Hospital Pharmacy - December 2017 - 715
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]
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
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.
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%
Defitelio
(n=176)
Adverse Reactiona
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].
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.
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]
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.
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%)
Excludes events considered to be due to the underlying disease: multi-organ failure, venoocclusive 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 from gestational day (GD) 6 to 15 at 0, 240, 1200,
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