ONIVYDE PEGYLATED LIPOSOMAL 4.3mg / ml concentrate for dispersion for infusion medication leaflet

ONIVYDE pegylated liposomal 4.3 mg/ml concentrate for dispersion for infusion

One 10 ml vial of concentrate contains 43 mg irinotecan anhydrous free base (as irinotecansucrosofate salt in a pegylated liposomal formulation).

One ml of concentrate contains 4.3 mg irinotecan anhydrous free base (as irinotecan sucrosofate salt ina pegylated liposomal formulation).

One ml of concentrate contains 0.144 mmol (3.31 mg) sodium.

For the full list of excipients, see section 6.1.

Concentrate for dispersion 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.

ONIVYDE pegylated liposomal is indicated:

- in combination with oxaliplatin, 5-fluorouracil (5-FU) and leucovorin (LV) for the first-linetreatment of adult patients with metastatic adenocarcinoma of the pancreas,

- in combination with 5-FU and LV for the treatment of metastatic adenocarcinoma of the pancreas inadult patients who have progressed following gemcitabine based therapy.

ONIVYDE pegylated liposomal must only be prescribed and administered to patients by healthcareprofessionals experienced in the use of anti-cancer therapies.

ONIVYDE pegylated liposomal is not equivalent to non-liposomal irinotecan formulations and shouldnot be interchanged.

ONIVYDE pegylated liposomal should not be administered as a single agent and should be continueduntil disease progression or no longer tolerated by the patient.

ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin:

ONIVYDE pegylated liposomal, oxaliplatin, LV and 5-FU should be administered sequentially. Therecommended dose of ONIVYDE pegylated liposomal is 50 mg/m² intravenously over 90 minutes,followed by oxaliplatin 60 mg/m2 intravenously over 120 minutes, followed by LV 400 mg/m2intravenously over 30 minutes, followed by 5-FU 2,400 mg/m2 intravenously over 46 hours. Thisregimen should be administered every 2 weeks.

Oxaliplatin may be discontinued if not well tolerated and treatment with ONIVYDE pegylatedliposomal + 5-FU/LV can continue.

The recommended starting dose of ONIVYDE pegylated liposomal in patients known to behomozygous for UGT1A1*28 allele is unchanged and remains 50 mg/m2 administered intravenouslyover 90 minutes (see sections 5.1 and 5.2).

ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin:

ONIVYDE pegylated liposomal, leucovorin and 5-fluorouracil should be administered sequentially.

The recommended dose and regimen of ONIVYDE pegylated liposomal is 70 mg/m2 intravenouslyover 90 minutes, followed by LV 400 mg/m2 intravenously over 30 minutes, followedby 5-FU 2,400 mg/m2 intravenously over 46 hours, administered every 2 weeks.

A reduced starting dose of ONIVYDE pegylated liposomal of 50 mg/m2 should be considered forpatients known to be homozygous for the UGT1A1*28 allele (see sections 4.8 and 5.1). A doseincrease of ONIVYDE pegylated liposomal to 70 mg/m2 should be considered if tolerated insubsequent cycles.

Pre-medication

It is recommended that patients receive pre-medication with standard doses of dexamethasone (or anequivalent corticosteroid) together with a 5-HT3 antagonist (or other antiemetic) at least 30 minutesprior to ONIVYDE pegylated liposomal infusion.

All dose modifications should be based on the worst preceding toxicity. The LV dose does not requireadjustment.

ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin:

Table 1: Recommended dose modifications for ONIVYDE pegylated liposomal + oxaliplatin/5-

FU/LV

Toxicity grade(value) by NCI ONIVYDE pegylated liposomal/Oxaliplatin/5-FU adjustments

CTCAE†

Neutropenia A new cycle of therapy should not begin until the absolute neutrophilcount is ≥2,000/mm3 (2x109/L)

Reduce ONIVYDE pegylated liposomal dose to

First occurrence 80% of initial dose

Reduce oxaliplatin and 5-FU dose by 20%

Reduce ONIVYDE pegylated liposomal dose to

Grade 3 or Grade 4 Second occurrence 65% of initial dose(<1,000 cells/mm3) Reduce oxaliplatin and 5-FU dose by an additionalor Neutropenic fever 15%

Reduce ONIVYDE pegylated liposomal dose to

Third occurrence 50% of initial dose

Reduce oxaliplatin and 5-FU dose by an additional15%

Fourth occurence Discontinue treatment

Thrombocytopenia A new cycle of therapy should not begin until the platelet count is

Leukopenia ≥100,000/mm3 (100x109/L).

Toxicity grade(value) by NCI ONIVYDE pegylated liposomal/Oxaliplatin/5-FU adjustments

CTCAE†

Dose modifications for leukopenia and thrombocytopenia are based on

NCI CTCAE toxicity grading and are the same as recommended forneutropenia above.

Non-haematological toxicities*

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

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

Reduce ONIVYDE pegylated liposomal dose to

First occurrence 80% of initial dose

Reduce oxaliplatin and 5-FU dose by 20%

Reduce ONIVYDE pegylated liposomal dose to

Second occurrence 65% of initial dose

Grade 3 or 4 Reduce oxaliplatin and 5-FU dose by an additional15%

Reduce ONIVYDE pegylated liposomal dose to

Third occurrence 50% of initial dose

Reduce oxaliplatin and 5-FU dose by anadditional15%

Fourth occurrence Discontinue treatment

Reduce ONIVYDE pegylated liposomal dose to

All other toxicities* First occurrence 80% of initial dose

Grade 3 or 4 Reduce oxaliplatin and 5-FU dose by 20%

Reduce ONIVYDE pegylated liposomal dose to65%

Second occurrence of initial dose

Reduce oxaliplatin and 5-FU dose by an additional15%

Reduce ONIVYDE pegylated liposomal dose to

Third occurrence 50% of initial dose

Reduce oxaliplatin and 5-FU dose by an additional15%

Fourth occurrence Discontinue treatment

For Grade ≥ 3nausea and vomiting Reduce dose only if occurs despite optimal anti-emetic therapy

Hand foot syndrome:

Grade 3 or 4 First occurrence Discontinue treatment

Any gradeneurocerebellar or ≥ First occurrence Discontinue treatment

Grade 2 cardiactoxicity

Anaphylactic First occurrence Discontinue treatmentreaction

Interstitial lung First occurrence Discontinue treatmentdisease

* Excludes asthenia and anorexia;† NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events,current version

Patients homozygous for the UGT1A1*28 allele should initiate ONIVYDE pegylated liposomal at thesame dose and the same dose reduction requirements should apply.

ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin:

For patients who start treatment with 50 mg/m2 ONIVYDE pegylated liposomal and do not doseescalate to 70 mg/m2, the recommended first dose reduction is to 43 mg/m2 and the second dosereduction 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 duringthe first cycle of therapy (reduced dose of 50 mg/m2) may have the dose of ONIVYDE pegylatedliposomal increased to a total dose of 70 mg/m2 in subsequent cycles based on individual patienttolerance.

