SIDE EFFECTS
The majority of side effects observed in clinical trials
were of a mild and transient nature. Fewer than 3% of
adult patients without mycobacterial infections and fewer
than 2% of pediatric patients without mycobacterial infections
discontinued therapy because of drug-related side effects.
The most frequently reported events in adults were diarrhea
(3%), nausea (3%), abnormal taste (3%), dyspepsia (2%),
abdominal pain/discomfort (2%), and headache (2%). In
pediatric patients, the most frequently reported events
were diarrhea (6%), vomiting (6%), abdominal pain (3%),
rash (3%), and headache (2%). Most of these events were
described as mild or moderate in severity. Of the reported
adverse events, only 1% was described as severe.
In pneumonia studies conducted in adults comparing clarithromycin
to erythromycin base or erythromycin stearate, there were
fewer adverse events involving the digestive system in
clarithromycin-treated patients compared to erythromycin-treated
patients (13% vs. 32%; p<0.01). Twenty percent of erythromycin-treated
patients discontinued therapy due to adverse events compared
to 4% of clarithromycin-treated patients.
In two U.S. studies of acute otitis media comparing clarithromycin
to amoxicillin/potassium clavulanate in pediatric patients,
there were fewer adverse events involving the digestive
system in clarithromycin-treated patients compared to
amoxicillin/potassium clavulanate-treated patients (21%
vs. 40%, p<0.001). One-third as many clarithromycin-treated
patients reported diarrhea as did amoxicillin/potassium
clavulanate-treated patients.
Post-Marketing Experience
Allergic reactions ranging from urticaria and mild skin
eruptions to rare cases of anaphylaxis and Stevens-Johnson
syndrome have occurred. Other spontaneously reported adverse
events include glossitis, stomatitis, oral moniliasis,
vomiting, tongue discoloration, thrombocytopenia, leukopenia,
neutropenia, and dizziness. There have been reports of
tooth discoloration in patients treated with clarithromycin.
Tooth discoloration is usually reversible with professional
dental cleaning. There have been isolated reports of hearing
loss, which is usually reversible, occurring chiefly in
elderly women. Reports of alterations of the sense of
smell, usually in conjunction with taste perversion have
also been reported.
Transient CNS events including anxiety, behavioral changes,
confusional states, depersonalization, disorientation,
hallucinations, insomnia, manic behavior, nightmares,
psychosis, tinnitus, tremor and vertigo have been reported
during post-marketing surveillance. Events usually resolve
quickly with discontinuation of the drug.
Hepatic dysfunction, including increased liver enzymes,
and hepatocellular and/or cholestatic hepatitis, with
or without jaundice, has been infrequently reported with
clarithromycin. This hepatic dysfunction may be severe
and is usually reversible. In very rare instances, hepatic
failure with fatal outcome has been reported and generally
has been associated with serious underlying diseases and/or
concomitant medications.
There have been rare reports of hypoglycemia, some of
which have occurred in patients taking oral hypoglycemic
agents or insulin.
As with other macrolides, clarithromycin has been associated
with QT prolongation and ventricular arrhythmias, including
ventricular tachycardia and torsades de pointes.
Changes in Laboratory Values
Changes in laboratory values with possible clinical significance
were as follows:
Hepatic: Elevated SGPT (ALT) <1%;
SGOT (AST) <1%; GGT <1%; alkaline phosphatase <1%;
LDH <1%; total bilirubin <1%.
Hematologic: Decreased WBC <1%; elevated
prothrombin time 1%.
Renal: Elevated BUN 4%; elevated serum
creatinine <1%.
GGT, alkaline phosphatase, and prothrombin time data are
from adult studies only.
DRUG INTERACTIONS
Clarithromycin use in patients who are receiving theophylline
may be associated with an increase of serum theophylline
concentrations. Monitoring of serum theophylline concentrations
should be considered for patients receiving high doses
of theophylline or with baseline concentrations in the
upper therapeutic range. In two studies in which theophylline
was administered with clarithromycin (a theophylline sustained-release
formulation was dosed at either 6.5 mg/kg or 12 mg/kg
together with 250 or 500 mg q12h clarithromycin), the
steady-state levels of Cmax, Cmin, and the area under
the serum concentration time curve (AUC) of theophylline
increased about 20%.
Concomitant administration of single doses of clarithromycin
and carbamazepine has been shown to result in increased
plasma concentrations of carbamazepine. Blood level monitoring
of carbamazepine may be considered.
When clarithromycin and terfenadine were coadministered,
plasma concentrations of the active acid metabolite of
terfenadine were threefold higher, on average, than the
values observed when terfenadine was administered alone.
The pharmacokinetics of clarithromycin and the 14-hydroxy-clarithromycin
were not significantly affected by coadministration of
terfenadine once clarithromycin reached steady-state conditions.
Concomitant administration of clarithromycin with terfenadine
is contraindicated. (See CONTRAINDICATIONS.)
