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At least 19 recordsLinked to original sources
PubMed1996

Grapefruit juice alters the systemic bioavailability and cardiac repolarization of terfenadine in poor metabolizers of terfenadine.

A prospective cohort study was conducted to examine the effects of double-strength grapefruit juice on the pharmacokinetics and electrocardiographic repolarization pharmacodynamics of terfenadine in poor metabolizers of terfenadine. Six healthy volunteers who were previously found to be poor metabolizers of terfenadine were studied, with each participant serving as his or her own control. In phase I of the study, terfenadine was given to participants at recommended dosages until steady state was achieved (60 mg twice daily for 7 days). In phase II, participants began receiving concomitant twice-daily, double-strength servings of grapefruit juice for 7 days. Serial pharmacokinetic and pharmacodynamic determinations were made after each phase of the study. The main outcome measures were serum concentrations of terfenadine and terfenadine acid metabolite, and corrected QT intervals as determined by 12-lead electrocardiogram. Significant changes occurred in time to maximum concentration (t(max)) and area under the concentration-time curve (AUC) of terfenadine and terfenadine acid metabolite after addition of grapefruit juice. All participants had detectable concentrations of unmetabolized terfenadine at the end of Phase I, which were quantified in three of the six participants. Further, all participants had increased and quantifiable levels of unmetabolized terfenadine after addition of grapefruit juice that were associated with prolongation of the QT interval relative to the baseline control period without terfenadine. Grapefruit juice did not alter the elimination half-life (t1/2) of terfenadine acid metabolite. Because of the intraindividual variability in the pharmacokinetics of terfenadine, further study is needed to confirm these results.

Adolescent↗
PubMed1995

Blockade of multiple human cardiac potassium currents by the antihistamine terfenadine: possible mechanism for terfenadine-associated cardiotoxicity.

Use of the antihistamine terfenadine has been associated with QT prolongation and torsade de pointes. One possible mechanism is blockade of cardiac potassium channels. We therefore characterized the effects of terfenadine on potassium currents recorded from isolated human cardiac myocytes. We demonstrated terfenadine block of the transient outward current and a novel, ultra-rapidly activating, delayed rectifier K+ current (IKur), which is very sensitive to 4-aminopyridine. IKur is probably produced by the protein product of Kv1.5a, a Shaker-like potassium channel cDNA cloned from human heart. We also compared terfenadine blockade of fHK (Kv1.5a) currents stably expressed in a human embryonic kidney cell line with terfenadine blockade of IKur in human atrial myocytes. Using the patch-clamp technique, we found that terfenadine produced a time-dependent reduction in Kv1.5a current that was consistent with blockade from the cytoplasmic side of the channel. The terfenadine-sensitive Kv1.5a current in human embryonic kidney cells was similar to the 4-aminopyridine-sensitive current in human atrial myocytes. In addition to blockade of the transient outward current and IKur, terfenadine at clinically relevant concentrations blocked both the rapidly and slowly activating components of the delayed rectifier in human atrial myocytes. Blockade of these K+ currents may contribute to the cardiotoxicity associated with terfenadine usage.

Atrial Function↗
PubMed1988

Lack of subsensitivity to terfenadine during long-term terfenadine treatment.

Eleven healthy male volunteers ingested terfenadine, 60 mg, every 12 hours for 56 days. Compliance was monitored strictly throughout the study. Before the first terfenadine dose on day 0, and 12 hours after the evening terfenadine dose every seventh day and on randomly selected "unscheduled" days, wheal-and-flare areas were measured after intradermal injections of 0.01 ml of histamine phosphate (1.0 mg/ml and 0.1 mg/ml). On days 0, 28, and 56, six volunteers had skin tests hourly for 12 hours after the morning terfenadine dose. On all study days, serum terfenadine metabolite I concentrations were measured each time histamine skin tests were performed. On days 7, 14, 21, 28, 35, 42, 49, and 56, the mean areas of the histamine-induced wheals did not differ significantly from each other but were significantly decreased compared to the mean wheal area on day 0 (p less than 0.01). On these days, the mean areas of the histamine-induced flares also did not differ significantly from each other but remained significantly suppressed compared to the mean flare areas on day 0 (p less than 0.01). Wheal-and-flare suppression was noted in all unscheduled histamine skin tests performed 12 hours after the evening terfenadine dose. In the subgroup of volunteers who had hourly tests, on day 0, the mean wheal-and-flare areas were significantly suppressed from 2 to 12 hours after the dose, with maximal wheal suppression occurring at 5 hours (p less than 0.05) and maximal flare suppression occurring from 3 to 9 hours (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Determination of terfenadine and terfenadine acid metabolite in plasma using solid-phase extraction and high-performance liquid chromatography with fluorescence detection.

