Onivyde pegylated liposomal

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
ONIVYDE pegylated liposomal 4.3 mg/ml concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
One 10 ml vial of concentrate contains 43 mg irinotecan anhydrous free base (as irinotecan 
sucrosofate salt in a pegylated liposomal formulation).  
 
One ml of concentrate contains 4.3 mg irinotecan anhydrous free base (as irinotecan sucrosofate salt in 
a pegylated liposomal formulation).  
 
Excipient with known effect 
 
One ml of concentrate contains 0.144 mmol (3.31 mg) sodium. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion. 
White to slightly yellow opaque isotonic liposomal dispersion. 
The concentrate has a pH of 7.2 and an osmolality of 295 mOsm/kg. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of metastatic adenocarcinoma of the pancreas, in combination with 5-fluorouracil (5-FU) 
and leucovorin (LV), in adult patients who have progressed following gemcitabine based therapy. 
 
4.2 Posology and method of administration 
 
ONIVYDE pegylated liposomal (irinotecan) must only be prescribed and administered to patients by 
healthcare professionals experienced in the use of anti-cancer therapies. 
 
ONIVYDE pegylated liposomal (irinotecan) is not equivalent to non-liposomal irinotecan 
formulations and should not be interchanged. 
 
Posology 
 
ONIVYDE pegylated liposomal, leucovorin and 5-fluorouracil should be administered sequentially. 
The recommended dose and regimen of ONIVYDE pegylated liposomal is 70 mg/m2 intravenously 
over 90 minutes, followed by LV 400 mg/m2 intravenously over 30 minutes, followed 
by 5-FU 2,400 mg/m2 intravenously over 46 hours, administered every 2 weeks. ONIVYDE pegylated 
liposomal should not be administered as a single agent. 
 
A reduced starting dose of ONIVYDE pegylated liposomal (irinotecan) of 50 mg/m2 should be 
considered for patients known to be homozygous for the UGT1A1*28 allele (see sections 4.8 and 5.1). 
A dose increase of ONIVYDE pegylated liposomal to 70 mg/m2 should be considered if tolerated in 
subsequent cycles. 
 



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Pre-medication 
It is recommended that patients receive pre-medication with standard doses of dexamethasone (or an 
equivalent corticosteroid) together with a 5-HT3 antagonist (or other antiemetic) at least 30 minutes 
prior to ONIVYDE pegylated liposomal infusion. 
 
Dosage adjustments 
All dose modifications should be based on the worst preceding toxicity. The LV dose does not require 
adjustment. For Grade 1 and 2 toxicities there are no dose modifications recommended. Dose 
adjustments, as summarised in Table 1 and Table 2, are recommended to manage 
Grade 3 or 4 toxicities related to ONIVYDE pegylated liposomal. 
 
For patients who start treatment with 50 mg/m2 ONIVYDE pegylated liposomal and do not dose 
escalate to 70 mg/m2, the recommended first dose reduction is to 43 mg/m2 and the second dose 
reduction is to 35 mg/m2. Patients who require further dose reduction should discontinue treatment. 
 
Patients who are known to be homozygous for UGT1A1*28 and without drug related toxicities during 
the first cycle of therapy (reduced dose of 50 mg/m2) may have the dose of ONIVYDE pegylated 
liposomal increased to a total dose of 70 mg/m2 in subsequent cycles based on individual patient 
tolerance. 
 
Table 1: Recommended dose modifications for ONIVYDE pegylated liposomal +5-FU/LV for 
Grade 3-4 toxicities for patients not homozygous for UGT1A1*28 
 
Toxicity grade (value) 
by NCI CTCAE v 4.01 
 

ONIVYDE pegylated liposomal /5-FU adjustment 
(for patients not homozygous for UGT1A1*28) 

 
Haematological toxicities 

 
Neutropenia 
 

A new cycle of therapy should not begin until the absolute neutrophil 
count is ≥ 1,500 cells/mm3 
 

Grade 3 or 
Grade 4 (< 1,000 
cells/mm3) or 
Neutropenic fever 

First occurrence 
Reduce ONIVYDE pegylated liposomal dose 
to 50 mg/m2 
Reduce 5-FU dose by 25% (1,800 mg/m2). 

Second occurrence 

Reduce ONIVYDE pegylated liposomal dose 
to 43 mg/m2 
Reduce 5-FU dose by an additional 25% 
(1,350 mg/m2). 

Third occurrence Discontinue treatment  
Thrombocytopenia 
 
Leukopenia 
 

A new cycle of therapy should not begin until the platelet count is 
≥ 100,000 platelets/mm3 
Dose modifications for leukopenia and thrombocytopenia are based on 
NCI CTCAE toxicity grading and are the same as recommended for 
neutropenia above. 
 

Non haematological toxicities2 
 
Diarrhoea A new cycle of therapy should not begin until diarrhoea resolves 

to ≤ Grade 1 (2-3 stools/day more than pre-treatment frequency). 
 

Grade 2 
 

A new cycle of therapy should not begin until diarrhoea resolves 
to ≤ Grade 1 (2-3 stools/day more than pre-treatment frequency). 
 



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Toxicity grade (value) 
by NCI CTCAE v 4.01 
 

ONIVYDE pegylated liposomal /5-FU adjustment 
(for patients not homozygous for UGT1A1*28) 

 
Grade 3 or 4 
 First occurrence 

Reduce ONIVYDE pegylated liposomal dose 
to 50 mg/m2 
Reduce 5-FU dose by 25% (1,800 mg/m2) 

Second occurrence 

Reduce ONIVYDE pegylated liposomal dose 
to 43 mg/m2 
Reduce 5-FU dose by an additional 25% 
(1,350 mg/m2) 

Third occurrence Discontinue treatment  
Nausea/vomiting A new cycle of therapy should not begin until nausea/vomiting resolves 

to ≤ Grade 1 or baseline 
 

Grade 3 or 4 (despite 
antiemetic therapy) First occurrence 

Optimise antiemetic therapy 
Reduce ONIVYDE pegylated liposomal dose 
to 50 mg/m2 

Second occurrence 
Optimise antiemetic therapy 
Reduce ONIVYDE pegylated liposomal dose 
to 43 mg/m2  

Third occurrence Discontinue treatment  
Hepatic, renal, 
respiratory or 
other2 toxicities 
Grade 3 or 4 

A new cycle of therapy should not begin until the adverse reaction 
resolves to ≤ Grade 1 
 

First occurrence 
Reduce ONIVYDE pegylated liposomal dose 
to 50 mg/m2 
Reduce 5-FU dose by 25% (1,800 mg/m2) 

Second occurrence 

Reduce ONIVYDE pegylated liposomal dose 
to 43 mg/m2 
Reduce 5-FU dose by an 
additional 25% (1,350 mg/m2) 

Third occurrence Discontinue treatment  
Anaphylactic reaction 
 

First occurrence 
 

Discontinue treatment 
 

1 NCI CTCAE v 4.0 = National Cancer Institute Common Terminology Criteria for Adverse 
Events version 4.0 

2 Excludes asthenia and anorexia; Asthenia and Grade 3 anorexia do not require dose adjustment. 
 
Table 2: Recommended dose modifications for ONIVYDE pegylated liposomal +5-FU/LV for 
Grade 3-4 toxicities in patients homozygous for UGT1A1*28  
 

Toxicity grade (value)  
by NCI CTCAE v 4.01  

ONIVYDE pegylated liposomal /5-FU adjustment 
(for patients homozygous for UGT1A1*28 without previous 

increase3 to 70 mg/m2) 

Adverse reactions2 
Grade 3 or 4 

A new cycle of therapy should not begin until adverse event resolves 
to ≤ Grade 1 

First occurrence 
Reduce ONIVYDE pegylated liposomal dose to 
43 mg/m2 
5-FU dose modification as in Table 1 

Second occurrence 
Reduce ONIVYDE pegylated liposomal dose to 
35 mg/m2 
5-FU dose modification as in Table 1 



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Third occurrence Discontinue treatment 
1 NCI CTCAE v 4.0 = National Cancer Institute Common Terminology Criteria for Adverse 

Events version 4.0 
2 Excludes asthenia and anorexia; asthenia and Grade 3 anorexia do not require dose adjustment. 
3 In case of a dose increase of ONIVYDE pegylated liposomal to 70 mg/m2 if tolerated in 

subsequent cycles, recommended dose modifications should follow Table 1.  
 

Special populations 
 
Hepatic impairment 
No dedicated hepatic impairment study has been conducted with ONIVYDE pegylated liposomal. The 
use of ONIVYDE pegylated liposomal should be avoided in patients with bilirubin > 2.0 mg/dl, or 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 2.5 times upper limit of 
normal (ULN) or > 5 times ULN if liver metastasis is present (see section 4.4). 
 
Renal impairment 
No dedicated renal impairment study has been conducted with ONIVYDE pegylated liposomal. No 
dose adjustment is recommended in patients with mild to moderate renal impairment (see 
sections 4.4 and 5.2). ONIVYDE pegylated liposomal is not recommended for use in patients with 
severe renal impairment (CLcr < 30 ml/min). 
 
Elderly 
Forty-one percent (41%) of patients treated with ONIVYDE pegylated liposomal across the clinical 
program were ≥ 65 years. No dose adjustment is recommended. 
 
Paediatric population 
The safety and efficacy of ONIVYDE pegylated liposomal in children and adolescents aged ≤ 18 years 
have not yet been established. No data are available. 
 
