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The authors2 point out that hydroxyurea is a cytotoxic
chemotherapeutic drug that acts on an enzyme ribonucleotide reductase to inhibit DNA synthesis and promote cell
death. While hydroxyurea is generally well tolerated, occasional dermatologic adverse effects have been reported.
The authors explain that hydroxyurea is a cytotoxic chemotherapeutic drug that acts on the enzyme ribonucleotide
reductase to inhibit DNA synthesis and promote cell death.
Hydroxyurea is generally well tolerated; however, cases of
hydroxyurea dermopathy have occurred in patients receiving
hydroxyurea therapy after an average of 5 years. The exact
mechanism of this dermopathy is unknown; however, the
proposed mechanism is the cumulative toxicity of hydroxyurea in the proliferating cells of the stratum basale, the deepest layer of the 5 layers of the epidermis. Based on the
patient's laboratory test results and positive ANA, the authors
suspect hydroxyurea-induced chronic cutaneous lupus erythematosus. In conclusion, the authors' state, "This patient's
autoimmune profile and clinical appearance suggest that
drug-induced lupus is a distinct, albeit rare side effect of
hydroxyurea, separate from hydroxyurea dermopathy."

Cardiotoxicity and Fever Induced by
Clozapine
A 31-year-old Caucasian male with a 9-year history of
schizophrenia had received a number of atypical antipsychotics without success. The patient's symptoms including
hallucinations, delusional ideas of persecution and reference,
as well as apathy continued to recur. The patients was admitted to an inpatient facility and initiated on clozapine. On day
1, the patient received clozapine 25 mg and was titrated up to
100 mg daily over a period of 10 days. The clozapine titration was a gradual increase of 25 mg daily every 3 days up to
the 100 mg daily dosage and the patient's white blood cell
count was evaluated after each dosage increase.
On day 11 of clozapine therapy, the patient experienced a
significant elevation in leukocytes 13,660 cells/µL (normal
value, 4500-11,000 µL) and neutrophils 75% of WBC (normal value, 40%-60% of WBC). This increase in leukocytes
and neutrophils indicated a potential immune stimulation. On
day 13, the patient developed fever, rigors, and sweating with
a maximum temperature of 39.6°C (103.3°F) with a slight
tachycardia of 140 bpm and a blood pressure of 130/85 mm
Hg. The patient's clozapine was immediately discontinued,
and he was treated with acetaminophen and received rehydration with intravenous normal saline. An electrocardiogram
(EKG) revealed sinus tachycardia with a normal QTc interval
and a chest x-ray and urinalysis produced unremarkable findings. Blood tests were also within the normal range except for
the white blood cell count, which revealed a leukocytosis of
13,100 cells/µL and a corresponding increase in neutrophils
to 85% of white blood cells. At this time, the patient's high
sensitivity troponin (Hs-troponin) was normal at 11.7 pg/mL
(gray zone 14-53 pg/mL, pathological > 53 pg/mL).

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On day 14, the patient was feeling better with a resolution
of his leukocytosis; however, his Hs-troponin was elevated
to 28.7 pg/mL. A subsequent creatinine kinase-MB level was
normal as well as a procalcitonin level; however, the patient's
C-reactive protein (CRP) level was elevated to 88.6 mg/L
(normal range, 0.00-6.00 mg/L). Additional CRP levels
drawn on days 15 and 17 of his hospital stay decreased to
76.5 mg/L and 28.4 mg/L, respectively, with a Hs-troponin
of 20 pg/mL. By day 32, the patient was in good medical
condition, and his blood tests were within normal range.
The authors3 mention that clozapine-induced fever is a
common adverse effect with an incidence as high as 55% of
patients. They note that there seems to be a correlation
between the fever and the days after initiation of clozapine.
Prior research demonstrates the development of fever on day
5 to 20 after clozapine initiation. The authors state, "Recent
reports suggest that clozapine stimulates the production of
pro-inflammatory cytokines including TNFα, interluken1,
and interleukin 6. These have also been implicated in causing
myocardial depression by direct actions on the myocytes."
The Naranjo scale was utilized by the authors to evaluate
the causality of this adverse reaction relative to clozapine
administration and the scale revealed the causality as probable. They surmise that the case hints at the presence of initially subclinical cardiotoxicity as an underlying factor in
patients developing fever. The increase in troponin observed
1 day after resolution of fever, probably, is a late reaction of
cardiotoxicity. The authors state, "More case-control studies
are needed in order to clarify the putative model arising from
our clinical observations; specifically, a larger sample of
patients who develop clozapine-induced fever versus patients
commencing clozapine without developing fever."

Denosumab-Induced Hepatotoxicity
A 72-year-old female was evaluated for an increase in liver
enzymes around 5 times the upper limit of normal (ULN).
Her medication history included amlodipine, bisoprolol,
and occasional nonsteroidal anti-inflammatory drugs
(NSAIDs). Approximately 1 month prior to her increase in
liver enzymes, she had received a subcutaneous injection of
denosumab (Prolia) 60 mg for osteoporosis. The patient had
no evidence of chronic liver disease with negative results for
hepatitis B and C. Additional autoimmune testing was conducted and the results were unremarkable. During the following 6 weeks, the patient's serum transaminases increased to
12 times the ULN and then subsequently an elevation to 1500
IU/mL (aspartate transaminase [AST] normal range, 10-30
U/L; alanine transaminase [ALT] normal range, 10-40 U/L).
The patient's gamma-glutamyl transferase (GGT) was also
elevated to 755 U/L (GGT normal range, 2-30 U/L). The
patient became icteric with a bilirubin of 10 mg/dL (bilirubin,
total normal range, 0.3-1.2 mg/dL) which increased to 13.8
mg/dL. The patient's international normalized ratio (INR)
increased to 1.79 and would not correct with intravenous

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