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Terfenadine

Drug Approvals

(British Approved Name, US Adopted Name, rINN)

Synonyms: MDL-9918; RMI-9918; Terfenadiini; Terfenadin; Terfenadina; Terfenadinas; Terfenadinum
BAN: Terfenadine
USAN: Terfenadine
INN: Terfenadine [rINN (en)]
INN: Terfenadina [rINN (es)]
INN: Terfénadine [rINN (fr)]
INN: Terfenadinum [rINN (la)]
INN: Терфенадин [rINN (ru)]
Chemical name: 1-(4-tert-Butylphenyl)-4-[4-(α-hydroxybenzhydryl)piperidino]butan-1-ol
Molecular formula: C32H41NO2 =471.7
CAS: 50679-08-8
ATC code: R06AX12
Read code: y01uT

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed. (Terfenadine). A white or almost white, crystalline powder. It shows polymorphism. Very slightly soluble in water and in dilute hydrochloric acid freely soluble in dichlorometh-ane soluble in methyl alcohol. Protect from light.

Adverse Effects and Precautions

As for the non-sedating antihistamines in general. Erythema multiforme and galactorrhoea have also been reported. Ventricular arrhythmias, including torsade de pointes, have occurred rarely with terfenadine, particularly in association with raised blood concentrations (see Arrhythmias, below). To reduce the risk of developing such arrhythmias the recommended dose should not be exceeded and terfenadine should be avoided in patients with cardiac or significant hepatic disease, with hypokalaemia or other electrolyte imbalance, or with known or suspected prolonged QT interval. Use with drugs liable to interfere with the hepatic metabolism of terfenadine, other potentially arrhythmogenic drugs including those that prolong the QT interval, and drugs likely to cause electrolyte imbalance is contraindicated (see under Interactions, below). If palpitations, dizziness, syncope, or convulsions occur terfenadine should be withdrawn and the patient investigated for potential arrhythmias.

Alopecia. Hair loss was associated with use of terfenadine in a 24-year-old patient. Regrowth occurred when treatment was stopped.

Arrhythmias. Ventricular arrhythmias including torsade de pointes have occurred with terfenadine at doses greater than those recommended and also at normal doses in patients whose metabolism of terfenadine is impaired by drugs or by liver disease. Generalised convulsions and a quinine-like effect on the ECG have also been reported after a presumed overdose of terfenadine. Consequently a number of recommendations have been made to reduce the risk of developing serious arrhythmias (see Adverse Effects and Precautions, above, for details), including those from the UK CSM. Terfenadine should be stopped immediately, and the patient evaluated for potential arrhythmias, in those who experience syncope, palpitations, dizziness, or convulsions after taking terfenadine.

Studies have suggested that the ventricular arrhythmias are due to terfenadine itself rather than its active metabolite fexofenadine. Terfenadine has been shown to inhibit cardiac potassium channels, which results in prolongation of the QT interval, a risk factor for developing arrhythmias, while the non-sedating antihistamines cetirizine, fexofenadine, and loratadine have had no demonstrable effect.

Terfenadine

Breast feeding. No adverse effects have been observed in breast-fed infants whose mothers were receiving terfenadine, and the American Academy of Pediatrics considers that it is therefore usually compatible with breast feeding. In a study of 4 healthy lactating women given 60 mg of terfenadine every 12 hours for 48 hours, terfenadine was undetected in breast milk its active metabolite, fexofenadine, was excreted in limited amounts.

Effects on the liver. Three episodes of acute hepatitis with jaundice occurred in a patient taking terfenadine intermittently over a period of 17 months. Tiver function tests returned to normal after the drug was stopped. Two further cases of cholestatic hepatitis associated with terfenadine have been reported. Again, liver function tests returned to normal after drug withdrawal. A study by the Boston Collaborative Drug Surveillance Program of 210 683 patients who had received prescriptions for terfenadine concluded that the use of terfenadine was rarely associated with important idiopathic liver disease. The investigators found only 3 cases of acute liver disease where a causal connection to terfenadine could not be ruled out all these patients had also received a hepatotoxic drug and had made a full recovery.

Effects on the nervous system. Non-sedating effects on the CNS have been reported after a single dose of terfenadine these have included anxiety, palpitations, and insomnia. The UK manufacturers commented that clinical studies suggest that the incidence of such effects is similar to that seen after placebo. Workers who had described a generalised tonic-clonic seizure in a patient taking terfenadine later reported that the patient had subsequently had a second unprovoked seizure and now considered that terfenadine may not have been the cause of his original seizure. Convulsions have been reported after overdosage with terfenadine (see under Arrhythmias, above). The sedative effects of the older antihistamines and the lack of such effects with the non-sedating antihistamines including terfenadine are discussed under Sedation.

Hypersensitivity. Terfenadine use was associated with 108 reports of skin reactions, including rashes, urticaria, angioedema, photosensitivity reactions and peeling of the skin of the hands or feet.