Method of administration 
 
ONIVYDE pegylated liposomal is for intravenous use. The concentrate must be diluted prior to 
administration and given as single intravenous infusion over 90 minutes. For more details see 
section 6.6. 
 
Precautions to be taken before handling or administering the medicinal product 
ONIVYDE pegylated liposomal is a cytotoxic medicinal product. The use of gloves, goggles and 
protective clothing when handling or administering ONIVYDE pegylated liposomal is recommended. 
Pregnant staff should not handle ONIVYDE pegylated liposomal. 
 
4.3 Contraindications 
 
History of severe hypersensitivity to irinotecan or to any of the excipients listed in section 6.1. 
 
Breast-feeding (see section 4.6). 
 
4.4 Special warnings and precautions for use 
 
General 
 
ONIVYDE pegylated liposomal is a liposomal formulation of irinotecan with different 
pharmacokinetic properties compared to non-liposomal irinotecan. The dose concentration and 
strength are different in comparison to non-liposomal irinotecans. 
 
ONIVYDE pegylated liposomal is not equivalent to other non-liposomal irinotecan formulations and 
should not be interchanged. 



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In the limited number of patients with prior exposure to non-liposomal irinotecan, no benefit of 
ONIVYDE pegylated liposomal has been demonstrated. 
 
Myelosuppression/neutropenia 
 
Complete blood cell count monitoring is recommended during ONIVYDE pegylated liposomal 
treatment. Patients should be aware of the risk of neutropenia and the significance of fever. The 
median time to nadir for ≥ Grade 3 neutropenia is 23 (range 8-104) days post first dose of treatment 
with ONIVYDE pegylated liposomal. Febrile neutropenia (body temperature > 38°C and neutrophil 
count ≤ 1,000 cells/mm³) should be urgently treated in the hospital with broad-spectrum intravenous 
antibiotics. ONIVYDE pegylated liposomal should be withheld if neutropenic fever occurs or the 
absolute neutrophil count drops below 1,500 cells/mm3. Sepsis with neutropenic fever and consequent 
septic shock with fatal outcome has been observed in patients with metastatic pancreatic 
adenocarcinoma treated with ONIVYDE pegylated liposomal. 
In patients who experienced severe haematological events, a dose reduction or treatment 
discontinuation is recommended (see section 4.2). Patients with severe bone marrow failure should not 
be treated with ONIVYDE pegylated liposomal. 
History of prior abdominal radiation increases the risk of severe neutropenia and febrile neutropenia 
following ONIVYDE pegylated liposomal treatment. Close monitoring of blood counts is 
recommended, and the use of myeloid growth factors should be considered for patients with a history 
of abdominal radiation. Caution should be exercised in patients receiving concurrent administration of 
ONIVYDE pegylated liposomal with irradiation. 
 
Patients with deficient glucuronidation of bilirubin, such as those with Gilbert’s syndrome, may be at 
greater risk of myelosuppression when receiving therapy with ONIVYDE pegylated liposomal. 
 
Compared to Caucasian patients, Asian patients have an increased risk of severe and febrile 
neutropenia following treatment with ONIVYDE pegylated liposomal +5-FU/LV (see 
sections 4.8 and 5.2). 
 
Immunosuppressive effects and vaccines 
 
Administration of live or live-attenuated vaccines in patients immunocompromised by 
chemotherapeutic medicinal products including ONIVYDE pegylated liposomal may result in serious 
or fatal infections; therefore vaccination with a live vaccine should be avoided. Killed or inactivated 
vaccines may be administered; however, the response to such vaccines may be diminished. 
 
Interactions with strong CYP3A4 inducers 
 
ONIVYDE pegylated liposomal should not be administered with strong CYP3A4-enzyme inducers 
such as anticonvulsants (phenytoin, phenobarbital or carbamazepine), rifampin, rifabutin and St. 
John’s wort unless there are no therapeutic alternatives. The appropriate starting dose for patients 
taking these anticonvulsants or other strong inducers has not been defined. Consideration should be 
given to substituting with non-enzyme inducing therapies at least 2 weeks prior to initiation of 
ONIVYDE pegylated liposomal therapy (see section 4.5). 
 
Interactions with strong CYP3A4 inhibitors or strong UGT1A1 inhibitors 
 
ONIVYDE pegylated liposomal should not be administered with strong CYP3A4-enzyme inhibitors 
(e.g. grapefruit juice, clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, 
ritonavir, saquinavir, telaprevir, voriconazole). Strong CYP3A4 inhibitors should be discontinued at 
least 1 week prior to starting ONIVYDE pegylated liposomal therapy. 
ONIVYDE pegylated liposomal should not be administered with strong UGT1A inhibitors 
(e.g. atazanavir, gemfibrozil, indinavir) unless there are no therapeutic alternatives. 
 
Diarrhoea 



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Diarrhoea can occur early (onset in ≤ 24 hours after starting ONIVYDE pegylated liposomal) or late 
(> 24 hours) (see section 4.8).  
In patients experiencing early diarrhoea, therapeutic and prophylactic atropine should be considered 
unless contraindicated. Patients should be made aware of the risk of delayed diarrhoea which can be 
debilitating and, on rare occasions, life threatening since persistent loose or watery stools can result in 
dehydration, electrolyte imbalance, colitis, gastrointestinal (GI) ulceration, infection or sepsis. 
As soon as the first liquid stool occurs, the patient should start drinking large volumes of beverages 
containing electrolytes. Patients should have loperamide (or equivalent) readily available to begin 
treatment for late diarrhoea. Loperamide should be initiated at first occurrence of poorly formed or 
loose stools or at the earliest onset of bowel movements more frequent than normal. Loperamide 
should be given until patient is without diarrhoea for at least 12 hours. 
If diarrhoea persists while patient is on loperamide for more than 24 hours, adding oral antibiotic 
support (e.g. fluoroquinolone for 7 days) should be considered. Loperamide should not be used for 
more than 48 consecutive hours due to risk of paralytic ileus. If diarrhoea persists for more 
than 48 hours, stop loperamide, monitor and replace fluid electrolytes and continue antibiotic support 
until resolution for accompanying symptoms. 
ONIVYDE pegylated liposomal treatment should be delayed until diarrhoea resolves 
to ≤ Grade 1 (2-3 stools/day more than pre-treatment frequency). ONIVYDE pegylated liposomal 
must not be administered to patients with bowel obstruction, and chronic inflammatory bowel disease, 
until it is resolved. 
Following Grade 3 or 4 diarrhoea, the subsequent dose of ONIVYDE pegylated liposomal should be 
reduced, (see section 4.2). 
 
Cholinergic reactions 
 
Early onset diarrhoea may be accompanied by cholinergic symptoms such as rhinitis, increased 
salivation, flushing, diaphoresis, bradycardia, miosis and hyperperistalsis. In case of cholinergic 
symptoms atropine should be administered.  
 
Acute infusion and related reactions 
 
Infusion reactions primarily consisting of rash, urticaria, periorbital oedema or pruritus were reported 
in patients receiving ONIVYDE pegylated liposomal treatment. New events (all grade 1 or grade 2) 
occurred generally early during ONIVYDE pegylated liposomal treatment, with only 2 out 
of 10 patients noted with events after the fifth dose. Hypersensitivity reactions, including acute 
infusion reaction may occur. ONIVYDE pegylated liposomal should be discontinued in case of severe 
hypersensitivitiy reactions. 
 
Prior Whipple procedure 
 
Patients with a history of a Whipple procedure have a higher risk of serious infections following 
ONIVYDE pegylated liposomal in combination with 5-FU and leucovorin (see section 4.8). Patients 
should be monitored for signs of infections.  
 
Vascular disorders 
 
Onivyde pegylated liposomal has been associated with thromboembolic events such as pulmonary 
embolism, venous thrombosis and arterial thromboembolism. A thorough medical history should be 
obtained in order to identify patients with multiple risk factors in addition to the underlying neoplasm. 
Patients should be informed about the signs and symptoms of thromboembolism and advised to 
contact their physician or nurse immediately if any such signs or symptoms should occur. 
 
Pulmonary toxicity 
 
Interstitial Lung Disease (ILD)-like events leading to fatalities have occurred in patients receiving 
non-liposomal irinotecan. No cases of ILD-like events have been reported with ONIVYDE pegylated 



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liposomal therapy in clinical studies. Risk factors include pre-existing lung disease, use of 
pneumotoxic medicinal products, colony stimulating factors or having previously received radiation 
therapy. Patients with risk factors should be closely monitored for respiratory symptoms before and 
during ONIVYDE pegylated liposomal therapy. A reticulo-nodular pattern on chest X-ray was 
observed in a small percentage of patients enrolled in a clinical study with irinotecan. New or 
progressive dyspnoea, cough, and fever should prompt interruption of ONIVYDE pegylated liposomal 
treatment, pending diagnostic evaluation. ONIVYDE pegylated liposomal should be discontinued in 
patients with a confirmed diagnosis of ILD. 
 
Hepatic impairment 
 
Patients with hyperbilirubinaemia had higher concentrations for total SN-38 (see section 5.2) and 
therefore the risk of neutropenia is increased. Regular monitoring of complete blood counts should be 
conducted in patients with total bilirubin of 1.0-2.0 mg/dl. Caution should be exercised in patients with 
hepatic impairment (bilirubin > 2 times upper limit of normal [ULN]; transaminases > 5 times ULN). 
Caution is required when ONIVYDE pegylated liposomal is given in combination with other 
hepatotoxic medicinal products, especially in patients with pre-existing hepatic impairment. 
 
