ASTEMIZOLE
DESCRIPTION:
WARNINGS:
QT PROLONGATION/VENTRICULAR ARRHYTHMIAS
RARE CASES OF SERIOUS CARDIOVASCULAR
ADVERSE EVENTS INCLUDING DEATH, CARDIAC
ARREST, QT PROLONGATION, TORSADES DE
POINTES, AND OTHER VENTRICULAR ARRHYTHMIAS
HAVE BEEN OBSERVED IN PATIENTS EXCEEDING
RECOMMENDED DOSES OF ASTEMIZOLE. WHILE THE
MAJORITY OF SUCH EVENTS HAVE OCCURRED
FOLLOWING SUBSTANTIAL OVERDOSES OF
ASTEMIZOLE, TORSADES DE POINTES
(ARRHYTHMIAS) HAVE VERY RARELY OCCURRED AT
REPORTED DOSES AS LOW AS 20-30 MG DAILY
(2-3 TIMES THE RECOMMENDED DAILY DOSE).
DATA SUGGEST THAT THESE EVENTS ARE
ASSOCIATED WITH ELEVATION OF ASTEMIZOLE
AND/OR ASTEMIZOLE METABOLITE LEVELS,
RESULTING IN ELECTROCARDIOGRAPHIC QT
PROLONGATION.
THESE EVENTS HAVE ALSO OCCURRED AT 10 MG
DAILY IN A FEW PATIENTS WITH POSSIBLE
AUGMENTING CIRCUMSTANCES (SEE
CONTRAINDICATIONS AND WARNINGS). IN VIEW OF
THE POTENTIAL FOR CARDIAC ARRHYTHMIAS,
ADHERENCE TO THE RECOMMENDED DOSE SHOULD BE
EMPHASIZED.
DO NOT EXCEED THE RECOMMENDED DOSE OF 10 MG
(ONE TABLET) DAILY.
SOME PATIENTS APPEAR TO INCREASE THE DOSE
OF HISMANAL(R) (ASTEMIZOLE) TABLETS IN AN
ATTEMPT TO ACCELERATE THE ONSET OF ACTION.
PATIENTS SHOULD BE ADVISED NOT TO DO THIS
AND NOT TO USE HISMANAL(R) ON AN AS-NEEDED
BASIS (I.E., P R N) FOR IMMEDIATE RELIEF OF
SYMPTOMS.
CONCOMITANT ADMINISTRATION OF ASTEMIZOLE
WITH SYSTEMIC KETOCONAZOLE, ITRACONAZOLE,
ERYTHROMYCIN, CLARITHROMYCIN,
TROLEANDOMYCIN, MIBEFRADIL OR QUININE IS
CONTRAINDICATED (SEE CONTRAINDICATIONS AND
PRECAUTIONS: DRUG INTERACTIONS.)
SINCE ASTEMIZOLE IS EXTENSIVELY METABOLIZED
BY THE LIVER, THE USE OF ASTEMIZOLE IN
PATIENTS WITH SIGNIFICANT HEPATIC
DYSFUNCTION IS CONTRAINDICATED.
IN SOME CASES, SEVERE ARRHYTHMIAS HAVE BEEN
PRECEDED BY EPISODES OF SYNCOPE. SYNCOPE IN
PATIENTS RECEIVING ASTEMIZOLE SHOULD LEAD
TO IMMEDIATE DISCONTINUATION OF TREATMENT
AND APPROPRIATE CLINICAL EVALUATION,
INCLUDING ELECTRO-CARDIOGRAPHIC TESTING
(LOOKING FOR QT PROLONGATION AND
VENTRICULAR ARRHYTHMIA).
(SEE ACTIONS/CLINICAL PHARMACOLOGY,
CONTRAINDICATIONS, WARNINGS, PRECAUTIONS,
OVERDOSAGE, AND DOSAGE AND ADMINISTRATION.)
HISMANAL(R) (astemizole) is a histamine H1-receptor antagonist available in
scored white tablets for oral use. Each tablet contains 10 mg of astemizole,
and, as inactive ingredients: lactose, cornstarch, microcrystalline cellulose,
pregelatinized starch, povidone K90, magnesium stearate, colloidal silicon
dioxide, and sodium lauryl sulfate. Astemizole is chemically designated as 1-
((4-fluorophenyl)-methyl)- N-(1- (2-(4-methoxyphenyl)ethyl) -4-piperidinyl)-1 H-
benzimidazol-2-amine, with a molecular weight of 458.58. The empirical formula
is C28H31FN4O.
Astemizole is a white to slightly off-white powder; it is insoluble in water,
slightly soluble in ethanol and soluble in chloroform and methanol.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION
Astemizole is a long-acting, selective histamine H1-receptor antagonist.