Table 2: 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) ONIVYDE pegylated liposomal /5-FU adjustmentby NCI CTCAE1 (for patients not homozygous for UGT1A1*28)

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

Grade 3 or Reduce ONIVYDE pegylated liposomal dose

Grade 4 (< 1,000 First occurrence to 50 mg/m2cells/mm3) or Reduce 5-FU dose by 25% (1,800 mg/m2).

Neutropenic fever Reduce ONIVYDE pegylated liposomal dose

Second occurrence to 43 mg/m

Reduce 5-FU dose by an additional 25%(1,350 mg/m2).

Third occurrence Discontinue treatment

Thrombocytopenia A new cycle of therapy should not begin until the platelet count is≥ 100,000 platelets/mm3

Leukopenia Dose modifications for leukopenia and thrombocytopenia are based on

NCI CTCAE toxicity grading and are the same as recommended forneutropenia above.

Non-haematological toxicities2

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

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

Grade 3 or 4 Reduce ONIVYDE pegylated liposomal dose

First occurrence to 50 mg/m2

Reduce 5-FU dose by 25% (1,800 mg/m2)

Reduce ONIVYDE pegylated liposomal dose

Second occurrence to 43 mg/m

Reduce 5-FU dose by an additional 25%(1,350 mg/m2)

Third occurrence Discontinue treatment

Toxicity grade (value) ONIVYDE pegylated liposomal /5-FU adjustmentby NCI CTCAE1 (for patients not homozygous for UGT1A1*28)

Nausea/vomiting A new cycle of therapy should not begin until nausea/vomiting resolvesto ≤ Grade 1 or baseline

Grade 3 or 4 (despite Optimise antiemetic therapyantiemetic therapy) First occurrence Reduce ONIVYDE pegylated liposomal doseto 50 mg/m2

Optimise antiemetic therapy

Second occurrence Reduce ONIVYDE pegylated liposomal doseto 43 mg/m2

Third occurrence Discontinue treatment

Hepatic, renal, A new cycle of therapy should not begin until the adverse reactionrespiratory or resolves to ≤ Grade 1other2 toxicities

Grade 3 or 4 Reduce ONIVYDE pegylated liposomal dose

First occurrence to 50 mg/m2

Reduce 5-FU dose by 25% (1,800 mg/m2)

Reduce ONIVYDE pegylated liposomal dose

Second occurrence to 43 mg/m2

Reduce 5-FU dose by anadditional 25% (1,350 mg/m2)

Third occurrence Discontinue treatment

Anaphylactic reaction First occurrence Discontinue treatment

Interstitial Lung First occurrence Discontinue treatment

Disease1 NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events,current version2 Excludes asthenia and anorexia; Asthenia and Grade 3 anorexia do not require dose adjustment.

Table 3: Recommended dose modifications for ONIVYDE pegylated liposomal +5-FU/LV for

Grade 3-4 toxicities in patients homozygous for UGT1A1*28

Toxicity grade (value) ONIVYDE pegylated liposomal /5-FU adjustmentby NCI CTCAE1 (for patients homozygous for UGT1A1*28 without previousincrease3 to 70 mg/m2)

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

Reduce ONIVYDE pegylated liposomal dose to

First occurrence 43 mg/m2

Adverse reactions2 5-FU dose modification as in Table 2

Grade 3 or 4 Reduce ONIVYDE pegylated liposomal dose to

Second occurrence 35 mg/m25-FU dose modification as in Table 2

Third occurrence Discontinue treatment

Anaphylactic reaction First occurrence Discontinue treatment

Interstitial Lung First occurrence Discontinue treatment

Disease1 NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events,current version2 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 insubsequent cycles, recommended dose modifications should follow Table 2.

No dedicated hepatic impairment study has been conducted with ONIVYDE pegylated liposomal. Theuse of ONIVYDE pegylated liposomal should be avoided in patients with bilirubin > 2.0 mg/dl, oraspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 2.5 times upper limit ofnormal (ULN) or > 5 times ULN if liver metastasis is present (see section 4.4).

No dedicated renal impairment study has been conducted with ONIVYDE pegylated liposomal. Nodose adjustment is recommended in patients with mild to moderate renal impairment (seesections 4.4 and 5.2). ONIVYDE pegylated liposomal is not recommended for use in patients withsevere renal impairment (CLcr < 30 ml/min).

Forty-nine percent (49.6 %) in NAPOLI-3 and forty-one percent (41%) in NAPOLI-1 of patientstreated with ONIVYDE pegylated liposomal were ≥ 65 years. No dose adjustment is recommended.

The safety and efficacy of ONIVYDE pegylated liposomal in children and adolescentsaged ≤ 18 years have not yet been established. No data are available.

ONIVYDE pegylated liposomal is for intravenous use. The concentrate must be diluted prior toadministration and given as a single intravenous infusion over 90 minutes. For more details, seesection 6.6.

ONIVYDE pegylated liposomal is a cytotoxic medicinal product. The use of gloves, goggles andprotective clothing when handling or administering ONIVYDE pegylated liposomal is recommended.

Pregnant staff should not handle ONIVYDE pegylated liposomal.

History of severe hypersensitivity to irinotecan or to any of the excipients listed in section 6.1.

Breast-feeding (see section 4.6).

ONIVYDE pegylated liposomal is a liposomal formulation of irinotecan with differentpharmacokinetic properties compared to non-liposomal irinotecan. The dose concentration andstrength are different in comparison to non-liposomal irinotecans.

ONIVYDE pegylated liposomal is not equivalent to other non-liposomal irinotecan formulations andshould not be interchanged.

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 liposomaltreatment. Patients should be aware of the risk of neutropenia and the significance of fever. Febrileneutropenia (body temperature > 38°C and neutrophil count ≤ 1,000 cells/mm³) should be urgentlytreated in the hospital with broad-spectrum intravenous antibiotics. Sepsis with neutropenic fever andconsequent septic shock with fatal outcome has been observed in patients with metastatic pancreaticadenocarcinoma treated with ONIVYDE pegylated liposomal.

In patients who experienced severe haematological events, a dose reduction or treatmentdiscontinuation is recommended (see section 4.2). Patients with severe bone marrow failure should notbe treated with ONIVYDE pegylated liposomal.

History of prior abdominal radiation increases the risk of severe neutropenia and febrile neutropeniafollowing ONIVYDE pegylated liposomal treatment. Close monitoring of blood counts isrecommended, and the use of myeloid growth factors should be considered for patients with a historyof 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 atgreater risk of myelosuppression when receiving therapy with ONIVYDE pegylated liposomal.

Immunosuppressive effects and vaccines

Administration of live or live-attenuated vaccines in patients immunocompromised bychemotherapeutic medicinal products including ONIVYDE pegylated liposomal may result in seriousor fatal infections; therefore vaccination with a live vaccine should be avoided. Killed or inactivatedvaccines 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 inducerssuch as anticonvulsants (phenytoin, phenobarbital or carbamazepine), rifampin, rifabutin and St.

