Hospital Pharmacy - April 2018 - 95

Mancano
administration of vitamin K. The patient's serum albumin
also decreased to 2.8 g/L (normal range, 3.5-5.5 g/dL).
A liver biopsy was performed which revealed inflammation of hepatic tissue, submassive hepatic necrosis, and bile
duct proliferation consistent with drug-induced liver disease
(DILI). The patient was initiated on oral prednisone 40 mg
once daily. Over the next 3 weeks, the INR decreased to 1.3
and the albumin initially rose to 3 g/dL, but then declined to
2.7 g/dL while the bilirubin decreased to 7.8 mg/dL. At this
time, ursodeoxycholic acid 300 mg twice daily was initiated.
Over the following months, there was a slow decline in the
levels of both the transaminases and the GGT with a concomitant increase in serum albumin. The patient's prednisone
was slowly tapered, and her ursodeoxycholic acid was discontinued and 1 month later there was a large increase in her
transaminase levels and a decrease in serum albumin from 3.2
to 2.9 mg/dL. The patient's prednisone was increased to 25
mg daily, and her ursodeoxycholic acid was reinitiated. Over
the next 3-month period, there was a decrease in transaminases with a slow tapering off of the patient's prednisone. The
patient remains healthy on maintenance therapy of prednisone 5 mg and ursodeoxycholic acid 600 mg daily.
The authors4 set out to identify the correlation between
denosumab and the patient's liver toxicity. They examined the
temporal relationship, the amount of drug administered, and
the duration of use. They also investigated the possibility of
exposure to over-the-counter medications, as well as herbal
and dietary supplements; however, there was no evidence of
exposure to these agents. To determine if the liver injury was
due to biologic therapy, they performed a lymphocyte toxicity
assay (LTA) to denosumab because reexposure to denosumab
would be unethical. The LTA to denosumab demonstrated a
hypersensitivity reaction to denosumab resulting in 31% toxicity while the control patient showed toxicity to denosumab.
The authors suggested a possible mechanism by which
denosumab could cause this severe liver toxicity. In reviewing densoumab's mechanism of action, it is noted that it
blocks receptor activator of nuclear factor-kB (NFkB) ligand
(RANKL). Initially, it was suggested that denosumab by
actively reducing RANKL might produce a cholestatic reaction. Denosumab may also induce an elevation of other
members of the tumor necrosis factor family, as well as other
inflammatory cytokines and chemokines. The authors state,
"Due to the prolonged half-life of denosumab (25.4 days), this
immune activation is a long-lasting event. Interestingly there is
a report in mice of RANKL protecting against hepatic ischemia
and reperfusion. In addition to prolonged immune activation,
there is concomitant loss of RANKL due to direct effect of the
denosumab, which deprived the liver of a means of defense."

Severe Cardiotoxicity Induced by
Bevacizumab
A 62-year-old female with stable colorectal cancer had
received combination chemotherapy with S-1 (tegafur/

gimeracil/oteracil) with oxaliplatin and bevacizumab
(Avastin) 7.5 mg/kg for 4 months. Partial remission was
documented and then the patient received 17 courses of S-1
and bevacizumab until her disease was stable. The next
month, the patient was admitted to the hospital complaining
of wheezing, dizziness, and edema of the legs. Her blood
pressure was 200/130 mm Hg with a heart rate of 116 bpm.
A color Doppler echocardiogram revealed tricuspid regurgitation, pulmonary hypertension, left ventricular diastolic
dysfunction, and a pericardial effusion. Additional significant laboratory data were an AST of 38 U/L, creatinine
kinase (CK) of 154 U/L (normal range, 26-192 U/L), creatinine kinase-MB (CK-MB) of 4.96 ng/mL (normal range,
0-2.88 ng/mL), and lactate dehydrogenase (LDH) of 511
U/L (normal range, 81-234 U/L). A thoracic puncture was
initiated in the area of the hydrothorax. The hydrothorax
reached 19,660 mL in total. The patient was forced to withdraw from the original chemotherapy regimen due to severe
cardiotoxicity.
Bevacizumab is a recombinant humanized monoclonal
antibody against vascular endothelial growth factor (VEGF).
Inhibition of VEGF, an initiator of tumor angiogenesis, inhibits tumor growth and invasion of surrounding tissue. The anticancer efficacy of bevacizumab has been established however
adverse effects such as hypertension, congestive heart failure,
and decreased left ventricular ejection fraction can occur. The
authors5 state, "Anti-angiogenesis drugs often cause reversible cardiac damage by either a "target effect" or "missed target effect." The former hypothesis means bevacizumab
inhibits VEGF which is indispensable for cardiac function.
Therefore, VEGF is crucial for normal cardiac function, and
its inhibition by bevacizumab can lead to cardiotoxicity. The
authors then pose the next question, "How long does the
latency of severe cardiotoxicity last before manifesting syndromes?" In their case, the patient had a latency period of 20
months after the first bevacizumab administration. The
authors call for an optimal recommended time course for
patients using bevacizumab to be evaluated to assure patients
have the most advantageous clinical efficacy.
References
1.

Liu W. Physician, beware! drug fever without skin rashes can
be caused by minocycline. J Investig Allergol Clin Immunol.
2017;27(4):268-269.
Yanes DA, Mosser-Goldfarb JL. A cutaneous lupus erythematosus-like eruption induced by hydroxyurea. Pediatr Dermatol.
2017;34(1):e30-e31.
Gerasimou C, Vitali GP, Vavougios GD, et al. Clozapine associated with autoimmune reaction fever and low level cardiotoxicity-a case report. In Vivo. 2017;31:141-144.
Malnick S, Maor Y, Melzer E, Ziv-Sokolowskaia NN, Neuman
MG. Severe hepatocytotoxicity linked to denosumab. Eur Rev
Med Pharmacol Sci. 2017;21(suppl 1):78-85.
Chen J, Du F, Hu B, et al. Severe cardiotoxicity in a patient
with colorectal cancer treated with bevacizumab. Anticancer
Res. 2017;37:4557-4561.

Table of Contents for the Digital Edition of Hospital Pharmacy - April 2018