ONIVYDE PEGYLATED LIPOSOMAL

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

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 a5HT3antagonist (or other antiemetic) at least30minutes 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-fluorouracil 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) 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% Grade 3 or Grade 4 (<1,000 cells/mm3) or Neutropenic fever Fourth occurence 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). 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% Grade 3 or 4 Fourth occurrence Discontinue treatment First occurrence Reduce ONIVYDE pegylated liposomal dose to 80% of initial dose Reduce oxaliplatin and 5-FU dose by 20% All other toxicities* Grade 3 or 4 Second Reduce ONIVYDE pegylated liposomal dose to65% Toxicity grade (value) by NCI CTCAE† ONIVYDE pegylated liposomal/Oxaliplatin/5-FU adjustments occurrence 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 […]

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. 5 % of patients; the most frequent adverse reaction resulting in discontinuation was neutropenia. 4% of patients; the most frequent adverse events requiring dose reduction (≥5%) were diarrhoea, nausea, neutropenia and neutrophil count decreased.

5% of patients. , 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), 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, […]

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. 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 CYP3A4inducers ONIVYDE pegylated liposomal should not be administered with strong CYP3A4enzyme 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. 5). g. grapefruit juice, clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole).

Strong CYP3A4inhibitors should be discontinued at least1week prior to starting ONIVYDE pegylated liposomal therapy. 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. 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. 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).

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 […]

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