John’s wort unless there are no therapeutic alternatives. The appropriate starting dose for patientstaking these anticonvulsants or other strong inducers has not been defined. Consideration should begiven 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 atleast 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.

ONIVYDE pegylated liposomal can cause severe and life-threatening diarrhoea. ONIVYDE pegylatedliposomal must not be administered to patients with bowel obstruction, and chronic inflammatorybowel disease.

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 or cholinergic symptoms, prophylactic or therapeutic atropineshould be considered unless contraindicated. Patients should be made aware of the risk of delayeddiarrhoea which can be debilitating and, on rare occasions, life threatening since persistent loose orwatery 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 beveragescontaining electrolytes. Patients should have loperamide (or equivalent) readily available to begintreatment for late diarrhoea. Loperamide should be initiated at first occurrence of poorly formed orloose stools or at the earliest onset of bowel movements more frequent than normal (maximum of 16mg/day). Loperamide should be given until the patient is without diarrhoea for at least 12 hours. Tohelp avoid severe diarrhoea, stop all lactose-containing products, maintain hydration and eat a low-fatdiet.

If diarrhoea persists while the patient is on loperamide for more than 24 hours, adding oral antibioticsupport (e.g. fluoroquinolone for 7 days) should be considered. Loperamide should not be used formore than 48 consecutive hours due to risk of paralytic ileus. If diarrhoea persists for morethan 48 hours, stop loperamide, monitor and replace fluid electrolytes and continue antibiotic supportuntil resolution for accompanying symptoms.

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

Following Grade 3 or 4 diarrhoea, the subsequent dose of ONIVYDE pegylated liposomal should bereduced (see section 4.2).

Cholinergic reactions

Early onset diarrhoea may be accompanied by cholinergic symptoms such as rhinitis, increasedsalivation, flushing, diaphoresis, bradycardia, miosis and hyperperistalsis. In case of cholinergicsymptoms atropine should be administered.

Hypersensitivity reaction including acute infusion related reactions

Infusion reactions primarily consisting of rash, urticaria, periorbital oedema or pruritus were reportedin 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 outof 10 patients noted with events after the fifth dose. Hypersensitivity reactions, including acuteinfusion reaction, anaphylactic/anaphylactoid reaction and angioedema may occur. ONIVYDEpegylated liposomal should be discontinued in case of severe hypersensitivity reactions (see section4.2).

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. Patients should bemonitored for signs of infections.

ONIVYDE pegylated liposomal has been associated with thromboembolic events such as pulmonaryembolism, venous thrombosis and arterial thromboembolism. A thorough medical history should beobtained 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 tocontact their physician or nurse immediately if any such signs or symptoms should occur.

Interstitial Lung Disease (ILD)-like events leading to fatalities have occurred in patients receivingnon-liposomal irinotecan. In NAPOLI-3 study, pneumonitis was reported in 0.3% of patients receiving

ONIVYDE pegylated liposomal in combination with oxaliplatin and 5-FU/LV. Risk factors includepre-existing lung disease, use of pneumotoxic medicinal products, colony stimulating factors or havingpreviously received radiation therapy. Patients with risk factors should be closely monitored forrespiratory symptoms before and during ONIVYDE pegylated liposomal therapy. A reticulo-nodularpattern on chest X-ray was observed in a small percentage of patients enrolled in a clinical study withirinotecan. New or progressive dyspnoea, cough, and fever should prompt interruption of ONIVYDEpegylated liposomal treatment, pending diagnostic evaluation. ONIVYDE pegylated liposomal shouldbe discontinued in patients with a confirmed diagnosis of ILD (see section 4.2).

Patients with hyperbilirubinaemia had higher concentrations for total SN-38 (see section 5.2) andtherefore the risk of neutropenia is increased. Regular monitoring of complete blood counts should beconducted in patients with total bilirubin of 1.0-2.0 mg/dl. Caution should be exercised in patients withhepatic 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 otherhepatotoxic medicinal products, especially in patients with pre-existing hepatic impairment.

Underweight patients (body mass index < 18.5 kg/m2)

In NAPOLI-1, 5 of 8 underweight patients experienced Grade 3 or 4 adverse reactions, mostlymyelosuppression, while 7 of the 8 patients required dose modification such as dose delay, dosereduction or dose discontinuation. Caution should be exercised when using ONIVYDE pegylatedliposomal in patients with body mass index < 18.5 kg/m2.

This medicinal product contains 33,1 mg sodium per vial, equivalent to 1,65% of the WHOrecommended maximum daily intake of 2g sodium for an adult.

Information about drug interactions with ONIVYDE pegylated liposomal is referenced from thepublished scientific literature for nonliposomal irinotecan.

Interaction affecting the use of ONIVYDE pegylated liposomal

Patients receiving concomitant non-liposomal irinotecan and CYP3A4 enzyme-inducinganticonvulsants phenytoin, phenobarbital or carbamazepine have substantially reduced exposure toirinotecan (AUC reduction by 12% with St John’s wort, 57%-79% with phenytoin, phenobarbital, orcarbamazepine) and SN-38 (AUC reduction by 42% with St John’s wort, 36%-92% with phenytoinphenobarbital, or carbamazepine). Therefore, co-administration of ONIVYDE pegylated liposomalwith 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. Basedon the drug interaction of non-liposomal irinotecan and ketoconazole, co-administration of ONIVYDEpegylated 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 pharmacokineticsof ONIVYDE pegylated liposomal based on the population pharmacokinetic analysis.

Antineoplastic agents (including flucytosine as a prodrug for 5-fluorouracil)

Adverse effects of irinotecan, such as myelosuppression, may be exacerbated by otherantineoplastic agents having a similar adverse-effect profile.

No interaction of ONIVYDE pegylated liposomal with other medicinal products is known.

Women of childbearing potential/contraception in males and females

Women of childbearing potential should use effective contraception during ONIVYDE pegylatedliposomal treatment and 7 months thereafter. Males should use condoms during ONIVYDE pegylatedliposomal treatment and 4 months thereafter.

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 pregnantwoman, as the main ingredient irinotecan has been shown to be embryotoxic and teratogenic inanimals (see section 5.3). Therefore, based on results from animal studies and the mechanism of actionof irinotecan, ONIVYDE pegylated liposomal should not be used during pregnancy unless clearlynecessary. If ONIVYDE pegylated liposomal is used during pregnancy or if the patient becomespregnant while receiving therapy, the patient should be informed about the potential hazard to thefoetus.

It is unknown whether ONIVYDE pegylated liposomal or its metabolites are excreted into humanmilk. Because of the potential for serious adverse reactions of ONIVYDE pegylated liposomal inbreast-feeding infants, ONIVYDE pegylated liposomal is contraindicated during breast-feeding (seesection 4.3). Patients should not breast-feed until one month after the last dose.

There are no data on the impact of ONIVYDE pegylated liposomal on human fertility. Non-liposomalirinotecan was shown to cause atrophy of male and female reproductive organs after multiple dailyirinotecan doses in animals (see section 5.3). Prior to starting the administration of ONIVYDEpegylated liposomal consider advising patients on the preservation of gametes.

