Onivyde® pegylated liposomal 4.3 mg/ml concentrate for dispersion for infusion (Irinotecan)

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

DOSAGE AND ADMINISTRATION: Onivyde must only be prescribed and administered to patients by healthcare professionals experienced in the use of anti‑cancer therapies. Recommended dose of Onivyde pegylated liposomal in combination with oxaliplatin, LV and 5-FU 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. The recommended starting dose in patients known to be homozygous for UGT1A1*28 allele is unchanged. Recommended dose and regimen of Onivyde pegylated liposomal in combination with 5-FU and LV is 70 mg/m² intravenously (i.v.) over 90 minutes, followed by LV 400 mg/m² i.v. over 30 minutes, followed by 5-FU 2,400 mg/m² i.v. 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. A dose increase of Onivyde pegylated liposomal to 70 mg/m² should be considered if tolerated in subsequent cycles. Hepatic impairment: 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 (SPC section 4.4). Renal impairment: No dose adjustment is recommended in patients with mild to moderate renal impairment (SPC 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. No dose adjustment is recommended.

CONTRAINDICATIONS: History of severe hypersensitivity to irinotecan or any of the excipients; breast‑feeding.

WARNINGS AND PRECAUTIONS: Onivyde is not equivalent to other non‑liposomal irinotecan formulations and should not be interchanged. Myelosuppression/neutropenia: Monitor complete blood cell count during treatment. Make patients aware of the risk of neutropenia and the significance of fever. Treat febrile neutropenia (body temperature > 38°C and neutrophil count ≤ 1,000 cells/mm³) urgently in hospital with broad‑spectrum intravenous antibiotics. Withhold treatment in the event of neutropenic fever or absolute neutrophil count below 1,500 cells/mm³. Reduce dose or discontinue treatment in patients with severe haematological events. Not recommended in patients with severe bone marrow failure. Patients with deficient glucuronidation of bilirubin, e.g. Gilbert’s syndrome, may be at greater risk of myelosuppression during treatment. Asian patients have an increased risk (compared to Caucasians) of severe febrile neutropenia following treatment with Onivyde+5‑FU/LV. Adverse effects of irinotecan, such as myelosuppression, may be exacerbated by other antineoplastic agents (including flucytosine as a prodrug for 5-fluorouracil). History of prior abdominal radiation: increases risk of severe neutropenia and febrile neutropenia. Monitor blood counts carefully, and consider use of myeloid growth factors. Exercise caution in patients receiving concurrent Onivyde with irradiation. Vaccines: Avoid concomitant live/live attenuated vaccines in patients immunocompromised by chemotherapy; killed/inactivated vaccines may be administered, but response may be diminished. Interactions with strong CYP3A4 inducers, strong CYP3A4 inhibitors or strong UGT1A1 inhibitors: Avoid concomitant use. Diarrhoea requires active management. Make patients aware of the risks of diarrhoea. Delay treatment until diarrhoea resolves to ≤ Grade 1. Avoid treating patients with concurrent bowel obstruction or chronic inflammatory bowel disease. 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) and given until patient is without diarrhoea for at least 12 hours. To help avoid severe diarrhoea, stop all lactose-containing products, maintain hydration and eat a lowfat diet. If diarrhoea persists on loperamide for > 24 hours, adding oral antibiotic support should be considered. Loperamide should not be used for more than 48 hours due to risk of paralytic ileus. A new cycle of therapy should not begin until diarrhoea resolves to ≤ Grade 1 (2-3 stools/day more than pre-treatment frequency). Cholinergic reactions: Administer atropine. Acute infusion and hypersensitivity reactions: Hypersensitivity reactions may occur. If severe, discontinue treatment. Prior Whipple procedure: Monitor carefully for signs of serious infections. Vascular disorders: Identify patients at risk of thromboembolic events such as pulmonary embolism, venous thrombosis and arterial thromboembolism. Make patients aware of signs and symptoms of thromboembolism and advise to seek immediate medical help in the event of any such signs or symptoms. Pulmonary toxicity: Interstitial Lung Disease (ILD)-like events leading to fatalities have occurred in patients receiving non-liposomal irinotecan. Patients with risk factors (preexisting lung disease, use of pneumotoxic medicinal products, colony stimulating factors or having previously received radiation therapy) should be closely monitored for respiratory symptoms before and during Onivyde pegylated liposomal therapy. Monitor patients at risk before and during treatment. Interrupt treatment in the event of new or progressive dyspnoea, cough and fever. Discontinue if interstitial lung disease confirmed. Hepatic impairment: Increased risk of neutropenia in patients with hyperbilirubinaemia. Perform regular complete blood counts in patients with total bilirubin of 1.0‑2.0 mg/dl. Exercise caution in hepatic impairment (bilirubin > 2 times upper limit of normal [ULN]; transaminases > 5 times ULN) and with concomitant hepatotoxic medicinal products, especially in patients with pre-existing hepatic impairment. Sodium content: contains 33.1 mg sodium per vial, equivalent to 1.65% of the WHO recommended maximum daily intake of 2g sodium for an adult.

