Defitelio

 Recommended Dosage

The recommended dosage of DEFITELIO for adult and pediatric patients is 6.25 mg/kg every 6 hours given as a 2‑hour intravenous infusion. The dose should be based on patient’s baseline body weight, defined as the patient’s weight prior to the preparative regimen for HSCT.

Administer DEFITELIO for a minimum of 21 days. If after 21 days signs and symptoms of hepatic VOD have not resolved, continue DEFITELIO until resolution of VOD or up to a maximum of 60 days.

 Administration Instructions

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DEFITELIO must be diluted prior to infusion [see Dosage and Administration (2.4)].

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Prior to administration of DEFITELIO, confirm that the patient is not experiencing clinically significant bleeding and is hemodynamically stable on no more than one vasopressor [see Warnings and Precautions (5.1)].

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Administer DEFITELIO by constant intravenous infusion over a 2-hour period.

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Administer the diluted DEFITELIO solution using an infusion set equipped with a 0.2 micron in-line filter. Flush the intravenous administration line (peripheral or central) with 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP immediately before and after administration.

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Do not co‑administer DEFITELIO and other intravenous drugs concurrently within the same intravenous line.

 Treatment Modification

Treatment modification, including temporary or permanent discontinuation of DEFITELIO, should follow the recommendations in Table 1.

Table 1: Treatment Modifications for Toxicity or Invasive Procedures

 Preparation Instructions

Dilute DEFITELIO in 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP to a concentration of 4 mg/mL to 20 mg/mL. Administer the diluted solution over 2 hours.

Vials contain no antimicrobial preservatives and are intended for a single-patient-use only. Partially used vials should be discarded. Use the diluted DEFITELIO solution within 4 hours if stored at room temperature or within 24 hours if stored under refrigeration. Up to four doses of DEFITELIO solution may be prepared at one time, if refrigerated.

Preparation Instructions:

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Determine the dose (mg) and number of vials of DEFITELIO based on the individual patient’s baseline weight (weight prior to the preparative regimen for HSCT).

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Calculate the volume of DEFITELIO needed, withdraw this amount from the vial(s) and add it to the infusion bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection for each dose to make a final concentration of 4 mg/mL to 20 mg/mL.

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Gently mix the solution for infusion.

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Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Only clear solutions without visible particles should be used. Depending on the type and amount of diluent, the color of the diluted solution may vary from colorless to light yellow.

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.

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.

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.

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.

Hemorrhage

DEFITELIO increased the activity of fibrinolytic enzymes in vitro, and it may increase the risk of bleeding in patients with VOD after hematopoietic stem-cell transplantation (HSCT). Do not initiate DEFITELIO in patients with active bleeding. Monitor patients for signs of bleeding. If patients on DEFITELIO develop bleeding, discontinue DEFITELIO, treat the underlying cause, and provide supportive care until the bleeding has stopped [see Dosage and Administration (2.3)].

Concomitant use of DEFITELIO and a systemic anticoagulant or fibrinolytic therapy (not including use for routine maintenance or reopening of central venous lines) may increase the risk of bleeding. Discontinue anticoagulants and fibrinolytic agents prior to DEFITELIO treatment, and consider delaying the start of DEFITELIO administration until the effects of the anticoagulant have abated [see Contraindications (4)].

Hypersensitivity Reactions

Hypersensitivity reactions have occurred in less than 2% of patients treated with DEFITELIO. These reactions include rash, urticaria and angioedema. One case of an anaphylactic reaction was reported in a patient who had previously received DEFITELIO. Monitor patients for hypersensitivity reactions, especially if there is a history of previous exposure. If a severe hypersensitivity reaction occurs, discontinue DEFITELIO, treat according to the standard of care, and monitor until symptoms resolve [see Dosage and Administration (2.3)].