Porphyria. Terfenadine has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Interactions

As for the non-sedating antihistamines in general. Terfenadine should not be given with drugs that inhibit its hepatic metabolism because of the increased risk of serious ventricular arrhythmias. These drugs include the triazole and imidazole antifungals such as itraconazole and ketoconazole, the macrolide antibacterials including clarithromycin, erythromycin, josamycin, and troleandomycin, the streptogramin antibacterial quinupristin/dalfopristin, the serotonin reuptake inhibitors citalopram, fluoxetine, fluvoxamine, nefazodone, and paroxetine, the HIV-protease inhibitors, the NNRTIs delavirdine and efavirenz, and zileuton. The metabolism of terfenadine may also be inhibited by grapefruit juice and use together should be avoided. Use with other potentially arrhythmogenic drugs (including those that prolong the QT interval) such as antiarrhythmics, tricyclic antidepressants, the antimalarials halofantrine and quinine, antipsychotics, cisapride, probucol, pentamidine isetionate, and the beta blocker sotalol should be avoided as should diuretics that cause electrolyte imbalances especially hypokalaemia. The use of terfenadine and astemizole together is not recommended.

Antibacterials. Pharmacokinetic studies have shown that the macrolide antibiotics erythromycin and clarithromycin interfere with the metabolism of terfenadine leading to its accumulation. A high plasma-terfenadine concentration is associated with prolongation of the QT interval, and arrhythmias such as torsade de pointes have been reported in patients given terfenadine with erythromycin or troleandomycin.

Antidepressants. Cardiac abnormalities have been reported in 2 patients taking fluoxetine with terfenadine. Similarly, the use of nefazodone with terfenadine has resulted in prolongation of the QT interval.

Antiepileptics. For reference to an interaction between terfenadine and carbamazepine.

Antifungals. Pharmacokinetic studies have shown that itraconazole and ketoconazole interfere with the metabolism of terfenadine leading to its accumulation. A high plasma-terfenadine concentration is associated with prolongation of the QT interval, and arrhythmias such as torsade de pointes have been reported in patients given terfenadine with ketoconazole or itraconazole. While there has been a pharmacokinetic study that suggested that the interaction between terfenadine and fluconazole might not be clinically significant, as the mechanism of the interaction appeared to involve the metabolite of terfenadine and did not lead to accumulation of the cardiotoxic parent compound, this may not always be the case. Studies in a small group of patients who had abnormal patterns of terfenadine metabolism found increases in terfenadine concentrations associated with ECG abnormalities when terfenadine was given with high doses of fluconazole.

Calcium-channel blockers. For reference to an interaction between terfenadine and nifedipine.

Grapefruit juice. A study in healthy subjects given terfenadine and grapefruit juice for 7 days found raised plasma-terfenadine concentrations and prolongation of the QT interval. These effects were less pronounced when terfenadine was given 2 hours before grapefruit juice, but were nevertheless quantifiable in some subjects. In another study QT interval changes were not found in healthy subjects given single doses ofterfenadine and grapefruit juice. However, the highly variable pharmacokinetics between individuals led the authors to conclude that prolongation of the QT interval was possible following single doses. The probable mechanism of the interaction is inhibition of the metabolism of terfenadine by the cytochrome P450 isoenzyme CYP3A4.

Pharmacokinetics

Terfenadine is rapidly absorbed from the gastrointestinal tract peak plasma concentrations are achieved within about 2 hours. It is a prodrug and undergoes extensive first-pass metabolism in the liver to its active metabolite the carboxylic acid derivative fexofenadine. The other main metabolite is an inactive piperidine-carbinol derivative. About 97% ofterfenadine is bound to plasma proteins fexofenadine is reported to be less extensively bound. Terfenadine does not appear to cross the blood-brain barrier to a significant extent limited amounts of fexofenadine, but not the parent drug, have been detected in breast milk. An elimination half-life of 16 to 23 hours has been reported for terfenadine. The metabolites, and traces of unchanged drug, are excreted in the urine and the faeces.

Uses and Administration

Terfenadine, a piperidine derivative, is a non-sedating antihistamine. It does not have significant antimuscarinic actions. It is used for the symptomatic relief of allergic conditions including and conjunctivitis and skin disorders such as urticaria.

The maximum oral dose ofterfenadine is 120 mg daily given either as 60 mg twice daily or 120 mg in the morning a starting dose of 60 mg daily in a single dose or in two divided doses is recommended for rhinitis and conjunctivitis. Children who are over 12 years of age and weigh more than 50 kg may receive the usual adult dosage. For dosage in renal impairment see below.

Administration in renal impairment. Half the usual oral daily dose of terfenadine has been suggested for patients with creatinine clearance less than 40 mL/minute.

Preparations

British Pharmacopoeia. Unless otherwise specified, BP references areto the 2008 edition: Terfenadine Oral Suspension Terfenadine Tablets.

