Palonosetron Accord

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 



 

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1. NAME OF THE MEDICINAL PRODUCT 

 

Palonosetron Accord 250 micrograms solution for injection 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

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

 

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

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Solution for injection. 

 

Clear, colourless solution. 

 

pH : Between 3.0 to 3.9 

 

Osmlolarity : 260-320 mOsm/l 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Palonosetron Accord 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 Accord 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 Accord 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 Accord should be injected over 30 seconds.  
 
The efficacy of palonosetron 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  



 

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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 in children aged less than 1 month have not been established. No 

data are available. These are limited data on the use of palonosetron 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 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-HT3 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 Accord 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’. 

 

4.5 Interaction with other medicinal products and other forms of interaction 



 

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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 

 



 

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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, were headache (9 %) and constipation (5 %).  
 
In the clinical studies the following adverse reactions (ARs) were observed as possibly or probably related to 

palonosetron. 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. 

 

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, 

 



 

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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 

 

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 

(≥1/1000 to <1/100) 

Nervous system disorders Headache Dizziness, dyskinesia 

Cardiac disorder  Electrocardiogram, QT prolonged 

conduction disorder, sinus 

tachycardia 

Respiratory, thoracic and 

mediastinal disorders 

 Cough, dyspnoea, epistaxis 

Skin and subcutaneous tissue 

disorders 

 Dermatitis, allergic, pruritus, skin 

disorder, urticaria. 

General disorders and 

administration site conditions 

 Pyrexia, infusion site pain, 

infusion site reaction, pain 

 

Adverse reactions were evaluated in paediatric patients receiving palonosetron for up to 4 chemotherapy 

cycles. 

 

Reporting of suspected adverse reactions 

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

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked 

to report any suspected adverse reactions via the national reporting system listed in Appendix V. 

 

4.9 Overdose 

 

No case of overdose has been reported.  



 

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Doses of up to 6 mg have been used in adult 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 , 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 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 (5HT3) antagonists. ATC code: 

A04AA05  
 

Palonosetron is a selective high-affinity receptor antagonist of the 5HT3 receptor.  
 

In two randomised, double-blind studies with a total of 1,132 patients receiving moderately emetogenic 

chemotherapy that included cisplatin ≤50 mg/m2, carboplatin, cyclophosphamide ≤1,500 mg/m2 and 

doxorubicin >25 mg/m2, 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/m2, cyclophosphamide > 1,500 mg/m2 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. 

 

Table 1: Percentage of patientsa responding by treatment group and phase in the Moderately 

Emetogenic Chemotherapy study versus ondansetron 

 

 Palonosetron  

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  



 

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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 palonosetron and comparator.  

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

 

Table 2: Percentage of patients a responding by treatment group and phase in the Moderately 

Emetogenic Chemotherapy study versus dolasetron 

 

 Palonosetron  

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 palonosetron 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 

 

 Palonosetron  

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 



 

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a Intent-to-treat cohort.  

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

between palonosetron and comparator.  

c 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 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 intravenous 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 intravenously at single doses of 3 mcg/kg and 10 mcg/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 mcg/kg compared to palonosetron 3mcg/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 intravenous 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 mcg/kg (maximum 0. 75 mg), palonosetron 20 mcg/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-naive to chemotherapy (78.5%) across all 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 mcg/kg, 20 mcg/kg and ondansetron groups, the proportion of patients with CR0-24h 

was 54.2%, 59.4% and 58.6%. Since the 97.5% confidence interval (stratum adjusted Mantel-Haenszel test) 

of the difference in CR0-24h between palonosetron 20 mcg/kg and ondansetron was [-11.7%, 12.4%], the 20 

mcg/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 intravenously at single doses 

of 1mcg/kg and 3mcg/kg was compared in the first 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 



 

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patients without emesis during 0-72 hours post-operatively was similar after palonosetron 1 mcg/kg or 3 

mcg/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 intravenous palonosetron (1 mcg/kg, max 0.075 

mg) versus intravenous. ondansetron. A total of 670 paediatric surgical patients participated, age 30 days to 

16.9 years. The primary efficacy endpoint, Complete Response (CR: no 1o0miting, 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 prespecified 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 (Cmax) and area under the concentration-time curve (AUC0-∞) are generally 

dose-proportional over the dose range of 0.3–90 mcg/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 Cmax 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 5HT3 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 [14C]-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  



 

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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 intravenous palonosetron pharmacokinetic data was obtained from a subset of paediatric cancer 

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

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

infusion of palonosetron  20 mcg/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 mcg/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 mcg/kg over 15 min and in Adult Cancer Patients receiving 3 and 10 mcg/kg 

palonosetron doses via intravenous bolus. 
 

