(terfenadine)
60 mg Tablets
WARNING BOX
DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED
PROLONGATION/VENTRICULAR
ARRHYTHMIA
RARE CASES OF SERIOUS CARDIOVASCULAR ADVERSE EVENTS, INCLUDING DEATH,
CARDIAC ARREST, TORSADES DE POINTES, AND OTHER VENTRICULAR ARRHYTHMIAS,
HAVE BEEN OBSERVED IN THE FOLLOWING CLINICAL SETTINGS, FREQUENTLY IN
ASSOCIATION WITH INCREASED TERFENADINE LEVELS WHICH LEAD TO
ELECTROCARDIOGRAPHIC QT PROLONGATION:
1. CONCOMITANT ADMINISTRATION OF KETOCONAZOLE (NIZORAL) OR
ITRACONAZOLE (SPORANOX)
2. OVERDOSE, INCLUDING SINGLE DOSES AS LOW AS 360 MG
3. CONCOMITANT ADMINISTRATION OF CLARITHROMLYCIN, ERYTHROMYCIN OR
TROLEANDOMYCIN
4. SIGNIFICANT HEPATIC SYSFUNCTION
TERFENADINE IS CONTRAINDICATED IN PATIENTS TAKING KETOCONAZOLE,
ITRACONAZOLE, ERYTHROMYCIN, CLARITHROMYCIN, OR TROLEANDOMYCIN, AND IN
PATIENTS WITH SIGNIFICANT HEPATIC DYSFUNCTION.
DO NOT EXCEED RECOMMENDED DOSE.
IN SOME CASES, SEVERE ARRHYTHMIAS HAVE BEEN PRECEDED BY EPISODES OF
SYNCOPE. SYNCOPE IN PATIENTS RECEIVING TERFENADINE SHOULD LEAD TO
DISCONTINUATION OF TREATMENT AND FULL EVALUATION OF POTENTIAL
ARRHYTHMIAS.
(See CONTRAINDICATIONS, WARNINGS, CLINICAL PHARMACOLOGY, AND
PRECAUTIONS:
DRUG INTERACTIONS.)
SELDANE (terfenadine) is available as tablets for oral administration. Each tablet contains 60
mg terfenadine. Tablets also contain, as inactive ingredients: corn starch, gelatin, lactose,
magnesium sterate, and sodium bicarbonate.
Terfenadine is a histamine H1-receptor antagonist with the chemical name alpha-[4-(1,1-Dimethylethyl) phenyl]-4-(hydroxydiphenylmethyl)-1-piperidinebutanol(+/-). The molecular weight is
471.68. The molecular formula is C32H41NO2.
It has the following chemical structure:
Terfenadine occurs as a white to off-white crystalline
powder. It is freely soluble in chloroform, soluble in ethanol, and very slightly soluble in water.
Terfenadine is chemically distinct from other antihistamines.
Histamine skin wheal studies have shown that SELDANE in single and repeated doses of 60 mg
in 64 subjects has an antihistaminic effect beginning at 1-2 hours, reaching its maximum at 3-4
hours, and lasting in excess of 12 hours. The correlation between response on skin wheal testing
and clinical efficacy is unclear. The four best controlled and largest clinical trials each lasted 7
days and involved about 1,000 total patients in comparisons of SELDANE (60 mg b.i.d.) with an
active drug (chlorpheniramine, 4 mg t.i.d.; dexchlorpheniramine, 2 mg t.i.d. or clemastine 1 mg
b.i.d. About 50-70% of SELDANE or other antihistamine recipients had moderate to complete
relief of symptoms, compared with 30-50% of placebo recipients. The frequency of drowsiness with SELDANE was
similar to the frequency with placebo and less than with other antihistamines. None of these
studies showed a difference between SELDANE and other anithistamines in the frequency of
anticholinergic effects. In studies which included 52 subjects in whom EEG assessments were
made, no depressant effects have been observed.
Animal studies have demonstrated that terfenadine is a histamine H1-receptor antagonist. In
these animal studies, no sedative or anticholinergic effects were observed at effective
antihistaminic doses. Radioactive disposition and autoradiographic studies in rats and
radioligand binding studies with guinea pig brain H1-receptors indicate that, at effective
antihistamine doses, neither terfenadine nor its metabolites penetrate the blood brain barrier
well.
