Skip to Content

RASAGILINE CRESCENT 1MG TABLETS

Active substance(s): RASAGILINE HEMITARTRATE / RASAGILINE HEMITARTRATE

View full screen / Print PDF » Download PDF ⇩

PDF Transcript

SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Rasagiline Crescent 1mg Tablets

2

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

3

PHARMACEUTICAL FORM
Tablet
White to off white round, flat tablets with bevelled edges and engraved with
“1” in one side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Rasagiline 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 1mg 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 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 listed in
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 serotonin-norepinephrine 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 1mg 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 1mg/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/fetal 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 rasagiline do 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 1mg/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 1mg/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 1mg/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, <1/10), uncommon
(≥1/1000, <1/100), rare (≥1/10000, <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
post-marketing 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 ≤ 50mg/daily, trazodone ≤

100mg/daily, citalopram ≤ 20mg/daily, sertraline ≤ 100mg/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 3mg to 100mg 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 20mg/day and in a
ten-day study healthy volunteers received 10mg/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 10mg/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 nonselective 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 as adjunct therapy to levodopa in the studies II and III.
Monotherapy:
In study I, 404 patients were randomly assigned to receive placebo (138
patients), rasagiline 1mg/day (134 patients) or rasagiline 2mg/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 1mg compared to placebo -4.2,
95% CI [-5.7, -2.7]; p<0.0001; for rasagiline 2mg compared to placebo -3.6,
95% CI [-5.0, -2.1]; p<0.0001, UPDRS Motor, part II: for rasagiline 1mg
compared to placebo -2.7, 95% CI [-3.87, -1.55], p<0.0001; for rasagiline 2mg
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 1mg/day (231 patients) or the catechol-O–methyl transferase
(COMT) inhibitor, entacapone, 200mg 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 0.5mg/day (164 patients), or rasagiline 1mg/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
1mg 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 0.5mg 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: N-dealkylation 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 0.5-2mg. 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 reproductive
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 1mg/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 1mg/day.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Cellulose, microcrystalline
(Maize) starch (partially) pregelatinised
Silica, colloidal anhydrous
Magnesium stearate

6.2

Incompatibilities
Not applicable

6.3

Shelf life
3 years

6.4

Special precautions for storage
This medicinal product does not require any special temperature storage
conditions. Store in the original immediate package in order to protect from
light.

6.5

Nature and contents of container
Aluminium/aluminium blister packs of 28 tablets.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited,
Units 3 & 4, Quidhampton Business Units,
Polhampton Lane, Overton,
Hants RG25 3ED
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 20416/0430

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
13/12/2016

10

DATE OF REVISION OF THE TEXT
13/12/2016

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.

Hide