Mizolastine
ALLERGIC RHINITIS - Rhinitis affects 1 in 6 people in the U.K. Treatment includes avoiding allergens (where possible), intranasal corticosteroids, short term decongestants, oral or topical antihistamines, intranasal cromoglycate, anticholinergic agents, and allergen immunotherapy. It is reported that in treating allergic rhinitis oral antihistamines are more successful than intranasal corticosteroids in treating nasal itch, sneezing, and associated eye symptoms and that intranasal corticosteroids are more successful in controlling nasal blockage and discharge. However a recently published systematic review disputes this view and concludes that intranasal corticosteroids should be used first line over oral antihistamines in the treatment of allergic rhinitis.
CHRONIC URTICARIA - Chronic urticaria is defined as the occurrence of widespread wheals daily or almost daily for at least six weeks. It is believed that between 15 and 23% of the US population have experienced this condition and that a similar prevalence in the UK seems probable. Except for a few patients for whom an avoidable cause can be identified, treatment is symptomatic. The mainstay of treatment is antihistamines, with oral corticosteroids being used in patients who do not respond to antihistamines.
Pharmacology & pharmacokinetics
Mizolastine is a peripherally acting, selective H1-receptor antagonist. Following oral administration it is rapidly absorbed and peak plasma concentrations are reached in a median time of 1.5 hours. Bioavailability is around 65% and linear kinetics has been demonstrated. The drug is highly protein bound and has an elimination half-life of around 13 hours. The principal metabolic pathway is glucuronidation of the parent compound and the cytochrome P4503A4 enzyme system is involved in one of the additional metabolic pathways seen. A 50% increase in AUC is seen in patients with hepatic insufficiency - mainly because of prolonged absorption and distribution phases. Concomitant ketoconazole or erythromycin leads to an increase in mizolastine plasma levels equivalent to those obtained after giving 15-20mg mizolastine instead of the licensed 10mg dose.
Efficacy
SEASONAL ALLERGIC RHINOCONJUNCTIVITIS - Leynadier at al conducted a placebo-controlled study in 494 patients with seasonal allergic rhinitis [5]. Patients were randomised to receive mizolastine 5mg, 10mg or 15mg daily or placebo for two weeks during the pollen season. Patients with chronic rhinitis or conjunctivitis were excluded from participation. Efficacy was assessed by both the patient and the physician scoring the severity of the following symptoms of seasonal allergy: blocked nose, running nose, itching nose, itching eyes, watery eyes and sneezing at Days 0, 7 and 14. Patients were also asked to assess overall discomfort using a visual analogue scale. Physicians additionally assessed severity of red eyes, itching throat, itching ears and red ears to produce a total score that encompassed nasal, ocular, throat and ear scores. They were also asked to quantify the clinical global impression as a ratio score of therapeutic effect to adverse events. Using physician-rated total symptoms score as a measure of efficacy it was shown that mizolastine (10mg and 15mg) resulted in a statistically significant improvement in the score after 7 days (p=0.002). However, by 14 days there were no statistically significant differences between placebo and mizolastine (10mg or 15mg daily) due to improvement in the placebo scores. These findings were also reflected in the patient ratings, significant improvements were noted in the mizolastine 10mg group by Day 2 but any difference from placebo was lost by Day 14. The physician-rated clinical global impression ratio was only marginally in favour of mizolastine (all strengths) when compared with placebo. If a responder is defined as a patient with a 50% improvement on the visual analogue scale - then after 14 days 39.7 and 50.0% of patients who received placebo and mizolastine (10mg) respectively were responders - this equates to an NNT of about 10 to produce one additional responder using mizolastine instead of placebo after two weeks of treatment. Sabbah et al undertook a four week comparison of mizolastine (10mg) with cetirizine (10mg) and placebo in 375 patients [6]. This study has not yet been published - so has not been subjected to peer review. It was a randomised, double blind, placebo-controlled study with 3 parallel groups. Outcome was primarily assessed using investigator-assessed total, nasal and ocular symptom scores (as above). Secondary criteria included global discomfort assessed by the patient on a visual analogue scale and patient-assessed symptom scores. In this study mizolastine demonstrated efficacy at least equal to that of cetirizine both for symptoms of seasonal allergic rhitinis and overall discomfort.
PERENNIAL ALLERGIC RHINITIS - Mizolastine has been compared with loratadine in a 68-patient trial, in which patients received mizolastine (10mg) or loratadine (10mg) for four weeks after a 1-week placebo run-in period [7]. Comparable symptom relief was seen with both drugs in terms of total nasal score (66.6% and 61.3% for mizolastine and loratadine), decreases in total ocular score (74.8% and 76.4%) and decreases in global total score (69% and 64.8%). This latter difference is statistically significant in favour of mizolastine over cetirizine, however, the clinical significance of the result is difficult to interpret given that patients in the mizolastine group had a significantly higher score at baseline.
