ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Aloxi 250 micrograms solution for injection.
2.
Each ml of solution contains 50 micrograms palonosetron (as hydrochloride).
Each vial of 5 ml of solution contains 250 micrograms palonosetron (as hydrochloride).
For a full list of excipients, see section 6.1.
3.
Solution for injection.
Clear, colourless solution.
Aloxi is indicated for
•
the prevention of acute nausea and vomiting associated with highly emetogenic cancer
chemotherapy in adults,
•
the prevention of nausea and vomiting associated with moderately emetogenic cancer
chemotherapy in adults.
Aloxi should be used only before chemotherapy administration. This medicinal product should be
administered by a healthcare professional under appropriate medical supervision.
Posology
Adults
250 micrograms palonosetron administered as a single intravenous bolus approximately 30 minutes
before the start of chemotherapy. Aloxi should be injected over 30 seconds.
The efficacy of Aloxi in the prevention of nausea and vomiting induced by highly emetogenic
chemotherapy may be enhanced by the addition of a corticosteroid administered prior to
chemotherapy.
Elderly population
No dose adjustment is necessary for the elderly.
Paediatric population
The safety and efficacy in children have not been established. Currently available data are described
in section 5.1 and section 5.2, but no recommendation on posology can be made.
Hepatic impairment
No dose adjustment is necessary for patients with impaired hepatic function.
2
Renal impairment
No dose adjustment is necessary for patients with impaired renal function.
No data are available for patients with end stage renal disease undergoing haemodialysis.
Method of administration
For intravenous use.
Hypersensitivity to the active substance or to any of the excipients.
As palonosetron may increase large bowel transit time, patients with a history of constipation or signs
of subacute intestinal obstruction should be monitored following administration. Two cases of
constipation with faecal impaction requiring hospitalisation have been reported in association with
palonosetron
750
micrograms.
At all dose levels tested, palonosetron did not induce clinically relevant prolongation of the QTc
interval. A specific thorough QT/QTc study was conducted in healthy volunteers for definitive data
demonstrating the effect of palonosetron on QT/QTc (see section 5.1).
However, as for other 5-HT
3
antagonists, caution should be exercised in the concomitant use of
palonosetron with medicinal products that increase the QT interval or in patients who have or are
likely to develop prolongation of the QT interval.
Aloxi should not be used to prevent or treat nausea and vomiting in the days following chemotherapy
if not associated with another chemotherapy administration.
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium-
free’.
Palonosetron is mainly metabolised by CYP2D6, with minor contribution by CYP3A4 and CYP1A2
isoenzymes. Based on
in vitro
studies, palonosetron does not inhibit or induce cytochrome P450
isoenzyme at clinically relevant concentrations.
Chemotherapeutic agents
In preclinical studies, palonosetron did not inhibit the antitumour activity of the five chemotherapeutic
agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C).
Metoclopramide
In a clinical study, no significant pharmacokinetic interaction was shown between a single intravenous
dose of palonosetron and steady state concentration of oral metoclopramide, which is a CYP2D6
inhibitor.
CYP2D6 inducers and inhibitors
In a population pharmacokinetic analysis, it has been shown that there was no significant effect on
palonosetron clearance when co-administered with CYP2D6 inducers (dexamethasone and rifampicin)
and inhibitors (including amiodarone, celecoxib, chlorpromazine, cimetidine, doxorubicin, fluoxetine,
haloperidol, paroxetine, quinidine, ranitidine, ritonavir, sertraline or terbinafine).
Corticosteroids
Palonosetron has been administered safely with corticosteroids.
Other medicinal products
3
Palonosetron has been administered safely with analgesics, antiemetic/antinauseants, antispasmodics
and anticholinergic medicinal products.
For Palonosetron no clinical data on exposed pregnancies are available. Animal studies do not indicate
direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition
or postnatal development. Only limited data from animal studies are available regarding the placental
transfer (see section 5.3).
There is no experience of palonosetron in human pregnancy. Therefore, palonosetron should not be
used in pregnant women unless it is considered essential by the physician.
As there are no data concerning palonosetron excretion in breast milk, breast-feeding should be
discontinued during therapy.
There are no data concerning the effect of palonosetron on fertility.
No studies on the effects on the ability to drive and use machines have been performed.
Since palonosetron may induce dizziness, somnolence or fatigue, patients should be cautioned when
driving or operating machines.
In clinical studies at a dose of 250 micrograms (total 633 patients) the most frequently observed
adverse reactions, at least possibly related to Aloxi, were headache (9 %) and constipation (5 %).
In the clinical studies the following adverse reactions (ARs) were observed as possibly or probably
related to Aloxi. These were classified as common (≥1/100 to <1/10) or uncommon (≥1/1,000 to
<1/100).
Very rare (<1/10,000) adverse reactions were reported post-marketing.
Within each frequency grouping, adverse reactions are presented below in order of decreasing
seriousness.
4
System organ class
Common ARs
(
≥
1/100 to<1/10)
Uncommon ARs
(
≥
1/1,000 to <1/100)
Very rare
ARs°
(<1/10,000)
Immune system disorders
Hypersensitivity
Metabolism and nutrition
disorders
Hyperkalaemia, metabolic
disorders, hypocalcaemia,
hypokalaemia, anorexia,
hyperglycaemia, appetite
decreased
Psychiatric disorders
Anxiety, euphoric mood
Nervous system disorders
Headache
Dizziness
Somnolence, insomnia,
paraesthesia, hypersomnia,
peripheral sensory
neuropathy
Eye disorders
Eye irritation, amblyopia
Ear and labyrinth
disorders
Motion sickness, tinnitus
Cardiac disorders
Tachycardia, bradycardia,
extrasystoles, myocardial
ischaemia, sinus tachycardia,
sinus arrhythmia,
supraventricular
extrasystoles
Vascular disorders
Hypotension, hypertension,
vein discolouration, vein
distended
Respiratory, thoracic and
mediastinal disorders
Hiccups
Gastrointestinal disorders
Constipation
Diarrhoea
Dyspepsia, abdominal pain,
abdominal pain upper, dry
mouth, flatulence
Hepatobiliary disorders
Hyperbilirubinaemia
Skin and subcutaneous
tissue disorders
Dermatitis allergic, pruritic
rash
Musculoskeletal and
connective tissue
disorders
Arthralgia
Renal and urinary
disorders
Urinary retention, glycosuria
General disorders and
administration site
conditions
Asthenia, pyrexia, fatigue,
feeling hot, influenza like
illness
Injection site
reaction*
Investigations
Elevated transaminases-
,
electrocardiogram QT
prolonged
° From post-marketing experience
* Includes the following: burning, induration, discomfort and pain
5
No case of overdose has been reported.
