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RASAGILINE MILPHARM 1 MG TABLETS

Active substance(s): RASAGILINE TARTRATE / RASAGILINE TARTRATE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Rasagiline Milpharm 1 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 1 mg rasagiline (as tartrate).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet.
White to off-white, oblong (approximately 11.5 mm x 6 mm), biconvex tablets,
debossed with ‘R9SE’ on one side and ‘1’ on the other side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Rasagiline Milpharm is indicated for the treatment of idiopathic Parkinson’s disease
(PD) as monotherapy (without levodopa) or as adjunct therapy (with levodopa) in
patients with end of dose fluctuations.

4.2

Posology and method of administration
Posology
Rasagiline is administered orally, at a dose of 1 mg once daily with or without
levodopa.
It may be taken with or without food.
Elderly
No change in dose is required for elderly patients.

Paediatric population
Rasagiline Milpharm is not recommended for use in children and adolescents due to
lack of data on safety and efficacy.
Patients with hepatic impairment
Rasagiline use in patients with severe hepatic impairment is contraindicated (see
section 4.3). Rasagiline use in patients with moderate hepatic impairment should be
avoided. Caution should be used when initiating treatment with rasagiline in patients
with mild hepatic impairment. In case patients progress from mild to moderate
hepatic impairment rasagiline should be stopped (see section 4.4).
Patients with renal impairment
No change in dose is required for renal impairment.

4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
Concomitant treatment with other monoamine oxidase (MAO) inhibitors (including
medicinal and natural products without prescription e.g. St. John's Wort) or pethidine
(see section 4.5). At least 14 days must elapse between discontinuation of rasagiline
and initiation of treatment with MAO inhibitors or pethidine.
Rasagiline is contraindicated in patients with severe hepatic impairment.

4.4

Special warnings and precautions for use
The concomitant use of rasagiline and fluoxetine or fluvoxamine should be avoided
(see section 4.5). At least five weeks should elapse between discontinuation of
fluoxetine and initiation of treatment with rasagiline. At least 14 days should elapse
between discontinuation of rasagiline and initiation of treatment with fluoxetine or
fluvoxamine.
Impulse control disorders (ICDs) can occur in patients treated with dopamine agonists
and/or dopaminergic treatments. Similar reports of ICDs have also been received
post-marketing with rasagiline. Patients should be regularly monitored for the
development of impulse control disorders. Patients and carers should be made aware
of the behavioural symptoms of impulse control disorders that were observed in
patients treated with rasagiline, including cases of compulsions, obsessive thoughts,
pathological gambling, increased libido, hypersexuality, impulsive behaviour and
compulsive spending or buying.

Since rasagiline potentiates the effects of levodopa, the adverse effects of levodopa
may be increased and pre-existing dyskinesia exacerbated. Decreasing the dose of
levodopa may ameliorate this side effect.
There have been reports of hypotensive effects when rasagiline is taken
concomitantly with levodopa.Patients with Parkinson’s disease are particularly
vulnerable to the adverse effects of hypotension due to existing gait issues.
The concomitant use of rasagiline and dextromethorphan or sympathomimetics such
as those present in nasal and oral decongestants or cold medicinal product containing
ephedrine or pseudoephedrine is not recommended (see section 4.5).
During the clinical development program, the occurrence of cases of melanoma
prompted the consideration of a possible association with rasagiline. The data
collected suggests that Parkinson’s disease, and not any medicinal products in
particular, is associated with a higher risk of skin cancer (not exclusively melanoma).
Any suspicious skin lesion should be evaluated by a specialist.
Caution should be used when initiating treatment with rasagiline in patients with mild
hepatic impairment. Rasagiline use in patients with moderate hepatic impairment
should be avoided. In case patients progress from mild to moderate hepatic
impairment, rasagiline should be stopped (see section 5.2).

4.5

Interaction with other medicinal products and other forms of interaction
There are a number of known interactions between non selective MAO inhibitors and
other medicinal products.
Rasagiline must not be administered along with other MAO inhibitors (including
medicinal and natural products without prescription e.g. St. John's Wort) as there may
be a risk of non-selective MAO inhibition that may lead to hypertensive crises (see
section 4.3).
Serious adverse reactions have been reported with the concomitant use of pethidine
and MAO inhibitors including another selective MAO-B inhibitor. The concomitant
administration of rasagiline and pethidine is contraindicated (see section 4.3).
With MAO inhibitors there have been reports of medicinal product interactions with
the concomitant use of sympathomimetic medicinal products. Therefore, in view of
the MAO inhibitory activity of rasagiline, concomitant administration of rasagiline
and sympathomimetics such as those present in nasal and oral decongestants or cold
medicinal products, containing ephedrine or pseudoephedrine, is not recommended
(see section 4.4).