This work describes the methodology for the analysis of terfenadine and the acid metabolite of terfenadine in plasma using high-performance liquid chromatography. The use of solid-phase extraction allows the use of robotic or manual sample preparation for the efficient clean-up of terfenadine and terfenadine acid metabolite from plasma. Additional selectivity is obtained through the use of fluorescence detection. For terfenadine, the validated quantitation range of this method is 10.0-84.2 ng/ml with coefficients of variation of 5.7-30%. For terfenadine acid metabolite, the validated quantitation range of this method is 8.2-500 ng/ml with coefficients of variation of 4.1-24%.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Comparison of terfenadine once daily with terfenadine twice daily for the treatment of perennial allergic rhinitis.

In a double-blind, parallel-group study to compare the efficacy of 120 mg terfenadine taken orally once daily with that of the conventional regimen of 60 mg terfenadine taken twice daily, 30 patients with perennial allergic rhinitis were enrolled. Groups of 15 patients were treated for 7 days with either 60 mg terfenadine twice daily, morning and evening, or 120 mg terfenadine once daily in the morning and placebo in the evening. The physician detected marked to total relief of symptoms (sneezing, rhinorrhoea, nasal pruritus and nasal obstruction) at similar rates (60% and 66%) in the two groups and patients in both groups reported a reduction in symptoms. The incidence of reported side-effects (sedation and mild headache) was low and not significantly different using either regimen. The results indicate that the new once-daily regimen of terfenadine was as effective and as well tolerated as the twice-daily regimen for the treatment of perennial allergic rhinitis.

Administration, Oral↗
PubMed1998

Comparative efficacy and safety of terfenadine with pseudoephedrine and terfenadine alone in allergic rhinitis.

A randomized, double-blind clinical trial was conducted on 41 adult patients to compare the efficacy and safety of the combination of terfenadine and pseudoephedrine with that of terfenadine alone. Efficacy of treatment evaluated by the physician and patients showed an excellent rating in 45.45% patients in the combination treatment group compared with an excellent rating in 10.53% in the single treatment group. The difference between both treatments was statistically significant, with a z value of 1.660 (p < 0.05). The combination of terfenadine and pseudoephedrine was found to result in faster relief in a greater number of patients than terfenadine alone. However, both drugs were well tolerated.

Adolescent↗
PubMed1991

Direct enantiomeric separation of terfenadine and its major acid metabolite by high-performance liquid chromatography, and the lack of stereoselective terfenadine enantiomer biotransformation in man.

Direct enantiomeric separation of terfenadine and its major acid metabolite was achieved by using two different chiral stationary phase columns with two different mobile phase systems. Further, the enantiomeric composition of the human urinary acid metabolite has been determined, indicating a non-stereoselective biotransformation in man.

Biotransformation↗
PubMed1989

Terfenadine once daily in chronic urticaria. A multi-centre double-blind comparison of terfenadine once daily versus twice daily.

The objective of these three double-blind multi-centre studies was to determine whether terfenadine 120 mg once daily has similar efficacy and tolerability as the standard dosage of 60 mg twice daily in the treatment of chronic urticaria. A total of 252 patients were randomly allocated to two parallel groups and treated for 2 weeks with either regimen. Evaluation of efficacy was based on rating scales for investigator and patient, i.e. itch, number of wheals, wheal size and an overall rating of efficacy. A similar improvement was seen in all variables, and there were no statistically significant differences between treatment groups. The power of the studies combined is greater than 80%, i.e. sufficient to state convincingly that treatment effects are not different. Both treatments were also equally well tolerated.

Adult↗
PubMed1995

Metabolism of terfenadine associated with CYP3A(4) activity in human hepatic microsomes.

Terfenadine (Seldane) undergoes extensive metabolism to form azacyclonol and terfenadine alcohol. Terfenadine alcohol is subsequently metabolized to azacyclonol and terfenadine acid. Although testosterone 6 beta-hydroxylation [CYP3A(4)] has been shown to be the principal enzyme involved in the first step in terfenadine's biotransformation (formation of azacyclonol and terfenadine alcohol), the enzymes catalyzing the subsequent metabolic steps in the conversion of terfenadine alcohol to azacyclonol and terfenadine acid have not been identified. The purpose of these studies was to determine the role of cytochrome P450 isoforms in the biotransformation of terfenadine and terfenadine alcohol. To this end, both terfenadine and its alcohol were incubated with 10 individual human liver microsomal samples that have been characterized for major isozyme activities. The metabolites and parent drugs were quantified by HPLC. The formation of azacyclonol and terfenadine alcohol from terfenadine is confirmed to be catalyzed predominantly by CYP3A(4) isozyme, and the ratio of the rate of terfenadine alcohol formation to that of azacyclonol is 3:1. Involvement of the CYP3A(4) in terfenadine metabolism was further confirmed by the following studies: a) inhibition of terfenadine alcohol formation by ketoconazole and troleandomycin, two specific inhibitors of CYP3A(4), and b) time course of terfenadine alcohol formation by cloned human CYP3A(4). When terfenadine alcohol was used as substrate, both the terfenadine acid and azacyclonol formation were also catalyzed by CYP3A(4) isozyme. However, the rate of formation of the terfenadine acid metabolite is almost 9 times faster than that of azacyclonol. The net ratio of terfenadine acid to azacyclonol is 2:1.

Alcohols↗
PubMed1996

Safe coadministration of terbinafine and terfenadine: a placebo-controlled crossover study of pharmacokinetic and pharmacodynamic interactions in healthy volunteers.

The pharmacokinetic and pharmacodynamic interactions of terbinafine (Lamisil) and terfenadine (Seldane) were assessed in 26 healthy volunteers randomized to receive either terbinafine (250 mg tablet) or its placebo (terbinafine placebo), which were administered in a double-blind manner once daily for 18 days. On days 12 through 18, terfenadine was coadministered (60 mg twice daily, unblinded). Pharmacokinetic profiles were obtained for terbinafine and its desmethyl metabolite on day 11 (in the absence of terfenadine), day 12, and day 18. Terfenadine and terfenadine acid metabolite levels were also assayed on days 12 and 18. After a 4-week washout period, subjects were crossed over to the alternate treatment (terbinafine or terbinafine placebo). Pharmacodynamic measures were electrocardiographic (ECG) rhythm abnormalities, corrected QT interval (QTc), and plasma ALT levels. Terfenadine levels were evaluated; however, only eight of 1502 samples assayed were above the limit of quantitation. No effect of terbinafine administration on pharmacokinetic parameters for the terfenadine acid metabolite was observed, except for a decrease of approximately 20% in through terbinafine concentrations (C0hr; p < 0.05) on the last day of terfenadine plus terbinafine coadministration. Pharmacokinetic parameters for terbinafine were unchanged on the first day of terfenadine coadministration, and only small increases in area under the plasma concentration versus time curve from 0 to 24 hours and peak plasma concentrations (16.1%[p < 0.01] and 6.63% [p < 0.05]) were observed on the last day of terfenadine and terbinafine coadministration. Values for C0hr were also about 20% to 25% higher (p < 0.05). Steady-state levels of the terfenadine acid metabolite were achieved after 2 days of terfenadine coadministration, and steady-state levels of terbinafine and its desmethyl metabolite were achieved after 14 days of terbinafine administration. The incidence of ECG rhythm abnormalities was not significantly higher in any treatment group; however, the incidence of prolongation of QTc > 10% above baseline was significantly higher in the groups treated with terfenadine. No QTc prolongation occurred in the absence of terfenadine treatment. Both terbinafine and terfenadine were well tolerated when coadministered during this study, as indicated by the low incidence of complaints, abnormalities, and adverse events. The results of this study indicate that terbinafine and terfenadine can be safely coadministered.

Adult↗
PubMed1997

Assessment of the potential for a pharmacokinetic interaction between fluoxetine and terfenadine.

OBJECTIVE: To assess whether fluoxetine and its metabolite, norfluoxetine, are inhibitors of the metabolism of CYP3A substrates. BACKGROUND: Because inhibition of the first-pass metabolism of terfenadine may be associated with fatal arrhythmia, we assessed the possibility that fluoxetine inhibits this metabolism as a model for CYP3A drug interactions. METHODS: Male subjects (n = 12) were given two single doses of 60 mg terfenadine alone (treatment 1) and again after the eighth dose in a 9-day regimen of 60 mg fluoxetine once a day (treatment 2). Blood samples, collected up to 48 hours after each terfenadine dose, were assayed for terfenadine and terfenadine acid metabolite. The assay limits of quantification were 0.1 ng/ml and 5.0 ng/ml, respectively. Noncompartmental pharmacokinetic data for terfenadine and terfenadine acid metabolite were compared between treatments. RESULTS: Mean value +/- SD plasma concentrations of fluoxetine (165 +/- 45 ng/ml) and norfluoxetine (83 +/- 23 ng/ml) achieved after the eighth dose did not cause a significant change in terfenadine acid metabolite pharmacokinetics. All terfenadine concentrations were less than 5 ng/ml and they were approximately 30% lower after fluoxetine pretreatment compared with terfenadine alone. The area under the concentration-time curve for terfenadine was lower after fluoxetine administration, a statistically significant difference, but the peak concentration of terfenadine was not significantly different. Because most antihistaminic activity after terfenadine administration is attributed to its acid metabolite, the small decrease in terfenadine concentration is not clinically significant. No subject discontinued the drugs because of an adverse event. CONCLUSION: Fluoxetine did not inhibit the metabolism of terfenadine and is unlikely to affect the metabolism of terfenadine or other drugs that are CYP3A substrates.

Area Under Curve↗
PubMed1996

Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram.

OBJECTIVES: To establish whether the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine are affected by concomitant administration of grapefruit juice and to determine whether any effect of grapefruit juice is dependent on the timing of administration in relation to the dose of terfenadine. METHODS: Twelve healthy volunteers were studied in a prospective randomized trial. The primary end points were QT prolongation on the surface electrocardiogram and the pharmacokinetic parameters: area under the concentration-time curve (AUC), maximum concentration, and time to maximum concentration of terfenadine and its acid metabolite terfenadine carboxylate. All subjects received 60 mg terfenadine twice a day with 240 ml water for 7 days. They were then randomized to drink 240 ml of double-strength grapefruit juice simultaneously with terfenadine (simultaneous group) for an additional 7 days or to drink the same dose of grapefruit juice 2 hours after terfenadine for 7 days (delayed group). Twelve timed electrocardiograms and plasma terfenadine and metabolite levels were measured on days 7 and 14. RESULTS: None of the 12 subjects had quantifiable levels of terfenadine when the drug was administered with water. All six subjects who took terfenadine and drank grapefruit juice simultaneously had quantifiable terfenadine levels. Only two of six who drank grapefruit juice 2 hours after terfenadine had quantifiable levels. The AUC of the acid metabolite increased 55% (p < 0.05) in the simultaneous group and 22% (p = NS) in the delayed group. The mean QT interval increased from 420 to 434 msec (p < 0.05) in the simultaneous group and decreased from 408 to 407 msec (p = NS) in the delayed group. CONCLUSIONS: Administration of grapefruit juice concomitantly with terfenadine may lead to an increase in systemic terfenadine bioavailability and result in increases in QT interval. The clinical significance of an increase in QT interval of this magnitude is unclear.

Adult↗
PubMed1997

Grapefruit juice-terfenadine single-dose interaction: magnitude, mechanism, and relevance.