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.

ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin(NALIRIFOX):

The following adverse reactions, related to the administration of ONIVYDE pegylated liposomal,were reported in 370 patients treated in combination with oxaliplatin/5-FU/LV, who had notpreviously received chemotherapy for metastatic adenocarcinoma of the pancreas.

The most common adverse reactions (incidence ≥20%) were diarrhoea, nausea, vomiting, decreasedappetite, fatigue, asthenia, neutropenia, neutrophil count decreased and anaemia. The most common,severe adverse reactions (≥5% Grade 3 or 4) were diarrhoea, nausea, vomiting, decreased appetite,fatigue, asthenia, neutropenia, neutrophil count decreased, anaemia and hypokalaemia. The mostcommon serious adverse reactions (≥2%) were diarrhoea, nausea, vomiting and dehydration.

Adverse reactions seen with ONIVYDE pegylated liposomal which led to its permanentdiscontinuation occurred in 9.5 % of patients; the most frequent adverse reaction resulting indiscontinuation was neutropenia.

Dose reductions of ONIVYDE pegylated liposomal due to adverse events (regardless of causalityassessment), occurred in 52.4% of patients; the most frequent adverse events requiring dose reduction(≥5%) were diarrhoea, nausea, neutropenia and neutrophil count decreased.

ONIVYDE pegylated liposomal was withheld due to adverse events (regardless of causalityassessment), in 1.9% of patients; the most frequent adverse events requiring interruption werehypersensitivity and infusion related reactions that occurred in 0.5% of patients.

ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin:

The following adverse reactions, related to the administration of ONIVYDE pegylated liposomal,were reported in 264 patients with metastatic adenocarcinoma of the pancreas treated after diseaseprogression following gemcitabine-based therapy.

The most common adverse reactions (incidence ≥ 20%) of ONIVYDE pegylated liposomal +5-FU/LVwere: diarrhoea, nausea, vomiting, decreased appetite, neutropenia, fatigue, asthenia, anaemia,stomatitis and pyrexia. The most common serious adverse reactions (≥ 2%) of ONIVYDE pegylatedliposomal 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.

The most frequently reported adverse reactions leading to discontinuation were infection and diarrhoeafor ONIVYDE pegylated liposomal +5-FU/LV arm.

The adverse reactions described in this section are derived from studies data and post-marketingexperience of ONIVYDE pegylated liposomal.

The adverse reactions that may occur during treatment with ONIVYDE pegylated liposomal aresummarised below and are presented by system organ class and frequency category (Table 4). Withineach system organ class and frequency category, adverse reactions are presented in order of decreasingseriousness. Frequencies categories used for adverse reactions are: very common (≥ 1/10); common(≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000)* and not known(cannot be estimated from the available data).

Table 4: Adverse reactions reported in patients treated with ONIVYDE pegylated liposomal

SOC In combination with oxaliplatin/5- In combination with 5-FU/LV

Frequency* FU/LV (in NAPOLI-3) (in NAPOLI-1 and in post-marketingexperience)

Infections and Infestations

Sepsis, Urinary tract infection, Candida Septic shock, Sepsis, Pneumonia,

Common infection, Nasopharyngitis Febrile neutropenia, Gastroenteritis,

Oral candidiasis

Diverticulitis,Pneumonia, Anal abscess, Biliary sepsis

Febrile infection, Gastroenteritis,

Mucosal infection, Oral fungalinfection, Clostridium difficile

Uncommon infection, Conjunctivitis, Furuncle,

Herpes simplex, Laryngitis,

Periodontitis, Rash pustular, Sinusitis,

Tooth infection, Vulvovaginal mycoticinfection

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Uncommon Peritumoural oedema

Blood and lymphatic disorders

Very common Anaemia, Neutropenia, Neutropenia, Leukopenia, Anaemia,

Thrombocytopenia Thrombocytopenia

Common Febrile neutropenia, Leukopenia, Lymphopenia

Lymphopenia

Uncommon Pancytopenia, Haemolytic anaemia

Uncommon Hypersensitivity Hypersensitivity

Not known Anaphylactic/Anaphylactoid reaction,

Very common Hypokalaemia, Decreased appetite, Hypokalaemia, Hypomagnesaemia,

Dehydration, Decreased appetite

Dehydration, Hyponatraemia, Hypoglycaemia, Hyponatraemia,

Common Hypophosphataemia, Hypophosphataemia

Hypomagnesaemia,

Hypoalbuminaemia, Hypocalcaemia

Electrolyte imbalance, Hypercalcaemia,

Uncommon Cell death, Hypochloraemia, Gout,

Hyperglycaemia, Hyperkalaemia, Irondeficiency, Malnutrition

Common Insomnia

Uncommon Insomnia, Confusional state,

Depression, Neurosis,

Very common Neuropathy peripheral, Dysgeusia, Dizziness

Paraesthesia

Tremor, Neurotoxicity, Dysaesthesia, Cholinergic syndrome, Dysgeusia

Common Cholinergic syndrome, Headache,

Dizziness

Seizure, Cerebral haemorrhage,

Cerebral ischaemia, Ischaemic stroke,

Anosmia, Ageusia, Balance disorder,

Uncommon Hypersomnia, Hypoaesthesia,

Intellectual disability, Lethargy,

Memory impairment, Presyncope,

Syncope, Transient ischaemic attack

Common Vision blurred

Uncommon Eye irritation, Visual acuity reduced

Ear and labyrinth disorders

Uncommon Vertigo

Common Tachycardia Hypotension

Uncommon Angina pectoris, Acute myocardialinfarction, Palpitations

Common Hypotension, Thromboembolic events Pulmonary embolism, Thomboembolicevents

Uncommon Hypertension, Peripheral coldness,

Haematoma, Phlebitis

Common Pulmonary embolism, Hiccups, Dyspnoea, Dysphonia

Dyspnoea, Epistaxis

Oropharyngeal pain, Cough, Hyperoxia, Hypoxia, Interstitial lung disease

Uncommon Nasal inflammation, Atelectasis, (including pneumonitis)

Dysphonia, Pneumonitis

Gastro-intestinal disorders

Very common Diarrhoea, Nausea, Vomiting, Diarrhoea, Vomiting, Nausea,

Abdominal pain/discomfort, Stomatitis Abdominal pain, Stomatitis

Common Colitis, Enterocolitis, Constipation, Dry Colitis, Haemorrhoidsmouth, Flatulence, Abdominaldistension, Dyspepsia,

Gastrooesophageal reflux disease,

Haemorrhoids, Dysphagia,

Gastrointestinal toxicity, Duodenal Oesophagitis, Proctitisobstruction, Anal incontinence,