 Paediatric Cancer Patientsa Adults Cancer Patientsb 

 <2y 2 to <6 y 6 to <12 y 12 to <17 y 3.0 mcg/kg 10 mcg/kg 

 N=3 N=5 N=7 N=10 N=6 N=5 

AUC0-∞, 

h.mcg/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) 

t1/2, hours 24.0 28 23.3 30.5 56.4 (5.81) 49.8 (14.4) 

 N=6 N=14 N=13 N=19 N=6 N=5 

Clearancec, 

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 of 

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) 

 
a PK parameters expressed as Geometric Mean (CV) except forT1/2, which is median. 

 
b PK parameters expressed as Arithmetic mean (SD) 

 
c Clearance and Volume of distribution in paediatric patients were calculated weight-adjusted from both 10 

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

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

 

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. 



 

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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 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 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,  

Citric acid monohydrate,  

Sodium citrate,  

Disodium edetate,  

Sodium hydroxide (for pH adjustment),  

Hydrochloric acid, concentrated (for pH adjustment), 

Water for injections. 

 

6.2 Incompatibilities 

 

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

 

6.3 Shelf life 

 

3 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  

 

6 ml Type I tubular clear glass vial, closed with chlorobutyl rubber stopper and sealed with a flip-off 

aluminium seal. 

 

Available in pack of 1 vial containing 5 ml of solution. 

 

6.6 Special precautions for disposal and other handling 

 

Single use only, any unused solution should be discarded.  



 

13 

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

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona, s/n,  

Edifici Est 6ª planta,  

08039 Barcelona,  

Spain 

 

8. MARKETING AUTHORISATION NUMBER  

 

EU/1/16/1104/001 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 26th May 2016 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


 

14 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RETRICTIONS REGARDING SUPPLY AND 
USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETNG 

AUTHORISATION 

 

D.       CONDITIONS OR RETRICTIONS WITH REGARD TO THE SAFE AND 

 EFFECTIVE USE OF THE MEDICINAL PRODUCT 



 

15 

 

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturers responsible for batch release 

 

Accord Healthcare Ltd 

Ground Floor 

Sage House 

319 Pinner Road 

North Harrow 

Middlesex 

HA1 4HF 

United Kingdom 

 

Accord Healthcare B.V.,  

Winthontlaan 200,  

3526 KV Utrecht,  

The Netherlands  

 

Accord Healthcare Polska Sp.z o.o., 

ul. Lutomierska 50,95-200 Pabianice, Poland 

 

The printed package leaflet of the medicinal product must state the name and address of the manufacturer 

responsible for the release of the concerned batch. 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to medical prescription. 

 

 

C.     OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  

 

 Periodic Safety Update Reports 
 

The requirements for submission of periodic safety update reports for this medicinal product  are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

 

D.      CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE 

OF THE MEDICINAL PRODUCT 

 

 Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed 

RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the 

RMP. 

 

An updated RMP should be submitted:  

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information being 
received that may lead to a significant change to the benefit/risk profile or as the result of an important 

(pharmacovigilance or risk minimisation) milestone being reached. 

 



 

16 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



 

17 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 



 

18 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Palonosetron Accord 250 micrograms solution for injection 

palonosetron (as hydrochloride) 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each vial contains 250 micrograms of palonosetron (as hydrochloride) in 5 ml (50 micrograms/ml). 

 

 

3. LIST OF EXCIPIENTS 

 

Excipients: mannitol, citric acid monohydrate, sodium citrate ,disodium edetate, sodium hydroxide, 

hydrochloric acid concentrated, water for injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for injection 

 

1 x  5 ml vial  

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Single use only. 

Read the package leaflet before use. 

Intravenous use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP: 

 

 

9. SPECIAL STORAGE CONDITIONS 

 



 

19 

 

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. 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona, s/n,  

Edifici Est 6ª planta,  

08039 Barcelona,  

Spain 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/16/1104/001 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

PC: 

SN: 

NN: 

 



 

20 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Palonosetron Accord 250 micrograms solution for injection 

palonosetron (as hydrochloride) 

  

I.V. use 

 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

250 mcg/5 ml 

 

 

6. OTHER 

 

 



 

21 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



 

22 

Package leaflet: Information for the patient 

 

Palonosetron Accord 250 micrograms solution for injection 

palonosetron   

 

Read all of this leaflet carefully before you are given 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 or pharmacist or nurse. 
- If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. See section 4. 

