DEFITELIO (Page 3 of 5)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on DEFITELIO use in pregnant women. When administered to pregnant rabbits during the period of organogenesis at doses that were comparable to the recommended human dose based on body surface area, defibrotide sodium decreased the number of implantations and viable fetuses. Advise pregnant women of the potential risk of miscarriage.

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

Data

Animal Data

Embryo-Fetal toxicity assessment was attempted in rats and rabbits, but was not possible because of high maternal mortality, abortion, and fetal resorption at all doses. Pregnant rats were administered defibrotide sodium from gestational day (GD) 6 to 15 at 0, 240, 1200, and 4800 mg/kg/day by continuous intravenous infusion over 24 hours or at 60, 120, and 240 mg/kg/day by 2-hour infusions 4 times per day. Pregnant rabbits were administered defibrotide sodium at 0, 30, 60, or 120 mg/kg/day from GD 6 to 18 by 2-hour infusions 4 times per day.

In another study in pregnant rabbits, 3 separate subgroups of animals were treated with doses of 80 mg/kg/day defibrotide sodium administered by 2-hour infusions 4 times per day for 5 days each in a staggered manner during the organogenesis period. The dose of 80 mg/kg/day is approximately equivalent to the recommended clinical dose on a mg/m2 basis. Subgroup 1 was dosed from GD 6 to 10, subgroup 2 was dosed from GD 10 to 14, and subgroup 3 was dosed from GD 14 to 18. An increased incidence of unilateral implantation was observed in defibrotide sodium-treated animals. Treatment with defibrotide sodium resulted in a decreased number of implantations and viable fetuses.

8.2 Lactation

Risk Summary

There is no information regarding the presence of DEFITELIO in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with DEFITELIO.

8.4 Pediatric Use

The safety and effectiveness of DEFITELIO have been established in pediatric patients. Use of DEFITELIO is supported by evidence from an adequate and well-controlled study and a dose finding study of DEFITELIO in adult and pediatric patients with VOD with evidence of renal or pulmonary dysfunction following HSCT. The clinical trials enrolled 66 pediatric patients in the following age groups: 22 infants (1 month up to less than 2 years), 30 children (2 years up to less than 12 years), and 14 adolescents (12 years to less than 17 years). The efficacy and safety outcomes were consistent across pediatric and adult patients in the clinical trials [see Adverse Reactions (6) and Clinical Studies (14)].

Juvenile Animal Toxicity Data

A juvenile toxicity study in 21-day-old rats was conducted with intravenous bolus administration of defibrotide sodium at 40, 150, or 320 mg/kg/day for 4 weeks. A delayed mean age of preputial separation was observed at all doses, suggesting a delay in onset of male puberty. The dose of 40 mg/kg/day is approximately 0.4 times the clinical dose on a mg/m2 basis for a child. The relevance of this finding for the onset of male puberty in humans is unknown.

8.5 Geriatric Use

Clinical studies of DEFITELIO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

10 OVERDOSAGE

There are no known cases of overdose with DEFITELIO. There is no known antidote for DEFITELIO, and DEFITELIO is not dialyzable. If an overdose occurs, institute general supportive measures.

11 DESCRIPTION

Defibrotide sodium is an oligonucleotide mixture with profibrinolytic properties. The chemical name of defibrotide sodium is polydeoxyribonucleotide, sodium salt. Defibrotide sodium is a polydisperse mixture of predominantly single-stranded (ss) polydeoxyribonucleotide sodium salts derived from porcine intestinal tissue having a mean weighted molecular weight of 13-20 kDa, and a potency of 27-39 and 28-38 biological units per mg as determined by two separate assays measuring the release of a product formed by contact between defibrotide sodium, plasmin and a plasmin substrate. The primary structure of defibrotide sodium is shown below.

chemical structure
(click image for full-size original)

DEFITELIO (defibrotide sodium) injection is a clear, light yellow to brown, sterile, preservative-free solution in a single-patient-use vial for intravenous use. Each milliliter of the injection contains 80 mg of defibrotide sodium and 10 mg of Sodium Citrate, USP, in Water for Injection, USP. Hydrochloric Acid, NF, and/or Sodium Hydroxide, NF, may have been used to adjust pH to 6.8-7.8.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of defibrotide sodium has not been fully elucidated. In vitro , defibrotide sodium enhances the enzymatic activity of plasmin to hydrolyze fibrin clots. Studies evaluating the pharmacological effects of defibrotide sodium on endothelial cells (ECs) were conducted primarily in the human microvascular endothelial cell line. In vitro , defibrotide sodium increased tissue plasminogen activator (t-PA) and thrombomodulin expression, and decreased von Willebrand factor (vWF) and plasminogen activator inhibitor‑1 (PAI-1) expression, thereby reducing EC activation and increasing EC‑mediated fibrinolysis. Defibrotide sodium protected ECs from damage caused by chemotherapy, tumor necrosis factor-α (TNF-α), serum starvation, and perfusion.