Aphthous ulcer, Oral dysaesthesia, Oralpain, Tongue disorder, Anal fissure,

Angular cheilitis, Dyschezia,

Paraesthesia oral, Dental caries,

Uncommon Eructation, Gastric disorder, Gastritis,

Gingival disorder, Gingival pain,

Haematochezia, Hyperaesthesia teeth,

Ileus paralytic, Lip swelling, Mouthulceration, Oesophageal spasm,

Periodontal disease, Rectalhaemorrhage

Common Hyperbilirubinaemia Hypoalbuminaemia

Uncommon Cholangitis, Hepatitis toxic,

Cholestasis, Hepatic cytolysis,

Very common Alopecia Alopecia

Dry skin, Palmar-plantar Pruritus

Common erythrodysaesthesia syndrome, Rash,

Skin hyperpigmentation

Pruritus, Hyperhidrosis, Dermatitis Urticaria, Rash, Nail discolourationbullous, Dermatitis exfoliative

Uncommon generalised, Erythema, Nail toxicity,

Papule, Petechiae, Psoriasis, Sensitiveskin, Skin exfoliation, Skin lesion,

Telangiectasia, Urticaria

Not known Erythema

Common Muscular weakness, Myalgia, Musclespasms

Uncommon Arthralgia, Back pain, Bone pain, Painin extremity, Polyarthritis

Common Acute kidney injury Acute renal failure

Uncommon Renal impairment, Renal failure,

Dysuria, Proteinuria

Uncommon Vulvovaginal dryness

Very common Asthenia, Mucosal inflammation Pyrexia, Peripheral oedema, Mucosalinflammation, Asthenia

Common Pyrexia, Oedema, Chills Infusion related reaction, Oedema

Malaise, General physical healthdeterioration, Inflammation, Multipleorgan dysfunction syndrome, Influenza

Uncommon like illness, Non-cardiac chest pain,

Axillary pain, Chest pain, Hypothermia,

Pain, Swelling face, Temperatureintolerance, Xerosis

Very common Weight decreased Weight decreased

Transaminases (ALT and AST) Increased bilirubin, Transaminases

Common increased, Blood alkaline phosphatase (ALT and AST) increased, Internationalincreased, Gamma-glutamyltransferase normalised ratio increasedincreased, Blood creatinine increased

International normalised ratio increased,

Protein total decreased, Creatinine renal

Uncommon clearance decreased, Electrocardiogram

QT prolonged, Monocyte countincreased, Troponin I increased

Common Infusion related reaction

* Rare occurrence cannot be estimated from NAPOLI-1 study due to the small sample size.

ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin:

Fatal events were febrile neutropenia or pancytopenia, each occurred in 0.3% of patients receiving

NALIRIFOX arm.

ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin:

Myelosuppression (neutropenia/leukopenia, thrombocytopenia and, anaemia) was more common inthe ONIVYDE pegylated liposomal +5-FU/LV arm compared to the 5-FU/LV control arm.

Neutropenia/leukopenia

ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin:

Grade 3 or 4 leukopenia occurred in 0.8% of patients receiving NALIRIFOX.

In NAPOLI-3, where ONIVYDE pegylated liposomal plus oxaliplatin/5-FU/LV (NALIRIFOX) wascompared to gemcitabine plus nab-paclitaxel (Gem+NabP), safety data showed a higher incidence ofneutropenia reported in the Gem+NabP arm. Grade 3 or 4 neutropenia, neutrophil count decreased andfebrile neutropenia occurred in 14.1%, 9.7% and 1.9% (respectively) in patients receiving

NALIRIFOX.

ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin:

Neutropenia/leukopenia was the most notable important haematological toxicity. Grade 3 or higherneutropenia 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/sepsisappeared 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%)].

The median time to nadir for ≥ Grade 3 neutropenia is 23 (range 8-104) days post first dose oftreatment with ONIVYDE pegylated liposomal.

ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin:

Grade 3 or 4 thrombocytopenia occurred in 0.5% of patients receiving NALIRIFOX.

ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin:

Grade 3 or higher thrombocytopenia occurred in 2.6% of patients treated with ONIVYDE pegylatedliposomal +5-FU/LV and 0% in patients treated with 5-FU/LV.

ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin:

Grade 3 or 4 anaemia occurred in 7.3% of patients receiving NALIRIFOX.

ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin:

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.

ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin:

In NAPOLI-3, renal impairment occurred in 0.3% of patients and was of Grade 3 or 4, renal failureoccurred with Grade 1 to 4 in 0.5% of patients, among them 0.3% was Grade 3 or 4, acute kidneyinjury occurred with Grade 1 to 4 in 1.1% of patients, among them 0.8% were of Grade 3 or 4 inpatients receiving NALIRIFOX. Blood creatinine increased occurred with all Grade 1 to 4 in 1.4% ofpatients, among them, 0.3% was Grade 3 or 4, creatinine renal clearance decreased occurred with

Grade 1 or 2 in 0.3% of patients receiving NALIRIFOX. There was one case (0.3%) of renal failurewith a fatal outcome in the NALIRIFOX arm.

ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin:

In NAPOLI-1, renal impairment and acute renal failure have been identified, usually in patients whobecome volume depleted from nausea/vomiting and/or diarrhoea. Acute renal failure was reportedin 6 of 117 patients (5.1%) in the ONIVYDE pegylated liposomal +5-FU/LV arm.

Diarrhoea and related adverse reactions

ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin:

In NAPOLI-3, safety data showed a higher incidence of diarrhoea reported in the NALIRIFOX armfor all grades and for grade 3 or 4. Grade 1 to 4 diarrhoea occurred in 64.3% of patients and Grade 3 or4 diarrhoea occurred in 19.5% of patients receiving NALIRIFOX arm. Cholinergic reactionmanifestations such as rhinitis, rhinorrhoea, salivary hypersecretion, flushing, hot flush andlacrimation increased, were reported in patients receiving NALIRIFOX.

ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin:

In NAPOLI-1, Grade 3 or Grade 4 diarrhoea occurred in 12.8% receiving ONIVYDE pegylatedliposomal +5-FU/LV. For patients experiencing late diarrhoea, the median time to late diarrhoea onsetwas 8 days from the previous dose of ONIVYDE pegylated liposomal. Early onset diarrhoea, typicallyappearing ≤ 24 hours after dose administration, can occur and is usually transient. Early onsetdiarrhoea may also be accompanied by cholinergic symptoms that can include rhinitis, increasedsalivation, flushing, diaphoresis, bradycardia, miosis and hyperperistalsis that can induce abdominalcramping.

Early diarrhoea onset occurred in 29.9% and cholinergic events occurred in 3.4% receiving

ONIVYDE pegylated liposomal +5-FU/LV.

Infusion reaction

ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin:

In NAPOLI-3, Infusion related reaction occurred in 1.4% of patients receiving NALIRIFOX. All ofthem were mild or moderate (Grade 1 and 2).

ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin:

In NAPOLI-1, acute infusion reactions were reported in 6.8% in the ONIVYDE pegylated liposomal+5-FU/LV arm.

Overall, no major clinical differences in safety were reported between patients ≥ 65 years andpatients < 65 years.

ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin:

In NAPOLI-3, the median age was 65 years (range from 20 to 85), 50.1% of patients were at least 65years of age with 6.9% of patients of 75 years or older. The safety data by age groups, were in linewith the data of NALIRIFOX arm in the whole population.

ONIVYDE pegylated liposomal in combination with 5-fluorouracil and leucovorin:

In NAPOLI-1, a higher frequency of discontinuation was noted for patients between ≥ 65 years and <65 years treated with ONIVYDE pegylated liposomal +5-FU/LV (14.8% vs 7.9% respectively) and insome cases the adverse reactions did not resolve. Grade 3 or higher and serious treatment emergentadverse reactions were more frequent in patients < 65 years (84.1% and 50.8%) compared topatients ≥ 65 years (68.5 % and 44.4%). Conversely, patients > 75 years (n=12) experienced morefrequent serious adverse reactions, dose delay, dose reduction and discontinuation compared topatients ≤ 75 years (n=105) when treated with ONIVYDE pegylated liposomal +5-FU/LV in thepancreatic adenocarcinoma study.

Asian population

In NAPOLI-1, compared to Caucasians, Asian patients were observed with a lower incidence ofdiarrhoea [14 (19.2%) out of 73 Caucasians had a ≥ Grade 3 diarrhoea, and 1 out of 33 (3.3%) Asianshad a ≥ Grade 3 diarrhoea], but a higher incidence and higher severity of neutropenia. In patientsreceiving ONIVYDE pegylated liposomal +5-FU/LV, the incidence of ≥ Grade 3 neutropenia washigher among Asian patients [18 of 33 (55%)] compared to Caucasian patients [13 of 73 (18%)].

Neutropenic fever/neutropenic sepsis was reported in 6% of Asian patients compared to 1% of

Caucasian patients. This is consistent with the population pharmacokinetic analysis that showed alower exposure to irinotecan and a higher exposure to its active metabolite SN-38 in Asians than in

Caucasians.

In clinical studies of non-liposomal irinotecan administered on a weekly dosage schedule, patientswith modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dl) had a significantlygreater likelihood of experiencing first cycle Grade 3 or Grade 4 neutropenia than those with bilirubinlevels that were less than 1.0 mg/dl.

Patients with UGT1A1 allele

Individuals who are 7/7 homozygous for the UGT1A1*28 allele are at increased risk for neutropeniafrom non-liposomal irinotecan. In NAPOLI-1, the frequency of ≥ Grade 3 neutropenia in thesepatients [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 liposomalof 70 mg/m2 [30 of 110 (27.3%)] (see section 5.1). This observation was not evaluated in NAPOLI-3.

Underweight patients (body mass index < 18.5 kg/m2)

In NAPOLI-1, 5 of 8 underweight patients experienced a grade 3 or 4 adverse reaction, mostlymyelosuppression, while 7 of the 8 patients required dose modification such as dose delay, dosereduction or dose discontinuation (see section 4.4). This observation was not evaluated in NAPOLI-3.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In clinical studies, ONIVYDE pegylated liposomal was administered at doses up to 210 mg/m2 topatients with various cancers. The adverse reactions in these patients were similar to those reportedwith the recommended dose and regimen.

There have been reports of overdose with non-liposomal irinotecan at doses up to approximately twicethe recommended therapeutic dose of irinotecan, which may be fatal. The most significant adversereactions reported were severe neutropenia and severe diarrrhoea.

There is no known antidote for overdose of ONIVYDE pegylated liposomal. Maximum supportivecare should be instituted to prevent dehydration due to diarrhoea and to treat any infectiouscomplications.

Pharmacotherapeutic group: Topoisomerase 1 (TOP1) inhibitors. ATC Code: L01CE02.

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 thetopoisomerase I-DNA complex and induce single-strand DNA lesions which block the DNAreplication fork and are responsible for the cytotoxicity. Irinotecan is metabolised by carboxylesteraseto 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.

In animal models, ONIVYDE pegylated liposomal has been shown to extend plasma levels ofirinotecan and prolong the exposure to the active metabolite SN-38 at the site of the tumour.

NAPOLI-3:

The safety and efficacy of ONIVYDE pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin (NALIRIFOX) was evaluated in NAPOLI-3, a randomised, multicenter,open-label, active-controlled study that included 770 patients with metastatic adenocarcinoma of thepancreas who had not previously received chemotherapy in the metastatic setting. Randomisation wasstratified by region, liver metastases and ECOG performance status. Patients were randomized (1:1) toreceive one of the following treatment arms:

NALIRIFOX: ONIVYDE pegylated liposomal 50 mg/m2 as an intravenous infusion over 90 minutes,followed by oxaliplatin 60 mg/m2 as an intravenous infusion over 120 minutes, followed byleucovorin 400 mg/m2 intravenously over 30 minutes, followed by 5-FU 2,400 mg/m2 intravenouslyover 46 hours, administered every 2 weeks.

Gem+NabP: Nab-paclitaxel 125 mg/m2 as an intravenous infusion over 35 minutes, followed bygemcitabine 1000 mg/m2 intravenously over 30 minutes on days 1, 8 and 15 of each 28-day cycle.

Patients homozygous for the UGT1A1*28 allele initiated ONIVYDE pegylated liposomal at the samedose (50 mg/m2 ONIVYDE pegylated liposomal) and were closely monitored for safety.

Treatment continued until RECIST V1.1 defined disease progression or unacceptable toxicity. Tumorstatus assessments were conducted at baseline and every 8 weeks thereafter as assessed by theinvestigator according to RECIST v1.1.

The main efficacy outcome measures were Overall Survival (OS), Progression-Free Survival (PFS)and Objective Response Rate (ORR).

Baseline demographics and patient characteristics were: median age of 65 years (range: 20-85); 50%age 65 or older ; 56% male; 83% White; 5% Asian; 3% Black or African American; ECOGperformance status was 0 in 43% or 1 in 57% of patients; 87% liver metastases.

NAPOLI-3 demonstrated a statistically significant improvement in OS and PFS for the NALIRIFOXarm over Gem+NabP arm as per original strata definition in the statistical analysis plan. Median OSwas 11.1 months (95% CI: 10.0, 12.1; HR 0.84 (95% CI: 0.71, 0.99); p=0.04) for the NALIRIFOXarm and 9.2 months (95% CI: 8.3, 10.6) for the Gem+NabP arm at the final analysis. Results from anupdated OS analysis are summarized in Table 5 and Figure 1 (OS).