There have been reports of medicinal product interactions with the concomitant use of
dextromethorphan and non selective MAO inhibitors. Therefore, in view of the MAO
inhibitory activity of rasagiline, the concomitant administration of rasagiline and
dextromethorphan is not recommended (see section 4.4).
The concomitant use of rasagiline and fluoxetine or fluvoxamine should be avoided
(see section 4.4).
For concomitant use of rasagiline with selective serotonin reuptake inhibitors
(SSRIs)/selective serotoninnorepinephrine reuptake inhibitors (SNRIs) in clinical
trials, see section 4.8. Serious adverse reactions have been reported with the
concomitant use of SSRIs, SNRIs, tricyclic/tetracyclic antidepressants and MAO
inhibitors. Therefore, in view of the MAO inhibitory activity of rasagiline,
antidepressants should be administered with caution.
In Parkinson's disease patients receiving chronic levodopa treatment as adjunct
therapy, there was no clinically significant effect of levodopa treatment on rasagiline
clearance.
In vitro metabolism studies have indicated that cytochrome P450 1A2 (CYP1A2) is
the major enzyme responsible for the metabolism of rasagiline. Co-administration of
rasagiline and ciprofloxacin (an inhibitor of CYP1A2) increased the AUC of
rasagiline by 83%. Co-administration of rasagiline and theophylline (a substrate of
CYP1A2) did not affect the pharmacokinetics of either product. Thus, potent
CYP1A2 inhibitors may alter rasagiline plasma levels and should be administered
with caution.
There is a risk that the plasma levels of rasagiline in smoking patients could be
decreased, due to induction of the metabolising enzyme CYP1A2.
In vitro studies showed that rasagiline at a concentration of 1 μg/ml (equivalent to a
level that is 160 times the average Cmax ~ 5.9-8.5 ng/ml in Parkinson’s disease
patients after 1 mg rasagiline multiple dosing), did not inhibit cytochrome P450
isoenzymes, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4
and CYP4A. These results indicate that rasagiline’s therapeutic concentrations are
unlikely to cause any clinically significant interference with substrates of these
enzymes.
Concomitant administration of rasagiline and entacapone increased rasagiline oral
clearance by 28%.
Tyramine/rasagiline interaction: Results of five tyramine challenge studies (in
volunteers and PD patients), together with results of home monitoring of blood
pressure after meals (of 464 patients treated with 0.5 or 1 mg/day of rasagiline or
placebo as adjunct therapy to levodopa for six months without tyramine restrictions),
and the fact that there were no reports of tyramine/rasagiline interaction in clinical

studies conducted without tyramine restriction, indicate that rasagiline can be used
safely without dietary tyramine restrictions.

4.6

Fertility, pregnancy and lactation
Pregnancy
For rasagiline no clinical data on exposed pregnancies is available. Animals studies
do not indicate direct or indirect harmful effects with respect to pregnancy,
embryonal/foetal development, parturition or postnatal development (see section 5.3).
Caution should be exercised when prescribing to pregnant women.
Breast-feeding
Experimental data indicated that rasagiline inhibits prolactin secretion and thus, may
inhibit lactation.It is not known whether rasagiline is excreted in human milk. Caution
should be exercised when rasagiline is administered to a breast-feeding mother.

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed.
Patients should be cautioned about operating hazardous machines, including motor
vehicles, until they are reasonably certain that [Product name] does not affect them
adversely.

4.8

Undesirable effects
In the rasagiline clinical program overall, 1,361 patients were treated with rasagiline
for 3,076.4 patient years. In the double blind placebo controlled studies, 529 patients
were treated with rasagiline 1 mg/day for 212 patient years and 539 patients received
placebo for 213 patient years.
Monotherapy
The list below includes adverse reactions which were reported with a higher
incidence in placebo controlled studies, in patients receiving 1 mg/day rasagiline
(rasagiline group n=149, placebo group n=151).
Adverse reactions with at least 2% difference over placebo are marked in italics.
In parentheses is the adverse reaction incidence (% of patients) in rasagiline vs.
placebo, respectively.

Adverse reactions are ranked under headings of frequency using the following
conventions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000
to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000).