Receptor binding studies in animals demonstrated that at pharmacological doses,
astemizole occupies peripheral H1-receptors but does not reach H1-receptors in
the brain. Whole body autoradiographic studies in rats, radiolabel tissue
distribution studies in dogs and radioligand binding studies of guinea pig brain
H1-receptors have shown that astemizole does not readily cross the blood-brain
barrier. Screening studies in rats at effective antihistaminic doses showed no
anticholinergic effects. Studies in humans using the recommended dosage regimens
have not been performed to determine whether astemizole is associated with a
different frequency of anticholinergic effects than therapeutic doses of other
antihistamines.
PHARMACOKINETICS
The absorption of astemizole is reduced by 60% when taken with meals. In single
oral dose studies, astemizole was rapidly absorbed from the gastrointestinal
tract; peak plasma concentrations of unchanged astemizole were reached within
one hour. Due to extensive first pass metabolism and significant tissue
distribution, plasma concentrations of unchanged drug were low. Elimination of
unchanged astemizole occurred with a half-life of approximately one day.
Elimination of astemizole plus hydroxylated metabolites, considered together to
represent the pharmacologically active fraction in plasma, was biphasic with
half-lives of 20 hours for the distribution phase and 7-11 days for the
elimination phase. The pharmacokinetics of astemizole plus hydroxylated
metabolites are dose proportional following single doses of 10 to 30 mg.
Following chronic administration, steady state plasma concentrations of
astemizole plus hydroxylated metabolites (mainly desmethylastemizole) were
reached within four to eight weeks; concentrations of the metabolites are
substantially higher than those of unchanged astemizole. Astemizole plus
hydroxylated metabolites decayed biphasically with an initial half-life of 7-9
days, with plasma concentrations being reduced by 75% within this phase, and
with a terminal half-life of about 19 days. The initial phase (t1/2=7-9 days)
appears to determine the time to reach steady state plasma concentrations of
astemizole plus hydroxylated metabolites. Steady state plasma concentrations of
unchanged astemizole were reached by 6 days (with a range of 6-9 days);
unchanged astemizole was eliminated from plasma with a half-life of
approximately 2 days (with a range of 1-2.5 days).
The in-vitro plasma protein binding of unchanged astemizole (100 ng/mL) as 96.7%
with 2.3% being found as free drug in the plasma water. In human blood with an
astemizole concentration of 100 ng/mL, 61.5% of astemizole was bound to the
plasma proteins, with 36.2% being distributed to the blood cell fraction. The
concentration of astemizole found in the blood was the same as that found in the
plasma fraction of the blood. Binding studies for the astemizole metabolite(s)
which achieve much higher concentrations than astemizole under chronic dosing
conditions have not been conducted.
METABOLISM
Excretion and metabolism studies with 14C-labeled astemizole in volunteers
demonstrated that the drug is almost completely metabolized and primarily
excreted in the feces.
In-vitro metabolism studies with human liver microsomes indicate that astemizole
is metabolized to its principle circulating metabolite, desmethylastemizole,
predominantly by a specific cytochrome P-450 isozyme, CYP 3A4. These in-vitro
studies also indicate that the P- 450 isozymes CYP 1A2 and CYP 2D6 are involved
in the minor metabolic pathways of astemizole. The relative contributions of the
CYP 3A4 isozymes in the liver and gastrointestinal mucosa to the presystemic
clearance of astemizole are unknown. Concurrent administration of astemizole
with the CYP 3A4 inhibitors ketoconazole or erythromycin to healthy volunteers
was associated with significantly increased plasma concentrations of astemizole.
(See WARNING BOX; CONTRAINDICATIONS; WARNINGS; PRECAUTIONS, Drug Interactions;
ADVERSE REACTIONS; and DOSAGE AND ADMINISTRATION.)
SPECIAL POPULATIONS
Elevated levels of unmetabolized astemizole, whether due to significant hepatic
dysfunction, concomitant use of interacting medications, or overdose, have been
associated with QTC interval prolongation and serious cardiac events. (See
WARNING BOX; CONTRAINDICATIONS; WARNINGS; PRECAUTIONS, Drug Interactions;
ADVERSE REACTIONS; and DOSAGE AND ADMINISTRATION.)
Interpatient variability in pharmacokinetic parameters may be greater in
patients with liver disease as compared to normal subjects. Systematic
evaluation of the pharmacokinetics in patients with hepatic or renal dysfunction
has not been performed.
EFFECTS ON CARDIAC REPOLARIZATION
In controlled clinical trials, small mean increases from baseline in corrected
QT interval (QTC) of approximately 7 milliseconds were observed at daily doses
of 10 mg.
CLINICAL STUDIES:
CLINICAL TRIALS
SEASONAL ALLERGIC RHINITIS
Clinical trials supporting the approval of HISMANAL(R) (astemizole) Tablets for
seasonal allergic rhinitis involved 425 patients aged 12 and over who received
either HISMANAL(R) once daily or another antihistamine and/or placebo in double-
blind randomized controlled studies. HISMANAL(R) was superior to placebo in
effects on nasal and non-nasal symptoms of seasonal allergic rhinitis. In these
and other clinical studies, the efficacy of HISMANAL(R) versus placebo was not
demonstrated until several days after beginning dosing.
