Palonosetron Reig Jofre 250 mikrogram Injektionsvätska, lösning

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

22-04-2018

Produktens egenskaper Produktens egenskaper (SPC)

28-04-2018

Aktiva substanser:
palonosetronhydroklorid
Tillgänglig från:
Laboratorio Reig Jofre S.A.
ATC-kod:
A04AA05
INN (International namn):
palonosetronhydroklorid
Dos:
250 mikrogram
Läkemedelsform:
Injektionsvätska, lösning
Sammansättning:
mannitol Hjälpämne; palonosetronhydroklorid 281 mikrog Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Injektionsflaska, 1 st (5 ml)
Bemyndigande status:
Godkänd
Godkännandenummer:
52912
Tillstånd datum:
2016-06-22

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

03-08-2016

Produktens egenskaper Produktens egenskaper - engelska

03-08-2016

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

04-07-2016

Läs hela dokumentet

Package leaflet: Information for the user

Palonosetron Reig Jofre 250 micrograms solution for injection

palonosetron

Read all of this leaflet carefully before you start using this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor, pharmacist or nurse.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if

their signs of illness are the same as yours.

If you get any side effects, talk to your doctor, pharmacist,or nurse. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Palonosetron Reig Jofre is and what it is used for

What you need to know before you use Palonosetron Reig Jofre

How to use Palonosetron Reig Jofre

Possible side effects

How to store Palonosetron Reig Jofre

Contents of the pack and other information

1.

What Palonosetron Reig Jofre is and what it is used for

Palonosetron belongs to a group of medicines known as serotonin (5HT

) antagonists.

These have the ability to block the action of the chemical, serotonin, which can cause nausea and vomiting.

Palonosetron is used for the prevention of nausea and vomiting associated with cancer chemotherapy in adult,

adolescents and children over one month of age.

2.

What you need to know before you use Palonosetron Reig Jofre

Do not use Palonosetron Reig Jofre:

If you are allergic to palonosetron or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Talk to your doctor, pharmacist or nurse before using Palonosetron Reig Jofre

If you have acute bowel obstruction or a history of repeated constipation.

If you are using Palonosetron Reig Jofre 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).

If you have other heart problems.

If you have an imbalance of certain minerals in your blood such as potassium and magnesium

which has not been treated.

It is not recommended to take Palonosetron Reig Jofre in the days following chemotherapy unless you are

receiving another chemotherapy cycle.

Other medicines and Palonosetron Reig Jofre

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines,

including:

SSRIs (selective serotonin reuptake inhibitors) used to treat depression and/or anxiety including fluoxetine,

paroxetine, sertraline, fluvoxamine, citalopram, escitalopram

SNRIs (serotonin noradrenaline reuptake inhibitors) used to treat depression and/or anxiety including

venlafaxine, duloxetine.

Pregnancy, breast-feeding and fertility

Pregnancy

If you are pregnant or think you might be, your doctor will not administer Palonosetron Reig Jofre to you

unless it is clearly necessary.

It is not known whether Palonosetron Reig Jofre 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

Breast-feeding

It is not known if Palonosetron Reig Jofre is found in breast milk.

Ask your doctor or pharmacist for advice before using Palonosetron Reig Jofre if you are breast-feeding.

Driving and using machines

Palonosetron Reig Jofre may cause dizziness or tiredness. If affected, do not drive or use any tools or

machines.

Palonosetron Reig Jofre contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, but if the maximum dose for

children are administered (6 vials) the sodium content corresponds to 1.2 mmol sodium (27.90 mg).

3.

How to use Palonosetron Reig Jofre

A doctor or nurse will normally inject Palonosetron Reig Jofre about 30 minutes before the start of

chemotherapy.

Adults

The recommended dose of Palonosetron Reig Jofre is 250 micrograms given as a rapid injection into a

vein.

Children and Adolescents (aged 1 month to 17 years)

The doctor will decide the dose, depending on bodyweight, however the maximum dose is 1500 micrograms.

Palonosetron Reig Jofre will be given as a slow infusion into a vein.

If you have any further questions on the use of this medicine, ask your doctor.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Possible side effects and their frequencies are listed below:

Adults

Common (may affect up to 1 in 10 people):

headache, dizziness, constipation and diarrhoea.

Uncommon (may affect up to 1 in 100 people):

high or low blood pressure

abnormal heart rate or lack of blood flow to the heart

change in the colour 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

ringing in the ear

hiccups, flatulence, dry mouth or indigestion

abdominal (stomach) pain

difficulty urinating

joint pain

electrocardiogram abnormalities (QT prolongation)

Very rare (may affect up to 1 in 10,000 people):

Allergic reactions to Palonosetron Reig Jofre.

