ASH Clinical News February 2016 | Page 44

Literature Scan

addition, no study participants developed
antibodies to factor X or factor Xa. “These
results indicate that andexanet alfa has little
immunogenicity after a single IV exposure,”
wrote Dr. Siegal and colleagues.
One limitation of the study is that it does
not include data on the safety and efficacy of
andexanet alfa in patients who require urgent
reversal of factor Xa inhibitor activity due to
bleeding or emergency surgery. In addition,
the high frequency of coexisting conditions
among patients with acute bleeding makes it difficult to determine
whether complications are related
to the reversal agent or to the underlying medical condition.

“There are no
specific reversal agents for
factor Xa inhibitors. Based
[on our results]
andexanet alfa
is a promising
antidote for
factor Xa
inhibitors.”
—DEBORAH M. SIEGAL, MD

“Currently, there are no specific reversal agents for factor Xa
inhibitors, but based on its ability
to rapidly reverse factor Xa inhibitor anticoagulant effects without
serious safety concerns, andexanet
alfa is a promising antidote for
factor Xa inhibitors,” Dr. Siegal
said. “The rapid onset and offset
of action of andexanet alfa and the
ability to administer it as a bolus
or as a bolus plus an infusion may
provide flexibility with regard to
the restoration of hemostasis when
urgent factor Xa inhibitor reversal
is required.”
The ongoing phase IIIb/IV
ANNEXA-4 study is evaluating the
efficacy and safety of andexanet
alfa in factor Xa–treated patients
with major bleeding complications,
she added. “It is hoped that the
availability of a rapid-acting, safe

reversal agent will improve the outcomes of
factor Xa–treated patients requiring urgent
anticoagulant reversal for emergencies such
as severe bleeding or surgery.”
REFERENCE
Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa
inhibitor activity. N Engl J Med. 2015;373:2413-2424.

When multiple myeloma relapses

INDICATION
Kyprolis® (carfilzomib) for Injection is a proteasome inhibitor that is indicated in combination with lenalidomide and dexamethasone for the
treatment of patients with relapsed multiple myeloma who have received one to three prior lines of therapy.

IMPORTANT SAFETY INFORMATION
Cardiac Toxicities: New onset or worsening of pre-existing cardiac until resolved or returned to baseline and consider whether to restart

failure (e.g., congestive heart failure, pulmonary edema, decreased
ejection fraction), restrictive cardiomyopathy, myocardial ischemia,
and myocardial infarction including fatalities have occurred following
administration of Kyprolis. Death due to cardiac arrest has occurred
within a day of Kyprolis administration.
• Withhold Kyprolis for Grade 3 or 4 cardiac adverse events until
recovery, and consider whether to restart Kyprolis based on a
benefit/risk assessment.
• Adequate hydration is required prior to each dose in Cycle 1. Monitor
a ll patients for evidence of volume overload, especially patients at risk
for cardiac failure. Adjust total fluid intake as clinically appropriate
in patients with baseline cardiac failure or who are at risk for
cardiac failure.
• Patients ≥ 75 years, the risk of cardiac failure is increased. Patients
with New York Heart Association Class III and IV heart failure, recent
myocardial infarction, and conduction abnormalities may be at
greater risk for cardiac complications.

Kyprolis based on a benefit/risk assessment.

Dyspnea: Dyspnea was reported in patients treated with Kyprolis.
Evaluate dyspnea to exclude cardiopulmonary conditions including
cardiac failure and pulmonary syndromes. Stop Kyprolis for Grade 3 or
4 dyspnea until resolved or returned to baseline. Consider whether to
restart Kyprolis based on a benefit/risk assessment.
Hypertension: Hypertension, including hypertensive crisis and

hypertensive emergency, has been observed with Kyprolis. Some of
these events have been fatal. Monitor blood pressure regularly in all
patients. If hypertension cannot be adequately controlled, withhold
Kyprolis and evaluate. Consider whether to restart Kyprolis based on a
benefit/risk assessment.

Venous Thrombosis: Venous thromboembolic events (including

deep venous thrombosis and pulmonary embolism) have been observed
with Kyprolis. Thromboprophylaxis is recommended and should be
based on an assessment of the patient’s underlying risks, treatment
regimen, and clinical status.

Acute Renal Failure: Cases of acute renal failure and renal
insufficiency adverse events (renal impairment, acute renal failure,
renal failure) have occurred in patients receiving Kyprolis. Acute renal
failure was reported more frequently in patients with advanced relapsed
and refractory multiple myeloma who received Kyprolis monotherapy.
This risk was greater in patients with a baseline reduced estimated
creatinine clearance. Monitor renal function with regular measurement
of the serum creatinine and/or estimated creatinine clearance. Reduce
or withhold dose as appropriate.

Infusion Reactions: Infusion reactions, including life-threatening
reactions, have occurred in patients receiving Kyprolis. Symptoms
include fever, chills, arthralgia, myalgia, facial flushing, facial edema,
vomiting, weakness, shortness of breath, hypotension, syncope, chest
tightness, or angina. These reactions can occur immediately following
or up to 24 hours after administration of Kyprolis. Premedicate with
dexamethasone to reduce the incidence and severity of infusion
reactions. Inform patients of the risk and of symptoms of an infusion
reaction and to contact a physician immediately if they occur.

Tumor Lysis Syndrome: Cases of Tumor Lysis Syndrome (TLS),
including fatal outcomes, have occurred in patients receiving Kyprolis.
Patients with multiple myeloma and a high tumor burden should be
considered at greater risk for TLS. Adequate hydration is required prior
to each dose in Cycle 1, and in subsequent cycles as needed. Consider
uric acid lowering drugs in patients at risk for TLS. Monitor for evidence
of TLS during treatment and manage promptly. Withhold Kyprolis until
TLS is resolved.

Thrombocytopenia: Kyprolis causes thrombocytopenia with

recovery to baseline platelet count usually by the start of the next cycle.
Thrombocytopenia was reported in patients receiving Kyprolis. Monitor
platelet counts frequently during treatment with Kyprolis. Reduce or
withhold dose as appropriate.

Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure,
including fatal cases, have been reported during treatment with
Kyprolis. Kyprolis can cause increased serum transaminases. Monitor
liver enzymes regularly. Reduce or withhold dose as appropriate.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS),
acute respiratory failure, and acute diffuse infiltrative pulmonary
disease such as pneumonitis and interstitial lung disease have Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic
occurred in patients receiving Kyprolis. Some events have been fatal. Syndrome (TTP/HUS): Cases of TTP/HUS including fatal outcome
In the event of drug-induced pulmonary toxicity, discontinue Kyprolis. have occurred in patients receiving Kyprolis. Monitor for signs and
symptoms of TTP/HUS. Discontinue Kyprolis if diagnosis is suspected.
Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The
was reported in patients treated with Kyprolis. Evaluate with cardiac safety of reinitiating Kyprolis therapy in patients previously experiencing
imaging and/or other tests as indicated. Withhold Kyprolis for PAH TTP/HUS is not known.

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, KYPROLIS, and KYPROLIS logo are all trademarks of Onyx Pharmaceuticals, Inc.
©2015 Onyx Pharmaceuticals, Inc., an Amgen Inc. subsidiary, Thousand Oaks, CA USA-KYPR-118486 November 2015 Printed in USA

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