Alimemazine Decision Document

HERTFORDSHIRE MEDICINES MANAGEMENT COMMITTEE (HMMC): USE OF ALIMEMAZINE

NAME WHAT IT IS LICENSED INDICATION DATE DECISION DECISION NICE LAST REVISED STATUS GUIDANCE For urticaria, pruritus and a Oral pre-medication NICE –no Alimemazine antihistamine sedative prior to general April 2019 Final guidance anaesthesia in patients aged two and above

HMMC recommendation following discussion with local specialists:

FOR SEDATION IN PAEDIATRICS PRIOR TO DIAGNOSTIC SCANS (SUCH AS CT/MRI) WHERE OTHER TREATMENTS HAVE FAILED TO WORK – RED (NOT RECOMMENDED FOR PRIMARY CARE PRESCRIBING; SECONDARY CARE USE ONLY).

FOR PRESCRIBING IN ALL OTHER INDICATIONS OF USE – DOUBLE RED (NOT RECOMMENDED FOR PRESCRIBING IN PRIMARY OR SECONDARY CARE).

Existing patients being prescribed alimemazine within primary care should to be reviewed and switched to an alternative, more cost effective therapy where appropriate.

Produced by East and North Herts CCG and NHS Herts Valleys CCG Pharmacy and Medicines Optimisation Teams This HMMC recommendation is based upon the evidence available at the time of publication. The recommendation will be reviewed upon request in the light of new evidence becoming available.

HERTFORDSHIRE MEDICINES MANAGEMENT COMMITTEE (HMMC) Use of alimemazine

HMMC Recommendation Alimemazine is classified as RED drug for use as a sedative in paediatrics prior to diagnostic scans (for instance, MRI/CT scans) where other treatment options have failed to work (secondary care only). For all other indication of use, alimemazine has a DOUBLE RED status and therefore is not recommended for prescribing in primary and secondary care. Patients currently being prescribed alimemazine within primary care should to be reviewed and switched to an alternative, more cost effective therapy where appropriate.

Decision Rationale . Alimemazine is a first-generation antihistamine and was previously marketed in the UK under the brand name Vallergan®, which has subsequently been discontinued. Over time the price of generic alimemazine have risen dramatically. . There are many alternative antihistamine preparations (sedating and non- sedating) widely available on the UK market and there is no clinical evidence to suggest alimemazine is superior to other UK marketed antihistamine preparations. Alimemazine is significantly more expensive than other antihistamine preparations.

Background Information . In the UK, Alimemazine is licensed for the treatment of urticaria, pruritus and a pre- medication sedative prior to general anaesthesia in patients aged two and above. . Alimemazine is also known to be used for off-label purposes for instance, for allergic rhinitis and for sedation prior to CT/MRI or other imaging scans (in paediatric patients). . There are a range of alternative non-sedating antihistamine preparations available which are licensed to treat urticaria, pruritus and allergic rhinitis. If necessary, alternative sedating antihistamines can be considered. . In 2015, Medicines and Healthcare product Regulatory Agency (MHRA) released Drug Safety update which highlighted hydroxyzine use being associated with a small risk of QT-interval prolongation and Torsade de Pointes. Therefore hydroxyzine should not be used in people with prolonged QT interval or risk factors for QT prolongation

Evidence of Clinical Effectiveness . Alimemazine belongs to the group of ‘first generation’ histamines receptor antagonists, alongside chlorphenamine, hydroxyzine and promethazine, which are known to be relatively non-selective and therefore, block not only histamine receptors (H1, H2, H3 and H4) but also, muscarinic, adrenoreceptors and dopaminergic receptors. Due to this, they are known to elicit adverse effects on the body’s cardiovascular, urinary and gastrointestinal system. . The first generation antihistamines are known to be highly lipophilic, therefore readily cross the blood- brain barrier, resulting in sedation. They are known to display a relatively short half-life, thus require multiple doses per a day. . ‘Second generation’ antihistamines, such as cetirizine and loratadine have an increased affinity for H1 receptors (which are known to play the most important role in histamine-dependent allergic diseases) making them effective at reducing symptoms of allergic rhinitis and urticaria. . Their lower affinity for non-specific antihistamine receptors as well as adrenergic, muscarinic and dopaminergic receptors, results in a better safety profile and their lipophobic nature means they are less likely to penetrate the blood brain barrier, thus reduces the occurrence of sedation. . Alimemazine was previously marketed under the brand name Vallergan®. However, following Produced by East and North Herts CCG and NHS Herts Valleys CCG Pharmacy and Medicines Optimisation Teams This HMMC recommendation is based upon the evidence available at the time of publication. The recommendation will be reviewed upon request in the light of new evidence becoming available.

discontinuation, it is only available as a non-proprietary branded tablets (10mg strength) and also as liquid preparations (7.5mg/5ml, 30mg/5ml). The discontinuation of Vallergan® resulted in a drastic price increase of all alimemazine preparations, which means alternative first generation antihistamines are now much less costly to prescribe.