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.

Children and Adolescents:

Common (may affect up to 1 in 10 people):

headache

Uncommon (may affect up to 1 in 100 people):

dizziness

jerky body movements

abnormal heart rate

coughing or shortness of breath

nosebleed

itchy skin rash or hives

fever

pain at the site of infusion

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects

not listed in this leaflet.

You can also report side effects directly via the national reporting system (see details

below) [to be completed nationally]. By reporting side effects you can help provide more information on the

safety of this medicine.

5.

How to store Palonosetron Reig Jofre

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is 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.

Contents of the pack and other information

What Palonosetron Reig Jofre contains

The active substance is palonosetron (as hydrochloride).

Each ml of solution contains 50 micrograms of palonosetron. Each vial of 5 ml of solution contains

250 micrograms of palonosetron.

The other ingredients are mannitol, disodium edetate (dihydrate), sodium citrate (dihydrate), citric acid

monohydrate, and water for injections.

What Palonosetron Reig Jofre looks like and contents of the pack

Palonosetron solution for injection is a clear, colourless solution and is supplied in a pack of one Type I glass

vial with chlorobutyl siliconised fluorotec 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

Laboratorio Reig Jofre, S.A.

Gran Capitán, 10

08970 Sant Joan Despí (Barcelona)

Spain

Local representative

Bioglan AB

P.O. Box 50310

SE-202 13 Malmö

Sweden

This medicinal product authorised in the Member States of the EEA under the following names:

Denmark:

Palonosetron Reig Jofre

Finland:

Palonosetron Reig Jofre 250 mikrogrammaa, injektioneste, liuos

Norway:

Palonosetron Reig Jofre

Spain:

Palonosetron Sala 250 microgramos solución para inyección EFG

Sweden:

Palonosetron Reig Jofre

United Kingdom:

Palonosetron 250 micrograms solution for injection

This leaflet was last revised in 2016-08-03

Detailed information on this medicine is available on the website of {MS/Agency}.

Läs hela dokumentet

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Palonosetron Reig Jofre 250 micrograms solution for injection.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains 50 micrograms palonosetron (as hydrochloride).

Each vial of 5 ml of solution contains 250 micrograms palonosetron (as hydrochloride).

Excipient(s) with known effect:

Each vial contains less than 1 mmol sodium (23 mg) (see section 4.4).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection.

Clear, colourless solution.

The pH is between 4.5 and 5.5 and osmolality is between 250 and 375 mOsm/kg.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Palonosetron Reig Jofre is indicated in adults for:

the prevention of acute nausea and vomiting associated with highly emetogenic cancer

chemotherapy,

the prevention of nausea and vomiting associated with moderately emetogenic cancer

chemotherapy.

Palonosetron Reig Jofre is indicated in paediatric patients 1 month of age and older for:

the prevention of acute nausea and vomiting associated with highly emetogenic cancer

chemotherapy and prevention of nausea and vomiting associated with moderately

emetogenic cancer chemotherapy.

4.2

Posology and method of administration

Palonosetron Reig Jofre 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. Palonosetron Reig Jofre should be injected over 30 seconds.

The efficacy of Palonosetron Reig Jofre 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 people

No dose adjustment is necessary for the elderly.

Paediatric population

Children and Adolescents (aged 1 month to 17 years):

20 micrograms/kg (the maximum total dose should not exceed 1500 micrograms) palonosetron

administered as a single 15 minute intravenous infusion beginning approximately 30 minutes before

the start of chemotherapy.

The safety and efficacy of Palonosetron Reig Jofre in children aged less than 1 month have not been

established. No data are available. There are limited data on the use of Palonosetron Reig Jofre in the

prevention of nausea and vomiting in children under 2 years of age.

Hepatic impairment

No dose adjustment is necessary for patients with impaired hepatic function.

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.

4.3

Contraindications

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

4.4

Special warnings and precautions for use

As palonosetron may increase large bowel transit time, patients with a history of constipation or signs

subacute

intestinal

obstruction

should

monitored

following

administration.

cases

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

antagonists, caution should be exercised in the use of palonosetron in

patients who have or are likely to develop prolongation of the QT interval. These conditions include

patients with a personal or family history of QT prolongation, electrolyte abnormalities, congestive

heart failure, bradyarrhythmias, conduction disturbances and in patients taking anti-arrhythmic agents

or other medicinal products that lead to QT prolongation or electrolyte abnormalities. Hypokalemia and

hypomagnesemia should be corrected prior to 5-HT3-antagonist administration.