 

 

What is in this leaflet 

 

1. What Palonosetron Accord is and what it is used for  

2. What you need to know before you are given Palonosetron Accord  

3. How Palonosetron Accord is given   

4. Possible side effects  

5. How to store Palonosetron Accord 

6. Contents of the pack and other information 

 

 

1. What Palonosetron Accord is and what it is used for 

 

Palonosetron Accord belongs to a group of medicines known as serotonin (5HT3) antagonists.  
 
These have the ability to block the action of the chemical, serotonin, which can cause nausea and vomiting.  
 
Palonosetron Accord is used for the prevention of nausea and vomiting associated with cancer chemotherapy 

in adults, adolescents and children over one month of age. 

 

 

2. What you need to know before you are given Palonosetron Accord  

 

Do not use Palonosetron Accord: 

- 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 Accord. 

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

-  If you are using palonosetron accord 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 accord in the days following chemotherapy unless you are 

receiving another chemotherapy cycle. 

 

Other medicines and Palonosetron Accord 

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.  



 

23 

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

venlafaxine, duloxetine. 

 

Pregnancy and breast-feeding 

 

Pregnancy  

If you are pregnant or think you might be, your doctor will not administer palonosetron accord to you unless 

it is clearly necessary.  
It is not known whether palonosetron accord 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 palonosetron accord is found in breast milk.  
Ask your doctor or pharmacist for advice before using palonosetron accord if you are breast-feeding. 

 

Driving and using machines  
Palonosetron accord may cause dizziness or tiredness. If affected, do not drive or use any tools or machines.  
 
Important information about some of the ingredients of Palonosetron Accord 

This medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium- free’. 

 

 

3. How Palonosetron Accord is given 

 

A doctor or nurse will normally inject palonosetron accord about 30 minutes before the start of 

chemotherapy.  
 
Adults 
The recommended dose of palonosetron accord 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 accord 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, pharmacist or nurse. 

 

 

4. Possible side effects 

 

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

 These may affect up to 1 in 10 people 
- headache 
- dizziness 
- constipation and diarrhoea. 
 

Uncommon 

These 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 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 



 

24 

- 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 feeling 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  

These may affect up to 1 in 10,000 people 

Allergic reactions to palonosetron accord 

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  

 These may affect up to 1 in 10 people 
- headache 

 

Uncommon 

These may affect up to 1 in 100 people 

-  Dizziness 

- jerky body movement 

-  abnormal heart rate  

-  cough and shortness of breath 

- nose bleed 

- 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 or 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 listed in 

Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 
 

 

5. How to store Palonosetron Accord 

 

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 carton and the vial 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. 

 



 

25 

 

6. Contents of the pack and other information 

 

What Palonosetron Accord contains  

-  The active substance is palonosetron (as hydrochloride).  

 Each ml of solution contains 50 micrograms of palonosetron. One vial of 5 ml of solution contains 250 

micrograms of palonosetron. 

-  The other ingredients are mannitol, disodium edetate (refer section 2 for sodium content), sodium citrate, 

citric acid monohydrate, sodium hydroxide (refer section 2 for sodium content), hydrochloric acid, 

concentrated and water for injections.  

  

What Palonosetron Accord looks like and contents of the pack 

Palonosetron Accord solution for injection is a clear, colourless solution supplied in a 6 ml glass vial, closed 

with chlorobutyl rubber stopper and sealed with a flip-off aluminium seal. Each vial contains one dose. 

 

Pack size of one vial 

 

Marketing Authorisation Holder 

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona, s/n,  

Edifici Est 6ª planta,  

08039 Barcelona,  

Spain 

 

Manufacturers 

Accord Healthcare Limited 

Ground floor, Sage House 

319, Pinner Road, North Harrow 

Middlesex HA1 4HF 

United Kingdom 

 

Accord Healthcare B.V.,  

Winthontlaan 200,  

3526 KV Utrecht,  

The Netherlands  

 

Accord Healthcare Polska Sp.z o.o., 

ul. Lutomierska 50,95-200 Pabianice, Poland 

 

 

This leaflet was last revised in  

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu. 

 

 

 

 

 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET