Terfenadin

Tablets containing terfenadine should be stored in tight containers at 15 to 30 °C and should be protected from exposure to temperatures exceeding 40 °C and from moisture. Commercially available terfenadine tablets have an expiration date of 18 months or 2 years after the date of manufacture when packaged in the manufacture's unopened blister packages or high-density polyethylene bottles, respectively.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

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. Treatment of the signs and symptoms of overdosage should be symptomatic and supportive after the acute stage. (L1712)

Prolongation of the QT interval and QT interval corrected for rate (QTc) and, rarely, serious cardiovascular effects, including arrhythmias (eg, ventricular tachycardia, atypical ventricular tachycardia (torsades de pointes)), cardiac arrest, palpitations, syncope, and death, have been reported in patients receiving recommended dosages of terfenadine concomitantly with ketoconazole. Ketoconazole can markedly inhibit the metabolism of terfenadine, probably via inhibition of the cytochrome P-450 microsomal enzyme system resulting in increased plasma concentrations of unchanged terfenadine (to measurable levels) and reduced clearance of the active carboxylic acid metabolite fexofenadine.

Erythromycin and clarithromycin may alter the metabolism of terfenadine. In some individuals, concommitant administration of erythromycin and terfenadine has resulted in increased plasma concentrations of both unchanged terfenadine and fexofenadine. ...Rarely, cardiac arrest and death have been reported in patients receiving erythromycin and terfenadine concomitantly. Therefore, terfenadine is contraindicated in patients receiving clarithromycin, erythromycin, or troleandomycin.

Some evidence indicates that mibefradil may alter the pharmacokinetics of terfenadine. Increased plasma concentrations (up to 40 ng/mL) of terfenadine were reported in a study in healthy individuals receiving 60 mg of terfenadine twice daily and mibefradil 50 or 100 mg daily. These increases of plasma unchanged terfenadine concentrations were associated with a 12% prolongation in mean QT interval corrected for rate (QTc). Since prolongation of the QTc interval may be associated with life-threatening arrhythmias and death, concomitant use of terfenadine and mibefradil is contraindicated.

In vitro, ritonavir has been shown to inhibit the metabolism of terfenadine, but the clinical importance of this in vitro finding is not known. Pending further accumulation of data, the manufacturer of terfenadine states that concomitant administration of terfenadine and human immunodeficiency virus (HIV) protease inhibitors (eg, indinavir, nelfinavir, ritonavir, saquinavir) is not recommended ... because of the theoretical risk that the HIV protease inhibitor could produce substantially increased plasma concentrations of unchanged terfenadine resulting in potentially serious and/or life-threatening adverse effects.

For more Interactions (Complete) data for TERFENADINE (13 total), please visit the HSDB record page.

The excretion of terfenadine into breast milk has not been reported previously. Disposition of terfenadine was prospectively studied in four healthy lactating mothers (age, 33+/-4 years). Subjects received 60 mg terfenadine every 12 hours over a period of 48 hours to achieve steady-state milk and plasma concentrations. Milk and plasma samples were collected at 1/2, 1, 1 1/2, 2, 3, 4, 6, 8, 12, 24, and 30 hours after the last dose. Terfenadine and its active metabolite milk and plasma concentrations were quantitated by HPLC. Terfenadine was not detected in milk or plasma. Mean +/- SD active metabolite data for milk and plasma are as follows: Cmax (ng/ml), 41.0+/-16.4 for milk, 309.0+/-120.5 for plasma; tmax (hours), 4.3+/-2.4 for milk, 3.9+/-3.0 for plasma; t1/2 beta (hours), 14.2+/-5.4 for milk, 11.7+/-6.4 for plasma; AUC(0-12) (ng.hr/mL) 320.4+/-99.8 for milk, 1590.0+/-300.4 for plasma. Metabolite milk/plasma AUC(0-12) ratios ranged from 0.12 to 0.28 (mean, 0.21+/-0.07). Newborn dosage estimates based on the highest measured concentration of terfenadine metabolite in milk suggests the maximum level of newborn exposure would not exceed 0.45% of the recommended maternal weight-corrected dose. Estimated amounts consumed by the neonate after the mother is given the recommended dose of the drug are not likely to result in plasma levels producing untoward effects.

Terfenadine competes with histamine for binding at H1-receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of terfenadine to H1-receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier, CNS depression is minimal.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=50679-08-8]

/HUMAN EXPOSURE STUDIES/ A possible hypersensitivity reaction, manifested as exacerbation of an existing dermatologic condition has been reported in one patient receiving terfenadine. Stevens-Johnson syndrome, which recurred on rechallenge, also has been reported in at least one patient receiving terfenadine.

/SIGNS AND SYMPTOMS/ Several cases of terfenadine overdosage have been reported to date. Signs and Symptoms following acute overdosage of the drug generally have been absent or mild (eg, headache, nausea, confusion). However potentially serious cardiac adverse effects, including arrhythmias (eg, ventricular tachycardia, atypical ventricular tachycardia (torsades de pointes)). Arrest, and prolongation of the QT interval corrected for rate (QTc), occasionally have been reported in patients receiving terfenadine doses of 306 mg or more; such cardiotoxic effects are even more likely at doses exceeding 600 mg. In addition, prolongation of in the QTc interval of up to 30% have been reported in patients receiving terfenadine dosages of 300 mg twice daily; such prolongations also have been reported in patients receiving lower dosages of the drug. Seizures and syncope also have been associated with terfenadine overdosages.