There have been reports of serotonin syndrome with the use of 5-HT3 antagonists either alone or in

combination with other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRI)

and serotonin noradrenaline reuptake inhibitors (SNRIs). Appropriate observation of patients for

serotonin syndrome-like symptoms is advised.

Palonosetron Reig Jofre 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, but if the maximum dose for

children are administered (6 vials) the sodium content corresponds to 1.2 mmol sodium (27.90 mg).

4.5

Interaction with other medicinal products and other forms of interaction

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.

Serotonergic Drugs (e.g. SSRIs and SNRIs)

There have been reports of serotonin syndrome following concomitant use of 5-HT3 antagonists and

other serotonergic drugs (including SSRIs and SNRIs).

Other medicinal products

Palonosetron has been administered safely with analgesics, antiemetic/antinauseants, antispasmodics

and anticholinergic medicinal products.

4.6

Fertility, pregnancy and lactation

Pregnancy

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.

Breast-feeding

As there are no data concerning palonosetron excretion in breast milk, breast-feeding should be

discontinued during therapy.

Fertility

There are no data concerning the effect of palonosetron on fertility.

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.

Since palonosetron may induce dizziness, somnolence or fatigue, patients should be cautioned when

driving or operating machines.

4.8

Undesirable effects

In clinical studies in adults at a dose of 250 micrograms (total 633 patients) the most frequently

observed adverse reactions, at least possibly related to Palonosetron Reig Jofre, were headache (9 %)

and constipation (5 %).

In the clinical studies the following adverse reactions (ARs) were observed as possibly or probably

related

Palonosetron Reig Jofre.

These

were

classified

common

(≥1/100

<1/10)

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.

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,

anaphylaxis,

anaphylactic/

anaphylactoid

reactions and shock

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

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

prolonged

° From post-marketing experience

* Includes the following: burning, induration, discomfort and pain

Paediatric population

In paediatric clinical trials for the prevention of nausea and vomiting induced by moderately or highly

emetogenic chemotherapy, 402 patients received a single dose of palonosetron (3, 10 or 20 mcg/kg).

The following common or uncommon adverse reactions were reported for palonosetron, none were

reported at a frequency of >1%.

System organ class

Common ARs

(≥1/100 to<1/10)

Uncommon ARs

(≥1/1,000 to <1/100)

Nervous system disorders

Headache

Dizziness, dyskinesia

Cardiac disorders

Electrocardiogram QT

prolonged

conduction

disorder,

sinus

tachycardia

Respiratory,

thoracic

mediastinal disorders

Cough, dyspnoea, epistaxis

Skin

subcutaneous

tissue

disorders

Dermatitis

allergic,

pruritus,

skin disorder, urticaria

General

disorders

administration site conditions

Pyrexia, infusion site pain,

infusion site reaction, pain

Adverse

reactions

were

evaluated

paediatric

patients

receiving

palonosetron

chemotherapy cycles.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows

continued

monitoring

benefit/risk

balance

medicinal

product.

Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system

listed in <to be completed nationally).

4.9

Overdose

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 Palonosetron Reig Jofre, 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 Palonosetron Reig Jofre overdose.

Paediatric population

No case of overdose has been reported in paediatric clinical studies.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants, serotonin (5HT

) antagonists. ATC code:

A04AA05

Palonosetron is a selective high-affinity receptor antagonist of the 5HT

receptor.

randomised,

double-blind

studies

with

total

1,132

patients

receiving

moderately

emetogenic chemotherapy that included cisplatin ≤50 mg/m

, carboplatin, cyclophosphamide

1,500

mg/m

doxorubicin

>

mg/m

palonosetron

micrograms

micrograms

were

Palonosetron

250 micrograms

(n= 189)

Ondansetron

32 milligrams

(n= 185)

Delta

Complete Response (No Emesis and No Rescue Medication)

97.5 % CI

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

0 – 24 hours

76.2

65.4

10.8

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

0 – 24 hours

60.3

56.8

24 – 120 hours

51.9

39.5

12.4

0 – 120 hours

45.0

36.2

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

, cyclophosphamide > 1,500 mg/m

and dacarbazine,

palonosetron

micrograms

micrograms

were

compared

with

ondansetron

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

studies

moderately

emetogenic

chemotherapy

study

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.

Table 1:

Percentage of patients

a

responding by treatment group and phase in the Moderately

Emetogenic Chemotherapy study versus ondansetron

a

Intent-to-treat cohort.

The study was designed to show non-inferiority. A lower bound greater than –15 % demonstrates

non-inferiority between Palonosetron and comparator.

Chi-square test. Significance level at α=0.05.