Renal impairment 
 
The use of ONIVYDE pegylated liposomal in patients with significant renal impairment has not been 
established (see section 5.2). 
 
Underweight patients (body mass index < 18.5 kg/m2) 
 
In the clinical study evaluating ONIVYDE pegylated liposomal +5-FU/LV, 5 of 8 underweight 
patients experienced a Grade 3 or 4 adverse reactions, mostly myelosuppression, while 7 of the 
8 patients required dose modification such as dose delay, dose reduction or dose discontinuation. 
Caution should be exercised when using ONIVYDE pegylated liposomal in patients with body mass 
index < 18.5 kg/m2. 
 
Excipients 
 
Each ml of ONIVYDE pegylated liposomal contains 0.144 mmol (3.31 mg) sodium. This needs to be 
taken into consideration by patients on a controlled sodium diet. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Information about drug interactions with ONIVYDE pegylated liposomal is referenced from the 
published scientific literature for nonliposomal irinotecan. 
 
Interaction affecting the use of ONIVYDE pegylated liposomal 
 
Strong CYP3A4 inducers 
Patients receiving concomitant non-liposomal irinotecan and CYP3A4 enzyme-inducing 
anticonvulsants phenytoin, phenobarbital or carbamazepine have substantially reduced exposure to 
irinotecan (AUC reduction by 12% with St John’s wort, 57%-79% with phenytoin, phenobarbital, or 
carbamazepine) and SN-38 (AUC reduction by 42% with St John’s wort, 36%-92% with phenytoin 
phenobarbital, or carbamazepine). Therefore, co-administration of ONIVYDE pegylated liposomal 
with inducers of CYP3A4 may reduce systemic exposure of ONIVYDE pegylated liposomal. 
 
Strong CYP3A4 inhibitors and UGT1A1 inhibitors 
Patients receiving concomitant non-liposomal irinotecan and ketoconazole, a CYP3A4 and 
UGT1A1 inhibitor, have increased SN-38 exposure by 109%. Therefore, co-administration of 
ONIVYDE pegylated liposomal with other inhibitors of CYP3A4 (e.g. grapefruit juice, 
clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telaprevir, voriconazole) may increase systemic exposure of ONIVYDE pegylated liposomal. Based 



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on the drug interaction of non-liposomal irinotecan and ketoconazole, co-administration of ONIVYDE 
pegylated liposomal with other inhibitors of UGT1A1 (e.g. atazanavir, gemfibrozil, indinavir, 
regorafenib) may also increase systemic exposure of ONIVYDE pegylated liposomal. 
 
Co-administration of ONIVYDE pegylated liposomal +5-FU/LV does not alter the pharmacokinetics 
of ONIVYDE pegylated liposomal based on the population pharmacokinetic analysis. 
 
No interaction of ONIVYDE pegylated liposomal (irinotecan) with other medicinal products is 
known. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / contraception in males and females 
 
Women of childbearing potential should use effective contraception during ONIVYDE pegylated 
liposomal treatment and 1 month thereafter. Males should use condoms during ONIVYDE pegylated 
liposomal treatment and 4 months thereafter. 
 
Pregnancy 
 
There are no adequate data on the use of ONIVYDE pegylated liposomal in pregnant women. 
ONIVYDE pegylated liposomal can cause harm to the foetus when administered to the pregnant 
woman, as the main ingredient irinotecan has been shown to be embryotoxic and teratogenic in 
animals (see section 5.3). Therefore, based on results from animal studies and the mechanism of action 
of irinotecan, ONIVYDE pegylated liposomal should not be used during pregnancy unless clearly 
necessary. If ONIVYDE pegylated liposomal is used during pregnancy or if the patient becomes 
pregnant while receiving therapy, the patient should be informed about the potential hazard to the 
foetus. 
 
Breast-feeding 
 
It is unknown whether ONIVYDE pegylated liposomal or its metabolites are excreted into human 
milk. Because of the potential for serious adverse reactions of ONIVYDE pegylated liposomal in 
breast-feeding infants, ONIVYDE pegylated liposomal is contraindicated during breast-feeding (see 
section 4.3). Patients should not breast-feed until one month after the last dose. 
 
Fertility 
 
There are no data on the impact of ONIVYDE pegylated liposomal on human fertility. Non-liposomal 
irinotecan was shown to cause atrophy of male and female reproductive organs after multiple daily 
irinotecan doses in animals (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
ONIVYDE pegylated liposomal has moderate influence on the ability to drive and use machines. 
During treatment patients should observe caution when driving or using machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The following adverse reactions, considered to be possibly or probably related to the administration of 
ONIVYDE pegylated liposomal, were reported in 264 patients with metastatic adenocarcinoma of the 
pancreas, 147 of whom received ONIVYDE pegylated liposomal monotherapy (100 mg/m2) 
and 117 received ONIVYDE pegylated liposomal (70 mg/m2) in combination with 5-FU/LV. 
The most common adverse reactions (incidence ≥ 20%) of ONIVYDE pegylated liposomal +5-FU/LV 
were: diarrhoea, nausea, vomiting, decreased appetite, neutropenia, fatigue, asthenia, anaemia, 



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stomatitis and pyrexia. The most common serious adverse reactions (≥ 2%) of ONIVYDE pegylated 
liposomal therapy were diarrhoea, vomiting, febrile neutropenia, nausea, pyrexia, sepsis, dehydration, 
septic shock, pneumonia, acute renal failure, and thrombocytopenia. 
The rates of adverse reactions leading to permanent treatment discontinuation were 11% for the 
ONIVYDE pegylated liposomal +5-FU/LV arm and 12% for the monotherapy arm. 
The most frequently reported adverse reactions leading to discontinuation were infection and diarrhoea 
for ONIVYDE pegylated liposomal +5-FU/LV arm, and vomiting and diarrhoea for the monotherapy 
arm. 
 
Tabulated list of adverse reactions 
 
The adverse reactions that may occur during treatment with ONIVYDE pegylated liposomal are 
summarised below and are presented by system organ class and frequency category (Table 3). Within 
each system organ class and frequency category, adverse reactions are presented in order of decreasing 
seriousness. Frequencies categories used for adverse reactions are: very common (≥ 1/10); common 
(≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000)**. 
 
Table 3: Adverse reactions reported with ONIVYDE pegylated liposomal therapy in the 
NAPOLI-1 clinical study 
 

MedDRA* system organ 
class Adverse reaction frequency** 

Infections and infestations Common: Septic shock, Sepsis, Pneumonia, Febrile neutropenia, 
Gastroenteritis, Oral candidiasis 
Uncommon: Biliary sepsis 
 

Blood and lymphatic 
system disorders 

Very common: Neutropenia, Leukopenia, Anaemia, 
Thrombocytopenia 
Common: Lymphopenia 
 

Immune system disorders Uncommon: Hypersensitivity 
 

Metabolism and nutrition 
disorders 

Very common: Hypokalaemia, Hypomagnesaemia, Dehydration, 
Decreased appetite 
Common: Hypoglycaemia, Hyponatraemia, Hypophosphataemia 
 

Psychiatric disorders Common: Insomnia 
 

Nervous system disorders Very common: Dizziness 
Common: Cholinergic syndrome, Dysgeusia 
 

Cardiac disorders Common: Hypotension 
 

Vascular disorders Common: Pulmonary embolism, Embolism, Deep vein thrombosis 
Uncommon: Thrombosis 
 

Respiratory, thoracic and 
mediastinal disorders 

Common: Dyspnoea, Dysphonia 
Uncommon: Hypoxia 
 

Gastrointestinal disorders Very common: Diarrhoea, Vomiting, Nausea, Abdominal pain, 
Stomatitis 
Common: Colitis, Haemorrhoids 
Uncommon: Oesophagitis, Proctitis 
 

Hepatobiliary disorders Common: Hypoalbuminaemia 
 



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MedDRA* system organ 
class Adverse reaction frequency** 

Skin and subcutaneous 
tissue disorders 

Very common: Alopecia 
Uncommon: Rash maculo-papular, Nail discolouration 
 

Renal and urinary disorders Common: Acute renal failure 
 

General disorders and 
administration site 
conditions 

Very common: Pyrexia, Peripheral oedema, Mucosal inflammation, 
Fatigue, Asthenia 
Common: Infusion related reaction, Oedema 
 

Investigations Very common: Weight decrease 
Common: Increased bilirubin, Increased alanine aminotransferase, 
Increased aspartate aminotransferase, Increased international 
normalised ratio 
 

* MedDRA version 14.1 
** Rare occurrence cannot be estimated from the NAPOLI-1study due to the small sample size 
 
Description of selected adverse reactions 
 
The following adverse reactions were observed in the NAPOLI-1 clinical study: 
 
Myelosuppression 
Myelosuppression (neutropenia/leukopenia, thrombocytopenia and, anaemia) was more common in 
the ONIVYDE pegylated liposomal +5-FU/LV arm compared to the 5-FU/LV control arm. 
 
Neutropenia/leukopenia 
Neutropenia/leukopenia was the most notable important haematological toxicity. Grade 3 or higher 
neutropenia occurred more frequently in patients treated with ONIVYDE pegylated liposomal 
+5-FU/LV (27.4%) compared to patients treated with 5-FU/LV (1.5%). Neutropenic fever/sepsis 
appeared more frequently in the ONIVYDE pegylated liposomal +5-FU/LV combination arm 
[in 4 patients (3.4%)] compared to 5-FU/LV control arm [in 1 patient (0.7%)]. 
 
