Telfast/Telfast Oral Suspension

Fexofenadine hydrochloride.

Fexofenadine HCl is an equimolar mixture of 2 enantiomers. It is freely soluble in methanol, soluble in ethanol, slightly soluble in water (3.6 mg/mL), and only very slightly soluble in chloroform and hexane.
Fexofenadine is a carboxylic acid metabolite of terfenadine. It is orally active non-sedating histamine H₁-receptor antagonist that is administered as the hydrochloride salt in Telfast. The chemical name is benzeneacetic acid, 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethyl-,hydrochloride. Its molecular formula is C₃₂H₃₉NO₄·HCl and the molecular weight is 538.13.
Film-coated tablet: Each tablet contains 120 mg of fexofenadine hydrochloride, which is equivalent to 112 mg of fexofenadine.
Each tablet contains 180 mg of fexofenadine hydrochloride, which is equivalent to 168 mg of fexofenadine.
Excipients/Inactive Ingredients: Tablet core: Microcrystalline Cellulose, Pregelatinised Starch, Croscarmellose Sodium, Magnesium Stearate.
Film coat: Hypromellose, Povidone, Titanium Dioxide (E171), Colloidal Anhydrous Silica, Macrogol 400, Pink Iron oxide blend (120 mg only), Yellow Iron oxide blend (120 mg only), Iron oxide blend (180 mg only).
Oral suspension: Excipients/Inactive Ingredients: Telfast Pediatric Suspension also contains the following excipients: Propylene glycol, edentate disodium, propyl hydroxybenzoate, butyl hydroxybenzoate, xanthan gum, poloxamer 407, titanium dioxide, monobasic sodium phosphate monohydrate, dibasic sodium phosphate heptahydrate, artificial raspberry cream flavour (ARTG PI No. 12546), sucrose, xylitol and purified water.