Palonosetron

250 micrograms

(n= 185)

Dolasetron

100 milligrams

(n= 191)

Delta

Complete Response (No Emesis and No Rescue Medication)

97.5 % CI

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

0 – 24 hours

57.1

47.6

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

0 – 24 hours

48.7

41.4

24 – 120 hours

41.8

26.2

15.6

0.001

0 – 120 hours

33.9

22.5

11.4

0.014

Table 2:

Percentage of patients

a

responding by treatment group and phase in the Moderately

Emetogenic Chemotherapy study versus dolasetron

a

Intent-to-treat cohort.

The study was designed to show non-inferiority. A lower bound greater than –15 % demonstrates

non-inferiority between Palonosetron and comparator.

Chi-square test. Significance level at α=0.05.

Palonosetron

250 micrograms

(n= 223)

Ondansetron

32 milligrams

(n= 221)

Delta

Complete Response (No Emesis and No Rescue Medication)

97.5 % CI

0 – 24 hours

59.2

57.0

[-8.8 %, 13.1 %]

24 – 120 hours

45.3

38.9

[-4.6 %, 17.3 %]

0 – 120 hours

40.8

33.0

[-2.9 %, 18.5 %]

Complete Control (Complete Response and No More Than Mild Nausea)

p-value

0 – 24 hours

56.5

51.6

24 – 120 hours

40.8

35.3

0 – 120 hours

37.7

29.0

No Nausea (Likert Scale)

p-value

0 – 24 hours

53.8

49.3

24 – 120 hours

35.4

32.1

0 – 120 hours

33.6

32.1

Table 3:

Percentage of patients

a

responding by treatment group and phase in the

Highly Emetogenic Chemotherapy study versus ondansetron

a

Intent-to-treat cohort.

study

designed

show

non-inferiority.

lower

bound

greater

than

–15

demonstrates non-inferiority between Palonosetron and comparator.

Chi-square test. Significance level at α=0.05.

The effect of palonosetron on blood pressure, heart rate, and ECG parameters including QTc were

comparable

ondansetron

dolasetron

CINV

clinical

studies.

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

the first 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.

The efficacy of Palonosetron for the prevention of chemotherapy-induced nausea and vomiting in

paediatric cancer patients was demonstrated in a second non-inferiority pivotal trial comparing a

single intravenous infusion of palonosetron versus an i.v. ondansetron regimen. A total of 493

paediatric patients, aged 64 days to 16.9 years, receiving moderately (69.2%) or highly emetogenic

chemotherapy (30.8%) were treated with palonosetron 10 μg/kg (maximum 0.75 mg), palonosetron

20 μg/kg (maximum 1.5 mg) or ondansetron (3 x 0.15 mg/kg , maximum total dose 32 mg) 30

minutes prior to the start of emetogenic chemotherapy during Cycle 1. Most patients were non-

naïve

chemotherapy

(78.5%)

across

treatment

groups.

Emetogenic

chemotherapies

administered

included

doxorubicin,

cyclophosphamide

(<1500

mg/m2),

ifosfamide,

cisplatin,

dactinomycin, carboplatin, and daunorubicin. Adjuvant corticosteroids, including dexamethasone,

were administered with chemotherapy in 55% of patients. The primary efficacy endpoint was

Complete Response in the acute phase of the first cycle of chemotherapy, defined as no vomiting,

no retching, and no rescue medication in the first 24 hours after starting chemotherapy. Efficacy

was based on demonstrating non-inferiority of intravenous palonosetron compared to intravenous

ondansetron. Non-inferiority criteria were met if the lower bound of the 97.5% confidence interval

for the difference in Complete Response rates of intravenous palonosetron minus intravenous

ondansetron was larger than -15%. In the palonosetron 10 μg/kg, 20 μg/kg and ondansetron groups,

proportion

patients

with

CR0-24h

54.2%,

59.4%

58.6%.

Since

97.5%

confidence interval (stratum adjusted Mantel-Haenszel test) of the difference in CR0-24h between

palonosetron 20 μg/kg and ondansetron was [-11.7%, 12.4%], the 20 μg/kg palonosetron dose

demonstrated non-inferiority to ondansetron.

While this study demonstrated that paediatric patients require a higher palonosetron dose than

adults to prevent chemotherapy-induced nausea and vomiting, the safety profile is consistent with

the established profile in adults (see section 4.8). Pharmacokinetic information is provided in section

5.2.

Prevention of Post Operative Nausea and Vomiting (PONV):

Two paediatric trials were performed. 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%).