IDIOPATHIC CHRONIC URTICARIA
Clinical trials supporting the approval of HISMANAL(R) for idiopathic chronic
urticaria involved 142 patients aged 12 and over who received either HISMANAL(R)
once daily or another antihistamine and/or placebo in double-blind randomized
controlled studies. HISMANAL(R) was superior to placebo in the management of
idiopathic chronic urticaria as demonstrated by reduction in associated itching,
erythema, and hives. The onset of efficacy of HISMANAL(R) versus placebo in this
condition has not been adequately studied.
INDICATIONS AND USAGE:
HISMANAL(R) (astemizole) Tablets are indicated for the relief of symptoms
associated with seasonal allergic rhinitis and chronic idiopathic urticaria.
HISMANAL(R) should not be used on an as-needed (i.e., p r n) basis for immediate
relief of symptoms. Patients should be advised not to increase the dose in an
attempt to accelerate the onset of action.
Clinical studies have not been conducted to evaluate the effectiveness of
HISMANAL(R) in the common cold.
CONTRAINDICATIONS:
CONCOMITANT ADMINISTRATION OF ASTEMIZOLE WITH SYSTEMIC KETOCONAZOLE,
ITRACONAZOLE, ERYTHROMYCIN, CLARITHROMYCIN, TROLEANDOMYCIN, MIBEFRADIL
DIHYDROCHLORIDE OR QUININE IS CONTRAINDICATED. ASTEMIZOLE IS ALSO
CONTRAINDICATED IN PATIENTS WITH SEVERE HEPATIC IMPAIRMENT OR WHO ARE TAKING
OTHER CONCOMITANT MEDICATIONS KNOWN TO IMPAIR ITS METABOLISM. QT PROLONGATION
HAS BEEN DEMONSTRATED IN PATIENTS TAKING ASTEMIZOLE IN THESE SETTINGS AND CASES
OF SERIOUS CARDIOVASCULAR EVENTS, INCLUDING DEATH. CARDIAC ARREST, AND TORSADES
DE POINTES, HAVE BEEN REPORTED IN THESE PATIENT POPULATIONS. (See WARNING BOX;
WARNINGS; PRECAUTIONS), Special Populations; PRECAUTIONS, Drug Interactions;
ADVERSE REACTIONS; and DOSAGE AND ADMINISTRATION).)
HISMANAL(R) is contraindicated in patients with known hypersensitivity to
astemizole or any of the inactive ingredients.
WARNINGS:
WARNINGS: Astemizole undergoes extensive presystemic metabolism to its major
active metabolite predominantly by the cytochrome P-450 3A4 isozyme. Cytochromes
P-450 1A2 and 2D6 contribute to the overall metabolism of astemizole to a lesser
extent. These metabolic pathways may be impaired in patients with hepatic
dysfunction (e.g., alcoholic cirrhosis, hepatitis) or who are taking drugs
systemically such as ketoconazole, itraconazole, erythromycin, clarithromycin,
troleandomycin, mibefradil dihydrochloride, other potent inhibitors of this
isozyme or quinine. Interference with this metabolism can lead to elevated
astemizole and/or desmethylastemizole plasma levels associated with QT
prolongation and increased risk of ventricular tachyarrhythmias (such as
torsades de pointes, ventricular tachycardia, and ventricular fibrillation) at
the recommended dose. HISMANAL(R) (astemizole) Tablets are contraindicated for
use by patients with these conditions. (See WARNING BOX; CONTRAINDICATIONS;
PRECAUTIONS, Special Populations; PRECAUTIONS, Drug Interactions; and DOSAGE AND
ADMINISTRATION.)
Patients known to have conditions leading to QT prolongation may experience QT
prolongation and/or ventricular arrhythmia with astemizole at recommended doses.
The effect of astemizole in patients who are receiving other agents which alter
the QT interval is unknown. However, in view of astemizole's known potential for
QT prolongation, it is advisable to avoid its use in 1) patients with congenital
QT prolongation syndrome, 2) those taking medications which are reported to
prolong QT intervals (including certain antiarrhythmics, bepridil, certain
psychotropics, cisapride, sparfloxacin or terfenadine (this list may not be all
inclusive), 3) patients with electrolyte abnormalities such as hypokalemia or
hypomagnesemia, or 4) those taking diuretics with the potential for inducing
electrolyte abnormalities.
The relationship of underlying cardiac disease to the development of ventricular
tachyarrhythmias while on HISMANAL(R) therapy is unclear; nonetheless,
HISMANAL(R) should also be used with caution in these patients.
PRECAUTIONS:
GENERAL
Elevated concentrations of astemizole and/or its principal metabolite,
desmethylastemizole, whether due to overdose, significant hepatic dysfunction,
or concomitant medications, have been associated with altered cardiac
repolarization and/or serious cardiac arrhythmias. Patients with impaired
hepatic function or those receiving treatment with significant inhibitors of CYP
3A4 or quinine may experience QT prolongation and/or ventricular arrhythmias,
including torsades de pointes, at the recommended dose. Patients having
conditions leading to QT prolongation may also be at risk for these
cardiovascular events. (See WARNING BOX; ACTIONS/CLINICAL PHARMACOLOGY;
CONTRAINDICATIONS; WARNINGS; PRECAUTIONS, Special Populations; PRECAUTIONS, Drug
Interactions; ADVERSE REACTIONS; and DOSAGE AND ADMINISTRATION.)