Thrombocytopenia 
Grade 3 or higher thrombocytopenia occurred in 2.6% of patients treated with ONIVYDE pegylated 
liposomal +5-FU/LV and 0% in patients treated with 5-FU/LV. 
 
Anaemia 
Grade 3 or higher anaemia occurred in 10.3% of patients treated with ONIVYDE pegylated liposomal 
+5-FU/LV and in 6.7% of patients treated with 5-FU/LV. 
 
Acute renal failure 
Renal impairment and acute renal failure have been identified, usually in patients who become volume 
depleted from nausea/vomiting and/or diarrhoea. Acute renal failure was reported in 6 of 117 patients 
(5.1%) in the ONIVYDE pegylated liposomal +5-FU/LV arm, 10 of 147 (6.8%) in the ONIVYDE 
pegylated liposomal monotherapy arm and 6 of 134 patients (4.5%) in the 5-FU/LV arm. 
 
Diarrhoea and related adverse reactions 
Diarrhoea is a very common adverse reaction leading to colitis, ileus, gastroenteritis, fatigue, 
dehydration, weight loss, renal toxicities, hyponatraemia, and hypokalaemia. Renal impairment and 
acute renal failure have been identified, usually in patients who became volume depleted from severe 
vomiting and/or diarrhoea. In the clinical study Grade 3 or Grade 4 diarrhoea occurred in 15 out 
of 117 patients (12.8%) receiving ONIVYDE pegylated liposomal +5-FU/LV. For patients 
experiencing late diarrhoea, the median time to late diarrhoea onset was 8 days from the previous dose 
of ONIVYDE pegylated liposomal. Early onset diarrhoea, typically appearing ≤ 24 hours after dose 



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administration, can occur and is usually transient. Early onset diarrhoea may also be accompanied by 
cholinergic symptoms that can include rhinitis, increased salivation, flushing, diaphoresis, 
bradycardia, miosis and hyperperistalsis that can induce abdominal cramping. In the clinical study, 
early diarrhoea onset occurred in 35 patients (29.9%) and cholinergic events occurred in 4 patients 
(3.4%) receiving ONIVYDE pegylated liposomal +5-FU/LV. 
Withhold ONIVYDE pegylated liposomal for Grade 2-4 diarrhoea and initiate treatment for diarrhoea. 
Following recovery to Grade 1 diarrhoea, resume ONIVYDE pegylated liposomal at a reduced dose 
(see section 4.2). 
 
Infusion reaction 
Acute infusion reactions were reported in 8 of 117 patients (6.8%) in the ONIVYDE pegylated 
liposomal +5-FU/LV arm, 3 of 147 patients (2.0%) in the ONIVYDE pegylated liposomal 
monotherapy arm, and 8 of 134 patients (6.0%) in the 5-FU/LV arm. 
 
Other special populations 
 
Elderly 
Overall, no major clinical differences in safety or efficacy were reported between patients ≥ 65 years 
and patients < 65 years, although a higher frequency of discontinuation (14.8% vs 7.9%) was noted in 
the former group treated with ONIVYDE pegylated liposomal +5-FU/LV in the NAPOLI-1 study and 
in some cases the adverse reactions did not resolve. Grade 3 or higher and serious treatment emergent 
adverse reactions were more frequent in patients < 65 years (84.1% and 50.8%) compared to 
patients ≥ 65 years (68.5 % and 44.4%). Conversely, patients > 75 years (n=12) experienced more 
frequent serious adverse reactions, dose delay, dose reduction and discontinuation compared to 
patients ≤ 75 years (n=105) when treated with ONIVYDE pegylated liposomal +5-FU/LV in the 
pancreatic adenocarcinoma study. 
 
Asian population 
Compared to Caucasians, Asian patients were observed with a lower incidence of diarrhoea 
[14 (19.2%) out of 73 Caucasians had a ≥ Grade 3 diarrhoea, and 1 out of 33 (3.3%) Asians had a 
≥ Grade 3 diarrhoea], but a higher incidence and higher severity of neutropenia. In patients receiving 
ONIVYDE pegylated liposomal +5-FU/LV, the incidence of ≥ Grade 3 neutropenia was higher among 
Asian patients [18 of 33 (55%)] compared to Caucasians patients [13 of 73 (18%)]. Neutropenic 
fever/neutropenic sepsis was reported in 6% of Asian patients compared to 1% of Caucasians patients. 
This is consistent with the population pharmacokinetic analysis that showed a lower exposure to 
irinotecan and a higher exposure to its active metabolite SN-38 in Asians than in Caucasians. 
 
Patients with hepatic impairment 
In clinical studies of non-liposomal irinotecan administered on a weekly dosage schedule, patients 
with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dl) had a significantly 
greater likelihood of experiencing first cycle Grade 3 or Grade 4 neutropenia than those with bilirubin 
levels that were less than 1.0 mg/dl. 
 
Patients with prior Whipple procedure 
In the clinical study evaluating ONIVYDE pegylated liposomal +5-FU/LV, patients with a prior 
Whipple procedure had a higher risk of serious infections following treatment with ONIVYDE 
pegylated liposomal +5-FU/LV [9 of 29 (30%)] compared to 11 of 88 (12.5%) patients with no prior 
Whipple procedure. 
 
Patients with UGT1A1 allele 
Individuals who are 7/7 homozygous for the UGT1A1*28 allele are at increased risk for neutropenia 
from non-liposomal irinotecan. In the clinical study evaluating ONIVYDE pegylated liposomal 
+5-FU/LV, the frequency of ≥ Grade 3 neutropenia in these patients [2 of 7 (28.6%)] was similar to 
the frequency in patients not homozygous for the UGT1A1*28 allele who received a starting dose of 
ONIVYDE pegylated liposomal of 70 mg/m2 [30 of 110 (27.3%)] (see section 5.1). 
 



13 

Underweight patients (body mass index < 18.5 kg/m2) 
In the clinical study evaluating ONIVYDE pegylated liposomal +5-FU/LV, 5 of 8 underweight 
patients experienced a grade 3 or 4 adverse reaction, mostly myelosuppression, while 7 of 
the 8 patients required dose modification such as dose delay, dose reduction or dose discontinuation 
(see section 4.4).  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In clinical trials, ONIVYDE pegylated liposomal was administered at doses up to 210 mg/m2 to 
patients with various cancers. The adverse reactions in these patients were similar to those reported 
with the recommended dosage and regimen. 
 
There have been reports of overdosage with non-liposomal irinotecan at doses up to approximately 
twice the recommended therapeutic dose of irinotecan, which may be fatal. The most significant 
adverse reactions reported were severe neutropenia and severe diarrrhoea. 
 
There is no known antidote for overdose of ONIVYDE pegylated liposomal. Maximum supportive 
care should be instituted to prevent dehydration due to diarrhoea and to treat any infectious 
complications. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents, ATC code: L01XX19 
 
Mechanism of action 
 
The active substance in ONIVYDE pegylated liposomal is irinotecan (topoisomerase I inhibitor) 
encapsulated in a lipid bilayer vesicle or liposome. 
 
Irinotecan is a derivative of camptothecin. Camptothecins act as specific inhibitors of the enzyme 
DNA topoisomerase I. Irinotecan and its active metabolite SN-38 bind reversibly to the 
topoisomerase I-DNA complex and induce single-strand DNA lesions which block the DNA 
replication fork and are responsible for the cytotoxicity. Irinotecan is metabolized by carboxylesterase 
to SN-38. SN-38 is approximately 1,000 times as potent as irinotecan as an inhibitor of topoisomerase 
I purified from human and rodent tumour cell lines. 
 
Pharmacodynamic effects 
 
In animal models, ONIVYDE pegylated liposomal has been shown to extend plasma levels of 
irinotecan and prolong the exposure to the active metabolite SN-38 at the site of the tumour. 
 
Clinical efficacy and safety 
 
The safety and efficacy of ONIVYDE pegylated liposomal were investigated in a multinational, 
randomised, open label, controlled clinical trial (NAPOLI–1) that tested two treatment regimens for 
patients with metastatic pancreatic adenocarcinoma who had documented disease progression after 
gemcitabine or gemcitabine-containing therapy. The trial was designed to assess the clinical efficacy 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


14 

and safety of ONIVYDE pegylated liposomal monotherapy or ONIVYDE pegylated liposomal 
+5-FU/LV compared to an active control arm of 5-FU/LV. 
 
Patients randomised to ONIVYDE pegylated liposomal +5-FU/LV received ONIVYDE pegylated 
liposomal at 70 mg/m2 as an intravenous infusion over 90 minutes, followed by 
LV 400 mg/m2 intravenously over 30 minutes, followed by 5-FU 2,400 mg/m2 intravenously 
over 46 hours, administered every 2 weeks. Patients homozygous for the UGT1A1*28 allele were 
given a lower initial dose of ONIVYDE pegylated liposomal (see section 4.2). Patients randomised 
to 5-FU/LV received leucovorin 200 mg/m2 intravenously over 30 minutes, followed 
by 5-FU 2,000 mg/m2 intravenously over 24 hours, administered on Days 1, 8, 15 and 22 of a 6 week 
cycle. Patients randomised to ONIVYDE pegylated liposomal monotherapy received 100 mg/m2 as an 
intravenous infusion over 90 minutes every 3 weeks. 
 
