Hospital Pharmacy - July/August 2018 - 212

Defitelio® (defibrotide sodium)
BRIEF SUMMARY OF PRESCRIBING INFORMATION: Consult the Full Prescribing Information for complete product information.
Initial U.S. Approval: 2016
INDICATIONS AND USAGE
Defitelio® (defibrotide sodium) 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).
CONTRAINDICATIONS
The use of Defitelio is contraindicated in the following conditions:
* Concomitant administration with systemic anticoagulant or
fibrinolytic therapy [see Warnings and Precautions]
* Known hypersensitivity to Defitelio or to any of its excipients [see
Warnings and Precautions]

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%).
The table below presents adverse reactions independent of causality ≥10%
any grade or Grade 4/5 ≥2% reported in patients treated with Defitelio.
Adverse Reactionsa ≥10% or Grade 4-5 Adverse Reactions ≥2%

WARNINGS AND PRECAUTIONS
Hemorrhage
Defitelio increased the activity of fibrinolytic enzymes in vitro, and it may
increase the risk of bleeding in patients with VOD after hematopoietic stemcell 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.

Defitelio
(n=176)
Adverse Reactiona

Any grade

Grade 4-5b

Hypotension

65 (37%)

12 (7%)

Diarrhea

43 (24%)

0

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].

Vomiting

31 (18%)

0

Nausea

28 (16%)

0

Epistaxis

24 (14%)

0

Pulmonary alveolar
hemorrhage

15 (9%)

12 (7%)

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.

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%)

ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other
sections of the labeling:
* Hemorrhage [see Warnings and Precautions]
* Hypersensitivity Reactions [see Warnings and Precautions]

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%)

Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot 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. 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.

Excludes events considered to be due to the underlying disease: multi-organ failure, veno-occlusive
disease, respiratory failure, renal failure, and hypoxia
Adverse reactions considered life-threatening or fatal
c
Cerebral hemorrhage has been included in the table due to clinical relevance
a

b

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].
USE IN SPECIFIC POPULATIONS
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



Table of Contents for the Digital Edition of Hospital Pharmacy - July/August 2018