Rare cases of anaphylaxis, including anaphylactic shock, have been reported.
Caution should also be used when treating patients with renal impairment.
INFORMATION FOR PATIENTS
Patients taking HISMANAL(R) (astemizole) Tablets should receive the following
information and instructions. Antihistamines are prescribed to reduce allergic
symptoms. Patients taking HISMANAL(R) should be advised 1) to adhere to the
recommended dose, and 2) that the use of excessive doses may lead to serious
cardiovascular events. Some patients appear to increase the dose of HISMANAL(R)
in an attempt to accelerate the onset of action. PATIENTS SHOULD BE ADVISED NOT
TO DO THIS and not to use HISMANAL(R) on an as-needed (i.e., p r n) basis for
immediate relief of symptoms. Patients should be questioned about the use of any
other prescriptions or over-the-counter medication, and should be cautioned
regarding the potential for life-threatening arrhythmias with concurrent use of
ketoconazole, itraconazole, erythromycin, clarithromycin, troleandomycin,
mibefradil dihydrochloride, or quinine. Limited human data indicate that
although beverages containing quinine (up to 80 mg/day or about 32 ounces of
tonic water) may elevate plasma levels of astemizole and desmethylastemizole,
this effect is small and is not accompanied by significant prolongation of the
QT interval. Patients should be advised to consult their physician before
concurrent use of other medications with astemizole. Patients should also be
advised that HISMANAL(R) should not be taken with grapefruit juice. Patients
should be questioned about pregnancy or lactation before starting HISMANAL(R)
therapy, since the drug should be used in pregnancy or lactation only if the
potential benefit justifies the potential risk to fetus or baby (see Pregnancy
subsection). In addition, patients should be instructed to take HISMANAL(R) on
an empty stomach, e.g., at least 2 hours after a meal. No additional food should
be taken for at least 1 hour after dosing. Patients should also be instructed to
store this medication in a tightly closed container in a cool, dry place, away
from heat or direct sunlight, and away from children.
DRUG INTERACTIONS
Before prescribing or adding a newly available drug to the regimen of a patient
receiving astemizole, the package insert of the new drug and/or the medical
literature should be consulted to determine if an interaction between the new
drug and astemizole has been reported.
Astemizole is predominantly metabolized by the cytochrome P-450 3A4 (CYP 3A4)
isozyme with some metabolism by the 1A2 and 2D6 isozymes. Inhibition of CYP 3A4
in patients taking HISMANAL(R) can result in markedly elevated plasma
concentrations of astemizole and/or its principal metabolite,
desmethylastemizole. This could increase or prolong both the therapeutic effect
and adverse events.
Presence of elevated astemizole/desmethylastemizole concentrations is associated
with significant prolongation of the QT and QTC intervals. (See BOX WARNING;
CONTRAINDICATIONS; WARNINGS; PRECAUTIONS, Drug Interactions; ADVERSE REACTIONS;
and DOSAGE AND ADMINISTRATION.)
Concomitant administration of the drugs in Table A with astemizole is
contraindicated.
Table A
Drugs Contraindicated for Use with Astemizole
Azole antifungals: ketoconazole, itraconazole Macrolide antibiotics:
clarithromycin, erythromycin, troleandomycin Other: mibefradil, quinine
The drugs noted below have been demonstrated to be inhibitors of CYP 3A4 in-
vitro and have been shown to have clinically significant pharmacokinetic
interactions with other substrates of this isozyme. Because of the potential for
these drugs to influence the metabolism of astemizole and until the clinical
significance of these findings is fully established, concomitant use of
astemizole with the drugs in Table B is not recommended.
Table B
Drugs Not Recommended for Use with Astemizole
Other antifungals: fluconazole, metronidazole, miconazole i.v. Serotonin
Reuptake Inhibitors (SRI): fluoxetine, fluvoxamine, nefazodone, paroxetine,
sertraline HIV Protease Inhibitors: ritonavir, indinavir, saquinavir, nelfinavir
Other: grapefruit juice, zileuton, other potent CYP 3A4 inhibitors
KETOCONAZOLE/ITRACONAZOLE
Concomitant administration of ketoconazole or itraconazole with astemizole
results in markedly elevated concentrations of astemizole and its principal
metabolite, desmethylastemizole. Therefore, concomitant administration of
HISMANAL(R) with ketoconazole or itraconazole is contraindicated.
OTHER ANTIFUNGALS
Due to the chemical similarity of fluconazole, metronidazole, and miconazole
i.v. to ketoconazole, concomitant use of these products with astemizole is not
recommended.