Key eligibility criteria for patients with metastatic adenocarcinoma of the pancreas in the 
NAPOLI-1 clinical study were Karnofsky Performance Status (KPS) ≥ 70, normal bilirubin level, 
transaminase levels ≤ 2.5 times the ULN or ≤ 5 times the ULN for patients with liver metastases and 
albumin ≥ 3.0 g/dl. 
 
A total of 417 patients were randomised to the ONIVYDE pegylated liposomal +5-FU/LV 
arm (N=117), ONIVYDE pegylated liposomal monotherapy arm (N=151) and 5-FU/LV arm (N=149). 
Patient demographic and entry disease characteristics were well balanced between trial arms. 
 
In the intent to treat (all randomised) population, the median age was 63 years 
(range 31-87 years), 57 % were males, and 61% were Caucasian and 33% were Asian. Mean baseline 
albumin level was 3.6 g/dl, and baseline KPS was 90-100 in 55% of patients. Disease characteristics 
included 68% of patients with liver metastases and 31% with lung metastases; 12% of patients had no 
prior lines of metastatic therapy, 56 % of patients had 1 prior line of metastatic therapy, 32% of 
patients had 2 or more prior lines of metastatic therapy. 
 
Patients received treatment until disease progression or unacceptable toxicity. The primary outcome 
measure was Overall Survival (OS). Additional outcome measures included Progression Free Survival 
(PFS) and Objective Response Rate (ORR). Results are shown in Table 4. Overall survival is 
illustrated in Figure 1. 
 
Table 4: Efficacy results from NAPOLI-1 clinical study 
 

 
ONIVYDE pegylated liposomal 

+5-FU/LV 
(N= 117) 

5-FU/LV 
(N= 119) 

Overall Survival1 

Number of deaths, n (%) 75 (64) 80 (67) 

Median OS (months) 6.1 4.2 

(95% CI) (4.8, 8.9) (3.3, 5.3) 

Hazard Ratio (95% CI)3 0.67 (0.49-0.92) 

p-value4 0.0122 

Progression-Free Survival1,2 

Death or progression, n (%) 83 (71) 92 (77) 



15 

 
ONIVYDE pegylated liposomal 

+5-FU/LV 
(N= 117) 

5-FU/LV 
(N= 119) 

Median PFS (months) 3.1 1.5 

(95% CI) (2.7, 4.2) (1.4, 1.8) 

Hazard Ratio (95% CI)3 0.56 (0.41-0.75) 

p-value4 0.0001 

Objective Response Rate2 

N 19 1 

ORR (%) 16.2 0.8 

95% CI of Rate5 9.6, 22.9 0.0, 2.5 

Rate Difference (95% CI)5 15.4 (8.5, 22.3) 

p-value6 < 0.0001 
 
1 Median is the Kaplan-Meier estimate of the median survival time 
2 Per RECIST guidelines, v 1.1. 
3 Cox model analysis 
4 Unstratified log-rank test 
5 Based on Normal approximation 
6 Fisher’s exact test 
 
Abbreviations: 5-FU/LV=5-fluorouracil/leucovorin; CI=confidence interval 
 
 
Figure 1: Overall survival 

 
 
In the limited number of patients with prior exposure to non-liposomal irinotecan, no benefit of 
ONIVYDE pegylated liposomal has been demonstrated. 
 



16 

Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
ONIVYDE pegylated liposomal in all subsets of the paediatric population in treatment of 
adenocarcinoma of the pancreas (see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
Liposome encapsulation of irinotecan extends circulation and limits distribution relative to those of the 
non-liposomal irinotecan. 
 
The plasma pharmacokinetics of total irinotecan and total SN-38 were evaluated in patients with 
cancer who received ONIVYDE pegylated liposomal, as a single agent or as part of combination 
chemotherapy, at doses between 50 and 155 mg/m2. The pharmacokinetic parameters of total 
irinotecan and SN-38 analytes, following the administration of ONIVYDE pegylated liposomal 
70 mg/m2 are presented in Table 5. 
 
Table 5: Summary of mean (±standard deviation) total irinotecan and total SN-38 
 

Analyte PK parameters Unit ONIVYDE pegylated 
liposomal  

geomean (95% CI)a 
70 mg/m2 (n=353)b 

Non-liposomal 
irinotecan  
mean (SD)  

125 mg/m2 (n=99)c 
Total 

irinotecan 
AUC h×ng/ml 919,228 

(845,653-999,204) 
10,529 
(3,786) 

Cmax ng/ml 28,353 
(27,761-28,958) 

1,492 
(452) 

Clearance (CL) l/h/m2 0.087 
(0.080-0.094) 

13.0  
(5.6) 

Volume (V) l/m2 2.6 
(2.6-2.7) 

138 
(60.9) 

t1/2 effective h 20.8 
(19.4-22.3) 

6.07  
(1.19) 

Total 
SN-38 

AUC h×ng/ml 341 
(326-358) 

267 
(115) 

Cmax ng/ml 3.0 
(2.9-3.1) 

27.8  
(11.6) 

t1/2 effective h 40.9 
(39.8-42.0) 

11.7  
(4.29) 

SD= standard deviation 
AUC= area under the plasma concentration curve (extrapolated to infinity for ONIVYDE pegylated 
liposomal and AUC24h for non-liposomal irinotecan) 
Cmax= maximum plasma concentration 
t1/2 effective= effective half-lives 
aValues are estimated from population PK analysis 
bN=353 refers to all the subjects included in the population PK analysis 
cValues are obtained from published data [Schaaf LJ et al. Clin Cancer Res. 2006 Jun 15;12:3782-91] 
 
Distribution 
 
Direct measurement of liposomal irinotecan shows that 95% of irinotecan remains 
liposome-encapsulated during circulation. Non-liposomal irinotecan displays a large volume of 
distribution (138 l/m2). The volume of distribution of ONIVYDE pegylated 
liposomal 70 mg/m2 was 2.6 l/m2, which suggests that ONIVYDE pegylated liposomal is largely 
confined to vascular fluid. 



17 

The plasma protein binding of ONIVYDE pegylated liposomal is negligible (< 0.44% of total 
irinotecan in ONIVYDE pegylated liposomal). The plasma protein binding of non-liposomal 
irinotecan is moderate (30% to 68%), and SN-38 is highly bound to human plasma proteins 
(approximately 95%). 
 
Biotransformation 
 
Irinotecan released from liposome encapsulation follows a similar metabolic pathway reported with 
non-liposomal irinotecan. 
The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase 
enzymes. In vitro studies indicate that irinotecan, SN-38 and another metabolite aminopentane 
carboxylic acid (APC) do not inhibit cytochrome P-450 isozymes. SN-38 is subsequently conjugated 
predominantly by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide 
metabolite. UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to 
reduced enzyme activity such as the UGT1A1*28 polymorphism. In the population pharmacokinetic 
analysis in patients with ONIVYDE pegylated liposomal using the results of a subset with 
UGT1A1*28 genotypic testing, in which the analysis adjusted for the lower dose administered to 
patients homozygous for the UGT1A1*28 allele, patients homozygous (N=14) and non-homozygous 
(N=244) for this allele had total SN-38 average steady-state concentrations of 1.06 and 0.95 ng/ml, 
respectively. 
 
Elimination 
 
The disposition of ONIVYDE pegylated liposomal and non-liposomal irinotecan has not been fully 
elucidated in humans. 
The urinary excretion of non-liposomal irinotecan is 11% to 20%; SN-38 < 1%; and 
SN-38 glucuronide is 3%. The cumulative biliary and urinary excretion of irinotecan and its 
metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours following administration of 
non-liposomal irinotecan in two patients ranged from approximately 25% (100 mg/m2) to 50% 
(300 mg/m2). 
 
Renal impairment 
 
No dedicated pharmacokinetic study has been conducted in patients with renal impairment. In a 
population pharmacokinetic analysis, mild-to-moderate renal impairment had no effect on the 
exposure of total SN-38 after adjusting for BSA. The analysis included 68 patients with moderate 
(CLcr 30-59 ml/min), 147 patients with mild (CLcr 60-89 ml/min) renal impairment, and 135 patients 
with normal renal function (CLcr > 90 ml/min). There was insufficient data in patients with severe 
renal impairment (CLcr < 30 ml/min) to assess its effect on pharmacokinetics (see 
sections 4.2 and 4.4). 
 
Hepatic impairment 
 
No dedicated pharmacokinetic study has been conducted in patients with hepatic impairment. In a 
population pharmacokinetic analysis, patients with baseline total bilirubin concentrations of 1-2 mg/dl 
(n=19) had average steady state concentrations for total SN-38 that were increased 
by 37% (0.98 [95%CI: 0.94-1.02] and 1.29 [95%CI: 1.11-1.5] ng/ml, respectively) compared to 
patients with baseline bilirubin concentrations of < 1 mg/dl (n=329); however, there was no effect of 
elevated ALT/AST concentrations on total SN-38 concentrations. No data are available in patients 
with total bilirubin more than 2 times the ULN. 
 
Other special populations 
 
Age and gender 
The population pharmacokinetic analysis in patients aged 28 to 87 years, of whom 11% were 
≥75 years suggests that age had no clinically meaningful effect on the exposure to irinotecan and 
SN-38. 



18 

The population pharmacokinetic analysis in 196 male and 157 female patients suggests that gender 
had no clinically meaningful effect on the exposure to irinotecan and SN-38 after adjusting for body 
surface area (BSA). 
 
