Introduction
The use of medicines to quickly calm the severely agitated patient (in order to reduce the risk of imminent and serious violence to self or others rather than to treat the underlying psychiatric condition) is referred to as rapid tranquillisation (RT), and is widely used across psychiatric services (Innes & Sethi, Reference Innes and Sethi2013). According to the NICE guideline on violence and aggression (National Institute for Clinical Excellence, 2005), ‘All medication given in the short-term management of disturbed/violent behaviour should be considered as part of rapid tranquillisation (including pro re nata [PRN] medication)’. RT should only be used once non-pharmacological options have been explored.
Inhaled loxapine is a newly licensed medicine for the rapid control of mild-to-moderate agitation (Adasuve®; European Medicines Agency, 2013), and represents a potential change in practice as the first inhaled option. Currently the number of medicines available in the UK for RT is reasonably limited, and they are generally administered orally (and absorbed via the gastrointestinal tract) or by intramuscular (IM) injection (Innes & Sethi Reference Innes and Sethi2013). There haven't been any new products licensed for RT in the UK in the past five years. The most recent additions were: olanzapine IM which was licensed in the UK in 2001 and became available in 2004, and aripiprazole IM which was licensed in 2007 and has been available since 2008.
Practice varies across the UK (Pereira et al. Reference Pereira, Paton, Walkert, Shaw, Gray and Wildgust2005), but the currently recommended agents for RT are primarily antipsychotics and benzodiazepines (National Institute for Clinical Excellence, 2005), although a number of other agents are also used to a lesser extent (Innes & Sethi, Reference Innes and Sethi2013). The most commonly recommended agents for IM use are the benzodiazepine lorazepam and the first generation antipsychotic haloperidol (National Institute for Clinical Excellence, 2005) as well as the second generation antipsychotic olanzapine (Innes & Sethi, Reference Innes and Sethi2013). The IM olanzapine formulation (Zyprexa®) is still licensed for use across the EU however the manufacturer has discontinued marketing it in the UK, but it can be imported if required (Eli Lilly & Co. Ltd. Reference Eli2013). This reduced availability is likely to impact on its usage. Furthermore, over recent years there have been ongoing difficulties with the supply of the only licensed formulation of lorazepam injection (Ativan®, Pfizer), leading trusts to source alternative supplies, such as unlicensed formulations of lorazepam injection, or alternative medicines.
Loxapine is a well established first generation antipsychotic that like all other first generation antipsychotics exerts its effects by antagonising central dopamine and serotonergic receptors (Keating, Reference Keating2013; Chakrabarti et al. Reference Chakrabarti, Bagnall, Chue, Fenton, Palaniswamy, Wong and Xia2007). It has been available in formulations for oral administration and for IM injection in a number of other countries worldwide (excluding the UK) for over 25 years (Chakrabarti et al. Reference Chakrabarti, Bagnall, Chue, Fenton, Palaniswamy, Wong and Xia2007; Lesem et al. Reference Lesem, Tran-Johnson, Riesenberg, Feifel, Allen, Fishman, Spyker, Kehne and Cassella2011). Oral loxapine has been used in the treatment of schizophrenia where it has demonstrated short term efficacy similar to that seen with other first generation antipsychotics. The short-acting IM injection has been studied for use in RT in a few trials where it was found to be of similar efficacy and tolerability as haloperidol IM (Chakrabarti et al. Reference Chakrabarti, Bagnall, Chue, Fenton, Palaniswamy, Wong and Xia2007). Inhaled loxapine recently received both EU and US marketing authorisation as an inhalation (Adusave®; European Medicines Agency, 2013) for adults with mild to moderate agitation associated with schizophrenia and bipolar disorder in the hospital setting. NICE began a Technology Appraisal 286 process for ‘Loxapine inhalation for treating acute agitation and disturbed behaviours associated with schizophrenia and bipolar disorder’ (National Institute for Health Care Excellence, 2013). For a technology appraisal of a single entity the NICE procedures require the manufacturers to submit an estimate of cost effectiveness using a specific appropriate analytical model. The manufacturer of loxapine informed NICE that they would not be making a submission due to insufficient evidence. NICE has therefore terminated the technology appraisal (it is not rejected nor recommended for use), leaving trusts to make their own formulary decisions prior to its UK launch in 2014.
