Data from FDA - Curated by Toby Galbraith - Last updated 16 May 2017

Indication(s)

1 INDICATIONS AND USAGE DEFITELIO is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).

DEFITELIO is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).

(1)

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Advisory information

contraindications

4 CONTRAINDICATIONS The use of DEFITELIO is contraindicated in the following conditions: •Concomitant administration with systemic anticoagulant or fibrinolytic therapy [see Warnings and Precautions (5.1)] •Known hypersensitivity to DEFITELIO or to any of its excipients [see Warnings and Precautions (5.2)] •Concomitant administration with systemic anticoagulant or fibrinolytic therapy.

(4) •Known hypersensitivity to DEFITELIO or to any of its excipients.

(4)

Adverse reactions

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: •Hemorrhage [see Warnings and Precautions (5.1)] •Hypersensitivity Reactions [see Warnings and Precautions (5.2)] The most common adverse reactions (incidence?10 % and independent of causality) with DEFITELIO treatment were hypotension, diarrhea, vomiting, nausea, and epistaxis.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1-800-520-5568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of DEFITELIO was determined in 176 adult and pediatric patients with hepatic VOD with pulmonary and/or renal dysfunction following HSCT who were treated with DEFITELIO 6.25 mg/kg every 6 hours [see Clinical Studies (14)].

Patients were excluded from these trials if at time of study entry they had significant acute bleeding, active grades B-D graft-versus-host disease, or a requirement for multiple vasopressors to provide blood pressure support.

For the purposes of adverse event recording in the clinical trials, events were not required to be reported if they were related to the hepatic VOD, or if they were expected to occur after hematopoietic stem-cell transplantation (HSCT), unless they were serious or Grade 4-5.

The median age of the safety population was 25 years (range: 1 month to 72 years), and 63 % were?17 years of age.

A total of 60 % of patients were male, 78 % were white, 89 % had undergone allogeneic HSCT, and the underlying diagnosis was acute leukemia for 43 %.

At study entry, 13 % were dialysis dependent and 18 % were ventilator dependent.

DEFITELIO was administered for a median of 21 days (range: 1 to 83 days).

Information about adverse reactions resulting in permanent discontinuation of DEFITELIO was available for 102 patients, and 35 (34 %) of these patients had an adverse reaction with permanent discontinuation.

Adverse reactions leading to permanent discontinuation included pulmonary alveolar hemorrhage in 5 (5 %) patients; pulmonary hemorrhage, hypotension, catheter site hemorrhage, and multi-organ failure, each in 3 (3 %) patients; and cerebral hemorrhage and sepsis, each in 2 (2 %) patients.

Information about adverse reactions of any grade was available for all 176 patients.

The most common adverse reactions (incidence?10 % and independent of causality) were hypotension, diarrhea, vomiting, nausea, and epistaxis.

The most common serious adverse reactions (incidence?5 % and independent of causality) were hypotension (11 %) and pulmonary alveolar hemorrhage (7 %).

Hemorrhage events of any type and any grade were reported for 104 (59 %) of the patients, and the events were grade 4-5 in 35 (20 %).

Table 2 presents adverse reactions independent of causality ?10 % any grade or Grade 4/5 ?2 % reported in patients treated with DEFITELIO. Table 2: Adverse Reactionsa ?10 % or Grade 4-5 Adverse Reactions?

2 % DEFITELIO (n=176) Adverse Reaction a Any grade Grade 4-5b Hypotension 65 (37 %) 12 (7 %) Diarrhea 43 (24 %) 0 Vomiting 31 (18 %) 0 Nausea 28 (16 %) 0 Epistaxis 24 (14 %) 0 Pulmonary alveolar hemorrhage 15 (9 %) 12 (7 %) Gastrointestinal hemorrhage 15 (9 %) 5 (3 %) Sepsis 12 (7 %) 9 (5 %) Graft versus host disease 11 (6 %) 7 (4 %) Lung infiltration 10 (6 %) 5 (3 %) Pneumonia 9 (5 %) 5 (3 %) Pulmonary hemorrhage 7 (4 %) 4 (2 %) Infection 6 (3 %) 4 (2 %) Hemorrhage intracranial 5 (3 %) 4 (2 %) Hyperuricemia 4 (2 %) 4 (2 %) Cerebral hemorrhagec 3 (2 %) 3 (2 %) a Excludes events considered to be due to the underlying disease: multi-organ failure, veno-occlusive disease, respiratory failure, renal failure

and hypoxia b Adverse reactions considered life-threatening or fatal c Cerebral hemorrhage has been included in the table due to clinical relevance

Usage information

Dosing and administration

2 DOSAGE AND ADMINISTRATION •Administer DEFITELIO 6.25 mg/kg every 6 hours given as a 2-hour intravenous infusion.

(2.1) •Treat for a minimum of 21 days.

If after 21 days signs and symptoms of VOD have not resolved, continue treatment until resolution.

(2.1) 2.1 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.

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

•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)].

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

•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.

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

2.3 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 Event Recommended Action Hypersensitivity Reaction Severe or life-threatening (anaphylaxis) 1. Discontinue DEFITELIO permanently; do not resume treatment.

Bleeding Persistent, severe or potentially life-threatening

1. Withhold DEFITELIO. 2. Treat the cause of bleeding and give supportive care as clinically indicated. 3. Consider resuming treatment (at the same dose and infusion volume) when bleeding has stopped and the patient is hemodynamically stable. Recurrent significant bleeding 1. Discontinue DEFITELIO permanently; do not resume treatment. Invasive Procedures 1. There is no known reversal agent for the profibrinolytic effects of DEFITELIO. Discontinue DEFITELIO infusion at least 2 hours prior to an invasive procedure.

2. Resume DEFITELIO treatment after the procedure as soon as any procedure-related risk of bleeding is resolved.

2.4 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: •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).

•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. •Gently mix the solution for infusion.

•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.

Use in special populations

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.

Interactions

7 DRUG INTERACTIONS Antithrombotic Agents DEFITELIO may enhance the pharmacodynamic activity of antithrombotic/fibrinolytic drugs such as heparin or alteplase. Concomitant use of DEFITELIO with antithrombotic or fibrinolytic drugs is contraindicated because of an increased risk of hemorrhage [see Contraindications (4) ]. •DEFITELIO may enhance the activity of antithrombotic/fibrinolytic drugs. (7)

More information

Category Value
Authorisation number NDA208114
Orphan designation No
Product NDC 68727-800
Date Last Revised 30-03-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 1746527
Marketing authorisation holder Jazz Pharmaceuticals, Inc.

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