t significant adverse reactions reported were severe neutropenia and severe diarrrhoea.
There is no known antidote for overdose of ONIVYDE. Maximum supportive care should be instituted to prevent dehydration due to diarrhoea and to treat any infectious complications.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents, ATC code: L01XX19
Mechanism of action
The active substance in ONIVYDE 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 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 1000 times as potent as irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumour cell lines.
Pharmacodynamic effects
In animal models, ONIVYDE has been shown to extend plasma levels of irinotecan and prolong the exposure to the active metabolite SN-38 at the site of the tumour.
Clinical efficacy and safety
The safety and efficacy of ONIVYDE were investigated in a multinational, randomized, open label, controlled clinical trial (NAPOLI–1) that tested two treatment regimens for patients with metastatic pancreatic adenocarcinoma who had documented disease progression after gemcitabine or gemcitabine-containing therapy. The trial was designed to assess the clinical efficacy and safety of ONIVYDE monotherapy or ONIVYDE+5-FU/LV compared to an active control arm of 5-FU/LV.
Patients randomized to ONIVYDE+5-FU/LV received ONIVYDE at 80 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 intravenously over 46 hours, administered every 2 weeks. Patients homozygous for the UGT1A1*28 allele were given a lower initial dose of ONIVYDE (see section 4.2). Patients randomised to 5-FU/LV received leucovorin 200 mg/m2 intravenously over 30 minutes, followed by 5-FU 2,000 mg/m2 intravenously over 24 hours, administered on Days 1, 8, 15 and 22 of a 6 week cycle. Patients randomised to ONIVYDE monotherapy received 120 mg/m2 as an intravenous 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 and albumin ≥ 3.0 g/dl.
A total of 417 patients were randomised to the ONIVYDE+5-FU/LV arm (N=117), ONIVYDE monotherapy arm (N=151) and 5-FU/LV arm (N=149). Patient demographic and entry disease characteristics were well balanced between trial 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 White and 33% were Asian. Mean baseline albumin level was 3.6 g/dl, and baseline KPS was 90-100 in 55% of patients. Disease characteristics included 68% of patients with liver metastases and 31% with lung metastases; 12% of patients had no prior lines of metastatic therapy, 56 % of patients had 1 prior line of metastatic therapy, |