Formulation
The powdered drug is inhaled from the device resulting in very quick absorption into the blood stream and with peak plasma levels occurring at approximately two minutes (Keating, Reference Keating2013; European Medicines Agency, 2013). This is very different from IM injections and oral doses. For example, the time to reach maximum serum concentration of olanzapine occurred much earlier following IM administration (15 to 45 minutes) compared to oral use (5 to 8 hours) (Eli Lilly & Co. Ltd. Reference Eli2013), whereas the time to reach maximum serum concentration following IM haloperidol is similar to that after oral administration, that is within 20 minutes (Janssen-Cilag Ltd. 2011). The onset of clinical effect was assessed and observed in trials at 10 minutes (Keating, Reference Keating2013). A number of IM RT medications have been shown to have significant clinical effects (e.g. sedation or tranquility, although end points vary) in similar time frames, however the exact timing is dependent on the trial design. For example, trials of other agents have tended to only assess the patient at 15 minutes (Raveendran et al. Reference Raveendran, Tharyan, Alexander and Adams2007; Alexander et al. Reference Alexander, Tharyan, Adams, John, Mol and Philip2004; Wright et al. Reference Wright, Birkett, David, Meehan, Ferchland, Alaka, Saunders, Krueger, Bradley, San, Bernardo, Reinstein and Breier2001), and 20 minutes (Huf et al. Reference Huf, Coutinho and Adams2007) post dose, therefore the perceived earlier onset of action of loxapine may be more related to trial design than actual clinical difference.
The device is a single use (single dose) hand held breath actuated inhalator. This is unlike many more familiar older inhalers often used in the management of asthma (e.g. salbutamol) which use a pressurised canister of propellant to deliver an aerosol of the drug to the lungs and require the patient to use a specific practised technique to achieve this.
There is a green indicator showing that the device is ready for use. The patient should be asked to take a steady deep breath and in doing so the dose of loxapine dry powder is inhaled, the green light turns off indicating that the drug dose has been delivered; the patient should be asked to hold their breath briefly (European Medicines Agency, 2013). Inhaled loxapine is available in two strengths 5 and 10 mg (European Medicines Agency, 2013). Patients in the trials found the device easy to use (but all were able to consent and listen to instructions on how to use the device). During testing the amount of dose delivered was not affected by the operating setting (flow rate, temperature, humidity, altitude, or orientation of the device; Keating, Reference Keating2013). The usual dose is 10 mg, and if needed a second dose may be given (using a second device) after two hours (European Medicines Agency, 2013). The dose doesn't need to be altered in view of the patients’ gender, age, smoking status, weight or body mass index (Keating, Reference Keating2013, European Medicines Agency, 2013).
Adverse Reactions
Bronchospasm was very commonly reported in the small phase I trials of patients with active airways disease. In these cases bronchospasm was usually mild to moderate in severity and short lived, developing within 25 minutes of dosing. In some cases it resolved spontaneously. In others, administration of a short-acting beta-agonist bronchodilator (salbutamol) was required and symptoms resolved with this treatment (Keating, Reference Keating2013). Consequently patients with airways diseases were excluded from phase III trials (Lesem et al. Reference Lesem, Tran-Johnson, Riesenberg, Feifel, Allen, Fishman, Spyker, Kehne and Cassella2011; Kwentus et al. Reference Kwentus, Riesenberg, Marandi, Manning, Allen, Fishman, Spyker, Kehne and Cassella2012), and inhaled loxapine is contra-indicated in patients with asthma, COPD or other active lung diseases associated with bronchospasm, or who have acute respiratory symptoms or signs (European Medicines Agency, 2013). Whenever inhaled loxapine is used a short-acting beta-agonist bronchodilator (i.e. salbutamol) should be available. After each dose the patient should be monitored for at least one hour for signs and symptoms of bronchospasm (European Medicines Agency, 2013).
The available data does not suggest that single doses of inhaled loxapine prolong the corrected QT interval on the ECG (QTc) (Keating, Reference Keating2013; European Medicines Agency, 2013). Additionally, ECG data from studies of (regular) oral loxapine is very limited but did not show any notable effects (Chakrabarti et al. Reference Chakrabarti, Bagnall, Chue, Fenton, Palaniswamy, Wong and Xia2007). However, as with all antipsychotics, inhaled loxapine is not recommended for use in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), and the manufacturers advise caution if using inhaled loxapine in patients with known cardiovascular disease or family history of QT prolongation, or in concomitant use with other medicinal products known to prolong the QT interval (which includes other antipsychotics) (European Medicines Agency, 2013).