OBJECTIVE: To investigate the single dose-response effects of grapefruit juice on terfenadine disposition and electrocardiographic measurements. METHODS: Twelve healthy males received 250 ml water or regular- or double-strength grapefruit juice with 60 mg terfenadine in a randomized crossover trial. Plasma concentrations of the cardiotoxic agent terfenadine and the active antihistaminic metabolite terfenadine carboxylate were determined over 8 hours. The QTc interval was monitored. RESULTS: Terfenadine concentrations were measurable (> 1 ng/ml) in 27 (20%; p < 0.001) and 39 (30%; p < 0.001) samples from individuals treated with regular- and double-strength grapefruit juice, respectively, compared to only four (3%) samples with water. Terfenadine plasma peak drug concentration (Cmax) was also higher. Terfenadine carboxylate area under the plasma drug concentration-time curve (AUC), Cmax, and time to reach Cmax (tmax) were increased by both strengths of juice. However, terfenadine carboxylate apparent elimination half-life (t1/2) was not altered. The magnitude of the interaction of terfenadine carboxylate AUC and Cmax ranged severalfold and correlated among individuals for regular-strength (r2 = 0.87; p < 0.0001) and double-strength (r2 = 0.78; p < 0.0001) grapefruit juice. No differences in the pharmacokinetics of terfenadine and terfenadine carboxylate were observed between the two strengths of grapefruit juice. QTc interval was not altered. CONCLUSIONS: A normal amount of regular-strength grapefruit juice produced maximum single-dose effects on terfenadine and carboxylic acid metabolite pharmacokinetics. The mechanism likely involved reduced presystemic drug elimination by inhibition of more than one metabolic pathway. The extent of the interaction was not sufficient to produce electrocardiographic changes. However, the pharmacokinetic effects were highly variable among individuals. This study further enhances the awareness of the potential for a serious interaction between grapefruit juice and terfenadine.

Adult↗
PubMed1996

Cardiotoxic and drug interaction profile of the second generation antihistamines ebastine and terfenadine in an experimental animal model of torsade de pointes.

Second generation antihistamines are widely used because of their efficacy in treating allergic disorders without significant sedative side effects. Recent clinical evidence shows that some of the early prototypes in this class, namely terfenadine and astemizole, have the potential for producing torsade de pointes, a rare form of ventricular arrhythmia that is life-threatening. Important questions have been raised as to whether this is a property shared by newer, recently-introduced second generation antihistamines. The objective of this study was to characterize and compare the ECG and cardiovascular effects of terfenadine (CAS 50679-08-8) and ebastine (CAS 90729-43-4), a new second generation antihistamine, in an experimental animal model predictive of the cardiotoxic proclivity of these agents. Also, the drug interaction effect of the antifungal drug ketoconazole (CAS 65277-42-1) was evaluated, which blocks hepatic first-pass biotransformation of ebastine and terfenadine leading to increased cardiotoxity of terfenadine in man, on the ECG effects of terfenadine and ebastine in this animal model. Terfenadine (10 mg/kg) and ebastine (50 mg/kg) were administered intravenously to anesthetized guinea pigs. Electrocardiographic (ECG) and cardiovascular parameters (blood pressure and heart rate) were measured during the course of the experiment. The ECG wave form was analyzed to determine QTc interval, PR interval, QRS interval and heart rate. In separate studies in conscious guinea pigs, the effect of oral ketoconazole (200 mg) on the ECG effects of oral terfenadine (60 mg) and ebastine (10 mg) was studied. Terfenadine (10 mg/kg) and ebastine (50 mg/kg) produced significant prolongation of the QTc interval and disruption of the ECG signal when given intravenously to anesthetized guinea pigs. The ECG effects were characterized by large amplitude, morphologically aberrant T-waves, and instances of arrhythmogenic activity. Both drugs produced pronounced bradycardia and hypotension. In conscious animals, pretreatment with oral ketoconazole significantly enhanced the QTc interval prolongation effects of terfenadine and ebastine. Oral terfenadine and ebastine, when given alone at the doses tested, were devoid of adverse QTc interval prolongation effects in the conscious guinea pig. In separate studies in conscious guinea pigs, oral loratadine (10 mg; CAS 79794-75-5) given alone or in animals pretreated with ketoconazole did not affect ECG parameters. The present studies show that terfenadine and ebastine share similar cardiotoxic properties characterized by QTc interval prolongation, bradycardia, hypotension and proarrhythmogenic activity in the anesthetized guinea pig. In addition, pretreatment with ketoconazole enhances the QTc interval effect of both drugs, most likely due to the accumulation of parent compound that occurs after blockade of hepatic metabolism by CYP3A4. In conclusion, our findings indicate that ebastine and terfenadine display similarities in their inherent potential for cardiotoxic and adverse drug interaction effects. In contrast, loratadine is devoid of adverse ECG and drug interaction effects.

