Hospital Pharmacy - May 2017 - 331

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Mancano
On hospital days 9 to 13, the patient's evening dosage of
levofloxacin was administered between 2:47 p.m. and 3:45
p.m. Melatonin was not administered on these days. The
patient did not exhibit emotional, cognitive, behavioral, or
perceptual disturbances. The patient did not have evidence of
graft-versus-host disease or acute rejection.
Husain et al1 review 2 possible mechanisms by which fluoroquinolones may cause excitatory effects. The first mechanism may be due to the fluoroquinolones blocking the binding
of the inhibitory neurotransmitter gamma-aminobutyric acid
(GABA); however, levofloxacin has a relatively low binding
affinity for GABA. The second mechanism may occur via
fluoroquinolones binding to and activating N-methyl-daspartate receptors, therefore causing direct neuroexcitation.
The patient in this case experienced agitation, confusion, and
overt hallucinations when levofloxacin was administered
after 8:00 p.m.
Husain et al1 state, "The fact that neuroexcitation, perceptual
disturbance, and behavioral disturbance only occurred with evening levofloxacin dosing and never with the morning dose may
suggest a relationship with the sleep-wake cycle, alertness neurocircuitry, or reduced environmental cues to maintain mentation in the evening." The authors conclude, "Recognizing this
adverse effect and adjusting the time of levofloxacin administration may alleviate neuroexcitation, thus allowing for continuation of the antibiotic while avoiding delays in care or unneeded
diagnostic testing and interventions."

Statin-Induced Muscle Rupture
Ekhart et al2 conducted a study to analyze the occurrence of
muscle rupture in 2 European pharmacovigilance databases.
The first database is maintained by the Netherlands
Pharmacovigilance Center, which has collected reports since
1990. Reports are primarily received from physicians, pharmacists, and consumers, either directly or via pharmaceutical
manufacturers. The authors' database search included all
reports entered from the start of 1991 up to January 2016.
The Netherlands Pharmacovigilance Database contained 15
cases of muscle rupture associated with the use of statins.
The 15 cases occurred in 12 males and 3 females. The median
age of patients was 63 years, and patients had been receiving
a statin therapy for a median time of 19 months.
Details of the muscle ruptures reported in the Netherlands
Pharmacovigilance Database are as follows: 4 patients ruptured biceps, 4 ruptured calf muscles, 2 hamstring ruptures, 1
quadriceps rupture, and 4 unspecified. Additional characteristics of the patient cases include 2 patients who had tendon
ruptures as well as muscle ruptures, and 4 patients who had
their muscle rupture during normal daily activities; however,
in 3 patient cases, exercise could have played a role in the
muscle rupture. The association of statin use and muscle rupture was disproportionally present in the Netherlands
Pharmacovigilance Database with a reporting odds ratio of
23.4% (95% confidence interval [CI], 11.9-46.0).

The second database utilized in this study was
EudraVigilance. The EudraVigilance database is a European
Union spontaneous reporting system that was established in
2001. This database was established to collect safety reports
of adverse drug reactions to medications licensed with the
European Union. All reports entered into the database up to
January 2016 were evaluated for this study. The
EudraVigilance database contained 165 reports of muscle
rupture associated with statin use. Of the 165 cases, 11
occurred in patients who did not utilize any other medication
besides a statin. These 11 cases were reported with a plausible time of statin exposure, and no alternative factors that
could explain the patient's muscle rupture. Eight cases
occurred in men and 3 cases occurred in women with the
median age in all cases of 57 years. The association of statin
use and muscle rupture was disproportionally present in the
EudraVigilance database with a reporting odds ratio of
14.6% (95% CI, 12.3-17.2).
Ekhart et al2 point out that there are at least 9 different
theories to explain statin-induced myopathy. Regardless of
the mechanism responsible for statin-induced myopathy, if
there is damage to a considerable proportion of muscle tissue, this may eventually result in muscle rupture. Mild
strains may heal quickly on their own with rest, but more
severe tears may require surgery and a rehabilitation program. Most patients recover from myopathy within 6
months after statin withdrawal; however, muscle symptoms
can linger beyond 14 months. The authors conclude, "Our
data suggest that statin-induced muscle rupture can occur in
patients receiving statins, also in the absence of intense
physical activities."

Mefloquine-Induced Rhabdomyolysis
A 36-year-old black male developed symptoms of malaise,
fatigue, and difficulty performing his usual daily activities.
He reported the symptoms had started several weeks ago.
The patient had recently returned from a trip to Nigeria
where he had stayed for 5 weeks. He was taking mefloquine
(Lariam) 250 mg once weekly as prophylaxis for malaria. He
initiated mefloquine 2 weeks before leaving home, and he
was to stop mefloquine 4 weeks after returning home from
his trip. The patient had no medical history or medication
history other than mefloquine. The patient also did not report
any febrile episodes before, during, or after return from his
trip to Nigeria.
Physical findings and laboratory results were normal
except for a creatine kinase (CK) of 2978 U/L (normal value,
≤195 in males), sodium 133 mEq/L (normal value, 135-145
mEq/L), and a modest increase in creatinine 1.24 mg/dL
(normal range, 0.9-1.2 mg/dL). The patient received intravenous infusions of normal saline alternated with 5% dextrose
at a rate of 300 mL/h for 12 hours. The patient's CK decreased
to 641 U/L and his creatinine concentration was 0.97 mg/dL.
Serological testing was also negative, which ruled out

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