Doses of up to 6 mg have been used in clinical studies. The highest dose group showed a similar
incidence of adverse reactions compared to the other dose groups and no dose response effects were
observed. In the unlikely event of overdose with Aloxi, this should be managed with supportive care.
Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is
unlikely to be an effective treatment for Aloxi overdose.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiemetics and antinauseants, serotonin (5HT
3
) antagonists. ATC code:
A04AA05
Palonosetron is a selective high-affinity receptor antagonist of the 5HT
3
receptor.
In two randomised, double-blind studies with a total of 1,132 patients receiving moderately
emetogenic chemotherapy that included cisplatin ≤50 mg/m
2
, carboplatin, cyclophosphamide
≤1,500 mg/m
2
and doxorubicin >25 mg/m
2
, palonosetron 250 micrograms and 750 micrograms were
compared with ondansetron 32 mg (half-life 4 hours) or dolasetron 100 mg (half-life 7.3 hours)
administered intravenously on Day 1, without dexamethasone.
In a randomised, double-blind study with a total of 667 patients receiving highly emetogenic
chemotherapy that included cisplatin ≥ 60 mg/m
2
, cyclophosphamide > 1,500 mg/m
2
and dacarbazine,
palonosetron 250 micrograms and 750 micrograms were compared with ondansetron 32 mg
administered intravenously on Day 1. Dexamethasone was administered prophylactically before
chemotherapy in 67 % of patients.
The pivotal studies were not designed to assess efficacy of palonosetron in delayed onset nausea and
vomiting. The antiemetic activity was observed during 0-24 hours, 24-120 hours and 0-120 hours.
Results for the studies on moderately emetogenic chemotherapy and for the study on highly
emetogenic chemotherapy are summarised in the following tables.
Palonosetron was non-inferior versus the comparators in the acute phase of emesis both in moderately
and highly emetogenic setting.
Although comparative efficacy of palonosetron in multiple cycles has not been demonstrated in
controlled clinical studies, 875 patients enrolled in the three phase 3 trials continued in an open label
safety study and were treated with palonosetron 750 micrograms for up to 9 additional cycles of
chemotherapy. The overall safety was maintained during all cycles.
6
Table 1: Percentage of patients
a
responding by treatment group and phase in the Moderately
Emetogenic Chemotherapy study versus ondansetron
Aloxi
250 micrograms
(n= 189)
Ondansetron
32 milligrams
(n= 185)
Delta
%
%
%
Complete Response (No Emesis and No Rescue Medication)
97.5 % CI
b
0 – 24 hours
81.0
68.6
12.4
[1.8 %, 22.8 %]
24 – 120 hours
74.1
55.1
19.0
[7.5 %, 30.3 %]
0 – 120 hours
69.3
50.3
19.0
[7.4 %, 30.7 %]
Complete Control (Complete Response and No More Than Mild Nausea)
p-value
c
0 – 24 hours
76.2
65.4
10.8
NS
24 – 120 hours
66.7
50.3
16.4
0.001
0 – 120 hours
63.0
44.9
18.1
0.001
No Nausea (Likert Scale)
p-value
c
0 – 24 hours
60.3
56.8
3.5
NS
24 – 120 hours
51.9
39.5
12.4
NS
0 – 120 hours
45.0
36.2
8.8
NS
a
Intent-to-treat cohort.
b
The study was designed to show non-inferiority. A lower bound greater than –15 % demonstrates
non-inferiority between Aloxi and comparator.
c
Chi-square test. Significance level at α=0.05.
7
Table 2: Percentage of patients
a
responding by treatment group and phase in the Moderately
Emetogenic Chemotherapy study
versus dolasetron
Aloxi
250 micrograms
(n= 185)
Dolasetron
100 milligrams
(n= 191)
Delta
%
%
%
Complete Response (No Emesis and No Rescue Medication)
97.5 % CI
b
0 – 24 hours
63.0
52.9
10.1
[-1.7 %, 21.9 %]
24 – 120 hours
54.0
38.7
15.3
[3.4 %, 27.1 %]
0 – 120 hours
46.0
34.0
12.0
[0.3 %, 23.7 %]
Complete Control (Complete Response and No More Than Mild Nausea)
p-value
c
0 – 24 hours
57.1
47.6
9.5
NS
24 – 120 hours
48.1
36.1
12.0
0.018
0 – 120 hours
41.8
30.9
10.9
0.027
No Nausea (Likert Scale)
p-value
c
0 – 24 hours
48.7
41.4
7.3
NS
24 – 120 hours
41.8
26.2
15.6
0.001
0 – 120 hours
33.9
22.5
11.4
0.014
a
Intent-to-treat cohort.
b
The study was designed to show non-inferiority. A lower bound greater than –15 % demonstrates
non-inferiority between Aloxi and comparator.
c
Chi-square test. Significance level at α=0.05.
Table 3: Percentage of patients
a
responding by treatment group and phase in the Highly
Emetogenic Chemotherapy study versus ondansetron
Aloxi
250 micrograms
(n= 223)
Ondansetron
32 milligrams
(n= 221)
Delta
%
%
%
Complete Response (No Emesis and No Rescue Medication)
97.5 % CI
b
0 – 24 hours
59.2
57.0
2.2
[-8.8 %, 13.1 %]
24 – 120 hours
45.3
38.9
6.4
[-4.6 %, 17.3 %]
0 – 120 hours
40.8
33.0
7.8
[-2.9 %, 18.5 %]
Complete Control (Complete Response and No More Than Mild Nausea)
p-value
c
0 – 24 hours
56.5
51.6
4.9
NS
24 – 120 hours
40.8
35.3
5.5
NS
0 – 120 hours
37.7
29.0
8.7
NS
No Nausea (Likert Scale)
p-value
c
0 – 24 hours
53.8
49.3
4.5
NS
24 – 120 hours
35.4
32.1
3.3
NS
0 – 120 hours
33.6
32.1
1.5
NS
a
Intent-to-treat cohort.
b
The study was designed to show non-inferiority. A lower bound greater than –15 % demonstrates
non-inferiority between Aloxi and comparator.
c
Chi-square test. Significance level at α=0.05.