Pharmacotherapeutic group: Antihistamines for systemic use. ATC code: R06A X26.
Film-coated tablet: Pharmacology: Pharmacodynamics: Mechanism of action: Fexofenadine hydrochloride is a non-sedating H₁ antihistamine. Fexofenadine is a pharmacologically active metabolite of terfenadine.
Clinical efficacy and safety: Human histamine wheal and flare studies following single and twice daily doses of fexofenadine hydrochloride demonstrate that the medicinal product exhibits an antihistaminic effect beginning within one hour, achieving maximum at 6 hours and lasting 24 hours. There was no evidence of tolerance to these effects after 28 days of dosing. A positive dose-response relationship between doses of 10 mg to 130 mg taken orally was found to exist. In this model of antihistaminic activity, it was found that doses of at least 130 mg were required to achieve a consistent effect that was maintained over a 24-hour period. Maximum inhibition in skin wheal and flare areas were greater than 80%. Clinical studies conducted in seasonal allergic rhinitis have shown that a dose of 120 mg is sufficient for 24-hour efficacy.
No significant differences in QTc intervals were observed in seasonal allergic rhinitis patients given fexofenadine hydrochloride up to 240 mg twice daily for 2 weeks when compared to placebo. Also, no significant change in QTc intervals was observed in healthy subjects given fexofenadine hydrochloride up to 60 mg twice daily for 6 months, 400 mg twice daily for 6.5 days and 240 mg once daily for 1 year, when compared to placebo. Fexofenadine at concentrations 32 times greater than the therapeutic concentration in man had no effect on the delayed rectifier K+ channel cloned from human heart.
Fexofenadine hydrochloride (5-10 mg/kg po) inhibited antigen-induced bronchospasm in sensitised guinea pigs and inhibited histamine release at supratherapeutic concentrations (10-100 μM) from peritoneal mast cells.
Pharmacokinetics: Absorption: Fexofenadine hydrochloride is rapidly absorbed into the body following oral administration, with T_max occurring at approximately 1-3 hours post-dose. The mean C_max value was approximately 427 ng/ml and 494 ng/ml following the administration of a 120 mg dose once daily and a 180 mg dose once daily, respectively.
Distribution: Fexofenadine is 60-70% plasma protein bound.
Biotransformation and elimination: Fexofenadine undergoes negligible metabolism (hepatic or non-hepatic), as it was the only major compound identified in urine and faeces of animals and man. The plasma concentration profiles of fexofenadine follow a bi-exponential decline with a terminal elimination half-life ranging from 11 to 15 hours after multiple dosing. The single and multiple dose pharmacokinetics of fexofenadine are linear for oral doses up to 120 mg BID. A dose of 240 mg BID produced slightly greater than proportional increase (8.8%) in steady-state area under the curve, indicating that fexofenadine pharmacokinetics are practically linear at these doses between 40 mg and 240 mg taken daily. The major route of elimination is believed to be via biliary excretion while up to 10% of ingested dose is excreted unchanged through the urine.
Toxicology: Preclinical safety data: Dogs tolerated 450 mg/kg administered twice daily for 6 months and showed no toxicity other than occasional emesis. Also, in single dose dog and rodent studies, no treatment-related gross findings were observed following necropsy.
Radiolabelled fexofenadine hydrochloride in tissue distribution studies of the rat indicated that fexofenadine did not cross the blood-brain barrier.
Fexofenadine hydrochloride was found to be non-mutagenic in various in vitro and in vivo mutagenicity tests.
The carcinogenic potential of fexofenadine hydrochloride was assessed using terfenadine studies with supporting pharmacokinetic studies showing fexofenadine hydrochloride exposure (via plasma AUC values). No evidence of carcinogenicity was observed in rats and mice given terfenadine (up to 150 mg/kg/day).
In a reproductive toxicity study in mice, fexofenadine hydrochloride did not impair fertility, was not teratogenic, and did not impair pre- or postnatal development.
Oral suspension: Pharmacology: The antihistaminic effects of fexofenadine have been demonstrated in the animal systems in vitro and in vivo. Oral administration of fexofenadine to guinea pigs indicated that fexofenadine antagonized histamine-induced skin wheals in a dose-dependent manner. Fexofenadine and terfenadine antagonized the contractile effects of histamine in the guinea pig ileum in vitro. In this model, fexofenadine was found to be a more selective histamine antagonist than terfenadine.
Fexofenadine inhibited antigen-induced bronchospasm in sensitised guinea pigs and, at high doses (>100-fold higher than those required for antihistaminic activity), inhibited histamine release from peritoneal mast cells of the rat. In laboratory animals, no anticholinergic or α1-adrenergic receptor blocking effects were observed. Radiolabelled tissue distribution studies in rat indicated that fexofenadine does not cross the blood-brain barrier.
Fexofenadine is not associated with significant ECG abnormalities. Studies have shown that fexofenadine does not affect the action potential or ion channel currents (I_K, I_Ca, I_Na) in either guinea pig or neonatal rat myocytes. Fexofenadine was 583 times less potent than terfenadine in blocking a delayed rectifier potassium channel cloned from human heart. Additionally, doses of fexofenadine 10 times greater than the dose of terfenadine that produces prolongation of QTc intervals do not prolong QTc intervals in anaesthetized rabbits and conscious dogs.
Clinical Trials: An escalating acute dose study demonstrated antihistaminic activity via skin wheal and flare inhibition at doses ranging from 40-800 mg, with maximum inhibition reaching a plateau at a dose of 130 mg. An escalating repeat dose study demonstrated increasing skin flare inhibition at twice daily doses ranging from 20-690 mg. During both acute and repeat dose studies, an antihistaminic effect was observed within 1 hr, achieving maximum effect within 2-4 hrs and lasting a minimum of 12 hrs. There was no evidence of tolerance to these effects after 28 days of dosing.
In dose ranging studies, fexofenadine HCl was shown to relieve the symptoms of seasonal allergic rhinitis, significantly reducing total symptom scores (including scores for sneezing, rhinorrhoea, itchy nose, palate and/or throat, and itchy, watery, red eyes) over a dosage range of 40-240 mg twice daily. In a double-blind, placebo-controlled trial of 208 patients with chronic idiopathic urticaria, fexofenadine HCl 180 and 240 mg once daily for 6 weeks were found to significantly reduce total symptom scores [number of wheals (hives) and pruritus].