INTERACTION(S): Precautions: Co-administration of Onivyde pegylated liposomal with inducers of CYP3A4 (e.g. anticonvulsants, rifampin, rifabutin, St. John’s wort) may reduce systemic exposure of Onivyde pegylated liposomal. Co-administration of Onivyde pegylated liposomal with inhibitors of CYP3A4 (e.g. grapefruit juice, clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) and UGT1A1 (e.g. atazanavir, gemfibrozil, indinavir, regorafenib) may increase systemic exposure of Onivyde pegylated liposomal. Co-administration with antineoplastic agents (including flucytosine) may exacerbate adverse effects of Onivyde pegylated liposomal.

FERTILITY, PREGNANCY AND LACTATION: Contraception: Women of childbearing potential should use effective contraception during Onivyde treatment and 7 months thereafter. Males should use condoms during Onivyde treatment and 4 months thereafter. Pregnancy: Do not use Onivyde unless clearly necessary. If treatment occurs during pregnancy inform the patient of the potential hazard to the foetus. Breast-feeding: Contraindicated. Patients should not breast-feed until one month after the last dose. Fertility: No data on Onivyde on human fertility, irinotecan was shown to cause reproductive organs atrophy in animals (see SPC). Prior to starting the administration of Onivyde consider advising patients on the preservation of gametes.

List of side effects (please refer to SPC for full list):
Onivyde pegylated liposomal in combination with oxaliplatin, 5-fluorouracil and leucovorin: Very common: Anaemia, neutropenia, thrombocytopenia, hypokalaemia, decreased appetite, neuropathy peripheral, dysgeusia, paraesthesia, diarrhoea, nausea, vomiting, abdominal pain/discomfort, stomatitis, alopecia, asthenia, mucosal inflammation, weight decreased. Common: Sepsis, urinary tract infection, candida infection, nasopharyngitis, febrile neutropenia, leukopenia, lymphopenia, dehydration, hyponatraemia, hypophosphataemia, hypomagnesaemia, hypoalbuminaemia, hypocalcaemia, tremor, neurotoxicity, dysaesthesia, cholinergic syndrome, headache, dizziness, vision blurred, tachycardia, hypotension, thromboembolic events, pulmonary embolism, hiccups, dyspnoea, epistaxis, colitis, enterocolitis, constipation, dry mouth, flatulence, abdominal distension, dyspepsia, gastroesophageal reflux disease, haemorrhoids, dysphagia, hyperbilirubinemia, dry skin, palmar-plantar erythrodysesthesia syndrome, rash, skin hyperpigmentation, muscular weakness, myalgia, muscle spasms, acute kidney injury, pyrexia, oedema, chills, transaminase (ALT and AST) increased, blood alkaline phosphatase increased, gammaglutamyltransferase increased, blood creatinine increased, infusion related reaction. Serious events: Uncommon: Pancytopenia, haemolytic anaemia, renal failure.

Onivyde pegylated liposomal in combination with 5-fluorouracil and leucovorin: Very common: Neutropenia, leukopenia, anaemia, thrombocytopenia, hypokalaemia, hypomagnesaemia, dehydration, decreased appetite, dizziness, diarrhoea, vomiting, nausea, abdominal pain, stomatitis, alopecia, pyrexia, peripheral oedema, mucosal inflammation, asthenia, weight decrease. Common: Septic shock, sepsis, pneumonia, febrile neutropenia, gastroenteritis, oral candidiasis, lymphopenia, hypoglycaemia, hyponatraemia, hypophosphataemia, insomnia, cholinergic syndrome, dysgeusia, hypotension, pulmonary embolism, thromboembolic events, dyspnoea, dysphonia, colitis, haemorrhoids, hypoalbuminaemia, pruritus, acute renal failure, infusion related reaction, oedema, increased bilirubin, transaminases (ALT and AST) increased, increased international normalised ratio. Serious events: Incidence not known: Anaphylactic/Anaphyactoid reaction, angioedema.

Further Information: Servier Laboratories Ltd., Sefton Park, Stoke Poges, SL2 4JS; Tel (01753) 666409.

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. Adverse events should also be reported to Servier Laboratories Ltd. Tel: 01753 666409. Email: uk.pharmacovigilance@servier.com.