MACROLIDE ANTIBIOTICS
Concomitant administration of erythromycin with astemizole results in markedly
elevated concentrations of astemizole and its principal metabolite,
desmethylastemizole. Because of the chemical similarity of clarithromycin and
troleandomycin to erythromycin and the known relative inhibitory potencies of
these macrolides, concomitant administration of erythromycin, clarithromycin or
troleandomycin with astemizole is also contraindicated.
MIBEFRADIL DIHYDROCHLORIDE
Mibefradil is an inhibitor of the P-450 isozyme primarily responsible for the
metabolism of astemizole (CYP 3A4). Coadministration of mibefradil with
terfenadine (also metabolized by CYP 3A4) in healthy subjects results in
inhibition of terfenadine metabolism and accumulation of unmetabolized
terfenadine with resulting clinically significant repolarization abnormalities.
Because of the potential for mibefradil to influence the metabolism of
astemizole, concomitant use of astemizole with mibefradil dihydrochloride is
contraindicated.
QUININE
Although quinine is not known to be an inhibitor of CYP 3A4, concomitant
administration of quinine with astemizole results in markedly elevated
concentrations of astemizole and its principal metabolite, desmethylastemizole.
The mechanism of this interaction is not known. Concomitant administration of
astemizole with quinine is therefore contraindicated.
OTHER 3A4 INHIBITORS
Astemizole is metabolized by the cytochrome P-450 3A4 isozyme (CYP 3A4).
Inhibition of this enzyme in patients taking HISMANAL(R) results in increased
plasma concentrations of astemizole and/or its principal metabolite,
desmethylastemizole. Presence of elevated astemizole/desmethylastemizole
concentrations is associated with significant prolongation of the QT and QTC
intervals. The drugs noted below have been demonstrated to be inhibitors of CYP
3A4 in- vitro and have been shown to have clinically significant pharmacokinetic
interactions with other substrates of this isozyme. Because of the potential for
these drugs to influence the metabolism of astemizole and until the clinical
significance is fully established, concomitant use of astemizole and the drugs
below is not recommended.
Serotonin Reuptake Inhibitors: fluoxetine, fluvoxamine, nefazodone, paroxetine,
sertraline
HIV Protease Inhibitors: ritonavir, indinavir, saquinavir, nelfinavir
Grapefruit juice
Zileuton
Other potent CYP 3A4 inhibitors
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Astemizole did not reveal any carcinogenic potential at oral doses up to 80
mg/kg/day for 24 months in rats and 18 months in mice (approximately 65 and 30
times, respectively, the maximum recommended daily oral dose in adults on a
mg/m(squared) basis). Micronucleus, dominant lethal, sister chromatid exchange
and Ames tests of astemizole have not revealed mutagenic activity. No impairment
of fertility was observed in rats at oral doses up to 40 mg/kg/day
(approximately 30 times the maximum recommended daily oral dose in adults on a
mg/m(squared) basis).
PREGNANCY: PREGNANCY CATEGORY C
Teratogenic effects were not observed in rats at oral doses up to 160 mg/kg/day
(approximately 130 times the maximum recommended daily oral dose in adults on a
mg/m(squared) basis) and in rabbits at oral doses up to 40 mg/kg/day
(approximately 65 times the maximum recommended daily oral dose in adults on a
mg/m(squared) basis). Maternal mortality was seen in rabbits at oral doses of
10mg/kg/day and above (approximately 16 times the maximum recommended daily oral
dose in adults on a mg/m(squared) basis). Embryocidal effects accompanied by
maternal effects were observed in rats at oral doses of 40 mg/kg/day and above
(approximately 30 times the maximum recommended daily oral dose in adults on a
mg/m(squared) basis). Embryotoxicity was not observed in rats at an oral dose of
10 mg/kg/day (approximately 8 times the maximum recommended daily oral dose in
adults on a mg/m(squared) basis) and maternal toxicity was not reported in
rabbits at an oral dose of 2.5 mg/kg/day (approximately 4 times the maximum
recommended daily oral dose in adults on a mg/m(squared) basis). There are no
adequate and well-controlled studies in pregnant women. HISMANAL(R) should be
used during pregnancy only if the potential benefit justifies the potential risk
to the fetus. Metabolites may remain in the body for as long as 4 months after
the end of dosing, calculated on the basis of 6 times the terminal half-life
(see ACTIONS/CLINICAL PHARMACOLOGY) section).
NURSING MOTHERS
Astemizole is excreted in the milk of dogs. It is not known whether astemizole
is excreted in human milk. Because certain drugs are known to be excreted in
human milk, caution should be exercised when HISMANAL(R) is administered to a
nursing woman.
PEDIATRIC USE
Safety and efficacy in children under 12 years of age have not been
demonstrated.
DRUG INTERACTIONS:
Before prescribing or adding a newly available drug to the regimen of a patient
receiving astemizole, the package insert of the new drug and/or the medical
literature should be consulted to determine if an interaction between the new
drug and astemizole has been reported.