8
The effect of palonosetron on blood pressure, heart rate, and ECG parameters including QTc were
comparable to ondansetron and dolasetron in CINV clinical studies. In non-clinical studies
palonosetron possesses the ability to block ion channels involved in ventricular de- and re-polarisation
and to prolong action potential duration.
The effect of palonosetron on QTc interval was evaluated in a double blind, randomised, parallel,
placebo and positive (moxifloxacin) controlled trial in adult men and women. The objective was to
evaluate the ECG effects of IV administered palonosetron at single doses of 0.25, 0.75 or 2.25 mg in
221 healthy subjects. The study demonstrated no effect on QT/QTc interval duration as well as any
other ECG interval at doses up to 2.25 mg. No clinically significant changes were shown on heart rate,
atrioventricular (AV) conduction and cardiac repolarisation.
Paediatric population
Prevention of Chemotherapy Induced Nausea and Vomiting (CINV):
The safety and efficacy of Palonosetron i.v at single doses of 3µg/kg and 10µg/kg was investigated in
a clinical study in 72 patients in the following age groups, >28 days to 23 months (12 patients), 2 to 11
years (31 patients), and 12 to 17 years of age (29 patients), receiving highly or moderately emetogenic
chemotherapy. No safety concerns were raised at either dose level. The primary efficacy variable was
the proportion of patients with a complete response (CR, defined as no emetic episode and no rescue
medication) during the first 24 hours after the start of chemotherapy administration. Efficacy after
palonosetron 10 µg/kg compared to palonosetron 3µg/kg was 54.1% and 37.1% respectively.
Pharmacokinetic information is provided in section 5.2.
Prevention of Post Operative Nausea and Vomiting (PONV):
The safety and efficacy of Palonosetron i.v at single doses of 1µg/kg and 3µg/kg was compared in a
clinical study in 150 patients in the following age groups, >28 days to 23 months (7 patients), 2 to 11
years (96 patients), and 12 to 16 years of age (47 patients) undergoing elective surgery. No safety
concerns were raised in either treatment group. The proportion of patients without emesis during 0-72
hours post-operatively was similar after palonosetron 1 µg/kg or 3 µg/kg (88% vs 84%).
Please see section 4.2 for information on paediatric use.
5.2 Pharmacokineticproperties
Absorption
Following intravenous administration, an initial decline in plasma concentrations is followed by slow
elimination from the body with a mean terminal elimination half-life of approximately 40 hours. Mean
maximum plasma concentration (C
max
) and area under the concentration-time curve (AUC0-∞) are
generally dose-proportional over the dose range of 0.3–90 μg/kg in healthy subjects and in cancer
patients.
Following intravenous administration of palonosetron 0.25 mg once every other day for 3 doses in 11
testicular cancer patients, the mean (± SD) increase in plasma concentration from Day 1 to Day 5 was
42 ± 34 %. After intravenous administration of palonosetron 0.25 mg once daily for 3 days in 12
healthy subjects, the mean (± SD) increase in plasma palonosetron concentration from Day 1 to Day 3
was 110 ± 45 %.
Pharmacokinetic simulations indicate that the overall exposure (AUC0-∞) of 0.25 mg intravenous
palonosetron administered once daily for 3 consecutive days was similar to a single intravenous dose
of 0.75 mg, although C
max
of the 0.75 mg single dose was higher.
Distribution
Palonosetron at the recommended dose is widely distributed in the body with a volume of distribution
of approximately 6.9 to 7.9 l/kg. Approximately 62 % of palonosetron is bound to plasma proteins.
9
Biotransformation
Palonosetron is eliminated by dual route, about 40 % eliminated through the kidney and with
approximately 50 % metabolised to form two primary metabolites, which have less than 1 % of the
5HT
3
receptor antagonist activity of palonosetron.
In vitro
metabolism studies have shown that
CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 isoenzymes are involved in the metabolism of
palonosetron. However, clinical pharmacokinetic parameters are not significantly different between
poor and extensive metabolisers of CYP2D6 substrates. Palonosetron does not inhibit or induce
cytochrome P450 isoenzymes at clinically relevant concentrations.
Elimination
After a single intravenous dose of 10 micrograms/kg [
14
C]-palonosetron, approximately 80 % of the
dose was recovered within 144 hours in the urine with palonosetron representing approximately 40 %
of the administered dose, as unchanged active substance. After a single intravenous bolus
administration in healthy subjects the total body clearance of palonosetron was 173 ± 73 ml/min and
renal clearance was 53 ± 29 ml/min. The low total body clearance and large volume of distribution
resulted in a terminal elimination half-life in plasma of approximately 40 hours. Ten percent of
patients have a mean terminal elimination half-life greater than 100 hours.
Pharmacokinetics in special populations
Elderly
Age does not affect the pharmacokinetics of palonosetron. No dosage adjustment is necessary in
elderly patients.
Gender
Gender does not affect the pharmacokinetics of palonosetron. No dosage adjustment is necessary
based on gender.
Paediatric population
Across all age groups, (>28 days to 23 months (11 patients), 2 to 11 years (30 patients), and 12 to 17
years of age (29 patients)) of CINV paediatric patients, exposure to palonosetron was generally dose
proportional for the 3μg/kg and 10μg/kg dose levels. Both clearance and volume of distribution appear
to increase with increasing age largely due to the expected increase in body weight among the age
groups. Mean terminal elimination half-life values ranged from 21-37 hours and did not change with
dose or age. There was no effect of gender on clearance, volume of distribution or half-life. Please see
section 4.2 for information on paediatric use.
Renal impairment
Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic
parameters. Severe renal impairment reduces renal clearance, however total body clearance in these
patients is similar to healthy subjects. No dosage adjustment is necessary in patients with renal
insufficiency. No pharmacokinetic data in haemodialysis patients are available.