Ethnicity 
The population pharmacokinetic analysis suggest that Asians have 56% lower total irinotecan average 
steady state concentration (3.93 [95%CI: 3.68-4.2] and 1.74 [95%CI: 1.58-1.93] mg/l, respectively) 
and 8% higher total SN-38 average steady state concentration (0.97 [95%CI: 0.92-1.03] 
and 1.05 [95%CI: 0.98-1.11] ng/ml, respectively) than Caucasians. 
 
Pharmacokinetic/pharmacodynamic relationship 
 
In a pooled analysis from 353 patients, higher plasma SN-38 Cmax was associated with increased 
likelihood of experiencing neutropenia, and higher plasma total irinotecan Cmax was associated with 
increased likelihood of experiencing diarrhoea. 
 
In the clinical trial demonstrating effectiveness of ONIVYDE pegylated liposomal, higher plasma 
exposures of total irinotecan and SN-38 for patients in the ONIVYDE pegylated liposomal +5-FU/LV 
treatment arm were associated with longer OS and PFS as well as with higher ORR (objective 
response rate). 
 
5.3 Preclinical safety data 
 
In single and repeated dose toxicity studies in mice, rats and dogs, the target organs of toxicity were 
the gastrointestinal tract and the hematologic system. The severity of effects was dose-related and 
reversible. The no-observed-adverse-effect level (NOAEL) in rats and dogs following 90 min 
intravenous infusion of ONIVYDE pegylated liposomal once every 3 weeks for 18 weeks was  
155 mg/m2. 
In safety pharmacology studies in dogs, ONIVYDE pegylated liposomal had no effect on 
cardiovascular, hemodynamic, electrocardiographic, or respiratory parameters at doses up to 18 mg/kg 
or 360 mg/m2  . No findings indicative of CNS related toxicity were observed in the repeated dose 
toxicity studies in rats. 
 
Genotoxic and carcinogenic potential 
 
No genotoxicity studies have been performed with ONIVYDE pegylated liposomal. Non-liposomal 
irinotecan and SN-38 were genotoxic in vitro in the chromosomal aberration test on CHO-cells as well 
as in the in vivo micronucleus test in mice. However, in other studies with irinotecan they have been 
shown to be devoid of any mutagenic potential in the Ames test. 
 
No carcinogenicity studies have been performed with ONIVYDE pegylated liposomal. For 
non-liposomal irinotecan, in rats treated once a week during 13 weeks at the maximum dose 
of 150 mg/m², no treatment related tumours were reported 91 weeks after the end of treatment. Under 
these conditions, there was a significant linear trend with dose for the incidence of combined uterine 
horn endometrial stromal polyps and endometrial stromal sarcomas. Due to its mechanism of action, 
irinotecan is considered a potential carcinogen. 
 
Reproduction toxicity 
 
No reproductive and developmental toxicity studies have been performed with ONIVYDE pegylated 
liposomal. 
Non-liposomal irinotecan was teratogenic in rats and rabbits at doses below the human therapeutic 
dose. In rats, pups born from treated animals and having external abnormalities showed a decrease in 
fertility. This was not seen in morphologically normal pups. In pregnant rats there was a decrease in 
placental weight and in the offspring a decrease in foetal viability and increase in behavioural 
abnormalities. 



19 

Non-liposomal irinotecan caused atrophy of male reproductive organs both in rats and dogs after 
multiple daily doses of 20 mg/kg and 0.4 mg/kg, respectively.These effects were reversible upon 
cessation of treatment. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Liposome forming lipids 
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) 
Cholesterol 
N-(carbonyl-methoxypolyethylene glycol-2000)-1, 2-distearoly-sn-glycero-3-phosphoethanolamine 
(MPEG-2000-DSPE) 
 
Other excipients 
Sucrose octasulphate 
2- [ 4- (2-Hydroxyethyl)piperazin-1-yl] ethanesulfonic acid (HEPES buffer) 
Sodium chloride 
Water for injections 
 
6.2 Incompatibilities 
 
ONIVYDE pegylated liposomal must not be mixed with other medicinal products except those 
mentioned in section 6.6. 
 
6.3 Shelf life 
 
Unopened vial 
3 years. 
 
After dilution 
Chemical and physical stability for the diluted solution for infusion has been demonstrated at 15-25°C 
for up to 6 hours or in the refrigerator (2ºC-8ºC) for no more than 24 hours. 
From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions are the responsibility of the user. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C-8°C). 
Do not freeze. 
Keep the vial in the outer carton in order to protect from light. 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Type I glass vial with a grey chlorobutyl stopper and an aluminium seal with a flip-off cap, 
containing 10 ml of concentrate. 
Each pack contains one vial. 
 
6.6 Special precautions for disposal and other handling 
 
ONIVYDE pegylated liposomal is a cytotoxic medicinal product, and caution should be exercised in 
handling it. The use of gloves, goggles and protective clothing when handling or administering 
ONIVYDE pegylated liposomal is recommended. If the solution contacts the skin, the skin should be 
washed immediately and thoroughly with soap and water. If the solution contacts mucous membranes, 



20 

they should be flushed thoroughly with water. Pregnant staff should not handle ONIVYDE pegylated 
liposomal considering the cytotoxic nature of the medicinal product. 
 
Preparation of the solution and administration 
 
ONIVYDE pegylated liposomal is supplied as a sterile liposomal dispersion at a concentration 
of 4.3 mg/ml and must be diluted prior to administration. Dilute with 5% glucose solution for injection 
or sodium chloride 9 mg/ml (0.9%) solution for injection to prepare a solution of the appropriate dose 
of ONIVYDE pegylated liposomal diluted to a final volume of 500 ml. Mix the diluted solution by 
gentle inversion. The diluted solution is clear to slightly white to slightly opalescent and free from 
visible particles. 
 
ONIVYDE pegylated liposomal should be administered before LV followed by 5-FU. ONIVYDE 
pegylated liposomal must not be administered as a bolus injection or an undiluted solution. 
 
Aseptic techniques must be followed during the preparation of the infusion. ONIVYDE pegylated 
liposomal is for single use only. 
 
Care should be taken to avoid extravasation, and the infusion site should be monitored for signs of 
inflammation. Should extravasation occur, flushing the site with sodium chloride 9 mg/ml (0.9%) 
solution for injection and/or sterile water and applications of ice are recommended. 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/16/1130/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 14 October 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/


21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) 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 
 
 



22 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
Les Laboratoires Servier Industrie 
905 Route de Saran 
45520 Gidy  
France  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs 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 marketing authorisation holder (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.  
 

 
 



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



25 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ONIVYDE pegylated liposomal 4.3 mg/ml concentrate for solution for infusion 
irinotecan  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
One 10 ml vial of concentrate contains 43 mg irinotecan anhydrous free base (as irinotecan 
sucrosofate salt in a pegylated liposomal formulation).  
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: 
DSPC 
Cholesterol 
MPEG-2000-DSPE 
Sucrose octasulphate 
HEPES buffer 
Sodium chloride 
Water for injections 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion. 
43 mg/10 ml 
1 vial 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
For single use only. 
Read the package leaflet before use. 
Intravenous use after dilution. 
 
 
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 
 
Onivyde pegylated liposomal (irinotecan) is not equivalent to non-liposomal formulations. Do not 
interchange. 
 



26 

 
8. EXPIRY DATE 
 
EXP: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Keep the vial in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Cytotoxic: handle with caution and special disposal. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France  
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/16/1130/001 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 



27 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC  
SN  
NN  
 



28 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ONIVYDE pegylated liposomal 4.3 mg/ml concentrate for solution for infusion 
irinotecan  
IV use after dilution 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
43mg/10 ml 
 
 
6. OTHER 
 



29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



30 

Package leaflet: Information for the user 
 

ONIVYDE pegylated liposomal 4.3 mg/ml concentrate for solution for infusion 
irinotecan  

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

not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What ONIVYDE pegylated liposomal is and what it is used for 
2. What you need to know before you use ONIVYDE pegylated liposomal 
3. How ONIVYDE pegylated liposomal is used 
4. Possible side effects 
5. How to store ONIVYDE pegylated liposomal 
6. Contents of the pack and other information 
 
 
1. What ONIVYDE pegylated liposomal is and what it is used for 
 
What ONIVYDE pegylated liposomal is and how it works 
 
ONIVYDE pegylated liposomal is a cancer medicine that contains the active substance irinotecan. 
This active substance is held in tiny lipid (fatty) particles called liposomes. 
 
Irinotecan belongs to a group of cancer medicines called ‘topoisomerase inhibitors’. It blocks an 
enzyme called topoisomerase I, which is involved in the division of cell DNA. This prevents the 
cancer cells from multiplying and growing, and they eventually die. 
 
The liposomes are expected to accumulate within the tumour and release the medicine slowly over 
time, thereby allowing it to act for longer. 
 
What ONIVYDE pegylated liposomal is used for 
 
ONIVYDE pegylated liposomal is used to treat adult patients with metastatic pancreatic cancer 
(cancer of the pancreas that has already spread elsewhere in the body) whose previously cancer 
treatment included a medicine called gemcitabine. ONIVYDE pegylated liposomal is used in 
combination with other cancer medicines, called 5-fluorouracil and leucovorin. 
 
If you have any questions about how ONIVYDE pegylated liposomal works or why this medicine has 
been prescribed for you, ask your doctor. 
 
