In chronic asthma studies, Ektalust. has been administered at doses up to 200 mg/day to patients for 22 weeks and in short term studies, up to 900 mg/day to patients for approximately one week without clinically important adverse experiences.
There have been reports of acute overdose in post-marketing experience and clinical studies with Ektalust.. These include reports in adults and children with a dose as high as 1000 mg (approximately 61 mg/kg in a 42 month old child). The clinical and laboratory findings observed were consistent with the safety profile in adults and paediatric patients.
Symptoms of overdose
There were no adverse experiences in the majority of overdose reports. The most frequently occurring adverse experiences were consistent with the safety profile of Ektalust. and included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity.
Management of overdose
No specific information is available on the treatment of overdose with Ektalust.. It is not known whether Ektalust. is dialysable by peritoneal- or haemo-dialysis.
Not applicable.
The frequency using the following convention: Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); Uncommon (>1/1,000 to <1/100); Rare (>1/10,000 to <1/1,000); Very rare (<1/10,000); not known (cannot be estimated from the available data).
Ektalust. has been evaluated in clinical studies as follows:
- 10 mg film-coated tablets in approximately 4000 adult and adolescent asthmatic patients 15 years of age and older.
- 10 mg film-coated tablets in approximately 400 adult and adolescent asthmatic patients with seasonal allergic rhinitis 15 years of age and older.
- 5 mg chewable tablets in approximately 1750 paediatric asthmatic patients 6 to 14 years of age.
The following drug-related adverse reactions in clinical studies were reported commonly (1/100 to <1/10) in asthmatic patients treated with Ektalust. and at a greater incidence than in patients treated with placebo:
| Body system Class | Adult Patients 15 years and older (two 12-week studies; n=795) | Paediatric and adolescents Patients 6 to 14 years old (one 8-week study; n=201) (two 56-week studies; n=615) |
| Nervous system disorders | headache | headache |
| Gastrointestinal disorders | abdominal pain |
With prolonged treatment in clinical trials with a limited number of patients for up to 2 years for adults, and up to 12 months for paediatric and adolescents patients 6 to 14 years of age, the safety profile did not change.
Adverse reactions reported in post-marketing use are listed, by System Organ Class and specific Adverse Experience Term, in the table below. Frequency Categories were estimated based on relevant clinical trials.
| System Organ Class | Adverse Experience Term | Frequency Category* |
| Infections and infestations | upper respiratory infection†| Very Common |
| Blood and lymphatic system disorders | increased bleeding tendency | Rare |
| Immune system disorder | hypersensitivity reactions including anaphylaxis | Uncommon |
| hepatic eosinophilic infiltration | Very Rare | |
| Psychiatric disorders | dream abnormalities including nightmares, insomnia, somnambulism, irritability, anxiety, restlessness, agitation including aggressive behaviour or hostility, depression, psychomotor hyperactivity (including irritability, restlessness, tremor§) | Uncommon |
| disturbance in attention, memory impairment | Rare | |
| hallucinations, disorientation, suicidal thinking and behaviour (suicidality) | Very Rare | |
| Nervous system disorder | dizziness, drowsiness paraesthesia/hypoesthesia, seizure | Uncommon |
| Cardiac disorders | palpitations | Rare |
| Respiratory, thoracic and mediastinal disorders | epistaxis | Uncommon |
| Churg-Strauss Syndrome (CSS) , pulmonary eosinophilia | Very Rare | |
| Gastrointestinal disorders | diarrhoea‡, nausea‡, vomiting‡ | Common |
| dry mouth, dyspepsia | Uncommon | |
| Hepatobiliary disorders | elevated levels of serum transaminases (ALT, AST) | Common |
| hepatitis (including cholestatic, hepatocellular, and mixed-pattern liver injury). | Very Rare | |
| Skin and subcutaneous tissue disorders | rash‡ | Common |
| bruising, urticaria, pruritus | Uncommon | |
| angiooedema | Rare | |
| erythema nodosum, erythema multiforme | Very Rare | |
| Musculoskeletal, connective tissue and bone disorders | arthralgia, myalgia including muscle cramps | Uncommon |
| General disorders and administration site conditions | pyrexia‡ | Common |
| asthenia/fatigue, malaise, oedema, | Uncommon | |