In a double-blind, placebo-controlled clinical efficacy study involving 821 patients with seasonal allergic rhinitis, fexofenadine HCl 120 and 180 mg once daily were found to be significantly superior to placebo in relieving symptoms of seasonal allergic rhinitis including sneezing, rhinorrhoea, itchy nose, palate and/or throat, itchy, red or watery eyes and nasal congestion after 24 hrs. There was no statistically significant difference in efficacy between the 2 doses of fexofenadine, however the 180 mg dose did show a trend toward greater reduction in the mean total symptom score.
In a double-blind placebo-controlled study, 861 patients 12-65 years were randomised to receive either fexofenadine 120 mg or fexofenadine 180 mg or placebo once daily for a 2-week period. The primary efficacy measure was change from baseline of average total symptom score. Both doses provided significant (≤0.05) improvement in symptoms of seasonal allergic rhinitis, compared to placebo. While there was no statistically significant difference in efficacy between the 2 doses, the 180 mg dose showed a trend toward greater reduction in the average total symptom score.
In a double-blind, placebo-controlled study investigating quality of life, 845 patients 12-65 years were randomised to receive fexofenadine 120 mg or fexofenadine 180 mg or placebo once daily for a 2-week period. The primary efficacy measures were change from baseline in a quality of life score and in a work/activity impairment score. Patients receiving either 120 or 180 mg dose reported a significant (p≤0.006) improvement in overall quality of life score and a significant (p≤0.004) reduction in work/activity impairment score, compared to placebo. No statistical comparison was made between the effects of the 2 doses of fexofenadine.
The incidence of drowsiness in controlled clinical seasonal allergic rhinitis trials was similar when comparing patients treated with fexofenadine and placebo. There was no dose-related increase in drowsiness.
The effects of fexofenadine on the QTc interval have been investigated in a variety of studies at doses up to 800 mg/day. There were no statistically significant differences in QTc interval between fexofenadine- and placebo-treated patients. Similarly, there were no statistically significant differences from placebo or dose-related changes in other ECG parameters as a result of fexofenadine treatment.
Also, no statistically significant change in QTc intervals was observed in long-term studies in healthy subjects given fexofenadine HCl 60 mg twice daily for 6 months and 240 mg once daily for 12 months, when compared to placebo.
Interaction studies in healthy volunteers between fexofenadine and erythromycin or ketoconazole demonstrated that although the plasma AUC for fexofenadine increased approximately 2- to 3-fold, there were no significant effects on mean or maximal QTc, nor were there any effects on the incidence of adverse events. Although these plasma levels were above those seen with the recommended dose, they were within the range of plasma levels achieved in controlled dose ranging clinical trials. Fexofenadine had no effect on the pharmacokinetics of erythromycin or ketoconazole (see Interactions).
Across the clinical trials, patients between 12-16 years have received doses ranging from 20-240 mg twice daily. Adverse events were similar in this group compared to patients >16 years.
Pharmacokinetics: Fexofenadine HCl is rapidly absorbed into the body following oral administration, with t_max occurring approximately 1-3 hrs post-dose. Following administration of a single 60 mg oral dose to healthy volunteers, fexofenadine HCl was rapidly absorbed, with a mean C_max of 209 ng/mL. Following the administration of single oral doses of fexofenadine HCl 120 and 180 mg, the mean C_max values were approximately 427 ng/mL and 494 ng/mL, respectively.
The absolute bioavailability following fexofenadine HCl administration was estimated to be 33%. Co-administration with food has no clinically significant effect on the absorption of fexofenadine HCl.
The single and multiple dose pharmacokinetics of fexofenadine are linear for oral doses up to 120 mg twice daily. A dose of 240 mg twice daily produced a slightly greater than proportional increase (8.8%) in steady-state area under the curve, indicating that fexofenadine pharmacokinetics are practically linear at daily doses between 40 and 240 mg. Fexofenadine is 60-70% bound to plasma proteins.
Fexofenadine undergoes negligible metabolism. Following a single radiolabelled 60 mg oral dose, approximately 80% and 11% of the total [¹⁴C]-fexofenadine dose was excreted in faeces and urine, respectively.
The plasma concentration versus time profiles of fexofenadine follow a bi-exponential decline with a mean terminal elimination half-life ranging from 14-15 hrs following multiple dosing.
The pharmacokinetics of fexofenadine in seasonal allergic rhinitis patients are similar to those in healthy subjects.
Studies indicated that females may be exposed to higher plasma levels than males, however, there was no indication of any difference in efficacy or in the frequency of adverse events reported. Elderly patients, patients with hepatic impairment and patients with cardiac disease exposed to fexofenadine by administration of terfenadine showed no statistically significant differences in pharmacokinetic parameters for fexofenadine compared to healthy individuals. Although peak plasma level and half-life were increased 68% and 15%, respectively, in elderly patients, and 54% and 19%, respectively, in patients with renal disease, regardless of disease severity, these levels are within the range of plasma levels shown to be tolerated in short-term dose ranging trials.
The pharmacokinetics of fexofenadine in children and adults are similar, including t_max, clearance (corrected for body surface area), half-life and volume of distribution, because fexofenadine undergoes negligible metabolism, with 80% of the dose being eliminated unchanged in the faeces. In contrast, other H₁-receptor antagonists, which are extensively metabolized in the hepatic cytochrome P450 system, usually have shorter half-life values in children than adults.
In children, studies indicate that fexofenadine 30 or 60 mg suppresses the histamine-induced wheal and flare within 1-2 hrs, with both doses producing similar mean maximal suppression.
A dose of Telfast Pediatric Suspension 5 mL containing fexofenadine 30 mg HCl is bioequivalent to a Telfast tablet 30 mg dose. Following oral administration of a Telfast Pediatric Suspension 30 mg dose to healthy adult subjects, the mean C_max was 118 ng/mL and occurred at approximately 1 hr.

