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 stearate, and sodium bicarbonate.

Terfenadine is a histamine H₁-receptor antagonist with the chemical name alpha-[4-(1,1-Dimethylethyl) phenyl]-4- (hydroxydiphenylmethyl) -1-piperidine-butanol (±). The molecular weight is 471.68. The molecular formula is C₃₂H₄₁NO₂.

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.

Last updated on RxList: 12/8/2004

Terfenadine 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.

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 PROLONGATIONS AND ADVERSE CARDIAC EVENTS. (See BOXED WARNING).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 DRUG INTERACTIONS).

Removed from market 1998

60 mg tablets in bottles of 100.

60 mg tablets in bottles of 500.

Tablets are round, white, and debossed "SELDANE". Store tablets at controlled room temperature (59-86°F) (15-30°C). Protect from exposure to temperatures above 104°F (40°C) and moisture.

Last updated on RxList: 12/8/2004

Cardiovascular Adverse Events

Rare reports of severe cardiovascular adverse effects have been received which include ventricular tachyarrhythmias (torsades de pointes, ventricular tachycardia, ventricular fibrillation, and cardiac arrest), hypotension, palpitations, syncope, and dizziness. Rare reports of deaths resulting from ventricular tachyarrhythmias have been received (see CONTRAINDICATIONS, WARNINGS, and DRUG INTERACTIONS). 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 BOXED WARNING). 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 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 of 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 terfenadine, 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 terfenadine was similar to that reported in patients receiving placebo. (See TABLE 1).

TABLE 1 - ADVERSE EVENTS REPORTED IN CLINICAL STUDIES

In addition to the more frequent side effects reported in clinical trials, adverse effects have been reported at a lower incidence in clinical trials and/or spontaneously during marketing of terfenadine that warrant listing as possibly associated with drug administration. These include: alopecia (hair loss or thinning), anaphylaxis, angioedema, bronchospasm, confusion, depression, galactorrhea, insomnia, menstrual disorder (including dysmenorrhea), musculoskeletal symptoms, nightmares, paresthesia, photosensitivity, rapid flare of psoriasis, seizures, sinus tachycardia, sweating, thrombocytopenia, tremor, urinary frequency and visual disturbances.

In clinical trials, severe instances of mild, or in one case, moderate transaminase elevations were seen in patients receiving terfenadine. 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.

Ketoconazole

Spontaneous 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 arrhythmia 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 terfenadine 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 terfenadine 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 terfenadine 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, and ADVERSE REACTIONS.) Pending full characterization of potential interactions, concomitant administration of terfenadine with other macrolide antibiotics, including azithromycin, is not recommended. Studies to evaluate potential interactions of terfenadine with azithromycin are in progress.

Last updated on RxList: 12/8/2004

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. Terfenadine is contraindicated for use by patients with these conditions (See BOXED WARNING, CONTRAINDICATIONS, and 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 prolongation. 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. Terfenadine is not recommended for use by patients with these conditions. The relationship of underlying cardiac disease to the development of ventricular tachyarrhythmias while on terfenadine therapy is unclear; nonetheless, terfenadine should also be used with caution in these patients.

Information for the Patient

Patients taking terfenadine should receive the following information and instructions. Antihistamines are prescribed to reduce allergic symptoms. Patients should be advised to take terfenadine only as needed and NOT TO EXCEED THE PRESCRIBED DOSE. Patients should be questioned about any 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 terfenadine therapy, since the drug should be used in pregnancy or lactation only if the potential benefit justifies the potential risk to the 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.

Carcinogenesis, Mutagenesis, and 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 teratogenicity. 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. Terfenadine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects: Terfenadine 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 pigs exposed to terfenadine 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 terfenadine in children below the age of 12 years have not been established.

Last updated on RxList: 12/8/2004

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 BOXED WARNING, CLINICAL PHARMACOLOGY, and ADVERSE REACTIONS).

In overdose cases where ventricular arrhythmias are associated with significant QTc prolongation, treatment with antiarrhythmics known to prolong QTc intervals is not recommended.

Therefore, in cases of overdosage, cardiac monitoring for at least 24 hours is recommended and 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 LD₅₀was 438 mg/kg in newborn rats.

CONCOMITANT ADMINISTRATION OF TERFENADINE WITH KETOCONAZOLE (NIZORAL) OR ITRACONAZOLE (SPORONOX) 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 DRUG INTERACTIONS).

Terfenadine is contraindicated in patients with a known hypersensitivity to terfenadine or any of its ingredients.

Last updated on RxList: 12/8/2004

Terfenadine is chemically distinct from other antihistamines. Histamine skin wheal studies have shown that terfenadine 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 terfenadine (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 terfenadine or other antihistamine recipients had moderate to complete relief of symptoms, compared with 30- 50% of placebo recipients. The frequency of drowsiness with terfenadine was similar to the frequency with placebo and less than with other antihistamines. None of these studies showed a difference between terfenadine and other antihistamines 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, systematic 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, the implications of this 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 indicates that in cases of hepatic impairment, significant concentrations of unchanged terfenadine 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, suggesting 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 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.

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 H₁blocking 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 terfenadine 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.

Last updated on RxList: 12/8/2004

Patient Package Insert

This leaflet is a summary of important information about terfenadine. Be sure to ask your doctor if you have any questions or want to know more.

What is Terfenadine and What is it Used For? Terfenadine is an antihistamine. It is used to relieve symptoms of seasonal allergies or hay fever. These symptoms include runny nose, sneezing, itching of the nose or throat, and itchy watery eyes.

Clinical studies conducted to date with terfenadine have not demonstrated effectiveness in relieving the symptoms of the common cold.

How Do I Take Terfenadine? Take terfenadine only as needed when you have symptoms of seasonal allergy or hay fever.

• The recommended dose of terfenadine is one tablet taken twice a day.DO NOT TAKE MORE OFTEN THAN ONE TABLET EVERY TWELVE HOURS
• Follow any other instructions your doctor gives you.

What Are the Important Warnings About Using terfenadine? WARNING: DO NOT USE TERFENADINE IF YOU ARE USING KETOCONAZOLE (NIZORAL), ITRACONAZOLE (SPORANOX), ERYTHROMYCIN, CLARITHROMYCIN (BIAXIN), OR TROLEANDOMYCIN (TAO). IF YOU HAVE ANY LIVER OR HEART PROBLEMS, TALK TO YOUR DOCTOR BEFORE YOU USE TERFENADINE.

Do not use terfenadine with any other prescription or nonprescription medicines without first talking to your doctor and pharmacist.

If you faint, become dizzy, have any unusual heartbeats, or any other unusual symptoms while using terfenadine, contact your doctor.

If you become pregnant or are nursing a baby, talk your doctor about whether you should take terfenadine. Your doctor will decide whether you should take terfenadine based on the benefits and the risks.

What Are the Risks of Using Terfenadine? The side effects which occur most often are headaches and mild stomach or intestinal problems.

In rare cases, terfenadine has caused IRREGULAR HEARTBEATS which may cause serious problems like fainting, dizziness, cardiac arrest, or death. In these rare cases, this occurred when terfenadine was taken:

• in more than the recommended dose (remember, do not take more often than one tablet every twelve hours);
• with the antifungal drugs ketoconazole (Nizoral), or itraconazole (Sporanox);
• with the antibiotic drugs erythromycin, clarithromycin (Biaxin), or troleandomycin (TAO);
• by patients with serious liver disease.

How do I Store Terfenadine? Terfenadine should be stored in a tightly closed container, in a cool place, out of direct sunlight. It should be kept away from children.

Last updated on RxList: 12/8/2004