Terfenadine

(BAN, USAN, rINN)
Terfenadine Chemical formula
Synonyms: MDL-9918; RMI-9918; Terfenadiini; Terfenadin; Terfenadina; Terfenadinas; Terfénadine; Terfenadinum. 1-(4tert-Butylphenyl)-4[4-(
Cyrillic synonym: Терфенадин.

💊 Chemical information

Chemical formula: C32H41NO2 = 471.7.
CAS — 50679-08-8.
ATC — R06AX12.
ATC Vet — QR06AX12.

Pharmacopoeias.

In Eur..

Ph. Eur. 6.2

(Terfenadine). A white or almost white, crystalline powder. It shows polymorphism. Very slightly soluble in water and in dilute hydrochloric acid; freely soluble in dichloromethane; soluble in methyl alcohol. Protect from light.

💊 Adverse Effects and Precautions

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 contra-indicated (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 If palpitations, dizziness, syncope, or convulsions occur terfenadine should be withdrawn and the patient investigated for potential arrhythmias.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.1 Regrowth occurred when treatment was stopped.
1. Jones SK, Morley WN. Terfenadine causing hair loss. BMJ 1985; 291: 940.

Arrhythmias.

Ventricular arrhythmias including torsade de pointes have occurred with terfenadine at doses greater than those recommended1 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.2 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.3,4 Terfenadine should be stopped immediately, and the patient evaluated for potential arrhythmias, in those who experience syncope, palpitations, dizziness, or convulsions after taking terfenadine. Studies5 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 effect5,6.
1. MacConnell TJ, Stanners AJ. Torsades de pointes complicating treatment with terfenadine. BMJ 1991; 302: 1469
2. Davies AJ, et al. Cardiotoxic effect with convulsions in terfenadine overdose. BMJ 1989; 298: 325
3. CSM. Ventricular arrhythmias due to terfenadine and astemizole. Current Problems 35 1992. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2024453&RevisionSelectionMethod= LatestReleased (accessed 14/07/08
4. CSM/MCA. Drug-induced prolongation of the QT interval. Current Problems 1996; 22: 2. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2024458&RevisionSelectionMethod= LatestReleased (accessed 14/07/08
5. Woolsey RL, et al. Mechanism of the cardiotoxic actions of terfenadine. JAMA 1993; 269: 1532–6
6. Rankin AC. Non-sedating antihistamines and cardiac arrhythmia. Lancet 1997; 350: 1115–16.

Breast feeding.

No adverse effects have been observed in breast-fed infants whose mothers were receiving terfenadine, and the American Academy of Pediatrics1 considers that it is therefore usually compatible with breast feeding. In a study2 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.
1. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. Correction. ibid.; 1029. Also available at: http://aappolicy.aappublications.org/cgi/content/full/ pediatrics%3b108/3/776 (accessed 08/04/04
2. Lucas BD, et al. Terfenadine pharmacokinetics in breast milk in lactating women. Clin Pharmacol Ther 1995; 57: 398–402.

Effects on the liver.

Three episodes of acute hepatitis with jaundice occurred in a patient taking terfenadine intermittently over a period of 17 months.1 Liver function tests returned to normal after the drug was stopped. Two further cases2 of cholestatic hepatitis associated with terfenadine have been reported. Again, liver function tests returned to normal after drug withdrawal. A study3 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.
1. Larrey D, et al. Terfenadine and hepatitis. Ann Intern Med 1985; 103: 634
2. Sahai A, Villeneuve JP. Terfenadine-induced cholestatic hepatitis. Lancet 1996; 348: 552–3
3. Myers MW, Jick H. Terfenadine and risk of acute liver disease. Br J Clin Pharmacol 1998; 46: 251–3.

Effects on the nervous system.

Non-sedating effects on the CNS have been reported after a single dose of terfenadine;1 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.2 Workers who had described a generalised tonic-clonic seizure in a patient taking terfenadine3 later reported that the patient had subsequently had a second unprovoked seizure4 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).
1. Napke E, Biron P. Nervous reactions after first dose of terfenadine in adults. Lancet 1989; ii: 615–16
2. Masheter HC. Nervous reactions to terfenadine. Lancet 1989; ii: 1034
3. Tidswell P, d’Assis-Fonseca A. Generalised seizure due to terfenadine. BMJ 1993; 307: 241
4. Tidswell P, d’Assis-Fonseca A. Generalised seizure due to terfenadine. BMJ 1993; 307: 736.

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.1
1. Stricker BHCh, et al. Skin reactions to terfenadine. BMJ 1986; 293: 536.

Porphyria.

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

💊 Interactions

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 HIVprotease 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.
1. Kivistö KT, et al. Inhibition of terfenadine metabolism: pharmacokinetic and pharmacodynamic consequences. Clin Pharmacokinet 1994; 27: 1–5.

