4.1. Therapeutic indications

ONIVYDE pegylated liposomal is indicated:

- in combination with oxaliplatin, 5-fluorouracil (5-FU) and leucovorin (LV) for the first-line treatment 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, in combination with 5fluorouracil (5FU) and leucovorin (LV), in adult patients who have progressed following gemcitabine based therapy.

4.2. Posology and method of administration

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

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

Posology

ONIVYDE pegylated liposomal should not be administered as a single agent and should be continued until 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. The recommended 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/m2 intravenously over 30 minutes, followed by 5-FU 2,400 mg/m2 intravenously over 46 hours. This regimen should be administered every 2 weeks.

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

The recommended starting dose of ONIVYDE pegylated liposomal in patients known to be homozygous for UGT1A1*28 allele is unchanged and remains 50 mg/m2 administered intravenously over 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 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.

A reduced starting dose of ONIVYDE pegylated liposomal 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.

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.

Dose adjustments

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

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

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

Toxicity grade (value) by NCI CTCAE†

ONIVYDE pegylated liposomal/Oxaliplatin/5-FU adjustments

Haematological toxicities

Neutropenia

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

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

First occurrence

Reduce ONIVYDE pegylated liposomal dose to 80% of initial dose

Reduce oxaliplatin and 5-FU dose by 20%

Second occurrence

Reduce ONIVYDE pegylated liposomal dose to 65% of initial dose

Reduce oxaliplatin and 5-FU dose by an additional 15%

Third occurrence

Reduce ONIVYDE pegylated liposomal dose to 50% of initial dose

Reduce oxaliplatin and 5-FU dose by an additional 15%

Fourth occurrence

Discontinue treatment

Thrombocytopenia Leukopenia

A new cycle of therapy should not begin until the platelet count is ≥100,000/mm3 (100x109/L).

Dose modifications for leukopenia and thrombocytopenia are based on NCI CTCAE toxicity grading and are the same as recommended for neutropenia above.

Non-haematological toxicities*

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).

Grade 3 or 4

First occurrence

Reduce ONIVYDE pegylated liposomal dose to 80% of initial dose

Reduce oxaliplatin and 5-FU dose by 20%

Second occurrence

Reduce ONIVYDE pegylated liposomal dose to 65% of initial dose

Reduce oxaliplatin and 5-FU dose by an additional 15%

Third occurrence

Reduce ONIVYDE pegylated liposomal dose to 50% of initial dose

Reduce oxaliplatin and 5-FU dose by an additional15%

Fourth occurrence

Discontinue treatment

All other toxicities*

Grade 3 or 4

First occurrence

Reduce ONIVYDE pegylated liposomal dose to 80% of initial dose

Reduce oxaliplatin and 5-FU dose by 20%

Second occurrence

Reduce ONIVYDE pegylated liposomal dose to65% of initial dose

Reduce oxaliplatin and 5-FU dose by an additional 15%

Third occurrence

Reduce ONIVYDE pegylated liposomal dose to 50% of initial dose

Reduce oxaliplatin and 5-FU dose by an additional 15%

Fourth occurrence

Discontinue treatment

For Grade ≥ 3 nausea and vomiting

Reduce dose only if occurs despite optimal anti-emetic therapy

Hand foot syndrome: Grade 3 or 4

First occurrence

Discontinue treatment

Any grade neurocerebellar or ≥ Grade 2 cardiac toxicity

First occurrence

Discontinue treatment

Anaphylactic reaction

First occurrence

Discontinue treatment

Interstitial lung disease

First occurrence

Discontinue treatment

* 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 the same 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 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 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) by NCI CTCAE1

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 (< 1,000cells/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).

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

Interstitial Lung Disease

First occurrence

Discontinue treatment

1 NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events, current version

2 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) by NCI CTCAE1

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 2

Second occurrence

Reduce ONIVYDE pegylated liposomal dose to 35 mg/m2 5-FU dose modification as in Table 2

Third occurrence

Discontinue treatment

Anaphylactic reaction

First occurrence

Discontinue treatment

Interstitial Lung Disease

First occurrence

Discontinue treatment

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

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 2.

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-nine percent (49.6 %) in NAPOLI-3 and forty-one percent (41%) in NAPOLI-1 of patients treated with ONIVYDE pegylated liposomal 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 a 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.

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. 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. 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.

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), rifampicin, 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

ONIVYDE pegylated liposomal can cause severe and life-threatening diarrhoea. ONIVYDE pegylated liposomal must not be administered to patients with bowel obstruction, and chronic inflammatory bowel 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 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 (maximum of 16 mg/day). Loperamide should be given until the patient is without diarrhoea for at least 12 hours. To help avoid severe diarrhoea, stop all lactose-containing products, maintain hydration and eat a low-fat diet.

If diarrhoea persists while the 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.

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

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.

Hypersensitivity reaction including acute infusion 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, anaphylactic/anaphylactoid reaction and angioedema may occur. ONIVYDE pegylated liposomal should be discontinued in case of severe hypersensitivity reactions (see section 4.2).

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 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. 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 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 (see section 4.2).

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.

