CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Irinotecan liposome injection is a topoisomerase 1 inhibitor encapsulated in a lipid bilayer vesicle or liposome. Topoisomerase 1 relieves torsional strain in DNA by inducing single-strand breaks. Irinotecan and its active metabolite SN-38 bind reversibly to the topoisomerase 1-DNA complex and prevent re- ligation of the single-strand breaks, leading to exposure time-dependent double-strand DNA damage and cell death. In mice bearing human tumor xenografts, irinotecan liposome administered at irinotecan HCl-equivalent doses 5-fold lower than irinotecan HCl achieved similar intratumoral exposure of SN-38.

12.3 Pharmacokinetics

The plasma pharmacokinetics of total irinotecan and total SN-38 were evaluated in patients with cancer who received ONIVYDE, as a single agent or as part of combination chemotherapy, at doses between 35 mg/m2 and 155 mg/m2 and concentration proportional to dose was observed.

The pharmacokinetic parameters of total irinotecan and total SN-38 following the administration of ONIVYDE 70 mg/m2 as a single agent or part of combination chemotherapy are presented in Table 7.

Table 7 Summary of Geometric Mean (CV) Total Irinotecan and Total SN-38

Distribution

Direct measurement of irinotecan liposome showed that 95% of irinotecan remains liposome -encapsulated, and the ratios between total and encapsulated forms did not change with time from 0 to 170 hours post-dose. The mean volume of distribution is summarized in Table 7.

Plasma protein binding is <0.44% of the total irinotecan in ONIVYDE.

Elimination

Metabolism

The metabolism of irinotecan liposome has not been evaluated. Irinotecan is subject to extensive metabolic conversion by various enzyme systems, including carboxylesterases to form the active metabolite SN-38, and UGT1A1 mediating glucuronidation of SN-38 to form the inactive glucuronide metabolite SN-38G. Irinotecan can also undergo CYP3A4-mediated oxidative metabolism to several inactive oxidation products, one of which can be hydrolyzed by carboxylesterase to release SN-38. In the population PK analysis of irinotecan liposome, UGT1A128 7/7 homozygous status (10.6%) had no effect on SN-38 clearance compared with patients not homozygous for UGT1A128 7/7.

Excretion

The disposition of ONIVYDE has not been elucidated in humans. Following administration of irinotecan HCl, the urinary excretion of irinotecan is 11 to 20%; SN-38, <1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide), over a period of 48 hours following administration of irinotecan HCl in two patients, ranged from approximately 25% (100 mg/m2) to 50% (300 mg/m2).

Specific Populations

Age, Sex, Ethnicity, Renal and Hepatic Impairment:

The population pharmacokinetic analyses suggest that age (20 to 87 years) and BSA (1.15 to 2.88 m2) had no clinically meaningful effect on the exposure of irinotecan and SN-38.

Irinotecan and SN-38 AUC in female patients were 28% and 32% higher, respectively, than those in male patients. Irinotecan AUC in patients of Asian ethnicity were 32% lower than that in non-Asian patients. The exposures of irinotecan and SN-38 in patients with mild or moderate renal impairment were comparable to patients with normal renal function after adjusting for BSA. The exposures of irinotecan and SN-38 in patients with mild hepatic impairment (based on NCI score) were comparable to patients with normal hepatic function. There was insufficient data in patients with severe renal impairment (CLcr < 30 mL/min) or in patients with moderate and severe hepatic impairment to assess their effects on the exposures of irinotecan and SN-38. Increased AST/ALT had no effect on irinotecan clearance; however, increased bilirubin level was associated with lower SN‑38 clearance. SN-38 AUC was increased by 32% in patients with bilirubin level of 1.14 mg/dL (95th of the overall population) compared with that of median bilirubin level of 0.44 mg/dL. No data are available in patients with bilirubin >2.8 mg/dL.

Drug Interactions

In a population pharmacokinetic analysis, the pharmacokinetics of total irinotecan and total SN-38 were not altered by the co-administration of fluorouracil/leucovorin. In Study MM‑398‑07‑02‑03 and NAPOLI-3, irinotecan AUC was decreased by 33% and SN-38 Cmax increased by 23% following co- administration with oxaliplatin.