On the basis of a mass balance study using 14C labeled terfenadine the oral absorption of
terfenadine was estimated to be at least 70%. Terfenadine itself undergoes extensive (99%) first
pass metabolism to two primary metabolites, an active acid metabolite and an inactive
dealkylated metabolite. Therefore, systemic availability of terfenadine is low under normal
conditions, and parent terfenadine is not normally detectable in plasma at levels > 10 ng/mL.
Although in rare cases there was measurable plasma terfenadine in apparently normal
individuals without identifiable risk factors, implications of the finding with respect to the
variability of terfenadine metabolism in the normal population cannot be assessed without
further study. Further studies of terfenadine metabolism in the general population are pending.
From information gained in the 14C study it appears that approximately forty percent of the total
dose is eliminated renally (40% as acid metabolite, 30% dealkyl metabolite, and 30% minor
unidentified metabolites). Sixty percent of the dose is eliminated in the feces (50% as the acid
metabolite, 2% unchanged terfenadine, and the remainder as minor unidentified metabolites).
Studies investigating the effect of hepatic and renal insufficiency on the metabolism and
excretion of terfenadine are incomplete. Preliminary information indicated that in cases of
hepatic impairment, significant concentrations of unchanged terfendadine can be detected with
the rate of acid metabolite formation being decreased. A single-dose study in patients with
hepatic impairment revealed increased parent terfenadine and impaired metabolism, suggestion
that additional drug accumulation may occur after repetitive dosing in such patients.
Terfenadine is contraindicated for use in patients with significant hepatic dysfunction. (See
CONTRAINDICATIONS and WARNINGS.) In subjects with normal hepatic function, unchanged
terfenadine plasma concentrations have not been detected. Elevated levels of parent
terfenadine, whether due to significant hepatic dysfunction, concomitant medications, or
overdose, have been associated with QT interval prolongation and serious cardiac adverse
events.(See CONTRAINDICATIONS and WARNINGS.) In controlled clinical trials in otherwise normal patients with rhinitis, small increases in QT interval were observed at doses of 60
mg b.i.d. In studies at 300 mg b.i.d. a mean increase in QTc of 10% (range -4% to +30%) (mean increase of 46 msec) was
observed.
Data have been reported demonstrating that compared to young subjects, elderly subjects
experience a 25% reduction in clearance of the acid metabolite after single-dose oral
administration of 120 mg. Further studies are necessary to fully characterize pharmacokinetics
in the elderly.
In vitro studies demonstrate that terfenadine is extensively (97%) bound to human serum protein
while the acid metabolite is approximately 70% bound to human serum protein. Based on data
gathered from in vitro models of antihistaminic activity, the acid metabolite of terfenadine has
approximately 30% of the H1 blocking activity of terfenadine. The relative contribution of
terfenadine and the acid metabolite to the pharmacodynamic effects have not been clearly
defined. Since unchanged terfenadine is usually not detected in plasma, and active acid
metabolite concentrations are relatively high, the acid metabolite may be the entity responsible
for the majority of efficacy after oral administration of terfenadine.
In a study involving the administration of a single 60 mg SELDANE tablet to 24 subjects, mean
peak plasma levels of the acid metabolite were 263 ng/mL (range 133-423 ng/mL) and occurred
approximately 2.5 hours after dosing. Plasma concentrations of unchanged terfenadine were not
detected. The elimination profile of the acid metabolite was biphasic in nature with an initial
mean plasma half-life of 3.5 hours followed by a mean plasma half-life of 6 hours. Ninety
percent of the plasma level time curve was associated with these half-lives. Although the
elimination profile is somewhat complex, the effective pharmacokinetic half-life can be estimated
at approximately 8.5 hours. However, receptor binding and pharmacologic effects, both
therapeutic and adverse, may persist well beyond that time.
SELDANE is indicated for the relief of symptoms associated with seasonal allergic rhinitis such
as sneezing, rhinorrhea, pruritus, and lacrimation.
Clinical studies conducted to date have not demonstrated effectiveness of terfenadine in the
common cold.