 
2. What you need to know before you use ONIVYDE pegylated liposomal 
 
Follow carefully all instructions given to you by your doctor. They may differ from the general 
information contained in this leaflet. 
 



31 

Do not use ONIVYDE pegylated liposomal 
 
- if you have a history of a severe allergy to irinotecan, or any of the other ingredients of this 

medicine (listed in section 6). 
- if you are breastfeeding 
 
Warnings and precautions 
 
Talk to your doctor or nurse before you are given ONIVYDE pegylated liposomal 
- if you have ever had any liver problems or jaundice 
- if you have ever had lung disease or have previously received medicines (colony stimulating 

factors) to increase your blood count or radiation therapy 
- if you are taking other medicines (see section “Other medicines and ONIVYDE pegylated 

liposomal”) 
- if you are planning to have a vaccination as many vaccinations must not be given during 

chemotherapy 
- if you are on a controlled sodium diet as this medicine contains sodium. 
 
Talk to your doctor or nurse immediately during treatment with ONIVYDE pegylated liposomal 
- if you feel sudden shortness of breath, flushing, headache, skin rash or hives (itchy rash with 

swollen red bumps on the skin that appear suddenly), itching, swelling around the eyes, 
tightness in the chest or throat during or shortly after your infusion 

- if you experience fever, chills or other symptoms of infection 
- if you get diarrhoea with frequent liquid stools and cannot control this after 12 to 24 hours of 

treatment (see below) 
- if you get breathlessness or cough.  
- if you experience signs or symptoms of a blood clot, like sudden pain and swelling in a leg or an 

arm, sudden onset of coughing, chest pain or difficulty breathing. 
 
What to do in case of diarrhoea 
 
As soon as the first liquid stool occurs, start drinking large volumes ofrehydration fluids (е.g. water, 
soda water, fizzy drinks, soup) to avoid losing too much liquid and salts from your body. Contact your 
doctor immediately to give you a suitable treatment. Your doctor may give you a medicine which 
contains loperamide to begin treatment at home but it must not be used for longer than 48 consecutive 
hours. If loose stools persist, contact your doctor. 
 
Blood tests and medical examinations 
 
Before you start treatment with ONIVYDE pegylated liposomal, your doctor will perform blood tests 
(or other medical examinations) to determine the best starting dose for you. You will need to have 
further (blood or other) tests during treatment so that your doctor can monitor your blood cells and 
assess how you are responding to the treatment. Your doctor may need to adjust the dose or stop 
treatment. 
 
Children and adolescents 
 
ONIVYDE pegylated liposomal is not recommended for use in adolescents and children below the age 
of 18 years. 
 
Other medicines and ONIVYDE pegylated liposomal 
 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
It is especially important that you tell your doctor if you have been given irinotecan in any form 
earlier. 



32 

ONIVYDE pegylated liposomal must not be used instead of other medicines containing irinotecan 
because it behaves differently when it is contained in the liposomes than when it is given in its free 
form. 
 
It is also especially important that you tell your doctor if you are also taking the following medicines, 
since they reduce the availability of irinotecan in your body: 
- phenytoin, phenobarbital or carbamazepine (medicines used to treat convulsions and falls) 
- rifampicin and rifabutin (medicines used to treat tuberculosis) 
- St. John´s wort (a plant based medicine used to treat depression and low mood) 
- as ONIVYDE pegylated liposomal should not be given to you together with these medicines. 
 
It is especially important that you tell your doctor if you are also taking the following medicines, since 
they increase the availability of irinotecan in your body: 
- ketoconazole, itraconazole or voriconazole (medicines used to treat fungal infections) 
- clarithromycin (an antibiotic medicine used to treat bacterial infections) 
- indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, atazanavir (medicines against HIV 

infection)  
- regorafenib (a medicine used to treat certain forms of cancer) 
- telaprevir (a medicine used to treat a liver disease called hepatitis C) 
- nefazodone (a medicine used to treat depression, low mood) 
- gemfibrozil (medicine used to treat high fat levels in the blood) 
 
ONIVYDE pegylated liposomal with food and drink 
 
Avoid eating grapefruits and drinking grapefruit juice while you are receiving ONIVYDE pegylated 
liposomal as it may increase the availability of the active substance of ONIVYDE pegylated liposomal 
in your body. 
 
Pregnancy and breast-feeding 
 
You should not be given ONIVYDE pegylated liposomal if you are pregnant as it may harm the baby. 
Tell your doctor if you are or think you may be pregnant. Ask your doctor for advice if you are 
planning to have a baby. If you are given ONIVYDE pegylated liposomal you should not breast-feed 
until one month after the last dose. 
 
During your ONIVYDE pegylated liposomal treatment and one month after you should choose an 
effective birth control method which suits you, to prevent pregnancy in this period of time. Males 
should use condoms during ONIVYDE pegylated liposomal treatment and 4 months thereafter. 
 
Tell your doctor if you are breast-feeding. You must not be given ONIVYDE pegylated liposomal if 
you are breast-feeding as this may be harmful to your baby. 
 
Driving and using machines 
 
ONIVYDE pegylated liposomal may influence your ability to drive and use machines (as you may be 
sleepy, dizzy and exhausted with the use of ONIVYDE pegylated liposomal). You should avoid 
driving, using machines or performing other tasks that need full attention if you feel sleepy, dizzy and 
exhausted. 
 
ONIVYDE pegylated liposomal contains sodium 
 
One millilitre of this medicine contains 0.144 mmol (3.31 mg) sodium—keep this in mind if you are 
on a controlled sodium diet. 
 
 



33 

3. How ONIVYDE pegylated liposomal is used 
 
ONIVYDE pegylated liposomal must only be given by healthcare professionals trained in giving 
anticancer medicines 
Carefully follow all instructions given to you by your doctor or nurse. 
 
Your doctor will decide upon the doses you will receive. 
ONIVYDE pegylated liposomal is given as a drip (infusion) into a vein, which should take at 
least 90 minutes and should be given as a single dose. 
After you have been given ONIVYDE pegylated liposomal you will be given two other medicines, 
leucovorin and 5-fluorouracil. 
The treatment will be repeated every two weeks. 
 
In certain cases, lower doses or longer dosing intervals may be required. 
 
You may receive pre-medication against nausea and vomiting. If you have experienced sweating, 
abdominal cramping and salivation together with early frequent and liquid stools in previous 
treatments with ONIVYDE pegylated liposomal, you may receive additional medicines before 
ONIVYDE pegylated liposomal to prevent or reduce this in the following treament cycles. 
 
If you have any further questions on the use of this medicine, ask your doctor or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. It is 
important that you are aware of what these side effects may be. 
 
Your doctor may also prescribe other medicines to help control your side effects. 
 
Tell your doctor or nurse about any of the following serious side effects straight away: 
 
- if you experience sudden shortness of breath, flushing, nausea, headache, skin rash or hives 

(itchy rash with swollen red bumps on the skin that appear suddenly), itching, swelling around 
the eyes, tightness in the chest or throat during the infusion or shortly after it (as the infusion 
may need to be stopped and you may need to be treated or observed for the side effects) 

- if you get fever, chills and signs of an infection (as this might require immediate treatment) 
- if you have severe persistent diarrhoea (liquid and frequent stools)—see section 2 
 
The following side effects may occur: 
 
Very common (may affect more than 1 in 10 people) 
- Low levels of white blood cells (neutropenia and leukopenia), Low level of red blood cells 

(anaemia) 
- Low level of blood platelets (thrombocytopenia) 
- Diarrhoea (loose or watery and frequent stools) 
- Nausea and vomiting 
- Pain in the stomach or in the gut area 
- Sore mouth 
- Loss of weight 
- Loss of appetite 
- Loss of body fluid (dehydration) 
- Low level of salts (electrolytes) in the body (e.g. of potassium, magnesium) 
- Unusual hair loss 
- Tiredness 
- Dizziness 
- Swelling and fluid retention in the soft tissues (peripheral oedema) 



34 

- Soreness and swelling of the digestive tract lining (mucosal inflammation) 
- Fever 
- Generalised weakness 
 
Common (may affect up to 1 in 10 people) 
- Chills 
- Infections, for example fungal infections in the mouth (oral candidiasis), fever with low counts 

of white blood cells (febrile neutropenia), infections related to the administration of the product 
into a vein 

- Inflammation of the stomach and the guts (gastroenteritis) 
- Systemic body inflammation, caused by infection (sepsis) 
- Potentially life-threatening complication of whole body inflammation (septic shock) 
- Infection of the lungs (pneumonia) 
- Low level of white blood cells subtype, called lymphocytes with important function for the 

immune system (lymphopenia) 
- Decrease in some salts (electrolytes) in the body (e.g. phosphate, sodium) 
- Low blood sugar (hypoglycaemia) 
- Sleeplessness 
- Bad taste in the mouth 
- A syndrome called cholinergic syndrome with sweating, salivation and abdominal cramping 
- Low blood pressure (hypotension) 
- Formation of a blood clot in a deep vein (deep vein thrombosis) or blockage of the main artery 

of the lung or one of its branches (pulmonary embolism), or blockage due to a blood clot 
elsewhere in the blood stream (embolism) 