Film-coated tablet: Telfast 120 mg is indicated in adults and children 12 years and older for the relief of symptoms associated with seasonal allergic rhinitis.
Telfast 180 mg is indicated in adults and children 12 years and older for the relief of symptoms associated with chronic idiopathic urticaria.
Oral suspension: Relief of symptoms associated with seasonal allergic rhinitis in children 6-11 years.
Relief of symptoms associated with allergic rhinitis or urticaria in adults and children ≥12 years.

Film-coated tablet: Posology: Adults: The recommended dose of fexofenadine hydrochloride for adults is 120 mg once daily or 180 mg once daily taken before a meal.
Fexofenadine is a pharmacologically active metabolite of terfenadine.
Paediatric population: Children aged 12 years and over: The recommended dose of fexofenadine hydrochloride for children aged 12 years and over is 120 mg once daily or 180 mg once daily taken before a meal.
Children under 12 years of age: The efficacy and safety of fexofenadine hydrochloride 120 mg or 180 mg has not been studied in children under 12.
Special populations: Studies in special risk groups (older people, renally or hepatically impaired patients) indicate that it is not necessary to adjust the dose of fexofenadine hydrochloride in these patients.
Oral suspension: Adults and Children ≥12 years: Allergic Rhinitis: 10 mL (60 mg) twice daily, when required.
Seasonal Allergic Rhinitis: 20 mL (120 mg) or 30 mL (180 mg) once daily, when required.
Urticaria: 30 mL (180 mg) once daily, when required.
Children 6-11 years: Seasonal Allergic Rhinitis: 5 mL (30 mg) twice daily, when required.
Dosage adjustment is not required in the elderly or in patients with hepatic or renal impairment.

Standard measures should be considered to remove any unabsorbed medicinal product. Symptomatic and supportive treatment is recommended. Haemodialysis does not effectively remove fexofenadine hydrochloride from blood.
Film-coated tablet: Dizziness, drowsiness, fatigue and dry mouth have been reported with overdose of fexofenadine hydrochloride. Single doses up to 800 mg and doses up to 690 mg twice daily for 1 month or 240 mg once daily for 1 year have been administered to healthy subjects without the development of clinically significant adverse reactions as compared with placebo. The maximum tolerated dose of fexofenadine hydrochloride has not been established.
Oral suspension: There is no clinical experience with a fexofenadine overdose. The maximum single dose tested in clinical trials is 800 mg in 6 healthy subjects. In a multiple-dose study, doses of 690 mg every 12 hrs for 28.5 days were given to 3 healthy subjects and, in another study with 40 subjects, a dose of 400 mg every 12 hrs was given for 6.5 days. No clinically significant adverse events were reported in these studies.