CONCOMITANT ADMINISTRATION OF TERFENADINE WITH KETOCONAZOLE (NIZORAL)
OR ITRACONAZOLE (SPORANOX) IS CONTRAINDICATED. TERFENADINE IS ALSO
CONTRAINDICATED IN PATIENTS WITH DISEASE STATES OR OTHER CONCOMITANT
MEDICATIONS KNOWN TO IMPAIR ITS METABOLISM, INCLUDING SIGNIFICANT HEPATIC
DYSFUNCTION, AND CONCURRENT USE OF CLARITHROMYCIN, ERYTHROMYCIN, OR
TROLEANDOMYCIN. QT PROLONGATION HAS BEEN DEMONSTRATED IN SOME
PATIENTS TAKING TERFENADINE IN THESE SETTINGS, AND RARE CASES OF SERIOUS
CARDIOVASCULAR EVENTS, INCLUDING DEATH, CARDIAC ARREST, AND TORSADES DE
POINTES, HAVE BEEN REPORTED IN THESE PATIENT POPULATIONS. (See WARNINGS
and PRECAUTIONS:
Drug Interactions.)
SELDANE is contraindicated in patients with a known hypersensitivity to terfenadine or any of its
ingredients.
Terfenadine undergoes extensive metabolism in the liver by a specific cytochrome P-450
isoenzyme. This metabolic pathway may be impaired in patients with hepatic dysfunction
(alcoholic cirrhosis, hepatitis) or who are taking drugs such as ketoconazole, itraconazole, or
clarithromycin, erythromycin, or troleandomycin (macrolide antibiotics), or other potent inhibitors
of this isoenzyme. Interference with this metabolism can lead to elevated terfenadine 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. SELADANE is contraindicated for use by patients with these conditions (see WARNING
BOX, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions).
Other patients who may be at risk for these adverse cardiovascular events include patients who
may experience new or increased QT prolongation while receiving certain drugs or having
conditions which lead to QT prolongations. These include patients taking certain
antiarrhythmics, bepridil, certain psychotropics, probucol, or astemizole; patients with electrolyte
abnormalities such as hypokalemia or hypomagnesemia, or taking diuretics with potential for
inducing electrolyte abnormalities; and patients with congenital QT syndrome. SELDANE is not
recommended for use by patients with these conditions.
The relationship of underlying cardiac disease to the development of ventricular
tachyarrhythmias while on SELDANE therapy is unclear; nonetheless, SELDANE should also be
used with caution in these patients.
Information for Patients
Patients taking SELDANE should receive the following information and instructions.
Antihistamines are prescribed to reduce allergic symptoms. Patients should be advised to take
SELDANE only as needed and NOT TO EXCEED THE PRESCRIBED DOSE. Patients should
be questioned about use of any other prescription or over-the-counter medication, and should
be cautioned regarding the potential for life-threatening arrhythmias with concurrent use of
ketoconazole, itraconazole, clarithromycin, erythromycin, or troleandomycin. Patients should be
advised to consult the physician before concurrent use of other medications with terfenadine.
Patients should be questioned about pregnancy or lactation before starting SELDANE therapy,
since the drug should be used in pregnancy or lactation only if the potential benefit justifies the
potential risk to fetus or baby. 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
Ketoconazole
Spontaneious adverse reaction reports of patients taking concomitant ketoconazole with
recommended doses of terfenadine demonstrate QT interval prolongation and rare serious
cardiac events, e.g. death, cardiac arrest, and ventricular arrhythemia including torsades de
pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of
terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine
is associated with statistically significant prolongation of the QT and Qtc intervals.
Concomitant administration of ketoconazole and terfenadine is contraindicated (see
CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS).
Itraconazole
Torsades de pointes and elevated parent terfenadine levels have been reported during
concomitant use of terenadine and itraconazole in clinical trials of itraconazole and from foreign
post-marketing sources. One death has also been reported from foreign post-marketing sources.
Concomitant administration of itraconazole and terfenadin is contraindicated (see
CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS.)
Due to the chemical similarity of other azole-type antifungal agents (including fluconazole,
metronidazole, and miconazole) to ketoconazole and itraconazole, concomitant use of these
products with terfenadine is not recommended pending full examination of potential interactions.
Macrolides
Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect
on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a
lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine
acid metabolite, its influence on terfenadin plasma levels is still under investigation. A few
spontaneous accounts of QT interval prolongation with ventricular arrhythmia, including torsades
de pointes, have been reported in patients receiving erythromycin or troleandomycin.
Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin
is contraindicated (see CONTRAINDICATIONS, WARNINGS, ADVERSE REACTIONS).
Pending full characterization of potential interactions, concomitant administration of terfenadine
with other macrolide antibiotics, including azithromycin, is not recommended. Studies to
evaluate the potential interaction of terfenadine with azithromycin are in progress.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Oral doses of terfenadine, corresponding to 63 times the recommended human daily dose, in
mice for 18 months or in rats for 24 months, revealed no evidence of tumorigenicity. Microbial
and micronucleus test assays with terfenadine have revealed no evidence of mutagenesis.
Reproduction and fertility studies in rats showed no effects on male or female fertility at oral
doses of up to 21 times the human daily dose. At 63
times the human daily dose there was a small but significant reduction in implants and at 125
times the human daily dose reduced implants and increased post-implantation losses were
observed, which were judged to be secondary to maternal toxicity.
Pregnancy Category C
There was no evidence of animal teratogencity. Reproduction studies have been performed in
rats at doses 63 times and 125 times the human daily dose and have revealed decreased pup
weight gain and survival when terfenadine was administered throughout pregnancy and
lactation. There are no adequate and well-controlled studies in pregnant women. SELDANE
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Nonteratogenic Effects
SELDANE is not recommended for nursing women. The drug has caused decreased pup weight
gain and survival in rats given doses 63 times and 125 times the human daily dose throughout
pregnancy and lactation. Effects on pups exposed to SELDANE only during lactation are not
known, and there are no adequate and well controlled studies in women during lactation.
Pediatric Use
Safety and effectiveness of SELDANE in pediatric patients below the age of 12 years have not
been established.
Cardiovascular Adverse Events
Rare reports of severe cardiovascular adverse effects have been received which include
ventriuclar tachyarrhythmias (torsades de pointes, ventricular tachycardia, ventricular fibrillation,
and cardiac arrest), hypotension, palpitations, syncope, and dizziness. Rare reports of deaths
resulting from ventriuclar tachyarrhythmias have been received (see CONTRAINDICATIONS,
WARNINGS and PRECAUTIONS: Drug Interactions).
Hypotension, palpitations, syncope, and dizziness could reflect undetected ventriucular arrhythmia.
IN SOME PATIENTS, DEATH, CARDIAC ARREST OR TORSADES DE POINTES HAVE
BEEN PRECEDED BY EPISODES OF SYNCOPE.(see WARNING BOX).
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; there is not conclusive evidence of a causal relationship of these events with
terfenadine. Although in rare cases there was measurable plasma terfenadine, the implications
of this finding with respect to the variability of terfenadine metabolism in the normal population
cannot be assessed without further study. In controlled clinical trials in otherwise normal patients
with rhinitis, small increases in QTc interval were observed at doses of 60 mg b.i.d. in studies at
300 mg b.i.d. a mean increase in QTc of 10% (range -4% to +30%)(mean increase of 46 msec)
was observed.
General Adverse Events
Experience from clinical studies, including both controlled and uncontrolled studies involving
more than 2,400 patients who received SELDANE, provides information on adverse experience
incidence for periods of a few days up to six months. The usual dose in these studies was 60
mg twice daily, but in a small number of patients the dose was as low as 20 mg twice a day, or
as high as 600 mg daily.
In controlled clinical studies using the recommended dose of 60 mg b.i.d., the incidence of
reported adverse effects in patients receiving SELDANE was similar to that reported in patients
receiving placebo.(See Table below)
Percent of Patients Reporting
Controlled Studies* All Clinical Studies**
SELDANE Placebo Control SELDANE Placebo
Adverse Event n=781 n=665 n=626*** n=2462 n=1478
Central Nervous System
Drowsiness 9.0 8.1 18.1 8.5 8.2
Headache 6.3 7.4 3.8 15.8 11.2
Fatigue 2.9 0.9 5.8 4.5 3.0
Dizziness 1.4 1.1 1.0 1.5 1.2
Nervousness 0.9 0.2 0.6 1.7 1.0
Weakness 0.9 0.6 0.2 0.6 0.5
Appetite Increase 0.6 0.0 0.0 0.5 0.0
Gastrointestinal System
Gastrointestinal Distress
(Abdominal distress,
Nausea, Vomiting,
Change in bowel habits) 4.6 3.0 2.7 7.6 5.4
Eye, Ear, Nose, and Throat
Dry Mouth/Nose/Throat 2.3 1.8 3.5 4.8 3.1
Cough 0.9 0.2 0.5 2.5 1.7
Sore Throat 0.5 0.3 0.5 3.2 1.6
Epistaxis 0.0 0.8 0.2 0.7 0.4
Skin
Eruption (including rash
and urticaria) or itching 1.0 1.7 1.4 1.6 2.0
* Duration of treatment in "CONTROLLED STUDIES" was usually 7-14 days.