Ed Board
TOC
Antibiotic Stewardship: The Health of the World Depends on It
ISMP Medication Error Report Analysis: CycloSPORINE Dispensing Errors
ISMP Adverse Drug Reactions
Summaries of Safety Labeling Changes Approved By FDA: Boxed Warnings Highlights January-March 2018
Restructuring a Pharmacy Department: Leadership Strategies for Managing Organizational Change
Angiotensin II
RxLegal: A Rapid Review of Right-To-Try
New Medications in the Treatment of Hereditary Transthyretin Amyloidosis
Significant Published Articles for Pharmacy Nutrition Support Practice in 2017
Utilization of Lean Techniques in Pharmacy Residency Training: Modifying the PGY1 Management and Leadership Experience
Impact of a Clinical Decision Support Tool on Cancer Pain Management in Opioid-Tolerant Inpatients
Lyme Carditis: A Case Report and Review of Management
Impact of the Implementation of Project Re-Engineered Discharge for Heart Failure patients at a Veterans Affairs Hospital at the Central Arkansas Veterans Healthcare System
Evaluation of Oritavancin Use at a Community Hospital
Hospital Pharmacy - July/August 2018 - Cover1
Hospital Pharmacy - July/August 2018 - Cover2
Hospital Pharmacy - July/August 2018 - 201
Hospital Pharmacy - July/August 2018 - 202
Hospital Pharmacy - July/August 2018 - 203
Hospital Pharmacy - July/August 2018 - 204
Hospital Pharmacy - July/August 2018 - 205
Hospital Pharmacy - July/August 2018 - Ed Board
Hospital Pharmacy - July/August 2018 - 207
Hospital Pharmacy - July/August 2018 - TOC
Hospital Pharmacy - July/August 2018 - 209
Hospital Pharmacy - July/August 2018 - 210
Hospital Pharmacy - July/August 2018 - 211
Hospital Pharmacy - July/August 2018 - 212
Hospital Pharmacy - July/August 2018 - 213
Hospital Pharmacy - July/August 2018 - Antibiotic Stewardship: The Health of the World Depends on It
Hospital Pharmacy - July/August 2018 - 215
Hospital Pharmacy - July/August 2018 - 216
Hospital Pharmacy - July/August 2018 - ISMP Medication Error Report Analysis: CycloSPORINE Dispensing Errors
Hospital Pharmacy - July/August 2018 - 218
Hospital Pharmacy - July/August 2018 - 219
Hospital Pharmacy - July/August 2018 - ISMP Adverse Drug Reactions
Hospital Pharmacy - July/August 2018 - 221
Hospital Pharmacy - July/August 2018 - 222
Hospital Pharmacy - July/August 2018 - Summaries of Safety Labeling Changes Approved By FDA: Boxed Warnings Highlights January-March 2018
Hospital Pharmacy - July/August 2018 - 224
Hospital Pharmacy - July/August 2018 - Restructuring a Pharmacy Department: Leadership Strategies for Managing Organizational Change
Hospital Pharmacy - July/August 2018 - 226
Hospital Pharmacy - July/August 2018 - 227
Hospital Pharmacy - July/August 2018 - 228
Hospital Pharmacy - July/August 2018 - 229
Hospital Pharmacy - July/August 2018 - Angiotensin II
Hospital Pharmacy - July/August 2018 - 231
Hospital Pharmacy - July/August 2018 - 232
Hospital Pharmacy - July/August 2018 - 233
Hospital Pharmacy - July/August 2018 - RxLegal: A Rapid Review of Right-To-Try
Hospital Pharmacy - July/August 2018 - 235
Hospital Pharmacy - July/August 2018 - New Medications in the Treatment of Hereditary Transthyretin Amyloidosis
Hospital Pharmacy - July/August 2018 - 237
Hospital Pharmacy - July/August 2018 - 238
Hospital Pharmacy - July/August 2018 - Significant Published Articles for Pharmacy Nutrition Support Practice in 2017
Hospital Pharmacy - July/August 2018 - 240
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Hospital Pharmacy - July/August 2018 - 244
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Hospital Pharmacy - July/August 2018 - 246
Hospital Pharmacy - July/August 2018 - Utilization of Lean Techniques in Pharmacy Residency Training: Modifying the PGY1 Management and Leadership Experience
Hospital Pharmacy - July/August 2018 - 248
Hospital Pharmacy - July/August 2018 - 249
Hospital Pharmacy - July/August 2018 - 250
Hospital Pharmacy - July/August 2018 - 251
Hospital Pharmacy - July/August 2018 - 252
Hospital Pharmacy - July/August 2018 - 253
Hospital Pharmacy - July/August 2018 - 254
Hospital Pharmacy - July/August 2018 - 255
Hospital Pharmacy - July/August 2018 - Impact of a Clinical Decision Support Tool on Cancer Pain Management in Opioid-Tolerant Inpatients
Hospital Pharmacy - July/August 2018 - 257
Hospital Pharmacy - July/August 2018 - 258
Hospital Pharmacy - July/August 2018 - 259
Hospital Pharmacy - July/August 2018 - 260
Hospital Pharmacy - July/August 2018 - 261
Hospital Pharmacy - July/August 2018 - 262
Hospital Pharmacy - July/August 2018 - Lyme Carditis: A Case Report and Review of Management
Hospital Pharmacy - July/August 2018 - 264
Hospital Pharmacy - July/August 2018 - 265
Hospital Pharmacy - July/August 2018 - Impact of the Implementation of Project Re-Engineered Discharge for Heart Failure patients at a Veterans Affairs Hospital at the Central Arkansas Veterans Healthcare System
Hospital Pharmacy - July/August 2018 - 267
Hospital Pharmacy - July/August 2018 - 268
Hospital Pharmacy - July/August 2018 - 269
Hospital Pharmacy - July/August 2018 - 270
Hospital Pharmacy - July/August 2018 - 271
Hospital Pharmacy - July/August 2018 - Evaluation of Oritavancin Use at a Community Hospital
Hospital Pharmacy - July/August 2018 - 273
Hospital Pharmacy - July/August 2018 - 274
Hospital Pharmacy - July/August 2018 - 275
Hospital Pharmacy - July/August 2018 - 276
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