| *Frequency Category: Defined for each Adverse Experience Term by the incidence reported in the clinical trials data base: Very Common (>1/10), Common (>1/100 to </10), Uncommon (>1/1000 to </100), Rare (>1/10,000 to </1000), Very Rare (</10,000). †This adverse experience, reported as Very Common in the patients who received Ektalust., was also reported as Very Common in the patients who received placebo in clinical trials. ‡This adverse experience, reported as Common in the patients who received Ektalust., was also reported as Common in the patients who received placebo in clinical trials. § Frequency Category: Rare | ||
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 via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
In animal toxicity studies, minor serum biochemical alterations in ALT, glucose, phosphorus and triglycerides were observed which were transient in nature. The signs of toxicity in animals were increased excretion of saliva, gastro-intestinal symptoms, loose stools and ion imbalance. These occurred at dosages which provided>17-fold the systemic exposure seen at the clinical dosage. In monkeys, the adverse effects appeared at doses from 150 mg/kg/day (>232-fold the systemic exposure seen at the clinical dose). In animal studies, Ektalust. did not affect fertility or reproductive performance at systemic exposure exceeding the clinical systemic exposure by greater than 24-fold. A slight decrease in pup body weight was noted in the female fertility study in rats at 200 mg/kg/day (>69fold the clinical systemic exposure). In studies in rabbits, a higher incidence of incomplete ossification, compared with concurrent control animals, was seen at systemic exposure>24-fold the clinical systemic exposure seen at the clinical dose. No abnormalities were seen in rats. Ektalust. has been shown to cross the placental barrier and is excreted in breast milk of animals.
No deaths occurred following a single oral administration of Ektalust. sodium at doses up to 5000 mg/kg in mice and rats (15,000 mg/m2 and 30,000 mg/m2 in mice and rats, respectively), the maximum dose tested. This dose is equivalent to 25,000 times the recommended daily adult human dose (based on an adult patient weight of 50 kg).
Ektalust. was determined not to be phototoxic in mice for UVA, UVB or visible light spectra at doses up to 500 mg/kg/day (approximately>200-fold based on systemic exposure).
Ektalust. was neither mutagenic in in vitro and in vivo tests nor tumorigenic in rodent species.
Ektalust. 10 mg film-coated tablets is indicated in the treatment of asthma as add-on therapy in adults and adolescents from 15 years of age and older with mild to moderate persistent asthma who are inadequately controlled on inhaled corticosteroids and in whom “as-needed†short acting beta-agonists provide inadequate clinical control of asthma. In those asthmatic patients in whom Ektalust. 10 mg film-coated tablets is indicated in asthma, Ektalust. 10 mg film-coated tablets can also provide symptomatic relief of seasonal allergic rhinitis.
Ektalust. 10 mg film-coated tablets is also indicated in the prophylaxis of asthma in which the predominant component is exercise-induced bronchoconstriction.
Pharmacotherapeutic group: Other systemic drugs for obstructive airway diseases, Leukotriene receptor antagonist
ATC code: R03D C03
The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory eicosanoids released from various cells including mast cells and eosinophils. These important pro-asthmatic mediators bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include bronchoconstriction, mucous secretion, vascular permeability, and eosinophil recruitment. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis. Intranasal challenge with CysLTs has been shown to increase nasal airway resistance and symptoms of nasal obstruction.
Ektalust. is an orally active compound which binds with high affinity and selectivity to the CysLT1 receptor. In clinical studies, Ektalust. inhibits bronchoconstriction due to inhaled LTD4 at doses as low as 5 mg. Bronchodilation was observed within 2 hours of oral administration. The bronchodilation effect caused by a beta agonist was additive to that caused by Ektalust.. Treatment with Ektalust. inhibited both early- and late phase bronchoconstriction due to antigen challenge. Ektalust., compared with placebo, decreased peripheral blood eosinophils in adult and paediatric patients. In a separate study, treatment with Ektalust. significantly decreased eosinophils in the airways (as measured in sputum) and in peripheral blood while improving clinical asthma control.
In studies in adults, Ektalust., 10 mg once daily, compared with placebo, demonstrated significant improvements in morning FEV1 (10.4% vs 2.7% change from baseline), AM peak expiratory flow rate (PEFR) (24.5 L/min vs 3.3 L/min change from baseline), and significant decrease in total beta-agonist use ( -26.1% vs -4.6% change from baseline). Improvement in patient-reported daytime and nighttime asthma symptoms scores was significantly better than placebo.