Urticaria

. In accordance with national guidance by NICE, Clinical Knowledge Summaries (CKS) advises that patients who require treatment for symptoms associated with urticaria, should be offered a non-sedating antihistamine as a first-line choice (as opposed to a sedating antihistamines), an example being cetirizine. . This is supported by Bernstein (2014) who acknowledged that whilst first-generation antihistamines are rapidly acting and effective in both paediatric and adult patients, they can be associated with sedation and impaired motor skills because of their ability to cross the blood-brain barrier, whereas these impairments are less evident with second-generation antihistamines as a class. . British Society for Allergy and Clinical Immunology (BSACI) guidance looked into the management of patients with chronic urticaria. Within this guidance, it is recommended that patients who require treatment for symptoms of chronic urticaria should be offered a standard dose of a non-sedating H1 antihistamine. Whilst it is acknowledged that there is a lack of head to head studies to compare the efficacy of antihistamines, BSACI recommends the use of second generation antihistamines, as the occurrence of sedation and impairment of psychomotor function is reduced compared to first generation antihistamines. . A Cochrane systematic review by Sharma et al (2014) looked into effects elicited by H1 antihistamines when used for treatment of chronic spontaneous urticaria. A total of 73 studies (involved 9759 participants) were reviewed (34 studies provided data for 23 comparisons). The duration of the intervention was up to two weeks (short‐term) or longer than two weeks and up to three months (intermediate‐term). Cetirizine, desloratadine, and levocetirizine are effective when compared with placebo. Loratadine showed no significant difference when compared with placebo. There was no strong evidence that one non-sedating antihistamine was more effective than the other. . Marzano (2015) noted that although first generation antihistamines are effective, they do not appear to display any superiority over second generation antihistamines in regards to efficacy. It was also reinforced that second generation antihistamines are better suited as a first line treatment choice for chronic urticaria because of the former being associated with sedation and cognitive impairment. . NICE does advise that if there is an inadequate response to the first-line antihistamine treatment, using clinical judgement, patients can be switched to an alternative non-sedating antihistamine or they can be prescribed an additional sedative antihistamine at night, if itching is interfering with sleep. It refers to chlorphenamine as ‘usual’ choice if a sedating antihistamine is required, as its long-term safety has been well established. Although the guidance does note any suitable sedating antihistamine can be considered as all are licensed for the treatment of urticaria, it also acknowledges that there is no strong evidence that one is more effective than the other. . A paper produced by the British Association of Dermatologists Therapy Guidelines and Audit Committee did note that the addition of sedating antihistamine (such as chlorphenamine and hydroxyzine) may aid in sleeping, but the effect they elicit on urticaria symptoms itself is likely to be minimal, if the H1 receptor is already saturated.

Allergic rhinitis

. BSACI guideline for the diagnosis and management of allergic and non-allergic rhinitis by Scadding et al (2017) recognised that antihistamines preparations (oral, intranasal and Produced by East and North Herts CCG and NHS Herts Valleys CCG Pharmacy and Medicines Optimisation Teams This HMMC recommendation is based upon the evidence available at the time of publication. The recommendation will be reviewed upon request in the light of new evidence becoming available.

intraocular) have all shown clinical efficacy in the management of rhinitis and their use in general forms first line therapy for mild to-moderate intermittent and mild persistent rhinitis. . However, it is recognised that first generation antihistamines are not that beneficial for use due to the sedation and cognitive impairment caused by their use, which in some cases can worsen impairment of activities from rhinitis. . Scadding et al (2017) also noted that in relation to the management of rhinitis symptoms and reducing nasal obstruction, topical antihistamines are considered to be more effective than oral antihistamines (although it should be noted that topical antihistamines do not help improve symptoms associated with histamine release at other sites, for instance skin). Therefore, topical antihistamines are also considered as first line therapy for mild-to-moderate intermittent and mild persistent rhinitis. . NICE also advises on first line management of allergic rhinitis with use of an intranasal (or oral) antihistamine, based on the guidelines by Scadding et al (2017) and on the 2016 revised Allergic Rhinitis and its Impact on Asthma (ARIA) international guidelines. The latter also advises the use of the new generation non-sedating oral antihistamines as first-line, however, CKS does state the choice of treatment will depend on personal preference, local availability, and cost. It should be noted however, that there are alternative, licensed, sedating antihistamines available where preferences dictate such use.