Infections and infestations
Common: influenza (4.7% vs. 0.7%)
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Common: skin carcinoma (1.3% vs. 0.7%)
Blood and lymphatic system disorders
Common: leucopenia (1.3% vs. 0%)
Immune system disorders
Common: allergy (1.3% vs. 0.7%)
Metabolism and nutrition disorders
Uncommon: decreased appetite (0.7% vs. 0%)
Psychiatric disorders
Common: depression (5.4% vs. 2%), hallucinations (1.3% vs. 0.7%)
Nervous system disorders
Very common: headache (14.1% vs. 11.9%)
Uncommon: cerebrovascular accident (0.7% vs. 0%)
Eye disorders
Common: conjunctivitis (2.7% vs. 0.7%)
Ear and labyrinth disorders
Common: vertigo (2.7% vs. 1.3%)
Cardiac disorders
Common: angina pectoris (1.3% vs. 0%);
Uncommon: myocardial infarction (0.7% vs. 0%)
Respiratory, thoracic and mediastinal disorders
Common: rhinitis (3.4% vs. 0.7%)
Gastrointestinal disorders
Common: flatulence (1.3% vs.0%)
Skin and subcutaneous tissue disorders
Common: dermatitis (2.0% vs. 0%)
Uncommon: vesiculobullous rash (0.7% vs. 0%)
Musculoskeletal and connective tissue disorders
Common: musculoskeletal pain (6.7% vs. 2.6%), neck pain (2.7% vs. 0%), arthritis
(1.3% vs.0.7%)
Renal and urinary disorders
Common: urinary urgency (1.3% vs. 0.7%).
General disorders and administration site conditions
Common: fever (2.7% vs. 1.3%), malaise (2% vs. 0%)
Adjunct Therapy
The list below includes adverse reactions which were reported with a higher
incidence in placebo controlled studies in patients receiving 1 mg/day rasagiline
(rasagiline group n=380, placebo group n=388). In parentheses is the adverse reaction
incidence (% of patients) in rasagiline vs. placebo, respectively.
Adverse reactions with at least 2% difference over placebo are in italics.

Adverse reactions are ranked under headings of frequency using the following
conventions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000
to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000).

Neoplasms benign, malignant and unspecified
Uncommon: skin melanoma (0.5% vs. 0.3%)
Metabolism and nutrition disorders
Common: decreased appetite (2.4% vs. 0.8%)
Psychiatric disorders
Common: hallucinations (2.9% vs. 2.1%), abnormal dreams (2.1% vs. 0.8%)
Uncommon: confusion (0.8% vs. 0.5%)
Nervous system disorders
Very common: dyskinesia (10.5% vs. 6.2%)
Common: dystonia (2.4% vs. 0.8%), carpal tunnel syndrome (1.3% vs. 0%),
balance disorder (1.6% vs. 0.3%)
Uncommon: cerebrovascular accident (0.5% vs. 0.3%)
Cardiac disorders
Uncommon: angina pectoris (0.5% vs. 0%)
Vascular disorders
Common: orthostatic hypotension (3.9% vs. 0.8%)
Gastrointestinal disorders
Common: abdominal pain (4.2% vs. 1.3%), constipation (4.2% vs. 2.1%),
nausea and vomiting (8.4% vs. 6.2%), dry mouth (3.4% vs. 1.8%)
Skin and subcutaneous tissue disorders
Common: rash (1.1% vs. 0.3%)
Musculoskeletal and connective tissue disorders
Common: arthralgia (2.4% vs. 2.1%), neck pain (1.3% vs. 0.5%)
Investigations
Common: decreased weight (4.5% vs. 1.5%)
Injury, poisoning and procedural complications
Common: fall (4.7% vs. 3.4%)
Parkinson's disease is associated with symptoms of hallucinations and confusion. In
post-marketing experience, these symptoms have also been observed in Parkinson's
disease patients treated with rasagiline.
Serious adverse reactions are known to occur with the concomitant use of SSRIs,
SNRIs, tricyclic/tetracyclic antidepressants and MAO inhibitors. In the postmarketing period, cases of serotonin syndrome associated with agitation, confusion,
rigidity, pyrexia and myoclonus have been reported by patients treated with
antidepressants/SNRI concomitantly with rasagiline.
Rasagiline clinical trials did not allow concomitant use of fluoxetine or fluvoxamine
with rasagiline, but the following antidepressants and doses were allowed in the
rasagiline trials: amitriptyline ≤ 50 mg/daily, trazodone ≤ 100 mg/daily, citalopram ≤
20 mg/daily, sertraline ≤ 100 mg/daily, and paroxetine ≤ 30 mg/daily. There were no
cases of serotonin syndrome in the rasagiline clinical program in which 115 patients
were exposed concomitantly to rasagiline and tricyclics and 141 patients were
exposed to rasagiline and SSRIs/ SNRIs.