Table 5: Efficacy Results from NAPOLI-3 clinical study

NALIRIFOX Gem+NabP(N=383) (N=387)

Updated Overall Survival, cut-off = 03 October 2023

Number of Deaths, n (%) 328 (85.6) 345 (89.1)

Median Overall Survival (months) 11.1 9.2(95% CI) (10.0, 12.1) (8.3, 10.6)

Hazard Ratio (95% CI) * 0.85 (0.73, 0.99)

Progression-Free Survival, cut-off = 23 July 2022**

Death or Progression, n (%) 249 (65) 259 (67)

Median Progression-Free Survival(months) 7.4 5.6(95% CI) (6.0, 7.7) (5.3, 5.8)

Hazard Ratio (95% CI) * 0.70 (0.59, 0.84)p-value † 0.0001

Objective Response Rate, cut-off = 23 July 2022

ORR (95% CI) 41.8 (36.8, 46.9) 36.2 (31.4, 41.2)

CR, n (%) 1 (0.3) 1 (0.3)

PR, n (%) 159 (41.5) 139 (35.9)

NALIRIFOX= ONIVYDE pegylated liposomal +oxaliplatin/5-fluorouracil/leucovorin;

Gem+NabP=gemcitabine+nab-paclitaxel

* Based on the stratified Cox proportional hazard model by baseline ECOG performance status,region (North America, East Asia and Rest of the World) and liver metastases

** Patients were censored when initiated subsequent anti-cancer therapy or withdrawal of studyconsent or lost to FU or if 2 consecutive tumour assessments were missed and followed byprogression or death† Based on stratified log-rank test.

Abbreviations: CR=complete response, PR=partial response; CI=confidence interval

Figure 1: Kaplan-Meier Curve for Updated Overall Survival, cut-off = 03 October 2023 in

NAPOLI-3

NAPOLI-1:

The safety and efficacy of ONIVYDE pegylated liposomal were investigated in a multinational,randomised, open label, controlled clinical study (NAPOLI-1) that tested two treatment regimens forpatients with metastatic pancreatic adenocarcinoma who had documented disease progression aftergemcitabine or gemcitabine-containing therapy. The study was designed to assess the clinical efficacyand 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 pegylatedliposomal 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 intravenouslyover 46 hours, administered every 2 weeks. Patients homozygous for the UGT1A1*28 allele weregiven a lower initial dose of ONIVYDE pegylated liposomal (see section 4.2). Patients randomisedto 5-FU/LV received leucovorin 200 mg/m2 intravenously over 30 minutes, followedby 5-FU 2,000 mg/m2 intravenously over 24 hours, administered on Days 1, 8, 15 and 22 of a 6-weekcycle. Patients randomised to ONIVYDE pegylated liposomal monotherapy received 100 mg/m2 as anintravenous 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 andalbumin ≥ 3.0 g/dl.

A total of 417 patients were randomised to the ONIVYDE pegylated liposomal +5-FU/LVarm (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 study 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 baselinealbumin level was 3.6 g/dl, and baseline KPS was 90-100 in 55% of patients. Disease characteristicsincluded 68% of patients with liver metastases and 31% with lung metastases; 12% of patients had noprior lines of metastatic therapy, 56 % of patients had 1 prior line of metastatic therapy, 32% ofpatients had 2 or more prior lines of metastatic therapy.

Patients received treatment until disease progression or unacceptable toxicity. The primary outcomemeasure was Overall survival (OS). Additional outcome measures included Progression free survival(PFS) and Objective response rate (ORR). Results are shown in Table 6. Overall survival is illustratedin Figure 2.

Table 6: Efficacy results from NAPOLI-1 clinical study

ONIVYDE pegylatedliposomal +5-FU/LV 5-FU/LV(N= 117) (N= 119)

Overall survival1

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

Median OS (months) 6.1 4.2(95% Confidence Interval (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)

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 0.895% CI of Rate5 9.6, 22.9 0.0, 2.5

Rate Difference (95% CI)5 15.4 (8.5, 22.3)p-value6 < 0.00011 Median is the Kaplan-Meier estimate of the median survival time2 Per RECIST guidelines, v 1.1.3 Cox model analysis4 Unstratified log-rank test5 Based on Normal approximation6 Fisher’s exact test

Abbreviations: 5-FU/LV=5-fluorouracil/leucovorin; CI=confidence interval

Figure 2: Kaplan-Meier Curve for Overall survival in NAPOLI-1

In the limited number of patients with prior exposure to non-liposomal irinotecan, no benefit of

ONIVYDE pegylated liposomal has been demonstrated.

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 pancreaticcancer (see section 4.2 for information on paediatric use).

Liposome encapsulation of irinotecan extends circulation and limits distribution relative to those of thenon-liposomal irinotecan.

The plasma pharmacokinetics of total irinotecan and total SN-38 were evaluated in patients withcancer who received ONIVYDE pegylated liposomal as a single agent or as part of combinationchemotherapy, at doses between 35 and 155 mg/m2 in 1058 patients with cancer using populationpharmacokinetic analysis. The pharmacokinetic parameters of total irinotecan and SN-38 analytes,following the administration of ONIVYDE pegylated liposomal 70 mg/m2 as a single agent or as partof combination chemotherapy and 50 mg/m2 in the NALIRIFOX regimen (ONIVYDE pegylatedliposomal/oxaliplatin/5-FU/LV) are presented in Table 7.

Table 7: Summary of geometric Mean (geometric CV) Total Irinotecan and Total SN-38

Starting Total Irinotecan Total SN-38dose Descriptive

C AUCSS

Statistics max [day∙µg/m t1/2 Cmax AUCSS(mg/m2) [µg/mL] L] [day] [ng/mL] [day∙ng/mL]

N 360 360 360 360 36050* Geometric Mean 25.1 37.8 1.93 2.09 12.1

Geometric CV 18.5 73.6 14 42.1 46.6(%)

N 116 116 116 116 11670** Geometric Mean 29.0 46.6 1.91 2.50 14.5

Geometric CV 17.6 60.3 8.4 57.3 45.0(%)

AUCSS: Area under the plasma concentration curve at steady-state per two weekst1/2: Terminal elimination half-life

Cmax = maximum plasma concentration

CV = coefficient of variation

* ONIVYDE pegylated liposomal/oxaliplatin/5-FU/leucovorin (NAPOLI-3)

** ONIVYDE pegylated liposomal/5-FU/leucovorin (NAPOLI-1)

Direct measurement of liposomal irinotecan shows that 95% of irinotecan remainsliposome-encapsulated during circulation. Non-liposomal irinotecan displays a large volume ofdistribution (138 l/m2). The volume of distribution of ONIVYDE pegylated liposomal is 4 L (obtainedfrom population pharmacokinetic analysis) which suggests that ONIVYDE pegylated liposomal islargely confined to vascular fluid.

The plasma protein binding of ONIVYDE pegylated liposomal is negligible (< 0.44% of totalirinotecan in ONIVYDE pegylated liposomal). The plasma protein binding of non-liposomalirinotecan is moderate (30% to 68%), and SN-38 is highly bound to human plasma proteins(approximately 95%).

Irinotecan released from liposome encapsulation follows a similar metabolic pathway reported withnon-liposomal irinotecan.

The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesteraseenzymes. In vitro studies indicate that irinotecan, SN-38 and another metabolite aminopentanecarboxylic acid (APC) do not inhibit cytochrome P-450 isozymes. SN-38 is subsequently conjugatedpredominantly by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronidemetabolite. UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead toreduced enzyme activity such as the UGT1A1*28 polymorphism. In the population pharmacokineticanalysis, there was no significant association between UGT1A1*28 polymorphism (7/7 homozygous(8%) vs non 7/7 homozygous) and SN-38 clearance.