Sedation

. Bailey et al highlighted the importance of using a sedation protocol in paediatrics, as it can be difficult for children to keep still for the duration of a scan. For CT scans, a child is required to lie still for 10-15 minutes. MRI and nuclear medicine scans take between 30-60 minutes. Although the use of alimemazine as a sedative agent for paediatrics in relation to imaging has not been extensively studied, there is some evidence which suggests benefit of use when used alongside chloral hydrate. . As per BNF for children, sedation of children during diagnostic and therapeutic procedures helps to reduce fear and anxiety, to control pain, and to minimise excessive movement. . NICE guidance CG112 lists chloral hydrate (for children under 15 kg) and midazolam for sedation in under 19s who are unable to tolerate painless procedure such as diagnostic scanning.

Cost Effectiveness . Alimemazine was previously marketed under the brand name Vallergan®. However, following discontinuation, it is only available as a non-proprietary branded tablets (10mg strength) and also as liquid preparations (7.5mg/5ml, 30mg/5ml). The discontinuation of Vallergan® resulted in a drastic price increase of all alimemazine preparations, which means alternative first generation antihistamines are now much less costly to prescribe. . It was acknowledged that there may be a specific need for alimemazine in patients who require CT/MRI or imaging scans, only when other treatments have not worked. alimemazine has been assigned as a red drug for this particular indication only so that it remains reserved for this use if required for a one-off use.

The needs of the population . The needs can be considered as being low as there are alternative clinically effective treatments (first generation and second generation antihistamines) available for use. . The older antihistamines in general can illicit unwanted adverse effects, therefore making them unsuitable for use during the day for many patients. Therefore ‘newer antihistamines’ are generally preferred. . Patients who require antihistamines for seasonal allergic rhinitis (self-care condition) should be advised to purchase their treatment in line with local over-the-counter (OTC) medicines policies (both HVCCG and ENHCCG have policies in place). This is provided the patient does not meet the general exceptions for prescribing as with all ‘self-care’ conditions. . Alimemazine is not available to be purchased. If a non-sedating preparation is required for allergy related symptoms, cetirizine, loratadine and acrivastine are available to be purchased OTC. If a sedating option is needed, chlorphenamine and promethazine are available as OTC medicines.

The needs of the community . The needs of the community can be considered as being low, since there are alternative antihistamines (sedating and non-sedating) which are available for use and are less costly than alimemazine. Alimemazine is to be used by secondary care only, where other treatments have failed to induce sedation in paediatric patients whilst undergoing imaging scans. Therefore treatment will be reserved for use by secondary care in a selective cohort of patients only when necessary. This should as a result free up NHS resources for other local health economy needs.

Policy Drivers . Royal Free Hospital advises for non-sedating antihistamines to be considered first when managing pruritus, urticaria and allergic rhinitis. Formulary options include; cetirizine (liquid and tablets) and loratadine (tablets and liquid). Levocetirizine and desloratadine are not recommended. If a sedating antihistamine is required, chlorphenamine is the first line choice. Other sedating antihistamines included within formulary; promethazine hydrochloride (tablets and elixir), which is 2nd line choice and hydroxyzine tablets. Alimemazine is not recommended. . Buckinghamshire NHS Trust/Buckinghamshire CCG has alimemazine 7.5mg/5ml syrup assigned as an amber restricted drug, with treatment on recommendation by the spinal team with continuation by GPs. Alimemazine 30mg/5ml syrup is assigned two traffic light ratings – amber rating on recommendation by paediatrics or haematology with continuation by GPs; red rating (hospital use only) for sedation of children undergoing MRI or CT scans. . North Central London (NCL) Joint Formulary Committee discussed alimemazine at their meeting in November 2018. It was agreed to remove alimemazine from formulary for all prescribing indications. Therefore, there should be no prescribing in primary or secondary care across NCL. . Cambridge and Peterborough CCG has alimemazine assigned as a red drug (i.e. secondary care only). Not to be prescribed in primary care. . Bedfordshire CCG does not have alimemazine listed in its primary care prescribing formulary. . West Essex CCG does not list alimemazine within its primary care prescribing formulary on antihistamine use. Not included within anaesthesia formulary either. . Luton and Dunstable University NHS Foundation Trust has assigned alimemazine with a RED status on their prescribing formulary. Prescribing is hospital only and is restricted for paediatric dermatology patients where no alternative is effective. . North East Essex CCG does not support the prescribing of alimemazine for the treatment of urticaria, pruritus, itching associated with dermatoses such as atopic eczema, pruritus associated with systemic causes, e.g. obstructive jaundice, allergic rhinitis and hay fever, any Produced by East and North Herts CCG and NHS Herts Valleys CCG Pharmacy and Medicines Optimisation Teams This HMMC recommendation is based upon the evidence available at the time of publication. The recommendation will be reviewed upon request in the light of new evidence becoming available.

off-label use.

Equity Equity will improve by having a consistent prescribing position on alimemazine across the whole of Hertfordshire.

Implementability No issues identified.

References

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