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

In NAPOLI-1, 5 of 8 underweight patients experienced 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

This medicinal product contains 33.1 mg sodium per vial, equivalent to 1.65% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

.

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 non-liposomal 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 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.

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

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

No interaction of ONIVYDE pegylated liposomal 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 7 months 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). Prior to starting the administration of ONIVYDE pegylated liposomal consider advising patients on the preservation of gametes.

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

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 not previously received chemotherapy for metastatic adenocarcinoma of the pancreas.

The most common adverse reactions (incidence ≥20%) were diarrhoea, nausea, vomiting, decreased appetite, 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 most common serious adverse reactions (≥2%) were diarrhoea, nausea, vomiting and dehydration.

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

Dose reductions of ONIVYDE pegylated liposomal due to adverse events (regardless of causality assessment), 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 causality assessment), in 1.9% of patients; the most frequent adverse events requiring interruption were hypersensitivity 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 disease progression following gemcitabine-based therapy.

The most common adverse reactions (incidence ≥ 20%) of ONIVYDE pegylated liposomal+5 FU/LV were: diarrhoea, nausea, vomiting, decreased appetite, neutropenia, fatigue, asthenia, anaemia, 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.

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

Tabulated list of adverse reactions

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

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 4). 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)* and not known (cannot be estimated from the available data).

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

SOC

Frequency*

In combination with oxaliplatin/5-FU/LV (in NAPOLI-3)

In combination with 5-FU/LV

(in NAPOLI-1 and in post-marketing experience)

Infections and Infestations

Common

Sepsis, Urinary tract infection, Candida infection, Nasopharyngitis

Septic shock, Sepsis, Pneumonia, Febrile neutropenia, Gastroenteritis, Oral candidiasis

Uncommon

Diverticulitis,Pneumonia, Anal abscess, Febrile infection, Gastroenteritis, Mucosal infection, Oral fungal infection, Clostridium difficile infection, Conjunctivitis, Furuncle, Herpes simplex, Laryngitis, Periodontitis, Rash pustular, Sinusitis, Tooth infection, Vulvovaginal mycotic infection

Biliary sepsis

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

Uncommon

Peritumoural oedema

Blood and lymphatic disorders

Very common

Anaemia, Neutropenia, Thrombocytopenia

Neutropenia, Leukopenia, Anaemia, Thrombocytopenia

Common

Febrile neutropenia, Leukopenia, Lymphopenia

Lymphopenia

Uncommon

Pancytopenia, Haemolytic anaemia

Immune system disorders

Uncommon

Hypersensitivity

Hypersensitivity

Not known

Anaphylactic/Anaphylactoid reaction, Angioedema

Metabolism and nutrition disorders

Very common

Hypokalaemia, Decreased appetite,

Hypokalaemia, Hypomagnesaemia, Dehydration, Decreased appetite

Common

Dehydration, Hyponatraemia, Hypophosphataemia, Hypomagnesaemia, Hypoalbuminaemia, Hypocalcaemia

Hypoglycaemia, Hyponatraemia, Hypophosphataemia

Uncommon

Electrolyte imbalance, Hypercalcaemia, Cell death, Hypochloraemia, Gout, Hyperglycaemia, Hyperkalaemia, Iron deficiency, Malnutrition

Psychiatric disorders

Common

Insomnia

Uncommon

Insomnia, Confusional state, Depression, Neurosis,

Nervous system disorders

Very common

Neuropathy peripheral, Dysgeusia, Paraesthesia

Dizziness

Common

Tremor, Neurotoxicity, Dysaesthesia, Cholinergic syndrome, Headache, Dizziness

Cholinergic syndrome, Dysgeusia

Uncommon

Seizure, Cerebral haemorrhage, Cerebral ischaemia, Ischaemic stroke, Anosmia, Ageusia, Balance disorder, Hypersomnia, Hypoaesthesia, Intellectual disability, Lethargy, Memory impairment, Presyncope, Syncope, Transient ischaemic attack

Eye disorders

Common

Vision blurred

Uncommon

Eye irritation, Visual acuity reduced

Ear and labyrinth disorders

Uncommon

Vertigo

Cardiac disorders

Common

Tachycardia

Hypotension

Uncommon

Angina pectoris, Acute myocardial infarction, Palpitations

Vascular disorders

Common

Hypotension, Thromboembolic events

Pulmonary embolism, Thomboembolic events

Uncommon

Hypertension, Peripheral coldness, Haematoma, Phlebitis

Respiratory, thoracic and mediastinal disorders

Common

Pulmonary embolism, Hiccups, Dyspnoea, Epistaxis

Dyspnoea, Dysphonia

Uncommon

Oropharyngeal pain, Cough, Hyperoxia, Nasal inflammation, Atelectasis, Dysphonia, Pneumonitis

Hypoxia, Interstitial lung disease (including pneumonitis)

Gastro-intestinal disorders

Very common

Diarrhoea, Nausea, Vomiting, Abdominal pain/discomfort, Stomatitis

Diarrhoea, Vomiting, Nausea, Abdominal pain, Stomatitis

Common

Colitis, Enterocolitis, Constipation, Dry mouth, Flatulence, Abdominal distension, Dyspepsia, Gastrooesophageal reflux disease, Haemorrhoids, Dysphagia,