Hepatic impairment
Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the
healthy subjects. While the terminal elimination half-life and mean systemic exposure of palonosetron
is increased in the subjects with severe hepatic impairment, this does not warrant dose reduction.
5.3 Preclinical safety data
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the
maximum human exposure indicating little relevance to clinical use.
Non-clinical studies indicate that palonosetron, only at very high concentrations, may block ion
channels involved in ventricular de- and re-polarisation and prolong action potential duration.
10
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,
embryonal/foetal development, parturition or postnatal development. Only limited data from animal
studies are available regarding the placental transfer (see section 4.6).
Palonosetron is not mutagenic. High doses of palonosetron (each dose causing at least 30 times the
human therapeutic exposure) applied daily for two years caused an increased rate of liver tumours,
endocrine neoplasms (in thyroid, pituitary, pancreas, adrenal medulla) and skin tumours in rats but not
in mice. The underlying mechanisms are not fully understood, but because of the high doses employed
and since Aloxi is intended for single application in humans, these findings are not considered relevant
for clinical use.
6.1 List of excipients
Mannitol
Disodium edetate
Sodium citrate
Citric acid monohydrate
Sodium hydroxide (for pH adjustment)
Hydrochloric acid (for pH adjustment)
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
5 years.
Upon opening of the vial, use immediately and discard any unused solution.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Type I glass vial with chlorobutyl siliconised rubber stopper and aluminium cap.
Available in packs of 1 vial containing 5 ml of solution.
6.6 Special precautions for disposal
Single use only, any unused solution should be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Helsinn Birex Pharmaceuticals Ltd.
Damastown
Mulhuddart
Dublin 15
Ireland
11
8.
EU/1/04/306/001
9.
22 March 2005/23 March 2010
Detailed information on this product is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu
12
1.
Aloxi 500 micrograms soft capsules
2.
Each capsule contains 500 micrograms palonosetron (as hydrochloride).
Excipient(s):
Each capsule contains 14.21 milligrams sorbitol.
For a full list of excipients, see section 6.1.
3.
Soft capsule.
Light beige, opaque, oval, soft gelatine capsules, imprinted with black logo “AlO”, filled with a clear
yellowish solution.
Aloxi is indicated for the prevention of nausea and vomiting associated with moderately emetogenic
cancer chemotherapy in adults.
Aloxi should be used only before chemotherapy administration.This medicinal product should be
administered by a healthcare professional under appropriate medical supervision.
Posology
Adults
500 micrograms palonosetron administered orally approximately one hour before the start of
chemotherapy.
Elderly population
No dose adjustment is necessary for the elderly.
Paediatric population
The safety and efficacy in children have not been established. Currently available data are described
in section 5.1 and section 5.2, but no recommendation on posology can be made.
Hepatic impairment
No dose adjustment is necessary for patients with impaired hepatic function.
13
Renal impairment
No dose adjustment is necessary for patients with impaired renal function.
No data are available for patients with end stage renal disease undergoing haemodialysis.
Method of administration
For oral use.
Aloxi can be taken with or without food.
Hypersensitivity to the active substance or to any of the excipients.
As palonosetron may increase large bowel transit time, patients with a history of constipation or signs
of subacute intestinal obstruction should be monitored following administration. Two cases of
constipation with faecal impaction requiring hospitalisation have been reported in association with
palonosetron 750 micrograms.
At all dose levels tested, palonosetron did not induce clinically relevant prolongation of the QT
corrected (QTc) interval. A specific thorough QT/QTc study was conducted in healthy volunteers for
definitive data demonstrating the effect of palonosetron on QT/QTc. (see section 5.1).
However, as for other 5-HT
3
antagonists, caution should be exercised in the concomitant use of
palonosetron with medicinal products that increase the QT interval or in patients who have or are
likely to develop prolongation of the QT interval.
Aloxi should not be used to prevent or treat nausea and vomiting in the days following chemotherapy
if not associated with another chemotherapy administration
.
Aloxi contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take
this medicinal product. Aloxi capsules may also contain a trace of lecithin derived from soya.
Therefore, patients with known hypersensitivity to peanut or soya, should be monitored closely for
signs of an allergic reaction.
Palonosetron is mainly metabolised by CYP2D6, with minor contribution by CYP3A4 and CYP1A2
isoenzymes. Based on
in vitro
studies, palonosetron does not inhibit or induce cytochrome P450
isoenzyme at clinically relevant concentrations.
Chemotherapeutic medicinal products
In preclinical studies, palonosetron did not inhibit the antitumour activity of the five chemotherapeutic
agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C).
Metoclopramide
In a clinical study, no significant pharmacokinetic interaction was shown between a single intravenous
dose of palonosetron and steady state concentration of oral metoclopramide, which is a CYP2D6
inhibitor.
CYP2D6 inducers and inhibitors
In a population pharmacokinetic analysis, it has been shown that there was no significant effect on
palonosetron clearance when co-administered with CYP2D6 inducers (dexamethasone and rifampicin)
and inhibitors (including amiodarone, celecoxib, chlorpromazine, cimetidine, doxorubicin, fluoxetine,
haloperidol, paroxetine, quinidine, ranitidine, ritonavir, sertraline or terbinafine).
14
Corticosteroids
Palonosetron has been administered safely with corticosteroids.
Other medicinal products
Palonosetron has been administered safely with analgesics, antiemetic/antinauseants, antispasmodics
and anticholinergic medicinal products.
For Palonosetron, no clinical data on exposed pregnancies are available. Animal studies do not
indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development,
parturition or postnatal development. Only limited data from animal studies are available regarding the
placental transfer (see section 5.3). There is no experience of palonosetron in human pregnancy so
palonosetron should not be used in pregnant women unless it is considered essential by the physician.
As there are no data concerning palonosetron excretion in breast milk, breast-feeding should be
discontinued during therapy.
There are no data concerning the effect of palonosetron on fertility.
No studies on the effects on the ability to drive and use machines have been performed.
Since palonosetron may induce dizziness, somnolence or fatigue, patients should be cautioned when
driving or operating machines.
In clinical studies at a dose of 500 micrograms (total 161 patients) the most frequently observed
adverse reaction, at least possibly related to Aloxi, was headache (3.7 %).