Animals↗
PubMed1998

Blockage by terfenadine of the adenosine triphosphate (ATP)-sensitive K+ current in rabbit ventricular myocytes.

We examined the blocking effects of terfenadine, an antihistaminic agent, on the ATP-sensitive K+ current (IK,ATP) in rabbit ventricular cells. IK,ATP was induced by cromakalim or NaCN. Terfenadine blocked the IK,ATP with an IC50 of 1.7 microM at -10 mV. This blockage was voltage dependent; depolarization induced a stronger blockage. According to the transmembrane electrical field model, terfenadine interacts with the site located 15 to 18% from the cytoplasmic membrane surface. In line with the assumption that the binding site is near the cytoplasmic surface, terfenadine applied to the cytoplasmic solution potently inhibited the single-channel activity for IK,ATP in the inside-out configuration (IC50 0.19 microM). In contrast, terfenadine applied to the external solution did not affect the channel activity in the cell-attached configuration, but inhibited it when applied into the pipette. The inhibition of the single channels by terfenadine was accompanied by flickering of the channels. These findings suggest that 1) terfenadine blocks the ATP-sensitive K+ channel in the open state, 2) the binding site is near the internal membrane surface and 3) terfenadine is poorly diffusible into the lipid biomembrane and accesses the binding site via the hydrophilic pathway. Terfenadine also inhibited the transient outward K+ current, inward rectifier K+ current and E4031-sensitive rectifier K+ current. However, the inhibition of these repolarization currents by terfenadine at 1 microM was not sufficient to prolong the action potential duration significantly. Whereas, terfenadine (1 microM) prolonged the action potential duration which had been shortened by cromakalim. Terfenadine may modify the ischemia-induced arrhythmias by blocking IK,ATP.

Action Potentials↗
PubMed1993

Effect of concomitant administration of cimetidine and ranitidine on the pharmacokinetics and electrocardiographic effects of terfenadine.

Terfenadine is a widely prescribed non-sedating antihistamine which undergoes rapid and almost complete first pass biotransformation to an active carboxylic acid metabolite. It is unusual to find unmetabolised terfenadine in the plasma of patients taking the drug. Terfenadine in vitro is a potent blocker of the myocardial potassium channel. Overdose, hepatic compromise and the coadministration of ketoconazole and erythromycin result in the accumulation of terfenadine, which is thought to be responsible of QT prolongation and Torsades de Pointes ventricular arrhythmia in susceptible individuals. Cimetidine and ranitidine are two popular H2 antagonists which are often taken with terfenadine. The effects of cimetidine and ranitidine on terfenadine metabolism were studied in two cohorts of 6 normal volunteers given the recommended dose of terfenadine (60 mg every 12 h) for 1 week prior to initiation of cimetidine 600 mg every 12 h or ranitidine 150 mg every 12 h. Pharmacokinetic profiles and morning pre-dose electrocardiograms were obtained whilst the patients were on terfenadine alone and after the addition of cimetidine or rantidine. One of the subjects in each cohort had a detectable plasma level of parent compound after 1 week of terfenadine therapy alone; it did not accumulate further after addition of the H2 antagonist. The pharmacokinetics of the carboxylic acid metabolite of terfenadine (Cmax, tmax, AUC) were not significantly changed after co-administration of either H2 antagonist. None of the remaining 5 subjects in either cohort demonstrated accumulation of unmetabolised terfenadine after addition of the respective H2 antagonist and electrocardiographic QT intervals and T-U morphology in them was not changed during the course of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1999

Pregnancy outcome after gestational exposure to terfenadine: A multicenter, prospective controlled study.