Film-coated tablet: Hypersensitivity to the active substance or to any of the excipients listed in Description.
Oral suspension: Known hypersensitivity to fexofenadine, terfenadine or any of the excipients of Telfast Pediatric Suspension.

Film-coated tablet: As with most new medicinal products, there is only limited data in the elderly and renally or hepatically impaired patients. Fexofenadine hydrochloride should be administered with care in these special groups.
Patients with a history of or ongoing cardiovascular disease should be warned that, antihistamines as a medicine class, have been associated with the adverse reactions, tachycardia and palpitations (see Adverse Reactions).
Effects on ability to drive and use machines: On the basis of the pharmacodynamic profile and reported adverse reactions, it is unlikely that fexofenadine hydrochloride tablets will produce an effect on the ability to drive or use machines. In objective tests, Telfast has been shown to have no significant effects on central nervous system function. This means that patients may drive or perform tasks that require concentration. However, in order to identify sensitive people who have an unusual reaction to medicinal products, it is advisable to check the individual response before driving or performing complicated tasks.
Oral suspension: Carcinogenicity, Mutagenicity & Impairment of Fertility: The carcinogenic potential and reproductive toxicity of fexofenadine HCl were assessed using terfenadine studies. No evidence of carcinogenicity was observed when mice and rats were given daily oral doses of terfenadine 50 and 150 mg/kg for 18 and 24 months, respectively; these doses resulted in plasma AUC values of fexofenadine that were 2-4 times the human therapeutic value (based on a fexofenadine HCl 60 mg twice daily dose).
Fexofenadine showed no genotoxic activity in a series of assays for gene mutations and chromosomal damage.
In rat fertility studies, dose-related reductions in implants and increases in post-implantation losses were observed at oral doses ≥150 mg/kg of terfenadine, respectively; these doses produced plasma AUC values of fexofenadine that were ≥3 times the human therapeutic value, respectively (based on a fexofenadine HCl 60 mg twice daily dose).
Use in Pregnancy & Lactation: Category B2: Reproductive toxicity of fexofenadine in animals was assessed through terfenadine exposure. No evidence of teratogenicity was observed in animal reproduction studies (rat and rabbit) when terfenadine was given at oral doses of up to 300 mg/kg/day throughout organogenesis, which corresponds to levels of systemic fexofenadine exposure 4- and 32-fold higher, respectively, than those anticipated in clinical use. Decreased pup weight and survival occurred in rats when terfenadine was given at oral doses of ≥150 mg/kg/day throughout pregnancy and lactation.
There are no studies in pregnant women exposed to fexofenadine alone or through the administration of terfenadine.
Telfast is not recommended for nursing women unless, in the physician's judgment, the potential benefit to the patient outweighs the potential risk to the infant. There are no data on the content of human milk after administering fexofenadine. However, when terfenadine was administered to nursing mothers, fexofenadine was found to cross into human breast milk.
Exposure of rats to fexofenadine and terfenadine through the administration of terfenadine at dietary doses of 150 and 300 mg/kg/day throughout pregnancy and lactation [corresponding to systemic exposure at levels (AUC) approximately 3- and 6-fold higher than those anticipated in clinical use] caused decreased pup weight gain and survival. The relative risks of these effects from terfenadine or fexofenadine are unknown. Effects on pups exposed to fexofenadine only during lactation are unknown.
Use in Children: Safety and effectiveness of Telfast in children <6 years have not been established.
Telfast Pediatric Suspension is intended for paediatric patients 6-11 years.

