SIDE EFFECTS
The safety database for zafirlukast consists of more
than 4000 healthy volunteers and patients who received
zafirlukast, of which 1723 were asthmatics enrolled in
trials of 13 weeks duration or longer. A total of 671
patients received zafirlukast for 1 year or longer. The
majority of the patients were 18 years of age or older;
however 222 patients between the age of 12 and 18 years
received zafirlukast.
A comparison of adverse events reported by ³1% of
zafirlukast-treated patients, and at rates numerically
greater than in placebo-treated patients, is shown for
all trials in TABLE 2.
| TABLE 2 |
| Adverse Event |
Zafirlukast (N=4058) |
Placebo (N=2032) |
| Headache |
12.9% |
11.7% |
| Infection |
3.5% |
3.4% |
| Nausea |
3.1% |
2.0% |
| Diarrhea |
2.8% |
2.1% |
| Pain (generalized) |
1.9% |
1.7% |
| Asthenia |
1.8% |
1.6% |
| Abdominal Pain |
1.8% |
1.1% |
| Accidental Injury |
1.6% |
1.5% |
| Dizziness |
1.6% |
1.5% |
| Myalgia |
1.6% |
1.5% |
| Fever |
1.6% |
1.1% |
| Back Pain |
1.5% |
1.2% |
| Vomiting |
1.5% |
1.1% |
| SGPT Elevation |
1.5% |
1.1% |
| Dyspepsia |
1.3% |
1.2% |
| The frequency
of less common adverse events was comparable between
zafirlukast and placebo. |
Rarely, elevations of one or more liver enzymes have occurred
in patients receiving zafirlukast in controlled clinical
trials. Most of these have been observed in asymptomatic
patients at doses four times higher than the recommended
dose and returned to the normal range after a variable period
of time upon discontinuation of zafirlukast therapy. Rare
cases of symptomatic hepatitis and hyperbilirubinemia, without
other attributable cause, have occurred in patients who
had received the recommended doses of zafirlukast (40 mg/day).
In these patients, the liver enzymes returned to normal
or near-normal after stopping zafirlukast.
In clinical trials, an increased proportion of zafirlukast
patients over the age of 55 years reported infections
as compared to placebo-treated patients. A similar finding
was not observed in other age groups studied. These infections
were mostly mild or moderate in intensity and predominantly
affected the respiratory tract. Infections occurred equally
in both sexes, were dose-proportional to total milligrams
of zafirlukast exposure, and were associated with coadministration
of inhaled corticosteroids. The clinical significance
of this finding is unknown.
In rare cases, patients on zafirlukast therapy may present
with systemic eosinophilia, sometimes presenting with
clincal features of vasculitis consistent with Churg-Strauss
syndrome, a condition which is often treated with systemic
steroid therapy. These events usually, but not always,
have been associated with the reduction of oral steroid
therapy. Physicians should be alert to eosinophilia, vasculitic
rash, worsening pulmonary symptoms, cardiac complications,
and/or neuropathy presenting in their patients. A causal
association between zafirlukast and these underlying conditions
has not been established. (See PRECAUTIONS, Eosinophilic
Conditions.)
Hypersensitivity reactions, including urticaria angioedema
and rashes, with or without blistering, have been reported
in association with zafirlukast therapy.
Rare cases of patients experiencing increased theophylline
levels with or without clinical signs or symptoms of theophylline
toxicity after the addition of zafirlukast to an existing
theophylline regimen have been reported. The mechanism
of the interaction between zafirlukast and theophylline
in these patients is unknown and not predicted by available
in vitro metabolism data and the results of a clinical
drug interaction study
(see CLINICAL PHARMACOLOGY and
DRUG INTERACTIONS
).
DRUG INTERACTIONS
In a drug interaction study in 16 healthy male volunteers,
co-administration of multiple doses of zafirlukast (160
mg/day) to steady state with a single 25-mg dose of warfarin
resulted in a significant increase in the mean AUC (+63%)
and half-life (+36%) of S-warfarin. The mean prothrombin
time (PT) increased by approximately 35%. This interaction
is probably due to an inhibition by zafirlukast of the
cytochrome P450 2C9 isoenzyme system. Patients on oral
warfarin anticoagulant therapy and zafirlukast should
have their prothrombin times monitored closely and anticoagulant
dose adjusted accordingly (see WARNINGS.) No formal drug-drug
interaction studies with zafirlukast and other drugs known
to be metabolized by the cytochrome P450 2C9 isoenzyme
(e.g., tolbutamide, phenytoin, carbamazepine) have been
conducted; however, care should be exercised when zafirlukast
is co-administered with these drugs.
In a drug interaction study in 16 healthy male volunteers,
co-administration of zafirlukast (320 mg/day), with terfenadine
(60 mg twice daily) to steady state resulted in a decrease
in the mean Cmax (-66%) and AUC (-54%) of zafirlukast.
No effect of zafirlukast on terfenadine plasma concentrations
or ECG parameters (i.e., QTc interval) was seen. No formal
drug-drug interaction studies between zafirlukast and
other drugs known to be metabolized by the P450 3A4 (CYP
3A4) isoenzyme (e.g., dihydropyridine calcium-channel
blockers, cyclosporin, cisapride, astemizole) have been
conducted. As zafirlukast is known to be an inhibitor
of CYP 3A4 in vitro, it is reasonable to employ appropriate
clinical monitoring when these drugs are coadministered
with zafirlukast.
In a drug interaction study in 11 asthmatic patients,
co-administration of a single dose of zafirlukast (40
mg) with erythromycin (500 mg three times daily for 5
days) to steady state resulted in decreased mean plasma
levels of zafirlukast by approximately 40% due to a decrease
in zafirlukast bioavailability.
Co-administration of zafirlukast (80 mg/day) at steady
state with a single dose of a liquid theophylline preparation
(6 mg/kg) in 13 asthmatic patients resulted in decreased
mean plasma levels of zafirlukast by approximately 30%,
but no effect on plasma theophylline levels was observed.
Rare cases of patients experiencing increased theophylline
levels with or without clinical signs or symptoms of theophylline
toxicity after the addition of zafirlukast to an existing
theophylline regimen have been reported. The mechanism
of the interaction between zafirlukast and theophylline
in these patients is unknown (see
SIDE EFFECTS
).
Co-administration of zafirlukast (40 mg/day) with aspirin
(650 mg four times daily) resulted in mean increased plasma
levels of zafirlukast by approximately 45%.
In a single-blind, parallel-group, 3-week study in 39 healthy
female subjects taking oral contraceptives, 40 mg twice
daily of zafirlukast had no significant effect on ethinyl
estradiol plasma concentrations or contraceptive efficacy.
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