Astemizole is predominantly metabolized by the cytochrome P-450 3A4 (CYP 3A4)
isozyme with some metabolism by the 1A2 and 2D6 isozymes. Inhibition of CYP 3A4
in patients taking HISMANAL(R) can result in markedly elevated plasma
concentrations of astemizole and/or its principal metabolite,
desmethylastemizole. This could increase or prolong both the therapeutic effect
and adverse events.
Presence of elevated astemizole/desmethylastemizole concentrations is associated
with significant prolongation of the QT and QTC intervals. (See BOX WARNING;
CONTRAINDICATIONS; WARNINGS; PRECAUTIONS, Drug Interactions; ADVERSE REACTIONS;
and DOSAGE AND ADMINISTRATION.)
Concomitant administration of the drugs in Table A with astemizole is
contraindicated.
Table A
Drugs Contraindicated for Use with Astemizole
Azole antifungals: ketoconazole, itraconazole Macrolide antibiotics:
clarithromycin, erythromycin, troleandomycin Other: mibefradil, quinine
The drugs noted below have been demonstrated to be inhibitors of CYP 3A4 in-
vitro and have been shown to have clinically significant pharmacokinetic
interactions with other substrates of this isozyme. Because of the potential for
these drugs to influence the metabolism of astemizole and until the clinical
significance of these findings is fully established, concomitant use of
astemizole with the drugs in Table B is not recommended.
Table B
Drugs Not Recommended for Use with Astemizole
Other antifungals: fluconazole, metronidazole, miconazole i.v. Serotonin
Reuptake Inhibitors (SRI): fluoxetine, fluvoxamine, nefazodone, paroxetine,
sertraline HIV Protease Inhibitors: ritonavir, indinavir, saquinavir, nelfinavir
Other: grapefruit juice, zileuton, other potent CYP 3A4 inhibitors
KETOCONAZOLE/ITRACONAZOLE
Concomitant administration of ketoconazole or itraconazole with astemizole
results in markedly elevated concentrations of astemizole and its principal
metabolite, desmethylastemizole. Therefore, concomitant administration of
HISMANAL(R) with ketoconazole or itraconazole is contraindicated.
OTHER ANTIFUNGALS
Due to the chemical similarity of fluconazole, metronidazole, and miconazole
i.v. to ketoconazole, concomitant use of these products with astemizole is not
recommended.
MACROLIDE ANTIBIOTICS
Concomitant administration of erythromycin with astemizole results in markedly
elevated concentrations of astemizole and its principal metabolite,
desmethylastemizole. Because of the chemical similarity of clarithromycin and
troleandomycin to erythromycin and the known relative inhibitory potencies of
these macrolides, concomitant administration of erythromycin, clarithromycin or
troleandomycin with astemizole is also contraindicated.
MIBEFRADIL DIHYDROCHLORIDE
Mibefradil is an inhibitor of the P-450 isozyme primarily responsible for the
metabolism of astemizole (CYP 3A4). Coadministration of mibefradil with
terfenadine (also metabolized by CYP 3A4) in healthy subjects results in
inhibition of terfenadine metabolism and accumulation of unmetabolized
terfenadine with resulting clinically significant repolarization abnormalities.
Because of the potential for mibefradil to influence the metabolism of
astemizole, concomitant use of astemizole with mibefradil dihydrochloride is
contraindicated.
QUININE
Although quinine is not known to be an inhibitor of CYP 3A4, concomitant
administration of quinine with astemizole results in markedly elevated
concentrations of astemizole and its principal metabolite, desmethylastemizole.
The mechanism of this interaction is not known. Concomitant administration of
astemizole with quinine is therefore contraindicated.
OTHER 3A4 INHIBITORS
Astemizole is metabolized by the cytochrome P-450 3A4 isozyme (CYP 3A4).
Inhibition of this enzyme in patients taking HISMANAL(R) results in increased
plasma concentrations of astemizole and/or its principal metabolite,
desmethylastemizole. Presence of elevated astemizole/desmethylastemizole
concentrations is associated with significant prolongation of the QT and QTC
intervals. The drugs noted below have been demonstrated to be inhibitors of CYP
3A4 in- vitro and have been shown to have clinically significant pharmacokinetic
interactions with other substrates of this isozyme. Because of the potential for
these drugs to influence the metabolism of astemizole and until the clinical
significance is fully established, concomitant use of astemizole and the drugs
below is not recommended.
Serotonin Reuptake Inhibitors: fluoxetine, fluvoxamine, nefazodone, paroxetine,
sertraline
HIV Protease Inhibitors: ritonavir, indinavir, saquinavir, nelfinavir
Grapefruit juice
Zileuton
Other potent CYP 3A4 inhibitors
(See also PRECAUTIONS)
ADVERSE REACTIONS:
CARDIOVASCULAR ADVERSE EVENTS
Rare reports of serious cardiovascular effects have been received which include
ventricular tachyarrhythmias (torsades de pointes, ventricular tachycardia,
ventricular fibrillation, and cardiac arrest), hypotension, syncope, and
dizziness. Rare reports of deaths resulting from ventricular tachyarrhythmias
have been received. In most instances, astemizole overdoses, QT-prolonging
conditions, drug interactions leading to impaired astemizole metabolism or other
factors which could have contributed to the events, were observed. (See WARNING
BOX; CONTRAINDICATIONS; WARNINGS; PRECAUTIONS, Drug Interactions; and DOSAGE AND
ADMINISTRATION.) Hypotension, palpitations, syncope, and dizziness could reflect
undetected ventricular arrhythmia. IN SOME PATIENTS, DEATH, CARDIAC ARREST, OR
TORSADES DE POINTES HAVE BEEN PRECEDED BY EPISODES OF SYNCOPE (see WARNINGS).