In the post-marketing period, cases of elevated blood pressure, including rare cases of
hypertensive crisis associated with ingestion of unknown amounts of tyramine-rich
foods, have been reported in patients taking rasagiline.
With MAO inhibitors, there have been reports of drug interactions with the
concomitant use of sympathomimetic medicinal products.In post marketing period,
there was one case of elevated blood pressure in a patient using the ophthalmic
vasoconstrictor tetrahydrozoline hydrochloride while taking rasagiline.
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 and/or other dopaminergic treatments. A similar pattern of
impulse control disorders has been reported post-marketing with rasagiline, which
also included compulsions, obsessive thoughts and impulsive behaviour (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 at: www.mhra.gov.uk/yellowcard.

4.9

Overdose
Overdosage: Symptoms reported following overdose of rasagiline in doses ranging
from 3 mg to 100 mg included dysphoria, hypomania, hypertensive crisis and
serotonin syndrome.
Overdose can be associated with significant inhibition of both MAO-A and MAO-B.
In a single-dose study healthy volunteers received 20 mg/day and in a ten-day study
healthy volunteers received 10 mg/day. Adverse events were mild or moderate and
not related to rasagiline treatment. In a dose escalation study in patients on chronic
levodopa therapy treated with 10 mg/day of rasagiline, there were reports of
cardiovascular undesirable reactions (including hypertension and postural
hypotension) which resolved following treatment discontinuation. These symptoms
may resemble those observed with non-selective MAO inhibitors.
There is no specific antidote. In case of overdose, patients should be monitored and
the appropriate symptomatic and supportive therapy instituted.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Anti-Parkinson-Drugs, Monoamine oxidase -B
inhibitors, ATC code: N04BD02
Mechanism of action
Rasagiline was shown to be a potent, irreversible MAO-B selective inhibitor, which
may cause an increase in extracellular levels of dopamine in the striatum. The
elevated dopamine level and subsequent increased dopaminergic activity are likely to
mediate rasagiline's beneficial effects seen in models of dopaminergic motor
dysfunction.
1-Aminoindan is an active major metabolite and it is not a MAO-B inhibitor.
Clinical studies
The efficacy of rasagiline was established in three studies: as monotherapy treatment
in study I and asadjunct therapy to levodopa in the studies II and III.
Monotherapy
In study I, 404 patients were randomly assigned to receive placebo (138 patients),
rasagiline 1 mg/day (134 patients) or rasagiline 2 mg/day (132 patients) and were
treated for 26 weeks, there was no active comparator.
In this study, the primary measure of efficacy was the change from baseline in the
total score of the Unified Parkinson’s Disease Rating Scale (UPDRS, parts I-III). The
difference between the mean change from baseline to week 26/termination (LOCF,
Last Observation Carried Forward) was statistically significant (UPDRS, parts I-III:
for rasagiline 1 mg compared to placebo -4.2, 95% CI [-5.7, -2.7]; p<0.0001; for
rasagiline 2 mg compared to placebo -3.6, 95% CI [-5.0, -2.1]; p<0.0001, UPDRS
Motor, part II: for rasagiline 1 mg compared to placebo -2.7, 95% CI [-3.87, -1.55],
p<0.0001; for rasagiline 2 mg compared to placebo -1.68, 95% CI [-2.85, -0.51],
p=0.0050). The effect was evident, although its magnitude was modest in this patient
population with mild disease. There was a significant and beneficial effect in quality
of life (as assessed by PD-QUALIF scale).
Adjunct therapy
In study II, patients were randomly assigned to receive placebo (229 patients), or
rasagiline 1 mg/day (231 patients) or the catechol-O–methyl transferase (COMT)
inhibitor, entacapone, 200 mg taken along with scheduled doses of levodopa
(LD)/decarboxylase inhibitor (227 patients), and were treated for 18 weeks. In study
III, patients were randomly assigned to receive placebo (159 patients), rasagiline 0.5
mg/day (164 patients), or rasagiline 1 mg/day (149 patients), and were treated for 26
weeks.
In both studies, the primary measure of efficacy was the change from baseline to
treatment period in the mean number of hours that were spent in the “OFF” state
during the day (determined from “24-hour” home diaries completed for 3 days prior
to each of the assessment visits).