CHRONIC URTICARIA - Brostoff et al randomised 56 patients with chronic idiopathic urticaria to mizolastine (10mg daily) or matching placebo for four weeks. Patients recruited had a documented history of chronic idiopathic urticaria of at least six weeks and suffered an average of at least two episodes per week. All patients underwent an appropriate washout period before entering the study. The investigator assessed patients for the main symptoms of chronic idiopathic urticaria using 4-point scales for itch and for wheals and erythema on days 0, 7 and 28. Patients also completed a diary in which they recorded the number of urticarial episodes and the intensity of itch using a visual analogue scale (VAS) and the number of wheals and intensity of the angioedema again using a 4-point scale. They also assessed the global severity of their symptoms over the previous 3 days using a VAS on days 0, 7 and 28. At the final assessment (day 28), the investigator made a global evaluation of treatment that comprised three components, the therapeutic effect, the adverse effects, and the therapeutic index (a ratio of the first two). Only 27 patients completed the study. In the mizolastine group out of 28 patients randomised to the drug, 5 stopped prematurely because of lack of efficacy, 1 due to drowsiness, 2 were lost to follow up, 1 was considered unco-operative and 1 discontinued for non-study related reasons. In the placebo group, 17 stopped due to lack of efficacy, 1 was considered uncooperative and 1 discontinued for non-study related reason. Results were analysed on an intention-to-treat basis. Mizolastine was shown to be statistically significantly superior to placebo in alleviating symptoms for all efficacy measures described. Overall it was felt that 74% of patients who received mizolastine and 28% of patients who received placebo were considered responders. This corresponds to an NNT of 2; i.e. you need to treat 2 patients with mizolastine instead of placebo for 28 days to produce 1 additional ‘responder’. It is stated within the paper that this result is consistent with results obtained using some other antihistamines. Lachapelle et al undertook a comparative study of mizolastine (10mg), cetirizine (10mg) and placebo in 91 patients with chronic idiopathic urticaria. At present, the results are only available in abstract form, but it would appear that mizolastine and cetirizine were similarly effective in improving urticarial symptoms and produced statistically significant improvements over placebo.
Adverse Effec
the largest trial in seasonal allergic rhinitis , 22.5% of patients taking mizolastine (5- 15mg daily) reported an adverse effect compared with 17% taking placebo. Overall the most common side effects were drowsiness (5.9% for mizolastine vs. 0.8% for placebo) and fatigue (4.6% vs. 1.6%). Other adverse effects listed in the Summary of Product Characteristics include dry mouth, diarrhoea, dyspepsia and increased appetite associated with weight gain in some individuals. Isolated cases of hypotension, anxiety and depression, neutropenia and raised liver enzymes have been reported rarely. Reports of bronchospasm and aggravation of asthma have also been reported however, a casual relationship has not been established. Minor changes in blood sugar and electrolytes have been observed rarely and patients at risk should be monitored periodically [4]. In a controlled trial, Vuurman et al [10] assessed the effects of mizolastine (5-40mg) on active driving performance in healthy volunteers. They concluded that doses of 20-40mg impaired driving performance but that doses of 5-10mg did not have a significant effect. However they did qualify this conclusion by stating that individual adverse reactions could not be ruled out. In a different analysis of these results by the same authors, it is stated that "it would appear that impairment begins after a single dose of about 10mg".
Precautions
Mizolastine has a weak potential to prolong the QT interval. This has been well reported with a few other antihistamines (terfenadine and astemizole) and can lead to arrhythmias - although after one year on the market there has not been reports linking mizolastine with this problem (personal communication: Medical Information, Lorex Synthelbo Ltd.). It is contraindicated in patients with clinically significant cardiac disease or a history of symptomatic arrhythmias and in patients with known or suspected QT prolongation, patients with electrolyte imbalance (particularly hypokalaemia), and in those with clinically significant bradycardia. Care should also be taken in prescribing it to elderly patients, as they may be particularly susceptible to the effect of the drug on cardiac repolarisation. Obviously concomitant therapy with drugs known to prolong the QT interval, such as Class I and III anti-arrhythmics are also contraindicated. Mizolastine is also contra-indicated in patients taking other drugs that decrease its metabolism (see below), in patients with significantly impaired liver function, and in patients who are hypersensitive to the drug. Most patients taking mizolastine may drive or perform tasks requiring concentration - however, it is advised that individual response to the drug is checked before driving or performing complicated tasks. Again it is stated that the elderly may be particularly susceptible to the sedative effects of mizolastine. Finally it is advised that mizolastine should be avoided in pregnancy (particularly the first trimester) and is not recommended during lactation .
Drug Interactions
Levels of mizolastine are modestly increased by ketoconazole or erythromycin. This could increase the risk of arrhythmias and so their concurrent use is contra-indicated. Similarly the concurrent use of other potent inhibitors of the cytochrome P4503A4 enzyme should be undertaken with caution - at present this caution would include the use of drugs like cimetidine, cyclosporin and nifedipine.