** Duration of treatment in "ALL CLINICAL STUDIES" was up to 6 months.
*** CONTROL DRUGS: Chlorpheniramine (291 patients), d-Chlorpheniramine (189
patients), Clemastine (146 patients)
In addition to the more frequent side efects reported in clinical trials (see Table), adverse effects have been reported at a lower incidence in clinical trials and/or spontaneously during marketing of SELDANE that warrant listing as possibly associated with drug administration.
These include: alopecia (hair loss or thinning), anaphylaxis, angioedema, bronchospasm,
confusion, depression, galactorrhea, insomnia, menstrual disorders (including dymenorrhea),
musculoskeletal symptoms, nightmares, paresthesia, photosensitivity, rapid flare of psoriasis,
seizures, sinus tachycardia, sweating, thrombocytopenia, tumor, urinary frequency and visual
disturbances.
In clinical trials, several instances of mild, or in one case, moderate transaminase elevations
were seen in patients receiving SELDANE. Mild elevations were also seen in placebo treated
patients. Marketing experiences include isolated reports of jaundice, cholestatic hepatitis, and
hepatitis. In most cases available information is incomplete.
Signs and symptoms of overdosage may be absent or mild (e.g headache, nausea, confusion);
but adverse cardiac events including cardiac arrest, ventricular arrhythmias including torsades
de pointes and QT prolongation have been reported at overdoses of 360 mg or more and
occur more frequently at doses in excess of 600 mg and QTc prolongations of up to 30% have
been observed at a dose of 300 mg b.i.d Seizures and syncope have also been reported. USE
OF DOSES IN EXCESS OF 60 MG B.I.D IS NOT RECOMMENDED. (SEE WARNING BOX,
CLINICAL PHARMACOLOGY, and ADVERSE REACTIONS.)
In overdose cases where ventricular arrhythmias are associated with significant QTc prolongation,
treatment with antiarrhythmics known to prolong QT intervals is not recommended.
Therefore, in cases of overdosage, cardiac monitoring for at least 24 hours is recomendedand
for as long as QTc is prolonged, along with standard measures to remove any unabsorbed drug.
Limited experience with the use of hemoperfusion (n=1) or hemodialysis (n=3) was not successful
in completely removing the acid metabolite of terfenadine from the blood.
Treatment of the signs and symptoms of overdosage should be symptomatic and supportive after
the acute stage.
Oral LD50 values for terfenadine were greater than 5000 mg/kg in mature mice and rats. The oral
LD50 was 438 mg/kg in newborn rats.
One tablet (60 mg) twice daily for adults and pediatric patients 12 years and older.
USE OF DOSES IN EXCESS OF 60 MG B.I.D IS NOT RECOMMENDED BECAUSE OF THE
INCREASED POTENTIAL FOR QT INTERVAL PROLONGATION AND ADVERSE CARDIAC
EVENTS.(See WARNING BOX.) USE OF TERFENADINE IN PATIENTS WITH SIGNIFICANT
HEPATIC DYSFUNCTION AND IN PATIENTS TAKING KETOCONAZOLE, ITRACONAZOLE,
CLARITHROMYCIN, ERYTHROMYCIN, OR TROLEANDOMYCIN IS CONTRAINDICATED. (See
CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions.)
NDC 0068-0723-61
NDC 0068-0723-65
Tablets are round, white, and debossed “SELDANE”. Store tablets at controlled room temperature (59-86oF) (15-30oC). PRotect form exposure to temperatures above 104oF (40oC) and moisture.
Prescribing Information as of January 1995
Merrell Dow Pharmaceuticals Inc.
Subsidiary of Marion Merrell Dow Inc.
Kansas City, MO 64114
U.S. Patent 4,254,129.
Other patent applications pending.