Film-coated tablet: Pregnancy: There are no adequate data from the use of fexofenadine hydrochloride in pregnant women. Limited animal studies do not indicate direct or indirect harmful effects with respect to effects on pregnancy, embryonal/foetal development, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical safety data under Actions). Fexofenadine hydrochloride should not be used during pregnancy unless clearly necessary.
Breast-feeding: There are no data on the content of human milk after administering fexofenadine hydrochloride. However, when terfenadine was administered to nursing mothers, fexofenadine was found to cross into human breast milk. Therefore, fexofenadine hydrochloride is not recommended for mothers breast-feeding their babies.
Fertility: No human data on the effect of fexofenadine hydrochloride on fertility are available. In mice, there was no effect on fertility with fexofenadine hydrochloride treatment (see Pharmacology: Toxicology: Preclinical safety data under Actions).

Film-coated tablet: The following frequency rating has been used, when applicable: Very common ≥1/10; Common ≥1/100 and <1/10; Uncommon ≥1/1,000 and <1/100; Rare ≥1/10,000 and <1/1,000; Very rare <1/10,000; not known (frequency cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
In adults, the following undesirable effects have been reported in clinical trials, with an incidence similar to that observed with placebo: Nervous system disorders: Common: headache, drowsiness, dizziness.
Gastrointestinal disorders: Common: nausea.
General disorders and administration site conditions: Uncommon: fatigue.
In adults, the following undesirable effects have been reported in post-marketing surveillance. The frequency with which they occur is not known (cannot be estimated from available data): Immune system disorders: hypersensitivity reactions with manifestations such as angioedema, chest tightness, dyspnoea, flushing and systemic anaphylaxis.
Psychiatric disorders: insomnia, nervousness, sleep disorders or nightmares/excessive dreaming (paroniria).
Cardiac disorders: tachycardia, palpitations.
Gastrointestinal disorders: diarrhoea.
Skin and subcutaneous tissue disorders: rash, urticaria, pruritus.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.
Oral suspension: Telfast is generally well tolerated. The most common adverse events reported in controlled clinical trials were headache, fatigue, dizziness or drowsiness and nausea.
The incidence of these effects was similar to that observed with placebo. No apparent dose trends were revealed in adverse events.
Events that have been reported during controlled trials with incidences <1% and similar to placebo and have been reported rarely during post-marketing surveillance include: Nervousness, insomnia, sleep disorders and paroniria. In rare cases, rash, urticaria, pruritus and hypersensitivity reactions with manifestations eg, angioedema, chest tightness dyspnoea, flushing and systemic anaphylaxis have been reported.
As with adults, the incidence of adverse events with fexofenadine in paediatric patients was similar to placebo.

Fexofenadine does not undergo hepatic biotransformation and therefore will not interact with other medicinal products through hepatic mechanisms.
Co-administration of fexofenadine hydrochloride with erythromycin or ketoconazole has been found to result in a 2-3 times increase in the level of fexofenadine in plasma. The changes were not accompanied by any effects on the QT interval and were not associated with any increase in adverse reactions compared to the medicinal products given singly.
Animal studies have shown that the increase in plasma levels of fexofenadine observed after co-administration of erythromycin or ketoconazole appears to be due to an increase in gastrointestinal absorption and either a decrease in biliary excretion or gastrointestinal secretion, respectively.
No interaction between fexofenadine and omeprazole was observed. However, the administration of an antacid containing aluminium and magnesium hydroxide gels 15 minutes prior to fexofenadine hydrochloride caused a reduction in bioavailability, most likely due to binding in the gastrointestinal tract. It is advisable to leave 2 hours between administration of fexofenadine hydrochloride and aluminium and magnesium hydroxide-containing antacids.
Oral suspension: The pharmacokinetics of fexofenadine HCl and pseudoephedrine are not altered when both drugs are co-administered.
Fexofenadine had no effect on the pharmacokinetics of erythromycin or ketoconazole.

Film-coated tablet: Special precautions for disposal and other handling: No special requirements.
Incompatibilities: Not applicable.

Film-coated tablet: Store at room temperature (15°C - 30°C).

Antihistamines & Antiallergics

R06AX26 - fexofenadine ; Belongs to the class of other antihistamines for systemic use.

P₁