Studies in adults demonstrated the ability of Ektalust. to add to the clinical effect of inhaled corticosteroid (% change from baseline for inhaled beclometasone plus Ektalust. vs beclometasone, respectively for FEV1: 5.43% vs 1.04%; beta-agonist use: -8.70% vs 2.64%). Compared with inhaled beclometasone (200 µg twice daily with a spacer device), Ektalust. demonstrated a more rapid initial response, although over the 12-week study, beclometasone provided a greater average treatment effect (% change from baseline for Ektalust. vs beclometasone, respectively for FEV1: 7.49% vs 13.3%; beta agonist use: -28.28% vs -43.89%). However, compared with beclometasone, a high percentage of patients treated with Ektalust. achieved similar clinical responses (e.g., 50% of patients treated with beclometasone achieved an improvement in FEV1 of approximately 11% or more over baseline while approximately 42% of patients treated with Ektalust. achieved the same response).
A clinical study was conducted to evaluate Ektalust. for the symptomatic treatment of seasonal allergic rhinitis in adult asthmatic patients 15 years of age and older with concomitant seasonal allergic rhinitis. In this study, Ektalust. 10 mg tablets administered once daily demonstrated a statistically significant improvement in the Daily Rhinitis Symptoms score, compared with placebo. The Daily Rhinitis Symptoms score is the average of the Daytime Nasal Symptoms score (mean of nasal congestion, rhinorrhea, sneezing, nasal itching) and the Nighttime Symptoms score (mean of nasal congestion upon awakening, difficulty going to sleep, and nighttime awakenings scores). Global evaluations of allergic rhinitis by patients and physicians were significantly improved, compared with placebo. The evaluation of asthma efficacy was not a primary objective in this study.
In an 8-week study in paediatric patients 6 to 14 years of age, Ektalust. 5 mg once daily, compared with placebo, significantly improved respiratory function (FEV1 8.71% vs 4.16% change from baseline; AM PEFR 27.9 L/min vs 17.8 L/min change from baseline) and decreased "as-needed" beta-agonist use (-11.7% vs +8.2% change from baseline).
Significant reduction of exercise-induced bronchoconstriction (EIB) was demonstrated in a 12-week study in adults (maximal fall in FEV1 22.33% for Ektalust. vs 32.40% for placebo; time to recovery to within 5% of baseline FEV1 44.22 min vs 60.64 min). This effect was consistent throughout the 12-week study period. Reduction in EIB was also demonstrated in a short term study in paediatric patients (maximal fall in FEV1 18.27% vs 26.11%; time to recovery to within 5% of baseline FEV1 17.76 min vs 27.98 min). The effect in both studies was demonstrated at the end of the once-daily dosing interval.
In aspirin-sensitive asthmatic patients receiving concomitant inhaled and/or oral corticosteroids, treatment with Ektalust., compared with placebo, resulted in significant improvement in asthma control (FEV1 8.55% vs -1.74% change from baseline and decrease in total beta-agonist use -27.78% vs 2.09% change from baseline).
Absorption
Ektalust. is rapidly absorbed following oral administration. For the 10 mg film-coated tablet, the mean peak plasma concentration (Cmax) is achieved 3 hours (Tmax) after administration in adults in the fasted state. The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal. Safety and efficacy were demonstrated in clinical trials where the 10 mg film-coated tablet was administered without regard to the timing of food ingestion.
For the 5 mg chewable tablet, the Cmax is achieved in 2 hours after administration in adults in the fasted state. The mean oral bioavailability is 73% and is decreased to 63% by a standard meal.
Distribution
Ektalust. is more than 99% bound to plasma proteins. The steady-state volume of distribution of Ektalust. averages 8-11 litres. Studies in rats with radiolabelled Ektalust. indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabelled material at 24 hours post-dose were minimal in all other tissues.
Biotransformation
Ektalust. is extensively metabolised. In studies with therapeutic doses, plasma concentrations of metabolites of Ektalust. are undetectable at steady state in adults and children.
