dosages up to 50
mg/kg/day there was no evidence of any carcinogenic effect in the mouse. In
the rat, the only ropinirole-related lesions were Leydig cell hyperplasia and
testicular adenoma resulting from the hypoprolactinaemic effect of ropinirole.
These lesions are considered to be a species specific phenomenon and do not
constitute a hazard with regard to the clinical use of ropinirole.
Safety Pharmacology
In vitro studies have shown that ropinirole inhibits hERG-mediated currents.
The IC50 is 5-fold higher than the expected maximum plasma concentration in
patients treated at the highest recommended dose (24 mg/day), see section 5.1.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core:
Ammonio Methacrylate Copolymer Type B
Hypromellose (E464)
Sodium lauryl sulfate
Copovidone
Magnesium stearate (E572)
Tablet coat:
Titanium dioxide(E171)
Hypromellose (E464)
Macrogol 400
Indigo carmine aluminium lake (E132)
Sunset yellow aluminium lake (E110)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years
HDPE bottle: Shelf life after first opening is 60 days.

6.4

Special precautions for storage
Do not store above 25ºC.

6.5

Nature and contents of container
Ropilynz XL is supplied in white opaque PVC/PCTFE-Aluminum foil blisters
and white opaque HDPE bottles with white cylindrical caps of polypropylene
with three break points on the tamper-evident ring and aperture of desiccant
insert.
Pack sizes of
Blister: 7, 21, 28, 30, 42, 84, 90, 100 prolonged-release tablets
Bottle: 7, 21, 28, 30, 42, 84, 90, 100 prolonged-release tablets
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Any unused product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Lupin (Europe) Limited
Victoria Court
Bexton Road
Knutsford
Cheshire
WA16 0PF
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 35507/0154

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
10/08/2015

10

DATE OF REVISION OF THE TEXT
05/09/2017

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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