Colitis, Haemorrhoids

Uncommon

Gastrointestinal toxicity, Duodenal obstruction, Anal incontinence, Aphthous ulcer, Oral dysaesthesia, Oral pain, Tongue disorder, Anal fissure, Angular cheilitis, Dyschezia, Paraesthesia oral, Dental caries, Eructation, Gastric disorder, Gastritis, Gingival disorder, Gingival pain, Haematochezia, Hyperaesthesia teeth, Ileus paralytic, Lip swelling, Mouth ulceration, Oesophageal spasm, Periodontal disease, Rectal haemorrhage

Oesophagitis, Proctitis

Hepatobiliary disorders

Common

Hyperbilirubinaemia

Hypoalbuminaemia

Uncommon

Cholangitis, Hepatitis toxic, Cholestasis, Hepatic cytolysis,

Skin and subcutaneous tissue disorders

Very common

Alopecia

Alopecia

Common

Dry skin, Palmar-plantar erythrodysaesthesia syndrome, Rash, Skin hyperpigmentation

Pruritus

Uncommon

Pruritus, Hyperhidrosis, Dermatitis bullous, Dermatitis exfoliative generalised, Erythema, Nail toxicity, Papule, Petechiae, Psoriasis, Sensitive skin, Skin exfoliation, Skin lesion, Telangiectasia, Urticaria

Urticaria, Rash, Nail discolouration

Not known

Erythema

Musculoskeletal and connective tissue disorders

Common

Muscular weakness, Myalgia, Muscle spasms

Uncommon

Arthralgia, Back pain, Bone pain, Pain in extremity, Polyarthritis

Renal and urinary disorders

Common

Acute kidney injury

Acute renal failure

Uncommon

Renal impairment, Renal failure, Dysuria, Proteinuria

Reproductive system and breast disorders

Uncommon

Vulvovaginal dryness

General disorders and administration site conditions

Very common

Asthenia, Mucosal inflammation

Pyrexia, Peripheral oedema, Mucosal inflammation, Asthenia

Common

Pyrexia, Oedema, Chills

Infusion related reaction, Oedema

Uncommon

Malaise, General physical health deterioration, Inflammation, Multiple organ dysfunction syndrome, Influenza like illness, Non-cardiac chest pain, Axillary pain, Chest pain, Hypothermia, Pain, Swelling face, Temperature intolerance, Xerosis

Investigations

Very common

Weight decreased

Weight decreased

Common

Transaminases (ALT and AST) increased, Blood alkaline phosphatase increased, Gamma-glutamyltransferase increased, Blood creatinine increased

Increased bilirubin, Transaminases (ALT and AST) increased, International normalised ratio increased

Uncommon

International normalised ratio increased, Protein total decreased, Creatinine renal clearance decreased, Electrocardiogram QT prolonged, Monocyte count increased, Troponin I increased

Injury, poisoning and procedural complications

Common

Infusion related reaction

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

Description of selected adverse reactions

Myelosuppression

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 in the 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) was compared to gemcitabine plus nab-paclitaxel (Gem+NabP), safety data showed a higher incidence of neutropenia reported in the Gem+NabP arm. Grade 3 or 4 neutropenia, neutrophil count decreased, and febrile 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 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%)].

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

Thrombocytopenia

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 pegylated liposomal+5-FU/LV and 0% in patients treated with 5-FU/LV.

Anaemia

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.

Acute renal failure

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 failure occurred with Grade 1 to 4 in 0.5% of patients, among them 0.3% was Grade 3 or 4, acute kidney injury occurred with Grade 1 to 4 in 1.1% of patients, among them 0.8% were of Grade 3 or 4 in patients receiving NALIRIFOX. Blood creatinine increased occurred with all Grade 1 to 4 in 1.4% of patients, 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 failure with 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 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.

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 arm for all grades and for grade 3 or 4. Grade 1 to 4 diarrhoea occurred in 64.3% of patients and Grade 3 or 4 diarrhoea occurred in 19.5% of patients receiving NALIRIFOX arm. Cholinergic reaction manifestations such as rhinitis, rhinorrhoea, salivary hypersecretion, flushing, hot flush and lacrimation 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 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 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. 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 of them 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.

Other special populations

Elderly

Overall, no major clinical differences in safety were reported between patients ≥ 65 years and patients < 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 65 years of age with 6.9% of patients of 75 years or older. The safety data by age groups, were in line with 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 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

In Napoli-1, 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 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 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 UGT1A1 allele

Individuals who are 7/7 homozygous for the UGT1A1*28 allele are at increased risk for neutropenia from non-liposomal irinotecan. In NAPOLI-1, 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). 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, mostly myelosuppression, while 7 of the 8 patients required dose modification such as dose delay, dose reduction or dose discontinuation (see section 4.4). This observation was not evaluated in NAPOLI-3.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In clinical studies, 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 dose and regimen.

There have been reports of overdose 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 diarrhoea.

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.