- Voice impairment, hoarse or excessively breathy voice 
- Shortness of breath 
- Inflammation in the gut 
- Piles(haemorrhoids) 
- Increases in liver enzymes (alanine aminotransferase or aspartate aminotransferase) in 

laboratory blood tests 
- Increase in bilirubin levels (an orange-yellow pigment, waste product of the normal breakdown 

of the red blood cells) in other laboratory measurements related to liver function 
- Increase in other laboratory measurements (increased international normalized ratio) related to 

the blood clotting system function 
- Abnormally low blood levels of albumin (major protein in the body) 
- Sudden problems with kidney function which may lead to rapid deterioration or loss of the 

kidney function 
- Abnormal reaction to the infusion causing symptoms like shortness of breath, flushing, 

headache, tightness in the chest or throat 
- Abnormal fluid retention in the body causing swelling in the affected tissues (oedema) 
 
Uncommon (may affect up to 1 in 100 people) 
- Systemic body inflammation, caused by infection of the gall bladder and bile ducts (biliary 

sepsis) 
- Allergic reaction to ONIVYDE pegylated liposomal (the active substance or the excipients) 
- Diminished availability of oxygen to the body tissues 
- Inflammation of the oesophagus (food pipe) 
- Formation or presence of a blood clot within a blood vessel – vein or artery (thrombosis) 
- Inflammation of the lining of the rectum (the end of the large intestine) 
- Type of rash, characterised by appearance of a flat, red area on the skin covered with bumps 

(maculo-papular rash) 
- Change in the colour of the nail plates 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor 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 



35 

Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store ONIVYDE pegylated liposomal 
 
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 vial after “EXP”. The 
expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C - 8°C). 
Do not freeze. 
Keep the vial in the outer carton in order to protect from light. 
 
Once the concentrate has been diluted for infusion with 5% glucose solution for injection or sodium 
chloride 9 mg/ml (0.9%) solution for injection, the solution should be used as soon as possible, but 
may be stored at ambient temperature (15°C to 25°C) for up to 6 hours. The diluted solution for 
infusion can be stored in the refrigerator (2°C - 8°C) for no more than 24 hours prior to use. It must be 
protected from light, and it must not be frozen. 
 
Do not throw away this medicine via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What ONIVYDE pegylated liposomal contains 
 
• The active substance is irinotecan. One 10 ml vial of concentrate contains 43 mg irinotecan 

anhydrous free base (as sucrosofate salt in a pegylated liposomal formulation).  
• The other ingredients are: 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); cholesterol, 

N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoly-sn-glycero-3-phosphoethanolam
ine (MPEG-2000-DSPE); Sucrose 
octasulphate; 2- [4- (2-Hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES buffer); 
sodium chloride and water for injections. ONIVYDE pegylated liposomal contains sodium, if 
you are on a controlled sodium diet, see section 2. 

 
What ONIVYDE pegylated liposomal looks like and contents of the pack 
 
ONIVYDE pegylated liposomal is supplied as a white to slightly yellow opaque isotonic liposomal 
dispersion in a glass vial. 
 
Each pack contains one vial with 10 ml of concentrate. 
 
Marketing Authorisation Holder 
Les Laboratoires Servier 
50, rue Carnot 
92284 Suresnes cedex 
France 
 
Manufacturer 
Les Laboratoires Servier Industrie 
905 Route de Saran 
45520 Gidy  
France  
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


36 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
S.A. Servier Benelux N.V. 
Tél/Tel: +32 (0)2 529 43 11 
 

Lietuva 
UAB “SERVIER PHARMA” 
Tel: +370 (5) 2 63 86 28 
 

България 
Сервие Медикал ЕООД 
Тел.: +359 2 921 57 00 
 

Luxembourg/Luxemburg 
S.A. Servier Benelux N.V. 
Tel: +32 (0)2 529 43 11 
 

Česká republika 
Servier s.r.o. 
Tel: +420 222 118 111 
 

Magyarország 
Servier Hungaria Kft. 
Tel: +36 1 238 7799 
 

Danmark 
Servier Danmark A/S 
Tlf: +45 36 44 22 60 
 

Malta 
V.J. Salomone Pharma Ltd  
Tel: + 356 21 22 01 74 
 
 

Deutschland 
Servier Deutschland GmbH 
Tel: +49 (0)89 57095 01 
 

Nederland 
Servier Nederland Farma B.V. 
Tel: + 31 (0)71 5246700 
 

Eesti 
Servier Laboratories OÜ  
Tel:+ 372 664 5040 
 

Norge 
Servier Danmark A/S 
Tlf: +45 36 44 22 60 
 

Eλλάδα 
ΣΕΡΒΙΕ ΕΛΛΑΣ ΦΑΡΜΑΚΕΥΤΙΚΗ ΕΠΕ 
Τηλ: + 30 210 939 1000 
 

Österreich 
Servier Austria GmbH 
Tel: +43 (1) 524 39 99 
 

España 
Laboratorios Servier S.L. 
Tel: + 34 91 748 96 30 
 

Polska 
Servier Polska Sp. z o.o. 
Tel: + 48 (0) 22 594 90 00 
 

France 
Les Laboratoires Servier 
Tél: + 33 (0)1 55 72 60 00 
 

Portugal 
Servier Portugal, Lda 
Tel: + 351 21 312 20 00 
 

Hrvatska 
Servier Pharma, d. o. o. 
Tel: + 385 (0)1 3016 222 
 

România 
Servier Pharma SRL 
Tel: + 4 021 528 52 80 
 

Ireland 
Servier Laboratories (Ireland) Ltd. 
Tel: + 353 (0)1 663 8110 
 

Slovenija 
Servier Pharma d. o. o.  
Tel: + 386 (0)1 563 48 11 
 

Ísland 
Servier Laboratories 
c/o Icepharma hf 
Sími: + 354 540 8000 
 

Slovenská republika 
Servier Slovensko spol. s r.o. 
Tel: + 421 2 5920 41 11 
 

Italia 
Servier Italia S.p.A. 
Tel: + 39 (06) 669081 
 

Suomi/Finland 
Servier Finland Oy 
P. /Tel: +358 (0)9 279 80 80 
 



37 

Κύπρος 
CA Papaellinas Ltd. 
Τηλ: + 357 22 741 741 
 

Sverige 
Servier Sverige AB 
Tel : +46 (0)8 522 508 00 
 

Latvija 
SIA Servier Latvia 
Tel: + 371 67502039 
 

United Kingdom 
Servier Laboratories Ltd 
Tel: +44 (0)1753 666409 
 

This leaflet was last revised in 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
------------------------------------------------------------------------------------------------------------------------ 
 
The following information is intended for healthcare professionals only: 
 
How to prepare and administer ONIVYDE pegylated liposomal 
 
• ONIVYDE pegylated liposomal is supplied as a sterile liposomal dispersion at a concentration 

of 4.3 mg/ml and must be diluted prior to administration. Dilute with 5% glucose solution for 
injection or sodium chloride 9 mg/ml (0.9%) solution for injection to prepare a dispersion of the 
appropriate dose of ONIVYDE pegylated liposomal diluted to a final volume of 500 ml. Mix 
diluted solution by gentle inversion. 

• ONIVYDE pegylated liposomal should be administered before leucovorin followed 
by 5-fluorouracil. ONIVYDE pegylated liposomal must not be administered as a bolus injection 
or an undiluted solution. 

• Aseptic techniques must be followed during the preparation of the infusion. ONIVYDE 
pegylated liposomal is for single use only. 

• From a microbiological point of view, the product should be used as soon as possible after 
dilution. The diluted solution for infusion can be stored at ambient temperature (15°C to 25°C) 
for up to 6 hours or in the refrigerator (2ºC - 8ºC) for no more than 24 hours prior to use. It must 
be protected from light, and it must not be frozen. 

• Care should be taken to avoid extravasation, and the infusion site should be monitored for signs 
of inflammation. Should extravasation occur, flushing the site with sodium chloride 9 mg/ml 
(0.9%) solution for injection and/or sterile water and applications of ice are recommended. 

 
How to handle and dispose of ONIVYDE pegylated liposomal 
 
• ONIVYDE pegylated liposomal is a cytotoxic medicinal product and caution should be 

exercised in handling it. The use of gloves, goggles and protective clothing when handling or 
administering ONIVYDE pegylated liposomal is recommended. If the solution contacts the 
skin, the skin should be washed immediately and thoroughly with soap and water. If the solution 
contacts mucous membranes, they should be flushed thoroughly with water. Pregnant staff 
should not handle ONIVYDE pegylated liposomal considering the cytotoxic nature of the 
medicinal product. 

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

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


38 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 
OF THE MARKETING AUTHORISATION(S) 



39 

Scientific conclusions 

Taking into account the PRAC Assessment Report on the PSUR(s) for irinotecan (liposomal 
formulations), the scientific conclusions of CHMP are as follows:  

In view of available data on the drug-drug interaction between irinotecan and an UGT1A1 inhibitor, 
regorafenib, the PRAC concluded that the product information of products containing irinotecan 
(liposomal formulations) should be amended accordingly.  

Update of section 4.5 of the SmPC to add regorafenib to the list of examples of UGT1A1 inhibitors. 
The Package leaflet is updated accordingly. The MAH also took the occasion to align the PI to QRD 
version 10.1. 

The CHMP agrees with the scientific conclusions made by the PRAC. 

 

Grounds for the variation to the terms of the marketing authorisation(s) 

On the basis of the scientific conclusions for irinotecan (liposomal formulations) the CHMP is of the 
opinion that the benefit-risk balance of the medicinal product(s) containing irinotecan (liposomal 
formulations) is unchanged subject to the proposed changes to the product information 

The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 

 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) 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
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)