In the clinical studies the following adverse reactions (ARs) were observed as possibly or probably
related to Aloxi. These were classified as common (≥1/100 to <1/10) or uncommon (≥1/1,000 to
<1/100).
System Organ Class
Common ARs
Uncommon ARs
Psychiatric disorders
Insomnia
Nervous system disorders
Headache
Eye disorders
Eye swelling
Cardiac disorders
Atrioventricular block first degree,
atrioventricular block second degree
Respiratory, thoracic and mediastinal
disorders
Dyspnoea
Gastrointestinal disorders
Constipation, nausea
Musculoskeletal and connective tissue
disorders
Myalgia
Investigations
Blood bilirubin increased
In post marketing very rare cases (<1/10,000) of hypersensitivity reactions occurred with palonosetron
solution for injection for intravenous use.
15
No case of overdose has been reported.
Doses of up to 6 mg have been used in clinical trials. The highest dose group showed a similar
incidence of adverse reactions compared to the other dose groups and no dose response effects were
observed. In the unlikely event of overdose with Aloxi, this should be managed with supportive care.
Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is
unlikely to be an effective treatment for Aloxi overdose.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiemetics and antinauseants, Serotonin (5HT
3
) antagonists, ATC code:
A04AA05
Palonosetron is a selective high-affinity receptor antagonist of the 5HT
3
receptor.
In a multicentre, randomised, double-blind active control clinical trial of 635 patients set to receive
moderately emetogenic cancer chemotherapy. A single-dose of 250 mcg, 500 mcg, or 750 mcg oral
palonosetron capsules given one hour prior to moderately emetogenic chemotherapy was compared to
a single-dose of 250 mcg intravenous Aloxi given 30 minutes prior to chemotherapy. Patients were
randomised to either dexamethasone or placebo in addition to their assigned treatment. The majority
of patients in the study were women (73 %), white (69 %), and naïve to previous chemotherapy
(59 %). The antiemetic activity was observed during 0-24 hours, 24-120 hours and 0-120 hours.
Efficacy was based on demonstrating non-inferiority of oral palonosetron doses compared to the
approved intravenous formulation. Non-inferiority criteria were met if the lower bound of the two-
sided 98.3 % confidence interval for the difference in complete response rates of oral palonosetron
dose minus approved intravenous formulation was larger than -15 %. The non-inferiority margin was
15 %.
As shown in Table 1, oral Aloxi capsules 500 micrograms demonstrated non-inferiority to the active
comparator during the 0 to 24 hour and 0 to 120 hour time intervals; however, for the 24 to 120 hour
time period, non-inferiority was not shown.
Although comparative efficacy of palonosetron in multiple cycles has not been demonstrated in
controlled clinical trials, 217 patients were enrolled in a multicentre, open label safety study and were
treated with palonosetron capsules 750 micrograms for up to 4 cycles of chemotherapy in a total of
654 chemotherapy cycles. Approximately 74 % of patients also received single dose oral or
intravenous dexamethasone 30 minutes before chemotherapy. Complete Response was not formally
evaluated for the repeat cycle application. However, in general the antiemetic effect for the 0-24 hour
interval was similar throughout the consecutively repeated cycles and the overall safety was
maintained during all cycles.
16
Table 1: Proportion of patients
a
responding by treatment group and phase
Aloxi Oral
500 micrograms
(n=160)
Aloxi Intravenous
250 micrograms
(n=162)
Delta
% % %
Complete Response (No Emesis and No Rescue Medication) 98.3 % CI
b
0-24 hours 76.3 70.4 5.9 [-6.5 %, 18.2 %]
24-120 hours 62.5 65.4 -2.9 [-16.3 %, 10.5 %]
0-120 hours 58.8 59.3 -0.5 [-14.2 %,
13.2 %]
Complete Control (Complete Response and No More Than Mild Nausea) p-value
c
0-24 hours 74.4 68.5 5.9 NS
24-120 hours 56.3 62.3 -6.0 NS
0-120 hours 52.5 56.2 -3.7 NS
No Nausea (Likert Scale) p-value
c
0-24 hours
58.8
57.4
1.4
NS
24-120 hours
49.4
47.5
1.9
NS
0-120 hours
45.6
42.6
3.0
NS
a
Intent-to-treat cohort
b
The study was designed to show non-inferiority. A lower bound greater that -15 % demonstrates non-
inferiority between Aloxi oral and comparator Aloxi intravenous
c
Chi-square test. Significance levels at alpha 0.0167 (adjusted for multiple comparisons).
In non-clinical studies palonosetron possesses the ability to block ion channels involved in ventricular
de- and re-polarisation and to prolong action potential duration.
The effect of palonosetron on QTc interval was evaluated in a double blind, randomised, parallel,
placebo and positive (moxifloxacin) controlled trial in adult men and women. The objective was to
evaluate the ECG effects of IV administered palonosetron at single doses of 0.25, 0.75 or 2.25 mg in
221 healthy subjects. The study demonstrated no effect on QT/QTc interval duration as well as any
other ECG interval at doses up to 2.25 mg. No clinically significant changes were shown on heart rate,
atrioventricular (AV) conduction and cardiac repolarization.
Paediatric population
Prevention of Chemotherapy Induced Nausea and Vomiting (CINV):
The safety and efficacy of Palonosetron i.v at single doses of 3µg/kg and 10µg/kg was investigated in
a clinical study in 72 patients in the following age groups, >28 days to 23 months (12 patients), 2 to 11
years (31 patients), and 12 to 17 years of age (29 patients), receiving highly or moderately emetogenic
chemotherapy. No safety concerns were raised at either dose level. The primary efficacy variable was
the proportion of patients with a complete response (CR, defined as no emetic episode and no rescue
medication) during the first 24 hours after the start of chemotherapy administration. Efficacy after
palonosetron 10 µg/kg compared to palonosetron 3µg/kg was 54.1% and 37.1% respectively.
Pharmacokinetic information is provided in section 5.2.
Prevention of Post Operative Nausea and Vomiting (PONV):
The safety and efficacy of Palonosetron i.v at single doses of 1µg/kg and 3µg/kg was compared in a
clinical study in 150 patients in the following age groups, >28 days to 23 months (7 patients), 2 to 11
years (96 patients), and 12 to 16 years of age (47 patients) undergoing elective surgery. No safety
concerns were raised in either treatment group. The proportion of patients without emesis during 0-72
hours post-operatively was similar after palonosetron 1 µg/kg or 3 µg/kg (88% vs 84%).
Please see section 4.2 for information on paediatric use.
5.2
Pharmacokinetic properties
Absorption
Following oral administration, palonosetron is well absorbed with its absolute bioavailability reaching
97 %. After single oral doses using buffered solution mean maximum palonosetron concentrations
17
(C
max
) and area under the concentration-time curve (AUC0-∞) were dose proportional over the dose
range of 3.0 to 80 µg/kg in healthy subjects.
In 36 healthy male and female subjects given a single oral dose of palonosetron capsules
500 micrograms, maximum plasma palonosetron concentration (C
max
) was 0.81 ± 0.17 ng/ml (mean ±
SD) and time to maximum concentration (Tmax) was 5.1 ± 1.7 hours. In female subjects (n=18), the
mean AUC was 35 % higher and the mean C
max
was 26 % higher than in male subjects (n=18).
In 12 cancer patients given a single oral dose of palonosetron capsules 500 micrograms one hour prior
to chemotherapy, C
max
was 0.93 ± 0.34 ng/ml and Tmax was 5.1 ± 5.9 hours. The AUC was 30 %
higher in cancer patients than in healthy subjects.
A high fat meal did not affect the C
max
and AUC of oral palonosetron. Therefore, Aloxi capsules may
be taken without regard to meals.
Distribution
Palonosetron at the recommended dose is widely distributed in the body with a volume of distribution
of approximately 6.9 to 7.9 l/kg. Approximately 62 % of palonosetron is bound to plasma proteins.
Biotransformation
Palonosetron is eliminated by dual route, about 40 % eliminated through the kidney and with
approximately 50 % metabolised to form two primary metabolites, which have less than 1 % of the
5HT
3
receptor antagonist activity of palonosetron.
In vitro
metabolism studies have shown that
CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 isoenzymes are involved in the metabolism of
palonosetron. However, clinical pharmacokinetic parameters are not significantly different between
poor and extensive metabolisers of CYP2D6 substrates. Palonosetron does not inhibit or induce
cytochrome P450 isoenzymes at clinically relevant concentrations.
Elimination
Following administration of a single oral 750 micrograms dose of [
14
C]-palonosetron to six healthy
subjects, 85 % to 93 % of the total radioactivity was excreted in urine, and 5 % to 8 % was eliminated
in feces. The amount of unchanged palonosetron excreted in the urine represented approximately 40 %
of the administered dose. In healthy subjects given palonosetron capsules 500 micrograms, the
terminal elimination half-life (t½) of palonosetron was 37 ± 12 hours (mean ± SD), and in cancer
patients, t½ was 48 ± 19 hours. After a single-dose of approximately 0.75 mg intravenous
palonosetron, the total body clearance of palonosetron in healthy subjects was 160 ± 35 ml/h/kg (mean
± SD) and renal clearance was 66.5 ± 18.2 ml/h/kg.
Pharmacokinetics in special populations
Elderly
Age does not affect the pharmacokinetics of palonosetron. No dose adjustment is necessary in elderly
patients.
Gender
Gender does not affect the pharmacokinetics of palonosetron. No dose adjustment is necessary based
on gender.
Paediatric patients
Across all age groups, (>28 days to 23 months (11 patients), 2 to 11 years (30 patients), and 12 to 17
years of age (29 patients)) of CINV paediatric patients, exposure to palonosetron was generally dose
proportional for the 3μg/kg and 10μg/kg dose levels. Both clearance and volume of distribution appear
to increase with increasing age largely due to the expected increase in body weight among the age
groups. Mean terminal elimination half-life values ranged from 21-37 hours and did not change with
dose or age. There was no effect of gender on clearance, volume of distribution or half-life. Please see
section 4.2 for information on paediatric use.
18
Renal impairment
Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic
parameters. Severe renal impairment reduces renal clearance, however total body clearance in these
patients is similar to healthy subjects. No dose adjustment is necessary in patients with renal
insufficiency. No pharmacokinetic data in haemodialysis patients are available.
Hepatic impairment
Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the
healthy subjects. While the terminal elimination half-life and mean systemic exposure of palonosetron
is increased in the subjects with severe hepatic impairment, this does not warrant dose reduction.
5.3 Preclinical safety data
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the
maximum human exposure indicating little relevance to clinical use.
Non-clinical studies indicate that palonosetron, only at very high concentrations, may block ion
channels involved in ventricular de- and re-polarisation and prolong action potential duration.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,
embryonal/foetal development, parturition or postnatal development. Only limited data from animal
studies are available regarding the placental transfer (see section 4.6).
Palonosetron is not mutagenic. High doses of palonosetron (each dose causing at least 15 times the
human therapeutic exposure) applied daily for two years caused an increased rate of liver tumours,
endocrine neoplasms (in thyroid, pituitary, pancreas, adrenal medulla) and skin tumours in rats but not
in mice.
The underlying mechanisms are not fully understood, but because of the high doses employed and
since Aloxi is intended for single application in humans, these findings are not considered relevant for
clinical use.
6.
6.1 List of excipients
Capsule content:
Mono/diglycerides of caprylic/capric acid
Polyglycerol oleate
Glycerol
Purified water
Butylhydroxyanisole (BHA)
Capsule shell:
Gelatin
Sorbitol (E420)
Glycerol
Titanium dioxide (E171)
Printing Ink:
Iron oxide black (E172)
Polyvinyl acetate phthalate
Macrogol 400
19
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 storage conditions.
6.5
Nature and contents of container
Polyamide/aluminium/PVC blister containing one or five soft capsules.
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.
Helsinn Birex Pharmaceuticals Limited.
Damastown
Mulhuddart
Dublin 15
Ireland
8.
EU/1/04/306/002
EU/1/04/306/003
9.
22 March 2005/23 March 2010
Detailed information on this product is available on the website of the European Medicines Agency
20
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
21
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Helsinn Birex Pharmaceuticals Ltd.
Damastown, Mulhuddart, Dublin 15
Ireland
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 3.1 presented in
Module 1.8.1 of the Marketing Authorisation, is in place and functioning before and whilst the product
is on the market.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached
•
At the request of the EMA
PSURs
The MAH will submit 6-monthly PSURs until otherwise notified by the CHMP.
22
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 3 of the Risk Management Plan (RMP) presented in
Module 1.8.2 of the Marketing Authorisation and any subsequent updates of the RMP agreed by the
CHMP.
ANNEX III
LABELLING AND PACKAGE LEAFLET
23
A. LABELLING
24
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Aloxi 250 micrograms solution for injection
Palonosetron (as hydrochloride)
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml of solution contains 50 micrograms palonosetron (as hydrochloride).
Each vial of 5 ml of solution contains 250 micrograms palonosetron (as hydrochloride).
3.
LIST OF EXCIPIENTS
Also contains mannitol, disodium edetate, sodium citrate, citric acid monohydrate, water for
injections, sodium hydroxide and hydrochloric acid.
4.
Solution for injection
1 x 5 ml vial
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use
Intravenous use
Single use only
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
25
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused solution should be discarded.
Helsinn Birex Pharmaceuticals Ltd.
Damastown
Mulhuddart
Dublin 15
Ireland
EU/1/04/306/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
26
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
VIAL
1.
Aloxi 250 micrograms solution for injection
Palonosetron
IV use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
5 ml
27
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Aloxi 500 micrograms soft capsules
Palonosetron
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 500 micrograms palonosetron. (as hydrochloride).
3.
LIST OF EXCIPIENTS
Also contains sorbitol. See package leaflet for further information.
4.
1 soft capsule.
5 soft capsules.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
28
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Helsinn Birex Pharmaceuticals Ltd.
Damastown
Mulhuddart
Dublin 15
Republic of Ireland
EU/1/04/306/002
EU/1/04/306/003
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Aloxi 500 micrograms
29
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
Aloxi
500 micrograms soft capsules
Palonosetron
2.
Helsinn
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
30
B. PACKAGE LEAFLET
31
PACKAGE LEAFLET: INFORMATION FOR THE USER
Aloxi 250 micrograms solution for injection
Palonosetron
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have further questions, please ask your doctor or your pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others.
It may harm them, even if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
:
1. What Aloxi is and what it is used for.
2. Before you use Aloxi.
3. How to use Aloxi.
4. Possible side effects.
5. How to store Aloxi.
6.
Further information.
1.
WHAT ALOXI IS AND WHAT IT IS USED FOR
Aloxi belongs to a group of medicines known as serotonin (5HT
3
) antagonists.
These have the ability to block the action of the chemical, serotonin, which can cause nausea and
vomiting.
Aloxi is used for the prevention of nausea and vomiting associated with cancer chemotherapy in adult
patients.
2.
BEFORE YOU USE ALOXI
Do not take Aloxi
-
If you are allergic to the active ingredient or any of the other ingredients of Aloxi.
Take special care with Aloxi
-
If you have acute bowel obstruction or a history of repeated constipation.
-
If you are taking Aloxi in addition to other medicines that may induce an abnormal heart rhythm
such as amiodarone, nicardipine, quinidine, moxifloxacin, erythromycin, haloperidol,
chlorpromazine, quetiapine, thioridazine, domperidone.
-
If you have a personal or family history of alterations in heart rhythm (QT prolongation).
It is not recommended to take Aloxi in the days following chemotherapy unless you are receiving
another chemotherapy cycle.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
32
Pregnancy
If you are pregnant or think you might be, your doctor will not administer Aloxi to you unless it is
clearly necessary.
It is not known whether Aloxi will cause any harmful effects when used during pregnancy.
Ask your doctor or pharmacist for advice before using any medicine if you are pregnant or think you
might be.
Breast-feeding
It is not known if Aloxi is found in breast milk.
Ask your doctor or pharmacist for advice before using Aloxi if you are breast-feeding.
Driving and using machines
Aloxi may cause dizziness or tiredness. If affected, do not drive or use any tools or machines.
Important information about some of the ingredients of Aloxi
This medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium- free’.
3. HOW TO USE ALOXI
A doctor or nurse will normally inject Aloxi about 30 minutes before the start of chemotherapy.
The usual dose of Aloxi is 250 micrograms given as a rapid injection into a vein.
If you have any further questions on the use of this product, ask your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Aloxi can cause side effects, although not everybody gets them.
The frequency of possible side effects listed below is defined using the following convention:
very common (affects more than 1 user in 10); common (affects 1 to 10 users in 100); uncommon
(affects 1 to 10 users in 1,000); rare (affects 1 to 10 users in 10,000); very rare (affects less than 1 user
in 10,000); not known (frequency cannot be estimated from the available data).
Common side effects:
headache, dizziness, constipation and diarrhoea.
Uncommon side effects:
•
high or low blood pressure
•
abnormal heart rate or lack of blood flow to the heart
•
change in the color of the vein and/or veins becoming larger
•
abnormally high or low levels of potassium in the blood
•
high levels of sugar in the blood or sugar in the urine
•
low levels of calcium in the blood
•
high levels of the pigment bilirubin in the blood
•
high levels of certain liver enzymes
•
elevated moods or feelings of anxiousness
•
sleepiness or trouble sleeping
•
decrease or loss of appetite
•
weakness, tiredness, fever or flu like symptoms
•
numbness, burning, prickling or tingling sensations on the skin
•
itchy skin rash
•
impaired vision or eye irritation
•
motion sickness
33
•
ringing in the ear
•
hiccups, flatulence, dry mouth or indigestion
•
abdominal (stomach) pain
•
difficulty urinating
•
joint pain
•
electrocardiogram abnormalities (QT prolongation)
Very rare side effects:
Allergic reactions to Aloxi (The signs may include swelling of the lips, face, tongue or throat, having
difficulty breathing or collapsing, you could also notice an itchy, lumpy rash (hives)), burning or pain
at the site of injection.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
5. HOW TO STORE ALOXI
Keep out of the reach and sight of children.
Do not use after the expiry date stated on the vial and carton after ‘EXP’. The expiry date refers to the
last day of that month.
This medicine does not require any special storage conditions.
Single use only, any unused solution should be disposed of.
6. FURTHER INFORMATION
What Aloxi contains
-
The active substance is palonosetron (as hydrochloride).