Antibacterials.

Pharmacokinetic studies have shown that the macrolide antibiotics erythromycin1 and clarithromycin2 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 erythromycin3 or troleandomycin.4
1. Honig PK, et al. Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther 1992; 52: 231–8
2. Honig P, et al. Effect of erythromycin, clarithromycin and azithromycin on the pharmacokinetics of terfenadine. Clin Pharmacol Ther 1993; 53: 161
3. Biglin KE, et al. Drug-induced torsades de pointes: a possible interaction of terfenadine and erythromycin. Ann Pharmacother 1994; 28: 282
4. Fournier P, et al. Une nouvelle cause de torsades de pointes: association terfenadine et troleandomycine. Ann Cardiol Angeiol (Paris) 1993; 42: 249–52.

Antidepressants.

Cardiac abnormalities have been reported in 2 patients taking fluoxetine with terfenadine.1,2 Similarly, the use of nefazodone with terfenadine has resulted in prolongation of the QT interval.3
1. Swims MP. Potential terfenadine-fluoxetine interaction. Ann Pharmacother 1993; 27: 1404–5
2. Marchiando RJ, Cook MD. Probable terfenadine-fluoxetine-associated cardiac toxicity. Ann Pharmacother 1995; 29: 937–8
3. Abernethy DR, et al. Loratadine and terfenadine interaction with nefazodone: both antihistamines are associated with QTc prolongation. Clin Pharmacol Ther 2001; 69: 96–103.

Antiepileptics.

For reference to an interaction between terfenadine and carbamazepine.

Antifungals.

Pharmacokinetic studies have shown that itraconazole1 and ketoconazole2 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 ketoconazole3 or itraconazole.1,4 While there has been a pharmacokinetic study5that 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.6
1. Pohjola-Sintonen S, et al. Itraconazole prevents terfenadine metabolism and increases risk of torsades de pointes ventricular tachycardia. Eur J Clin Pharmacol 1993; 45: 191–3
2. Honig PK, et al. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences. JAMA 1993; 269: 1513–18
3. Monahan BP, et al. Torsades de pointes occurring in association with terfenadine use. JAMA 1990; 264: 2788–90
4. Crane JK, et al. Syncope and cardiac arrhythmia due to an interaction between itraconazole and terfenadine. Am J Med 1993; 95: 445–6
5. Honig PK, et al. The effect of fluconazole on the steady-state pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine in humans. Clin Pharmacol Ther 1993; 53: 630–6
6. Cantilena LR, et al. Fluconazole alters terfenadine pharmacokinetics and electrocardiographic pharmacodynamics. Clin Pharmacol Ther 1995; 57: 185.

Calcium-channel blockers.

For reference to an interaction between terfenadine and nifedipine.

Grapefruit juice.

A study1 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 of terfenadine and grapefruit juice.2 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.
1. Benton RE, et al. Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram. Clin Pharmacol Ther 1996; 59: 383–8
2. Rau SE, et al. Grapefruit juice-terfenadine single-dose interaction: magnitude, mechanism, and relevance. Clin Pharmacol Ther 1997; 61: 401–9.

💊 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% of terfenadine 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.
1. Eller MG, et al. Pharmacokinetics of terfenadine in healthy elderly subjects. J Clin Pharmacol 1992; 32: 267–71.

💊 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 rhinitis and conjunctivitis and skin disorders such as urticaria. The maximum oral dose of terfenadine 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

BP 2008: Terfenadine Oral Suspension; Terfenadine Tablets.

Proprietary Preparations

Arg.: Te r f e m ax † ; Cz.: Lotanax†; Tergal†; Teridin†; Denm.: Teldanex†; Tenadin†; Terfin†; Ger.: Hisfedin†; Terfedura†; Terfemundin†; Hong Kong: Fenason†; Hisdane†; Histafen; Tamagon; Vida Fenadine†; India: Trexyl†; Indon.: Alpenaso; Histastop; Terfin; Ital.: Allerzil†; Malaysia: Neutramine†; Tamagon†; Mex.: Te l d a n e † ; Norw.: Teldanex†; Port.: Triludan†; S.Afr.: Fendin; Triludan†; Spain: Cyater; Rapidal†; Ternadin; Swed.: Teldanex†; Turk.: Teradin; Venez.: Terfanil†; Tetram†; Tirfen†. Multi-ingredient: Arg.: Cortaler Novo†; Cortistamin NF†; Sinlergia†; Terfenadina DG†; Vixidone T†; India: Alpha-Zedex†; Teguphen†; Tusant†; Indon.: Rhinofed; Malaysia: Trexydin†; Mex.: Teldane D†; Venez.: Rinodrina†; Rinotirfen†.
Published January 11, 2019.