Clarithromycin 500 mg every 8 hours was given in combination
with omeprazole 40 mg daily to healthy adult subjects.
The steady-state plasma concentrations of omeprazole were
increased (Cmax, AUC0-24, and T½ increases of 30%,
89%, and 34%, respectively), by the concomitant administration
of clarithromycin. The mean 24-hour gastric pH value was
5.2 when omeprazole was administered alone and 5.7 when
co-administered with clarithromycin.
Co-administration of clarithromycin with ranitidine bismuth
citrate resulted in increased plasma ranitidine concentrations
(57%), increased plasma bismuth trough concentrations
(48%), and increased 14-hydroxy-clarithromycin plasma
concentrations (31%). These effects are clinically insignificant.
Simultaneous oral administration of clarithromycin and
zidovudine to HIV-infected adult patients resulted in
decreased steady-state zidovudine concentrations. When
500 mg of clarithromycin were administered twice daily,
steady-state zidovudine AUC was reduced by a mean of 12%
(n=4). Individual values ranged from a decrease of 34%
to an increase of 14%. Based on limited data in 24 patients,
when clarithromycin was administered two to four hours
prior to oral zidovudine, the steady-state zidovudine
Cmax was increased by approximately 2-fold, whereas the
AUC was unaffected.
Simultaneous administration of clarithromycin and didanosine
to 12 HIV-infected adult patients resulted in no statistically
significant change in didanosine pharmacokinetics.
Concomitant administration of fluconazole 200 mg daily
and clarithromycin 500 mg twice daily to 21 healthy volunteers
led to increases in the mean steady-state clarithromycin
Cmin and AUC of 33% and 18%, respectively. Steady-state
concentrations of 14-OH clarithromycin were not significantly
affected by concomitant administration of fluconazole.
Concomitant administration of clarithromycin and ritonavir
(n=22) resulted in a 77% increase in clarithromycin AUC
and a 100% decrease in the AUC of 14-OH clarithromycin.
Clarithromycin may be administered without dosage adjustment
to patients with normal renal function taking ritonavir.
However, for patients with renal impairment, the following
dosage adjustments should be considered. For patients
with CLCR 30 to 60 mg/min, the dose of clarithromycin
should be reduced by 50%. For patients with CLCR <
30 ml/min, the dose of clarithromycin should be decreased
by 75%.
Spontaneous reports in the post-marketing period suggest
that concomitant administration of clarithromycin and
oral anticoagulants may potentiate the effects of the
oral anticoagulants. Prothrombin times should be carefully
monitored while patients are receiving clarithromycin
and oral anticoagulants simultaneously.
Elevated digoxin serum concentrations in patients receiving
clarithromycin and digoxin concomitantly have also been
reported in post-marketing surveillance. Some patients
have shown clinical signs consistent with digoxin toxicity,
including potentially fatal arrhythmias. Serum digoxin
levels should be carefully monitored while patients are
receiving digoxin and clarithromycin simultaneously.
The following drug interactions, other than increased
serum concentrations of carbamazepine and active acid
metabolite of terfenadine, have not been reported in clinical
trials with clarithromycin; however, they have been observed
with erythromycin products and/or with clarithromycin
in post-marketing experience.
Concurrent use of erythromycin or clarithromycin and
ergotamine or dihydroergotamine has been associated in
some patients with acute ergot toxicity characterized
by severe peripheral vasospasm and dysesthesia.
Erythromycin has been reported to decrease the clearance
of triazolam and, thus, may increase the pharmacologic
effect of triazolam. There have been post-marketing reports
of drug interactions and CNS effects (e.g., somnolence
and confusion) with the concomitant use of clarithromycin
and triazolam.
There have been reports of an interaction between erythromycin
and astemizole resulting in QT prolongation and torsades
de pointes. Concomitant administration of erythromycin
and astemizole is contraindicated. Because clarithromycin
is also metabolized by cytochrome P450, concomitant administration
of clarithromycin with astemizole is not recommended.
As with other macrolides, clarithromycin has been reported
to increase concentrations of HMG-CoA reductase inhibitors
(e.g., lovastatin and simvastatin), through inhibition
of cytochrome P450 metabolism of these drugs. Rare reports
of rhabdomyolysis have been reported in patients taking
these drugs concomitantly.
The use of erythromycin and clarithromycin in patients
concurrently taking drugs metabolized by the cytochrome
P450 system may be associated with elevations in serum
levels of these other drugs. There have been reports of
interactions of erythromycin and/or clarithromycin with
carbamazepine, cyclosporine, tacrolimus, hexobarbital,
phenytoin, alfentanil, disopyramide, lovastatin, bromocriptine,
valproate, terfenadine, cisapride, pimozide, rifabutin,
and astemizole. Serum concentrations of drugs metabolized
by the cytochrome P450 system should be monitored closely
in patients concurrently receiving these drugs.
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