Each ml of solution contains 50 micrograms palonosetron. Each vial of 5 ml of solution contains
250 micrograms of palonosetron.
-
The other ingredients are mannitol, disodium edetate, sodium citrate, citric acid monohydrate,
and water for injections, sodium hydroxide and hydrochloric acid.
What Aloxi looks like and the contents of the pack
Aloxi solution for injection is a clear, colourless solution and is supplied in a pack of one Type I glass
vial with chlorobutyl siliconised rubber stopper and aluminium cap, which contains 5 ml of the
solution. Each vial contains one dose.
Available in packs of 1 vial containing 5 ml of solution.
Marketing Authorisation Holder and Manufacturer
Helsinn Birex Pharmaceuticals Ltd.,
Damastown,
Mulhuddart,
Dublin 15,
Ireland.
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site:
http://www.ema.europa.eu
34
PACKAGE LEAFLET: INFORMATION FOR THE USER
Aloxi 500 micrograms soft capsules
Palonosetron
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
:
1. What Aloxi is and what it is used for
2. Before you use Aloxi
3. How to use Aloxi
4. Possible side effects
5. How to store Aloxi
6. Further information
1.
WHAT ALOXI IS AND WHAT IT IS USED FOR
Aloxi belongs to a group of medicines known as serotonin (5HT
3
) antagonists.
These have the ability to block the action of the chemical, serotonin, which can cause nausea and
vomiting.
Aloxi is used for the prevention of nausea and vomiting associated with cancer chemotherapy in adult
patients.
2.
BEFORE YOU USE ALOXI
Do not take Aloxi
-
If you are allergic to the active substance or any of the other ingredients of Aloxi (for a full list
of the ingredients, see section 6 “Further information”).
Take special care with Aloxi
-
If you have acute bowel obstruction or a history of repeated constipation.
-
If you are taking Aloxi in addition to other medicines that may induce an abnormal heart rhythm
such as amiodarone, nicardipine, quinidine, moxifloxacin, erythromycin, haloperidol,
chlorpromazine, quetiapine, thioridazine, domperidone.
-
If you have a personal or family history of alterations in heart rhythm (QT prolongation).
It is not recommended to take Aloxi in the days following chemotherapy unless you are receiving
another chemotherapy cycle.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
35
-
If you have further questions, please ask your doctor or your pharmacist.
Taking Aloxi with food and drink
Aloxi can be taken with or without food.
Pregnancy
If you are pregnant or think you might be, your doctor will not use Aloxi unless it is clearly necessary.
It is not known whether Aloxi will cause any harmful effects when used during pregnancy.
Ask your doctor or pharmacist for advice before using any medicine if you are pregnant or think you
might be.
Breast-feeding
It is not known if Aloxi is found in breast milk.
Ask your doctor or pharmacist for advice before using Aloxi if you are breast-feeding.
Driving and using machines
Aloxi may cause dizziness or tiredness. If affected, do not drive or operate machines.
Important information about some of the ingredients of Aloxi
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor
before taking this medicine.
This medicine may contain a trace of lecithin which is derived from soya. If you are allergic to peanut
or soya, see your doctor straight away if you notice any signs of an allergic reaction. The signs may
include swelling of the lips, face, tongue or throat, having difficulty breathing or collapsing, you could
also notice an itchy, lumpy rash (hives).
3. HOW TO USE ALOXI
A doctor or nurse will normally give you Aloxi capsules about 60 minutes before the start of
chemotherapy.
The usual dose is one capsule (500 micrograms) of Aloxi, taken with or without food.
If you take more Aloxi than you should
The usual dose is one Aloxi capsule. If you think you may have taken more Aloxi than you should,
inform your doctor immediately.
If you forget to take Aloxi
It is unlikely that you will forget to take Aloxi, as your dose will be given to you by a doctor or nurse.
However, if you think you have forgotten to take your dose, tell your doctor immediately.
If you stop taking Aloxi
Aloxi is taken to prevent nausea and vomiting caused by chemotherapy. If you do not wish to receive
Aloxi, you should discuss this fully with your doctor. If you decide not to take Aloxi (or other similar
medicine), you can expect your chemotherapy to cause you to feel nauseous and/or vomit.
If you have any further questions on the use of this medicine, ask your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Aloxi can cause side effects, although not everybody gets them.
The frequency of possible side effects listed below is defined using the following convention:
very common (affects more than 1 user in 10); common (affects 1 to 10 users in 100); uncommon
(affects 1 to 10 users in 1,000); rare (affects 1 to 10 users in 10,000); very rare (affects less than 1 user
in 10,000); not known (frequency cannot be estimated from the available data).
36
Common side effect:
headache
Uncommon side effects:
trouble sleeping
shortness of breath
eye swelling
abnormal electrical impulses in the heart
constipation
nausea
high levels of the pigment bilirubin (a marker of liver problems) in the blood
muscle pain
Very rare side effect:
allergic reaction
The signs may include swelling of the lips, face, tongue or throat, having difficulty breathing or
collapsing, you could also notice an itchy, lumpy rash (hives). See your doctor straight away if you
notice any of these signs of allergic reaction.
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please
tell your doctor.
5. HOW TO STORE ALOXI
Keep out of the reach and sight of children.
Do not use Aloxi after the expiry date which is stated on the blister and carton after “EXP”. The expiry
date refers to the last day of that month.
This medicine does not require any special storage conditions.
6. FURTHER INFORMATION
What Aloxi contains
-
The active substance is palonosetron.
Each capsule contains 500 micrograms palonosetron (as hydrochloride).
-
The other ingredients are mono/diglycerides of caprylic/capric acid, polyglycerol oleate,
glycerol, purified water, butylhydroxyanisole (BHA), gelatin, sorbitol (E420), titanium dioxide
(E171), iron oxide black (E172), polyvinyl acetate phthalate and macrogol 400.
What Aloxi looks like and contents of the pack
Aloxi 500 micrograms soft capsules are light beige, opaque, oval, imprinted with black logo “AlO”
and filled with a clear yellowish solution. They are supplied in polyamide/aluminium/PVC blisters
containing one or five capsules.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Helsinn Birex Pharmaceuticals Ltd.,
Damastown,
Mulhuddart,
Dublin 15,
Ireland.
37
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency website:
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Source: European Medicines Agency
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