In general inhaled loxapine was well tolerated (Keating, Reference Keating2013). Commonly reported adverse reactions with inhaled loxapine included dysgeusia (the distortion of the sense of taste or a bad taste in the mouth) and sedation (Keating Reference Keating2013; Kwentus et al. Reference Kwentus, Riesenberg, Marandi, Manning, Allen, Fishman, Spyker, Kehne and Cassella2012). When oral loxapine has been used regularly in the treatment of schizophrenia its adverse effects are similar to that of other first generation antipsychotics (Taylor et al. Reference Taylor, Paton and Kapur2012), i.e. it causes extrapyramidal side effects (EPS) is sedating and causes hyperprolactinaemia. In keeping with these effects, EPS including akathisia (Kwentus et al. Reference Kwentus, Riesenberg, Marandi, Manning, Allen, Fishman, Spyker, Kehne and Cassella2012), were noted in studies with inhaled loxapine (Keating Reference Keating2013; Allen et al. Reference Allen, Feifel, Lesem, Zimbroff, Ross, Munzar, Spyker and Cassella2011).
Efficacy
The efficacy of loxapine for the treatment of acute agitation in patients with bipolar affective disorder (BPAD) (Kwentus et al. Reference Kwentus, Riesenberg, Marandi, Manning, Allen, Fishman, Spyker, Kehne and Cassella2012) and schizophrenia (Lesem et al. Reference Lesem, Tran-Johnson, Riesenberg, Feifel, Allen, Fishman, Spyker, Kehne and Cassella2011; Allen et al. Reference Allen, Feifel, Lesem, Zimbroff, Ross, Munzar, Spyker and Cassella2011) has been studied in a couple of phase III placebo-controlled studies. These trials were conducted in patients who were able to give full written consent prior to accepting the trial medicine. It is inherently difficult to conduct robust ethical trials in highly disturbed individuals if consent is required. However, it is unlikely that these represent the patients needing RT in clinical practice. The published trials have already been extensively reviewed (Keating, Reference Keating2013; UKMi, 2013), and these documents provide a more in depth analysis of the efficacy measures and outcomes.
Potential benefits
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1. Quick onset of action: clinical effects were evident at 10 minutes.
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2. It has been used alongside lorazepam; in trials if a dose of loxapine was insufficient the ‘rescue’ medication allowed was a dose of IM lorazepam (Lesem et al. Reference Lesem, Tran-Johnson, Riesenberg, Feifel, Allen, Fishman, Spyker, Kehne and Cassella2011; Kwentus et al. Reference Kwentus, Riesenberg, Marandi, Manning, Allen, Fishman, Spyker, Kehne and Cassella2012; Allen et al. Reference Allen, Feifel, Lesem, Zimbroff, Ross, Munzar, Spyker and Cassella2011).
Potential drawbacks
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1. It has not been directly compared to other treatments (only placebo inhalation), so there is no data comparing its efficacy or safety to standard oral treatments.
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2. Issues around administration need to be taken into consideration: if a patient is refusing to swallow an oral medication, then they are also likely to refuse to inhale a medication.
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3. Bronchospasm was commonly reported in patients with active airways disease, and treatment with a short-acting beta-agonist bronchodilator may be required, i.e. salbutamol should be available. The patient should be monitored every 15 minutes for at least one hour after administration for signs and symptoms of bronchospasm. This may be a significant concern as national surveys (Pereira et al. Reference Pereira, Paton, Walkert, Shaw, Gray and Wildgust2005; Loynes et al. Reference Loynes, Innes and Dye2013) have shown that most trusts do not robustly monitor physical health checks of patients post RT, despite this being a NICE guideline recommendation (National Institute for Clinical Excellence, 2005). Furthermore, there are also no nationally agreed standards or recommendations on the specific intervals or duration of monitoring physical parameters post RT to drive this, and local trust guidelines vary considerably in their detail and recommended frequencies (Innes & Iyeke, Reference Innes and Iyeke2012).
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4. It should not be given to patients with asthma, COPD, other lung diseases associated with bronchospasm, or anyone with acute respiratory signs or symptoms. Therefore, all patients would need to be screened for such diseases prior to prescribing, which is not currently routine practice, and such medical history is not always immediately accessible at the point of admission.
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5. Cost: probably the last factor for consideration. As a newly licensed product under patent, and as a single use device, it is likely to be considerably more expensive than doses of currently available oral RT agents.
Potential place in therapy
This is a new formulation of a long existing antipsychotic. Formulated as an inhalation, this still requires the patient to agree to treatment, to open their mouth and comply with the administration instructions (after inhaling the patient must hold their breath for a short period). Therefore, this would only be suitable for patients who are not severely disturbed. As its licence says, ‘ADASUVE is indicated for the rapid control of mild-to-moderate agitation in adult patients with schizophrenia or bipolar disorder’ (European Medicines Agency, 2013), and as such may be an alternative to the range of established oral agents used in RT.
Statement of interest
There was no input from any pharmaceutical company into this article, and the author has no conflict of interest to declare.