12.2 Pharmacodynamics

Cardiac Electrophysiology

At a dose 2.4 times the maximum recommended dose, DEFITELIO does not prolong the QTc interval to any clinically relevant extent.

PAI-1 Inhibition

Plasma concentrations of PAI-1 were assessed on an exploratory basis as a potential pharmacodynamic marker for efficacy in Study 2. PAI-1 is an inhibitor of t-PA and therefore of fibrinolysis. Mean PAI-1 levels on Days 7 and 14 were lower than those at baseline in patients with complete response (CR) and in those who were alive at Day+100, but this trend did not reach statistical significance. There were no statistically significant differences in mean PAI-1 levels by treatment or outcome.

12.3 Pharmacokinetics

Absorption

After intravenous administration, peak plasma concentrations of defibrotide sodium occur approximately at the end of each infusion.

Distribution

Defibrotide sodium is highly bound to human plasma proteins (average 93%) and has a volume of distribution of 8.1 to 9.1 L.

Elimination

Metabolism followed by urinary excretion is likely the main route of elimination. The estimated total clearance was 3.4 to 6.1 L/h. The elimination half-life of defibrotide sodium is less than 2 hours. Similar plasma concentration profiles were observed in VOD patients after initial and multiple-dose administration of 6.25 mg/kg every 6 hours for 5 days. Therefore, no accumulation is expected following multiple-dose administration.

Metabolism

Though the precise pathway of defibrotide sodium degradation in plasma in vivo is largely unknown, it has been suggested that nucleases, nucleotidases, nucleosidases, deaminases, and phosphorylases metabolize polynucleotides progressively to oligonucleotides, nucleotides, nucleosides, and then to the free 2′-deoxyribose sugar, purine and pyrimidine bases.

The biotransformation of defibrotide sodium was investigated in vitro by incubation with human hepatocytes from donors of different ages and showed that defibrotide sodium does not undergo appreciable metabolism by human hepatocyte cells.

Excretion

After administration of 6.25 mg/kg to 15 mg/kg doses of DEFITELIO as 2-hour infusions, approximately 5-15% of the total dose was excreted in urine as defibrotide sodium, with the majority excreted during the first 4 hours.

Specific Populations

Age: Pediatric Population

Insufficient PK data were collected in pediatric patients to draw conclusions.

Renal Impairment

The safety, tolerability, and pharmacokinetics of 6.25 mg/kg as 2-hour intravenous infusions of DEFITELIO were evaluated in patients with Hemodialysis-dependent End Stage Renal Disease (ESRD) during hemodialysis and on days off dialysis, and in patients with severe renal disease or ESRD not requiring dialysis. Defibrotide sodium was not removed by hemodialysis, which had no notable effect on plasma clearance of defibrotide sodium. Terminal half-lives were consistently less than 2 hours, and there was no accumulation of defibrotide sodium following repeated dosing. Defibrotide sodium exposure (AUC) in patients with severe renal impairment or ESRD was 50% to 60% higher than that observed in matched healthy subjects. Peak concentration (Cmax ) was 35% to 37% higher following single- and multiple-dose administration of defibrotide sodium.

Drug Interactions

Pharmacokinetic drug-drug interactions are unlikely at therapeutic dose. Data from in vitro studies using human biomaterial demonstrate that defibrotide sodium does not induce (CYP1A2, CYP2B6, CYP3A4, UGT1A1) or inhibit (CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C9, CYP2C19, CYP2D6, UGT1A1, UGT2B7) the major drug metabolizing enzymes and is not a substrate or inhibitor of the major drug uptake transporters (OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3) or efflux transporters (P-gp and BCRP).

There is some evidence (animal studies, ex vivo human plasma, and healthy volunteers) that defibrotide sodium may enhance the pharmacodynamic activity of heparin and alteplase [see Drug Interactions (7)].

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