Proprietary Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Terfemax¤; Australia: Teldane¤; Austria: Terlane¤; Triludan¤; Belgium: Triludan¤; Brazil: Fenasil¤; Histadane¤; Pridinol¤; Teldane¤; Canada: Allergy Relief¤; Contac Allergy Formula¤; Seldane¤; Czech Republic: Lotanax; Tergal; Teridin; Denmark: Teldanex¤; Tenadin¤; Terfin; Finland: Teldanex¤; France: Teldane¤; Germany: Balkis Spezial¤; Fomos¤; Heuschnupfen Systral¤; Hisfedin; Histaterfen¤; Logomed Allergie-Tabletten¤; Logomed Juckreiz¤; Teldane¤; Terfedura; Terfemundin; Terfen-Diolan¤; Terfium¤; Vividrin mit Terfenadin¤; Hong Kong: Fenason¤; Hisdane; Histafen; Tamagon; Teldane¤; Vida Fenadine; India: Trexyl¤; Ireland: Triludan¤; Israel: Apoterfin¤; Ternalin¤; Italy: Allerplus¤; Allerzil; Teldane¤; Triludan¤; Malaysia: Neutramine¤; Tamagon; Mexico: Teldane¤; Netherlands: Triludan¤; Norway: Teldanex¤; Portugal: Triludan; South Africa: Fendin; Terfenor¤; Triludan; Spain: Aldira¤; Alergist¤; Cyater; Rapidal; Ternadin; Triludan¤; Sweden: Teldanex¤; Terfex¤; Switzerland: Teldane¤; Triludan¤; Thailand: Centerfen¤; Fenason¤; Servinadine¤; Tamagon¤; Teranic¤; Terden¤; Terdine¤; Terfadine¤; Terfegen¤; Terfen¤; Trexyl¤; United Kingdom: Aller-Eze Clear¤; Antihistamine Forte¤; Boots Hayfever Relief Antihistamine¤; Histafen¤; Seldane¤; Terfenor Antihistamine¤; Terfex¤; Triludan¤; United States: Seldane¤; Venezuela: Terfanil; Tetram; Tirfen

Multi-ingredient Preparations

Argentina: Cortaler Novo¤; Cortistamin NF¤; Sinlergia¤; Terfenadina DG¤; Vixidone T¤; Austria: Teldafed¤; Belgium: Teldafen¤; Brazil: Teldafen¤; India: Alpha-Zedex¤; Teguphen¤; Tusant¤; Israel: Ternalin-D¤; Malaysia: Trexydin; Mexico: Teldane D¤; Portugal: Trilufen¤; United States: Seldane-D¤; Venezuela: Rinodrina; Rinotirfen

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Terfemax¤; Australia: Teldane¤; Austria: Terlane¤; Triludan¤; Belgium: Triludan¤; Brazil: Fenasil¤; Histadane¤; Pridinol¤; Teldane¤; Canada: Allergy Relief¤; Contac Allergy Formula¤; Seldane¤; Czech Republic: Lotanax; Tergal; Teridin; Denmark: Teldanex¤; Tenadin¤; Terfin; Finland: Teldanex¤; France: Teldane¤; Germany: Balkis Spezial¤; Fomos¤; Heuschnupfen Systral¤; Hisfedin; Histaterfen¤; Logomed Allergie-Tabletten¤; Logomed Juckreiz¤; Teldane¤; Terfedura; Terfemundin; Terfen-Diolan¤; Terfium¤; Vividrin mit Terfenadin¤; Hong Kong: Fenason¤; Hisdane; Histafen; Tamagon; Teldane¤; Vida Fenadine; India: Trexyl¤; Ireland: Triludan¤; Israel: Apoterfin¤; Ternalin¤; Italy: Allerplus¤; Allerzil; Teldane¤; Triludan¤; Malaysia: Neutramine¤; Tamagon; Mexico: Teldane¤; Netherlands: Triludan¤; Norway: Teldanex¤; Portugal: Triludan; South Africa: Fendin; Terfenor¤; Triludan; Spain: Aldira¤; Alergist¤; Cyater; Rapidal; Ternadin; Triludan¤; Sweden: Teldanex¤; Terfex¤; Switzerland: Teldane¤; Triludan¤; Thailand: Centerfen¤; Fenason¤; Servinadine¤; Tamagon¤; Teranic¤; Terden¤; Terdine¤; Terfadine¤; Terfegen¤; Terfen¤; Trexyl¤; United Kingdom: Aller-Eze Clear¤; Antihistamine Forte¤; Boots Hayfever Relief Antihistamine¤; Histafen¤; Seldane¤; Terfenor Antihistamine¤; Terfex¤; Triludan¤; United States: Seldane¤; Venezuela: Terfanil; Tetram; Tirfen;

Multi-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Cortaler Novo¤; Cortistamin NF¤; Sinlergia¤; Terfenadina DG¤; Vixidone T¤; Austria: Teldafed¤; Belgium: Teldafen¤; Brazil: Teldafen¤; India: Alpha-Zedex¤; Teguphen¤; Tusant¤; Israel: Ternalin-D¤; Malaysia: Trexydin; Mexico: Teldane D¤; Portugal: Trilufen¤; United States: Seldane-D¤; Venezuela: Rinodrina; Rinotirfen;

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