Onivyde® pegylated liposomal (irinotecan)

COMPOSITION* 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 irinotecan sucrosofate salt in a pegylated liposomal formulation).

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 adult patients who have progressed following gemcitabine based therapy.

DOSAGE AND 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. It should not be administered as a single agent and should be continued until disease progression or no longer tolerated by the patient. 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. Dose adjustments are recommended to manage toxicities related to Onivyde pegylated liposomal.

CONTRAINDICATIONS* History of severe hypersensitivity to irinotecan or to any of the excipients. Breast-feeding.

WARNINGS* 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 should be urgently treated in the hospital with broad-spectrum intravenous antibiotics. In patients who experienced severe haematological events, a dose reduction or treatment discontinuation is recommended. 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. Caution should be exercised in patients receiving concurrent administration of Onivyde pegylated liposomal and irradiation. Patients with deficient glucuronidation of bilirubin may be at greater risk of myelosuppression. Immunosuppressive effects and vaccines: Administration of live or live-attenuated vaccines in patients immunocompromised may result in serious or fatal infections. Interactions with strong CYP3A4 inducers, strong CYP3A4 inhibitors or strong UGT1A1 inhibitors: Onivyde pegylated liposomal should not be administered with strong CYP3A4 enzyme inducers, strong CYP3A4 enzyme inhibitors or strong UGT1A1 inhibitors unless there are no therapeutic alternatives. Strong CYP3A4 inhibitors should be discontinued at least 1 week prior to starting Onivyde pegylated liposomal therapy. Diarrhoea: Onivyde pegylated liposomal can cause severe and life-threatening diarrhoea. It must not be administered to patients with bowel obstruction, and chronic inflammatory bowel disease. Unless contraindicated, therapeutic and prophylactic atropine should be considered in patients experiencing early diarrhoea (onset in ≤ 24 hours after starting Onivyde pegylated liposomal) or cholinergic symptoms. Patients should be made aware of the risk of delayed diarrhoea (> 24 hours) which can be debilitating and, on rare occasions, life threatening. 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 low-fat 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: Early onset diarrhoea may be accompanied by rhinitis, increased salivation, flushing, diaphoresis, bradycardia, miosis and hyperperistalsis. In case of symptoms atropine should be administered. Hypersensitivity reaction including acute infusion related reactions: Onivyde pegylated liposomal should be discontinued in case of severe hypersensitivity reactions. Prior Whipple procedure: Higher risk of serious infections. 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. 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. New or progressive dyspnoea, cough, and fever should prompt interruption of Onivyde pegylated liposomal treatment, pending diagnostic evaluation. Onivyde pegylated liposomal should be discontinued in patients with a confirmed diagnosis of ILD. Hepatic impairment: Patients with hyperbilirubinaemia had higher concentrations for total SN-38 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. Underweight patients (body mass index < 18.5 kg/m2): Caution should be exercised. Excipients: Each ml of Onivyde pegylated liposomal contains 0.144 mmol (3.31 mg) sodium.

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* Prior starting administration of Onivyde pegylated liposomal consider advising patients on the preservation of gametes.

CONTRACEPTION* 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.

UNDESIRABLE EFFECTS* 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, gamma-glutamyltransferase increased, blood creatinine increased, infusion related reaction 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, peritumoural oedema, pancytopenia, haemolytic anaemia, hypersensitivity, electrolyte imbalance, hypercalcaemia, cell death, hypochloraemia, gout, hyperglycaemia, hyperkalaemia, iron deficiency, malnutrition, insomnia, confusional state, depression, neurosis, seizure, cerebral haemorrhage, cerebral ischaemia, ischaemic stroke, anosmia, ageusia, balance disorder, hypersomnia, hypoaesthesia, intellectual disability, lethargy, memory impairment, presyncope, syncope, transient ischaemic attack, eye irritation, visual acuity reduced, vertigo, angina pectoris, acute myocardial infarction, palpitations, hypertension, peripheral coldness, haematoma, phlebitis, oropharyngeal pain, cough, hyperoxia, nasal inflammation, atelectasis, dysphonia, pneumonitis, 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, cholangitis, hepatitis toxic, cholestasis, hepatic cytolysis, pruritus, hyperhidrosis, dermatitis bullous, dermatitis exfoliative generalised, erythema, nail toxicity, papule, petechiae, psoriasis, sensitive skin, skin exfoliation, skin lesion, telangiectasia, urticaria, arthralgia, back pain, bone pain, pain in extremity, polyarthritis, renal impairment, renal failure, dysuria, proteinuria, vulvovaginal dryness, 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, international normalised ratio increased, protein total decreased, creatinine renal clearance decreased, electrocardiogram qt prolonged, monocyte count increased, troponin I increased. 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, fatigue, asthenia, weight decrease. Common: Septic shock, sepsis, pneumonia, febrile neutropenia, gastroenteritis, oral candidiasis, lymphopenia, hypoglycaemia, hyponatraemia, hypophosphataemia, insomnia, cholinergic syndrome, dysgeusia, hypotension, pulmonary embolism, thomboembolic 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. Uncommon: Biliary sepsis, hypersensitivity, hypoxia, oesophagitis, proctitis, urticaria, rash, nail discolouration. Not known: Anaphylactic/anaphylactoid reaction, angioedema, erythema.

OVERDOSE* PROPERTIES* Irinotecan (topoisomerase I inhibitor) encapsulated in a lipid bilayer vesicle or liposome. Irinotecan is a derivative of camptothecin. Camptothecins act as specific inhibitors of the enzyme DNA topoisomerase I. Irinotecan and its active metabolite SN-38 bind reversibly to the topoisomerase I-DNA complex and induce single-strand DNA lesions which block the DNA replication fork and are responsible for the cytotoxicity. Irinotecan is metabolized by carboxylesterase to SN-38. SN-38 is approximately 1,000 times as potent as irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumour cell lines.

MARKETING AUTHORISATION HOLDER LES LABORATOIRES SERVIER, 50 rue Carnot, 92284 Suresnes cedex, France, www.servier.com.

Legal Classification for Supply: POM. Further information available from: Servier Laboratories (Ireland) Ltd.1st Floor, Building Two, The Green Dublin Airport Central. Dublin Airport, Swords Co. Dublin K67 E2H3. Ireland. Tel (01) 6638110, www.servier.ie.

*For complete information, please refer to the Summary of Product Characteristics available on medicines.ie

Adverse events should be reported. Reporting forms and further information can be found on the Health Products Regulatory Agency (HPRA) website: https://www.hpra.ie/report-an-issue. Adverse events should also be reported to Servier Laboratories (Ireland) Ltd: pharmacovigilance-dublin@servier.com.