BACKGROUND: Terfenadine is a selective, nonsedative, H(1)-blocker antihistamine used for a variety of allergic conditions. The widespread popularity of terfenadine and its use by many women in their reproductive age raises concerns regarding its safety during pregnancy. Presently, no prospective controlled study has addressed its safety during gestation. OBJECTIVE: We sought to determine whether terfenadine use during pregnancy is associated with an increased risk of major malformations, decreased birth weight, perinatal complications, or developmental delays. METHODS: A multicenter, prospective controlled study was performed. Pregnant women exposed to terfenadine during gestation were matched with control subjects exposed to drugs not known to adversely affect pregnancy outcome. The primary end point was the incidence of major malformations. Secondary outcomes of interest were pregnancy outcome, rates of preterm delivery, birth weight, and developmental milestones. RESULTS: One hundred eighteen women were exposed to terfenadine during pregnancy. Among those exposed during the first trimester (n = 65), rates of major malformations in the terfenadine group did not differ from rates in their matched control subjects (0% vs 2%; relative risk, 0.57; 95% confidence interval, 0.06-5.39; P =.53). The birth weight in the terfenadine-exposed newborns was significantly lower compared with that in their matched control subjects (3335 +/- 582 vs 3499 +/- 617 g; P =.04). However, the rates of birth weight below 2500 g and birth weight below the 10th percentile for gestational age were not different between the groups. Univariate and multiple regression analysis revealed that none of the terfenadine therapy-related factors (daily dose, duration of therapy, and trimester of exposure) had a significant predictive effect on birth weight. Gestational age at delivery, rates of preterm deliveries, and developmental milestones were comparable between the groups. CONCLUSIONS: On the basis of the limited sample size of this study, it appears that terfenadine is not associated with a 6-fold or greater increased incidence of major malformations. Terfenadine use during gestation was not associated with increased rates of prematurity or developmental delays. Further studies will be needed to confirm the finding of lower birth weight in newborns exposed to terfenadine.

Adult↗
PubMedDate not supplied

Ipratropium bromide nasal spray 0.03% provides additional relief from rhinorrhea when combined with terfenadine in perennial rhinitis patients; a randomized, double-blind, active-controlled trial.

Medical treatment of perennial rhinitis is aimed at providing symptomatic relief of individual symptoms. Multiple agents are administered when no single agent provides complete relief. Studies assessing the benefit/risk of combined therapy are important, especially for newly available agents such as ipratropium bromide nasal spray, a topical anticholinergic agent approved for the treatment of rhinorrhea in allergic and nonallergic perennial rhinitis. The objective was to determine whether the combined use of ipratropium bromide nasal spray 0.03% (42 mcg per nostril) administered three times daily with a nonsedating antihistamine (terfenadine, 60 mg administered twice daily) is safe and provides greater clinical benefit than use of the placebo nasal spray plus terfenadine. Our method was a multicenter, 6-week, double-blind, randomized, active-controlled, crossover trial of 205 patients with perennial rhinitis (114 allergic and 91 nonallergic), 18 to 75 years of age, who had clinically significant rhinorrhea. After a 1-week run-in period, patients were treated for 2 weeks with one of the two treatment regimens, followed by a 1-week washout period, and then were treated for another 2 weeks with the other treatment regimen. Daily diary symptoms scores of rhinorrhea, congestion, and sneezing were obtained, as well as biweekly patient and physician global assessments of treatment effectiveness of each of the nasal symptoms. Ipratropium bromide nasal spray plus terfenadine was more effective than vehicle plus terfenadine in reducing the average severity (38% versus 28%) and duration (46% versus 30%) of rhinorrhea during the 2 weeks of treatment from baseline (p < 0.05). The advantage of ipratropium bromide nasal spray plus terfenadine was evident by the second day of treatment and continued throughout the 2-week treatment period. Of patients who responded more to one treatment than another, 69% responded to ipratropium bromide nasal spray plus terfenadine, compared to 31% to vehicle plus terfenadine (p < 0.05). Both physicians and patients rated control of rhinorrhea and sneezing by ipratropium bromide nasal spray plus terfenadine as superior to vehicle plus terfenadine (p < 0.05). The symptom of congestion was controlled equally well by both treatments. Combined active therapy was well tolerated with no increase in adverse events over that seen previously with ipratropium bromide nasal spray alone. The combination of ipratropium bromide nasal spray with terfenadine is more effective than vehicle plus terfenadine for the treatment of rhinorrhea, and does not result in a potentiation of adverse drug reactions.

Administration, Intranasal↗