Rare reports of serious cardiovascular adverse events have been received, some
involving QT prolongation and torsades de pointes, in apparently normal
individuals without identifiable risk factors and at recommended doses. There is
not conclusive evidence of a causal relationship of these events with
astemizole.
Reports of serious cardiovascular effects associated with patients intentionally
taking more than the recommended daily dose of astemizole in an attempt to
accelerate the onset of action have been received. Patients should be cautioned
not to exceed the recommended daily dose (see PRECAUTIONS, Information for
Patients).
GENERAL ADVERSE EVENTS
The reported incidences of adverse reactions listed in the following table are
derived from controlled clinical studies in adults. In these studies the usual
maintenance dose of HISMANAL(R) (astemizole) Tablets was 10 mg once daily.
PERCENT OF PATIENTS REPORTING
CONTROLLED STUDIES(*)
--------------------------------------------------------------------------------------------------------------------------------------------------------------
ADVERSE EVENT HISMANAL(R) PLACEBO ACTIVE CONTROLS(**)
(N=1630) (N=1109) (N=304)
% % %
CENTRAL NERVOUS SYSTEM
Drowsiness 7.1 6.4 22.0
Headache 6.7 9.2 3.3
Fatigue 4.2 1.6 11.8
Appetite increase 3.9 1.4 0.0
Weight increase 3.6 0.7 1.0
Nervousness 2.1 1.2 0.3
Dizziness 2.0 1.8 1.0
GASTROINTESTINAL SYSTEM
Nausea 2.5 2.9 1.3
Diarrhea 1.8 2.0 0.7
Abdominal pain 1.4 1.2 0.7
EYE, EAR, NOSE, AND THROAT
Mouth dry 5.2 3.8 7.9
Pharyngitis 1.7 2.3 0.3
Conjunctivitis 1.2 1.2 0.7
OTHER
Arthralgia 1.2 1.6 0.0
* Duration of treatment in controlled studies ranged from 7 to 182 days
** Active Controls: Clemastine (N=137); Chlorpheniramine
(N=100); Pheniramine Maleate (N=47); d-Chlorpheniramine (N=20)
-------------------------------------------------------------------------------------------------------------------------------------------------------
Adverse reaction information has been obtained from more than 7500 patients in
all clinical trials. Weight gain has been reported in 3.6% of astemizole treated
patients involved in controlled studies, with an average treatment duration of
53 days. In 46 of the 59 patients for whom actual weight gain data was
available, the average weight gain was 3.2 kg.
Less frequently occurring adverse experiences reported in clinical trials or
spontaneously from marketing experience with HISMANAL(R) include: angioedema,
asymptomatic liver enzyme elevations, bronchospasm, depression, edema,
epistaxis, hepatitis, myalgia, palpitation, paresthesia, photosensitivity,
pruritus, and rash.
Rare cases of anaphylaxis, including anaphylactic shock, have been reported.
Marketing experiences include isolated cases of convulsions. A causal
relationship with HISMANAL(R) has not been established.
OVERDOSAGE:
In the event of overdosage, supportive measures including gastric lavage and
emesis should be employed. Substantial overdoses of HISMANAL(R) (astemizole)
Tablets can cause death, cardiac arrest, QT prolongation, torsades de pointes,
and other ventricular arrhythmias. These events can also occur, although rarely,
at doses (20-30 mg) close to the recommended dose (10 mg/daily). Patients should
be advised not to take more than the daily recommended dose of HISMANAL(R) in
attempts to accelerate the onset of action. (See WARNING BOX; CONTRAINDICATIONS;
WARNINGS; PRECAUTIONS, Information for Patients; PRECAUTIONS, Drug Interactions;
ADVERSE REACTIONS; and DOSAGE AND ADMINISTRATION.)
Seizures and syncope have also been reported with overdose and may be associated
with a cardiac event.
Overdose patients should be carefully monitored as long as the QT interval is
prolonged or arrhythmias are present. In some cases, this has been up to six
days. In overdose cases in which ventricular arrhythmias are associated with
significant QT prolongation, treatment with antiarrhythmics known to prolong QT
intervals is not recommended. HISMANAL(R) does not appear to be dialyzable.