Cytochrome P450 2C8 is the major enzyme in the metabolism of Ektalust.. Additionally CYP 3A4 and 2C9 may have a minor contribution, although itraconazole, an inhibitor of CYP 3A4, was shown not to change pharmacokinetic variables of Ektalust. in healthy subjects that received 10 mg Ektalust. daily. Based on in vitro results in human liver microsomes, therapeutic plasma concentrations of Ektalust. do not inhibit cytochromes P450 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. The contribution of metabolites to the therapeutic effect of Ektalust. is minimal.
Elimination
The plasma clearance of Ektalust. averages 45 ml/min in healthy adults. Following an oral dose of radiolabelled Ektalust., 86% of the radioactivity was recovered in 5-day faecal collections and <0.2% was recovered in urine. Coupled with estimates of Ektalust. oral bioavailability, this indicates that Ektalust. and its metabolites are excreted almost exclusively via the bile.
Characteristics in patients
No dosage adjustment is necessary for the elderly or mild to moderate hepatic insufficiency. Studies in patients with renal impairment have not been undertaken. Because Ektalust. and its metabolites are eliminated by the biliary route, no dose adjustment is anticipated to be necessary in patients with renal impairment. There are no data on the pharmacokinetics of Ektalust. in patients with severe hepatic insufficiency (Child-Pugh score>9).
With high doses of Ektalust. (20- and 60-fold the recommended adult dose), decrease in plasma theophylline concentration was observed. This effect was not seen at the recommended dose of 10 mg once daily.
Patients should be advised never to use oral Ektalust. to treat acute asthma attacks and to keep their usual appropriate rescue medication for this purpose readily available. If an acute attack occurs, a short-acting inhaled beta-agonist should be used. Patients should seek their doctor's advice as soon as possible if they need more inhalations of short-acting beta-agonists than usual.
Ektalust. should not be substituted abruptly for inhaled or oral corticosteroids.
There are no data demonstrating that oral corticosteroids can be reduced when Ektalust. is given concomitantly.
In rare cases, patients on therapy with anti-asthma agents including Ektalust. may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These cases have been sometimes associated with the reduction or withdrawal of oral corticosteroid therapy. Although a causal relationship with leukotriene receptor antagonism has not been established, physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. Patients who develop these symptoms should be reassessed and their treatment regimens evaluated.
Treatment with Ektalust. does not alter the need for patients with aspirin-sensitive asthma to avoid taking aspirin and other non-steroidal anti-inflammatory drugs.
This medicinal product contains lactose monohydrate.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Ektalust. has no or negligible influence on the ability to drive and use machines. However, individuals have reported drowsiness or dizziness.
Posology:
The dosage for adults and adolescents 15 years of age and older with asthma, or with asthma and concomitant seasonal allergic rhinitis, is one 10 mg tablet daily to be taken in the evening.
General recommendations:
The therapeutic effect of Ektalust. 10 mg film-coated tablets on parameters of asthma control occurs within one day. Ektalust. 10 mg film-coated tablets may be taken with or without food. Patients should be advised to continue taking Ektalust. 10 mg film-coated tablets even if their asthma is under control, as well as during periods of worsening asthma. Ektalust. 10 mg film-coated tablets should not be used concomitantly with other products containing the same active ingredient, Ektalust..
No dosage adjustment is necessary for the elderly, or for patients with renal insufficiency, or mild to moderate hepatic impairment. There are no data on patients with severe hepatic impairment. The dosage is the same for both male and female patients.
Therapy with Ektalust. 10 mg film-coated tablets in relation to other treatments for asthma
Ektalust. 10 mg film-coated tablets can be added to a patient's existing treatment regimen.
Inhaled corticosteroids:
Treatment with Ektalust. 10 mg film-coated tablets can be used as add-on therapy in patients when inhaled corticosteroids plus "as needed" short acting beta-agonists provide inadequate clinical control. Ektalust. 10 mg film-coated tablets should not be abruptly substituted for inhaled corticosteroids.
Paediatric population
Do not give Ektalust. 10 mg film-coated tablets to children less than 15 years of age. The safety and efficacy of Ektalust. 10 mg film-coated tablets in children less than 15 years has not been established.
10 mg film-coated tablets are available for adults and adolescents above 15 years old.
Other available strengths/pharmaceutical forms:
5 mg chewable tablets are available for paediatric and adolescents patients 6 to 14 years of age.
4 mg chewable tablets are available for paediatric patients 2 to 5 years of age.
Method of administration:
Oral use.
Any unused product or waste material should be disposed of in accordance with local requirements.