In study II, the mean difference in the number of hours spent in the “OFF” state
compared to placebo was -0.78h, 95% CI [-1.18, -0.39], p=0.0001. The mean total
daily decrease in the OFF time was similar in the entacapone group (-0.80h, 95% CI
[-1.20, -0.41], p<0.0001) to that observed in the rasagiline 1 mg group. In study III,
the mean difference compared to placebo was -0.94h, 95% CI [-1.36, -0.51],
p<0.0001. There was also a statistically significant improvement over placebo with
the rasagiline 0.5 mg group, yet the magnitude of improvement was lower. The
robustness of the results for the primary efficacy endpoint, was confirmed in a battery
of additional statistical models and was demonstrated in three cohorts (ITT, per
protocol and completers).
The secondary measures of efficacy included global assessments of improvement by
the examiner,Activities of Daily Living (ADL) subscale scores when OFF and
UPDRS motor while ON. Rasagiline produced statistically significant benefit
compared to placebo.

5.2

Pharmacokinetic properties
Absorption
Rasagiline is rapidly absorbed, reaching peak plasma concentration (Cmax) in
approximately 0.5 hours. The absolute bioavailability of a single rasagiline dose is
about 36%.Food does not affect the Tmax of rasagiline, although Cmax and exposure
(AUC) are decreased by approximately 60% and 20%, respectively, when the
medicinal product is taken with a high fat meal.Because AUC is not substantially
affected, rasagiline can be administered with or without food.
Distribution
The mean volume of distribution following a single intravenous dose of rasagiline is
243 l. Plasma protein binding following a single oral dose of 14C-labelled rasagiline
is approximately 60 to 70%.
Metabolism
Rasagiline undergoes almost complete biotransformation in the liver prior to
excretion. The metabolism of rasagiline proceeds through two main pathways: Ndealkylation and/or hydroxylation to yield: 1-Aminoindan, 3-hydroxy-N-propargyl-1
aminoindan and 3-hydroxy-1-aminoindan. In vitro experiments indicate that both
routes of rasagiline metabolism are dependent on cytochrome P450 system, with
CYP1A2 being the major iso-enzyme involved in rasagiline metabolism. Conjugation
of rasagiline and its metabolites was also found to be a major elimination pathway to
yield glucuronides.
Excretion
After oral administration of 14C-labelled rasagiline, elimination occurred primarily
via urine (62.6%) and secondarily via faeces (21.8%), with a total recovery of 84.4%
of the dose over a period of 38 days. Less than 1% of rasagiline is excreted as
unchanged product in urine.

Linearity/non-linearity
Rasagiline pharmacokinetics are linear with dose over the range of 0.5-2 mg. Its
terminal half-life is 0.6-2 hours.
Characteristics in patients
Patients with hepatic impairment: In subjects with mild hepatic impairment, AUC and
Cmax were increased by 80% and 38%, respectively. In subjects with moderate
hepatic impairment, AUC and Cmax were increased by 568% and 83%, respectively
(see section 4.4).
Patients with renal impairment: Rasagiline's pharmacokinetics characteristics in
subjects with mild (CLcr 50-80 ml/min) and moderate (CLcr 30-49 ml/min) renal
impairment were similar to healthy subjects.

5.3

Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of
safety pharmacology, repeated-dose toxicity and reproduction toxicity.
Rasagiline did not present genotoxic potential in vivo and in several in vitro systems
using bacteria or hepatocytes. In the presence of metabolite activation rasagiline
induced an increase of chromosomal aberrations at concentrations with excessive
cytotoxicity which are unattainable at the clinical conditions of use.
Rasagiline was not carcinogenic in rats at systemic exposure, 84 – 339 times the
expected plasma exposures in humans at 1 mg/day. In mice, increased incidences of
combined bronchiolar/alveolar adenoma and/or carcinoma were observed at systemic
exposures, 144 - 213 times the expected plasma exposure in humans at 1 mg/day.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Cellulose, microcrystalline
Tartaric acid
Maize starch
Starch, pregelatinized maize
Talc
Stearic acid

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
30 months.

6.4

Special precautions for storage
Do not store above 25ºC.

6.5

Nature and contents of container
OPA/Al/PVC/Al blister packs of 7, 10, 28, 30, 50, 90, 100 and 112 tablets.
PVC/PVDC/Al blister packs of 7, 10, 28, 30, 50, 90, 100 and 112 tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements for disposal.

7

MARKETING AUTHORISATION HOLDER
Milpharm Limited
Ares Block, Odyssey Business Park
West End Road
Ruislip HA4 6QD
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 16363/0501

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
12/11/2015

10

DATE OF REVISION OF THE TEXT
12/11/2015

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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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