/CASE REPORTS/ One patient (a 16 year old female) who intentionally ingested 1.5 g of terfenadine and underwent gastric lavage 1 hour after ingestion had a complete and uneventful recovery except for a decrease in blood pressure from 110/60 to 90/50 mm Hg 3 hours after ingestion.

/CASE REPORTS/ ...Atypical ventricular tachycardia (torsades de pointes) developed 15 hr after acute ingestion of about 3.4 g of terfenadine, 7 g of cephalexin, and 1.2 g of ibuprofen; the arrhythmia progressed to ventricular fibrillation which was responsive to cardiovesion and lidocain. Two tonic-clonic seizures reportedly occurred prior to admission and quinidine-like cardio-toxic effects, including QT-interval prolongation and widened, notched T waves were noted following admission in a patient who ingested an unknown quantity of terfenadine; plasma concentrations of unchanged drug and its carboxylic acid metabolite (fexofenadine) in this patient were 43 and 1504 ng/mL, respectively, upon admission and 26.5 and 389 ng/mL, respectively, 9 hours after admission. Although not clearly established, it was suggested that the seizures observed in this patient may have resulted from terfenadine-induced cardiotoxicity.

For more Human Toxicity Excerpts (Complete) data for TERFENADINE (10 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

terfenadine

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ No evidence of carcinogenesis was seen in mice and rats receiving oral terfenadine dosages up to 150 mg/kg daily (63 times the recommended human daily dosage) for 18 months and 2 years, respectively. Although mammary fibroadenomas, pituitary tumors, and other tumors occurred in the rats and lymphoreticular tumors, lung adenomas, and other tumors occurred in the mice in these studies, the number and types of tumors were those ususally expected in animals of the strains and age tested.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 41]

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Oral dosages 125 times the recommended human dosages were associated with delayed fetal growth (ie, small and unossified sternebrae) in the rabbits, but this finding was considered equivocal since the frequency was similar to that observed with controls in other studies.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 41]

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies in male and female rats using terfenadine dosages have not revealed evidence of impaired fertility; however, a decrease in implantation and an increased incidence of postimplantation losseswere reported at this dosage. A decreased in implantation also was observed at an oral terfenadine dosage of 150 mg/kg daily.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 42]

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies in rats and rabbits using oral terfenadine dosages of 300 mg/kg daily have not revealed evidence of fetal malformations; however, in rats, oral terfenadine dosages of 300 mg/kg daily throughout pregnancy and lactation were associated with decreased weight gain and neonatal survival in the pups.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 41]

/GENOTOXICITY/ No evidence of terfenadine-induced mutagenesis was seen in the Ames microbial mutagen test with or without metabolic activation or in the mouse micronucleus test assay.[McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 19 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements)., p. 41]

Hoechst Marion Roussel, the manufacturer of Seldane and Seldane-D announced that as of February 1, 1998, it will withdraw all single-entity (Seldane) and fixed combination (Seldane-D) preparations of terfenadine from the US market. This announcement was preceded by a declaration of the US Food and Drug administration (FDA) in January 1997 of the agency's intent to withdraw all terfenadine preparations from the US since continued marketing of terfenadine, which interacts with numerous drugs and is potentially cardiotoxic, was no longer necessary because of the availability of a single-entity preparation of fexofenadine (Allegra), the pharmacologically active metabolite of terfenadine that does not share the cardiotoxic and drug interaction potentials of the parent drug. As a result of fexofenadine availability (both as a single entity and fixed combination preparation) as alternatives, Hoechst Marion Roussel concluded that the benefits of continued availability of terfenadine preparations did not outweigh the risks.

The following drug products were withdrawn or removed from the market because such drug products or components of such drug products were found to be unsafe or not effective. The following drug products may not be compounded under the exemptions provided by section 503A(a) of the Federal Food, Drug, and Cosmetic Act: ... All drug products containing terfenadine.

Hoechst Marion Roussel, the manufacturer of Seldane and Seldane-D announced that as of February 1, 1998, it will withdraw all single-entity (Seldane) and fixed combination (Seldane-D) preparations of terfenadine from the US market. This announcement was preceded by a declaration of the US Food and Drug administration (FDA) in January 1997 of the agency's intent to withdraw all terfenadine preparations from the US since continued marketing of terfenadine, which interacts with numerous drugs and is potentially cardiotoxic, was no longer necessary because of the availability of a single-entity preparation of fexofenadine (Allegra), the pharmacologically active metabolite of terfenadine that does not share the cardiotoxic and drug interaction potentials of the parent drug. As a result of fexofenadine availability (both as a single entity and fixed combination preparation) as alternatives, Hoechst Marion Roussel concluded that the benefits of continued availability of terfenadine preparations did not outweigh the risks.

THERAP CAT: Antihistaminic

MEDICATION /Former use/

Use (kg; approx.) in Germany (2009): >100

For the treatment of allergic rhinitis, hay fever, and allergic skin disorders.

Oral tablets, 60 mg, Seldane, Hoechst Marion Roussel.

Oral tablets extended-release core (pseudoephedrine hydrochloride only), 60 mg with Pseudoephedrine Hydrochloride 120 mg, Seldane-D, Hoechst Marion Roussel. /Terfenadine Combinations/

Trade name: Teldane (Hoechst Marion Roussel)