The disposition of ONIVYDE pegylated liposomal and non-liposomal irinotecan has not been fullyelucidated 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 itsmetabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours following administration ofnon-liposomal irinotecan in two patients ranged from approximately 25% (100 mg/m2) to 50%(300 mg/m2).

No dedicated pharmacokinetic study has been conducted in patients with renal impairment. Creatinineclearance was not found as a significant covariate on SN-38 clearance. There was insufficient data inpatients with severe renal impairment (CLcr < 30 ml/min) to assess its effect on pharmacokinetics (seesections 4.2 and 4.4).

No dedicated pharmacokinetic study has been conducted in patients with hepatic impairment. In apopulation pharmacokinetic analysis, increased bilirubin level was associated with lower SN‑38clearance. Bilirubin level of 1.14 mg/dL (95th percentile of the overall population) leads to a 32%increase of SN-38 AUC in comparison to median bilirubin level of 0.44 mg/dL (of the 1055 patientsevaluated in the model, 54 had bilirubin levels ≥ 1.14 mg/dL). No data are available in patients withbilirubin >2.8 mg/dL). 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.

Age and gender

The population pharmacokinetic analysis in patients aged 20 to 87 years, of whom 11% in previousstudies and 6.9% in NAPOLI-3 were ≥75 years, suggests that age had no clinically meaningful effecton the exposure to irinotecan and SN-38.

Gender was found as a significant covariate in the population PK analysis with an irinotecan AUCincrease of 28% and a clinically meaningful SN-38 AUC increase of 32% in female, when notadjusted for any other covariate.

Population pharmacokinetic analysis shows that irinotecan AUC is 32% lower, being clinicallymeaningful, in participants of Asian ethnicity than in participants of other ethnicities.

NAPOLI-3:

In the exposure-safety analysis focusing on the data of 360 subjects included in NAPOLI-3 study andtreated with 50 mg/m² of ONIVYDE pegylated liposomal in combination with 5-FU, LV andoxaliplatin, probability of diarrhoea Grade 3 and higher or neutropenia Grade 3 or higher appeared toincrease with increasing exposures of both irinotecan and SN-38. Exposure-efficacy relationship wasnot found to be statistically significant.

NAPOLI-1:

In a pooled analysis from 353 patients, higher plasma SN-38 Cmax was associated with increasedlikelihood of experiencing neutropenia, and higher plasma total irinotecan Cmax was associated withincreased likelihood of experiencing diarrhoea.

In NAPOLI-1, higher plasma exposures of total irinotecan and SN-38 for patients in the ONIVYDEpegylated liposomal +5-FU/LV treatment arm were associated with longer OS and PFS as well as withhigher ORR (objective response rate).

In single and repeated dose toxicity studies in mice, rats and dogs, the target organs of toxicity werethe gastrointestinal tract and the hematologic system. The severity of effects was dose-related andreversible. The no-observed-adverse-effect level (NOAEL) in rats and dogs following 90 minintravenous infusion of ONIVYDE pegylated liposomal once every 3 weeks for 18 weeks was155 mg/m2.

In safety pharmacology studies in dogs, ONIVYDE pegylated liposomal had no effect oncardiovascular, hemodynamic, electrocardiographic, or respiratory parameters at doses up to 18 mg/kgor 360 mg/m2 . No findings indicative of CNS related toxicity were observed in the repeated dosetoxicity studies in rats.

Genotoxic and carcinogenic potential

No genotoxicity studies have been performed with ONIVYDE pegylated liposomal. Non-liposomalirinotecan and SN-38 were genotoxic in vitro in the chromosomal aberration test on CHO-cells as wellas in the in vivo micronucleus test in mice. However, in other studies with irinotecan they have beenshown to be devoid of any mutagenic potential in the Ames test.

No carcinogenicity studies have been performed with ONIVYDE pegylated liposomal. Fornon-liposomal irinotecan, in rats treated once a week during 13 weeks at the maximum doseof 150 mg/m², no treatment related tumours were reported 91 weeks after the end of treatment. Underthese conditions, there was a significant linear trend with dose for the incidence of combined uterinehorn 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 pegylatedliposomal.

Non-liposomal irinotecan was teratogenic in rats and rabbits at doses below the human therapeuticdose. In rats, pups born from treated animals and having external abnormalities showed a decrease infertility. This was not seen in morphologically normal pups. In pregnant rats there was a decrease inplacental weight and in the offspring a decrease in foetal viability and increase in behaviouralabnormalities.

Non-liposomal irinotecan caused atrophy of male reproductive organs both in rats and dogs aftermultiple daily doses of 20 mg/kg and 0.4 mg/kg, respectively.These effects were reversible uponcessation of treatment.

Liposome forming lipids1,2-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 octasulphate2- [ 4- (2-Hydroxyethyl)piperazin-1-yl] ethanesulfonic acid (HEPES buffer)

Sodium chloride

Water for injections

ONIVYDE pegylated liposomal must not be mixed with other medicinal products except thosementioned in section 6.6.

Unopened vial3 years.

Chemical and physical stability for the diluted dispersion for infusion has been demonstratedat 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 usedimmediately, in-use storage times and conditions are the responsibility of the user.

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.

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.

ONIVYDE pegylated liposomal is a cytotoxic medicinal product, and caution should be exercised inhandling it. The use of gloves, goggles and protective clothing when handling or administering

ONIVYDE pegylated liposomal is recommended. If the dispersion contacts the skin, the skin shouldbe washed immediately and thoroughly with soap and water. If the dispersion contacts mucousmembranes, 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 dispersion and administration

ONIVYDE pegylated liposomal is supplied as a sterile liposomal dispersion at a concentrationof 4.3 mg/ml and must be diluted prior to administration using a needle not larger than 21 gauge.

Dilute with 5% glucose solution for injection or sodium chloride 9 mg/ml (0.9%) solution for injectionto prepare a dispersion of the appropriate dose of ONIVYDE pegylated liposomal diluted to a finalvolume of 500 ml. Mix the diluted dispersion by gentle inversion. The diluted dispersion is clear toslightly white to slightly opalescent and free from visible particles.

For first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas, ONIVYDEpegylated liposomal should be administered before oxaliplatin, followed by LV, followed by 5-FU.

For treatment of metastatic adenocarcinoma of the pancreas in adult patients who have progressedfollowing gemcitabine based therapy, ONIVYDE pegylated liposomal should be administered before

LV followed by 5-FU. ONIVYDE pegylated liposomal must not be administered as a bolus injectionor an undiluted dispersion.

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

Care should be taken to avoid extravasation, and the infusion site should be monitored for signs ofinflammation. 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 localrequirements.

Les Laboratoires Servier50, rue Carnot92284 Suresnes cedex

France

EU/1/16/1130/001

Date of first authorisation: 14 October 2016

Date of latest renewal: 16 July 2021

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

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