Oral median lethal doses for astemizole were 2052mg/kg in mice (approximately
830 times the maximum recommended daily oral dose in adults on a mg/m(squared)
basis) and 3154 mg/kg in rats (approximately 2600 times the maximum recommended
daily oral dose in adults on a mg/m(squared) basis). In neonatal rats, the oral
median lethal dose was 1070 mg/kg (approximately 870 times the maximum
recommended daily oral dose in adults on a mg/m(squared) basis).
DOSAGE AND ADMINISTRATION:
The recommended dosage for adults and children 12 years of age and older is 10
mg (1 tablet) once daily.
DO NOT EXCEED THE RECOMMENDED DOSE. Patients should be advised not to increase
the dose of HISMANAL(R) (astemizole) Tablets in an attempt to accelerate the
onset of action. USE OF HISMANAL(R) IN PATIENTS WITH SIGNIFICANT HEPATIC
DYSFUNCTION OR IN PATIENTS TAKING KETOCONAZOLE, ITRACONAZOLE, ERYTHROMYCIN,
CLARITHROMYCIN, TROLEANDOMYCIN, MIBEFRADIL DIHYDROCHLORIDE, OR QUININE IS
CONTRAINDICATED. (See WARNING BOX; CONTRAINDICATIONS; WARNINGS; PRECAUTIONS,
Information for Patients; PRECAUTIONS, Drug Interactions; ADVERSE REACTIONS;
OVERDOSAGE; and DOSAGE AND ADMINISTRATION.)
Studies evaluating the need for dosage adjustments for patients with hepatic or
renal dysfunction have not been performed. Since astemizole is extensively
metabolized by the liver, use of HISMANAL(R) in patients with significant
hepatic dysfunction is contraindicated.
HISMANAL(R) should be taken on an empty stomach, e.g., at least two hours after
a meal. There should be no additional food intake for at least one hour post-
dosing.
INSTRUCTIONS FOR PATIENT :--
This is a summary of important information about HISMANAL. Be sure to
ask your doctor if you have any questions or want to known more.
WHAT IS HISMANAL AND WHAT IS IT USED FOR?
HISMANAL is an antihistamine (astemizole). It is used to relieve symptoms of
seasonal allergies or hay fever. These symptoms may include runny nose,
sneezing, itching of the nose or throat, and itchy, watery eyes. HISMANAL may
also be prescribed by your doctor to treat the symptoms and skin manifestations
of hives (urticaria). These symptoms include generalized itching and redness of
the skin.
HISMANAL has not been demonstrated to be effective in relieving the symptoms of
the common cold.
HOW DO I TAKE HISMANAL?
The recommended dose of HISMANAL is ONE tablet taken ONCE A DAY. DO NOT TAKE
MORE OFTEN THAN ONE TABLET ONCE A DAY.
HISMANAL does not work immediately and therefore should not be used for
immediate relief. Because taking more than the recommended dose can increase
your risk of having a serious side effect, you should not take more than one
tablet once a day to try to get it to work faster.
If you miss your daily dose of HISMANAL, do not take extra HISMANAL tablets to
make up for it.
HISMANAL should be taken on an empty stomach (at least 2 hours after having a
meal). Also, don't eat any food for at least 1 hour after taking your HISMANAL.
WHAT ARE IMPORTANT WARNINGS ABOUT USING HISMANAL?
WARNING: DO NOT TAKE HISMANAL IF YOUR ARE USING KETOCONAZOLE (NIZORAL),
ITRACONAZOLE (SPORANOX), ERYHTROMYCIN, CLARITHROMYCIN (BIAXIN), TROLEANDOMYCIN
(TAO), QUININE, OR MIBEFRADIL (POSICOR). IF YOU HAVE ANY LIVER OR HEART
PROBLEMS, TALK TO YOUR DOCTOR BEFORE YOU USE HISMANAL.
Do not use HISMANAL with any other prescription or nonprescription medicines
without first talking to your doctor and pharmacist.
Do not take HISMANAL with grapefruit juice.
If you faint, become dizzy, have unusual heartbeats, or any other unusual
symptoms while using HISMANAL, contact your doctor.
If you become pregnant or are nursing a baby, talk to your doctor about whether
you should take HISMANAL. Your doctor will decide whether you should take
HISMANAL based on the benefits and risks.
WHAT ARE THE RISKS OF USING HISMANAL?
The side effects which occur most often are drowsiness, fatigue, and dry mouth.
Increased appetite and weight gain have also been reported by patients taking
HISMANAL.
In rare cases, HISMANAL has caused IRREGULAR HEARTBEATS which may cause serious
problems such as fainting, dizziness, cardiac arrest, or death.
In these rare cases, this occurred most often when HISMANAL was taken:
in more than the recommended dose (Remember, do not take more than one tablet
once a day);
with antifungal drugs such as ketoconazole (Nizoral) or itraconazole (Sporanox);
with the antibiotic drugs erythromycin, clarithromycin (Biaxin), or
troleandomycin (TAO);
with oral quinine preparations;
by patients with severe liver disease.
HOW DO I STORE HISMANAL?
HISMANAL should be stored in a tightly closed container, at room temperature out
of direct sunlight. It should be kept away from children.
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