The second paediatric trial was a multicenter, double-blind, double-dummy, randomised, parallel

group, active control, single-dose non-inferiority study, comparing i.v. palonosetron (1 μg/kg, max

0.075 mg) versus I.V. ondansetron. A total of 670 paediatric surgical patients participated, age 30

days to 16.9 years. The primary efficacy endpoint, Complete Response (CR: no vomiting, no

retching, and no antiemetic rescue medication) during the first 24 hours postoperatively was

achieved in 78.2% of patients in the palonosetron group and 82.7% in the ondansetron group. Given

the pre-specified non-inferiority margin of -10%, the stratum adjusted Mantel-Haenszel statistical

non-inferiority confidence interval for the difference in the primary endpoint, complete response

(CR), was [-10.5, 1.7%], therefore non-inferiority was not demonstrated. No new safety concerns

were raised in either treatment group.

Please see section 4.2 for information on paediatric use.

5.2

Pharmacokinetic properties

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

) 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

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

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.

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

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 [

C]-palonosetron, approximately 80 % of the

dose was recovered within 144 hours in the urine with palonosetron representing approximately 40 %

administered

dose,

unchanged

active

substance.

After

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 people

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

Single-dose i.v. Palonosetron pharmacokinetic data was obtained from a subset of paediatric cancer

patients (n=280) that received 10 μg/kg or 20 μg/kg. When the dose was increased from10 μg/kg to 20

μg/kg a dose-proportional increase in mean AUC was observed. Following single dose intravenous

infusion of Palonosetron 20 μg/kg, peak plasma concentrations (CT) reported at the end of the 15 minute

infusion were highly variable in all age groups and tended to be lower in patients < 6 years than in older

paediatric patients. Median half-life was 29.5 hours in overall age groups and ranged from about 20 to

30 hours across age groups after administration of 20 μg/kg.

The total body clearance (L/h/kg) in patients 12 to 17 years old was similar to that in healthy adults.

There are no apparent differences in volume of distribution when expressed as L/kg.

Table 4: Pharmacokinetic Parameters in Paediatric Cancer Patients following intravenous

infusion of Palonosetron at 20 μg/kg over 15 min and in Adult Cancer Patients receiving 3 and

10

g/kg palonosetron doses via intravenous bolus.

Paediatric Cancer Patients

a

Adults Cancer Patients

b

<2 y

2 to <6 y

6 to <12 y

12 to <17 y

3.0 μg/kg

10 μg/kg

N=3

N=5

N=7

N=10

N=6

N=5

0-∞

, h·μg/L

69.0

(49.5)

103.5

(40.4)

98.7

(47.7)

124.5

(19.1)

35.8 (20.9)

81.8 (23.9)

, hours

24.0

23.3

30.5

56.4 (5.81)

49.8 (14.4)

N=6

N=14

N=13

N=19

N=6

N=5

Clearance

, L/h/kg

0.31

(34.7)

0.23

(51.3)

0.19

(46.8)

0.16 (27.8)

0.10 (0.04)

0.13 (0.05)

Volume

distribution

c, d,

L/kg

6.08

(36.5)

5.29

(57.8)

6.26

(40.0)

6.20 (29.0)

7.91 (2.53)

9.56 (4.21)

PK parameters expressed as Geometric Mean (CV) except for T½ which is median.

PK parameters expressed as Arithmetic mean (SD)

Clearance and Volume of distribution in paediatric patients were calculated weight-adjusted from both

10 μg /kg and 20 μg /kg dose groups combined. In adults, different dose levels are indicated in column

title.

Vss is reported for paediatric cancer patients, whereas Vz is reported for adult cancer patients.

Renal impairment

Mild

to moderate

renal

impairment

does

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.

Animal

studies

indicate

direct

indirect

harmful

effects

with

respect

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 Palonosetron Reig Jofre is intended for single application in humans, these findings are not

considered relevant for clinical use.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Mannitol

Disodium edetate (dihydrate)

Sodium citrate (dihydrate) (to adjust pH)

Citric acid monohydrate (to adjust pH)

Water for injections

6.2

Incompatibilities

This medicinal product must not be mixed with other medicinal products.

6.3

Shelf life

24 months.

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 fluorotec 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.

MARKETING AUTHORISATION HOLDER

Marketing Authorisation Holder

Laboratorio Reig Jofre, S.A.

C/Gran Capitán, 10

08970 Sant Joan Despí (Barcelona)

Spain

8.

MARKETING AUTHORISATION NUMBER

To be completed nationally

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: To be completed nationally

Date of latest renewal: To be completed nationally

10.

DATE OF REVISION OF THE TEXT

2016-08-03

Liknande Produkter

Sök varningar relaterade till denna produkt

Visa dokumenthistorik

Dela den här informationen