Following administration of irinotecan HCl, dexamethasone (moderate CYP3A4 inducer) does not alter the pharmacokinetics of irinotecan.

In vitro studies indicate that irinotecan, SN-38 and another metabolite, aminopentane carboxylic acid (APC), do not inhibit cytochrome P-450 isozymes.

12.5 Pharmacogenomics

Individuals who are homozygous for the UGT1A128 allele are at increased risk for neutropenia from irinotecan HCl. In NAPOLI-1, patients homozygous for the UGT1A128 allele (N=7) initiated ONIVYDE at a reduced dose of 50 mg/m2 in combination with FU/LV. The frequency of Grade 3 or 4 neutropenia in these patients [2 of 7 (28.6%)] was similar to the frequency in patients not homozygous for the UGT1A128 allele who received a starting dose of ONIVYDE of 70 mg/m2 [30 of 110 (27.3%)]. In NAPOLI-3, patients homozygous for the UGT1A128 allele (N = 39) initiated ONIVYDE at the same starting dose of 50 mg/m2 as patients not homozygous for the UGT1A128 allele (N = 328). The frequency of Grade 3 or 4 neutropenia was 23% in patients homozygous for the UGT1A128 allele and 13% in patients not homozygous for the UGT1A128 allele. The frequency of dose reduction of ONIVYDE due to treatment-emergent adverse effects was 59% versus 51% in patients homozygous versus non-homozygous for the UGT1A128 allele.

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BOXED WARNING SECTION

WARNING: SEVERE NEUTROPENIA AND SEVERE DIARRHEA

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: * Lactation: Do not breastfeed. (8.2)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on animal data with irinotecan HCl and the mechanism of action of ONIVYDE, ONIVYDE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women. Embryotoxicity and teratogenicity were observed following treatment with irinotecan HCl, at doses resulting in irinotecan exposures lower than those achieved with ONIVYDE 70 mg/m2 in humans, administered to pregnant rats and rabbits during organogenesis [see Data]. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

No animal studies have been conducted to evaluate the effect of irinotecan liposome on reproduction and fetal development; however, studies have been conducted with irinotecan HCl. Irinotecan crosses the placenta of rats following intravenous administration. Intravenous administration of irinotecan at a dose of 6 mg/kg/day to rats and rabbits during the period of organogenesis resulted in increased post-implantation loss and decreased numbers of live fetuses. In separate studies in rats, this dose resulted in an irinotecan exposure of approximately 0.002 times the exposure of irinotecan based on area under the curve (AUC) in patients administered ONIVYDE at the 70 mg/m2 dose. Administration of irinotecan HCl resulted in structural abnormalities and growth delays in rats at doses greater than 1.2 mg/kg/day (approximately 0.0002 times the clinical exposure to irinotecan in ONIVYDE based on AUC). Teratogenic effects included a variety of external, visceral, and skeletal abnormalities. Irinotecan HCl administered to rat dams for the period following organogenesis through weaning at doses of 6 mg/kg/day caused decreased learning ability and decreased female body weights in the offspring.

8.2 Lactation

Risk Summary

There is no information regarding the presence of irinotecan liposome, irinotecan, or SN-38 (an active metabolite of irinotecan) in human milk, or the effects on the breastfed infant or on milk production. Irinotecan is present in rat milk [see Data].

Because of the potential for serious adverse reactions in breastfed infants from ONIVYDE, advise a nursing woman not to breastfeed during treatment with ONIVYDE and for one month after the last dose.

Data

Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabeled irinotecan HCl and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations.

8.3 Females and Males of Reproductive Potential

Contraception

Females

ONIVYDE can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with ONIVYDE and for seven months after the last dose.

Males

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with ONIVYDE and for four months after the last dose [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness of ONIVYDE have not been established in pediatric patients.

8.5 Geriatric Use

Of the 634 patients who received ONIVYDE as a single agent, in combination with FU and leucovorin or in combination with oxaliplatin, FU and leucovorin in NAPOLI-1 and NAPOLI 3, 49% were ≥ 65 years old and 10% were ≥ 75 years old. No overall differences in safety and effectiveness were observed between these patients and younger patients.

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OVERDOSAGE SECTION

10 OVERDOSAGE

There are no treatment interventions known to be effective for management of overdosage of ONIVYDE.

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