Graylands Hospital Drug Bulletin

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1 Graylands Hospital Drug Bulletin Lurasidone (Latuda ) North Metropolitan Health Service - Mental Health April 2016 Vol 23 No.1 ISSN Introduction Lurasidone is the latest antipsychotic medication to have been listed on the Pharmaceutical Benefits Scheme for the treatment of schizophrenia. It was approved for the treatment of schizophrenia in the USA in 2010, Canada in 2012 and in the UK in European Union marketing authority was granted for once daily dosing of lurasidone for schizophrenia in In 2013, the FDA also approved lurasidone for the treatment of depressive episodes in bipolar disorder. In 2015, lurasidone was ranked by Medscape as the 78 th most prescribed drug in the USA and is the third most prescribed antipsychotic behind aripiprazole and quetiapine. It is now six years since lurasidone was licenced for treatment of schizophrenia in the USA and three years since approval for bipolar treatment was granted. In preparing this drug bulletin, 56 articles were read and of those, only 12 had no drug company affiliation. Receptor Effects 1-4 D 2 Dopamine antagonist 5HT 2A antagonist 5HT 7 antagonist 5HT 1A - partial agonist Lurasidone has potent D 2 and 5-HT 2A affinity and also greater affinity than other second generation antipsychotics to 5-HT 7, 5-HT 1A and α 2c receptors. 5, 6 Lurasidone has little affinity for α 1, H 1 and M 1 receptors. The lack of α 1 affinity predicts for a lower risk of postural hypotension, the absence of 5-HT 2C, H 1 and M 1 affinity predict lurasidone will be less sedating, will not cause weight gain and will have a lower chance of causing anticholinergic effects and 1, 7, 8 4 negative cognitive effects. Despite this, there have been reports of modest sedation and dizziness and it has been proposed that these side effects may relate to as yet uncharacterized properties of potent 5HT 7 antagonism. 5 5-HT 7 has relatively recently been linked to circadian rhythm, sleep cycles, and areas of the brain implicated in mood regulation. 1 Positive effects of 5-HT 7 antagonism have been shown. Research in animal models indicates impairments of learning and memory are reversed by lurasidone. 5 The same tests using risperidone and clozapine showed only weak reversal of impairment. Preclinical lurasidone results indicate there may be advantages in the effects on cognition compared to other antipsychotics. 5 Lurasidone is expected to possess anxiolyticor antidepressant-like activity because of its higher affinities for 5-HT 7 and 5-HT 1A receptors. In terms of its receptor affinities, of the other second generation antipsychotics, lurasidone is probably most similar to risperidone and paliperidone, although there are significant Lurasidone Summary Approval : Schizophrenia Uses outside Australia: Bipolar Disorder, Depressive symptoms Recommended Dose: 40mg at night Maximum Dose : 160mg daily To be taken with food Metabolism: CYP3A4 Common Side Effects: akathisia, nausea, parkinsonism, and somnolence Availability: 40mg and 80mg filmcoated tablet Graylands Hospital Drug Bulletin April 2016 Vol 23 No.1 Page 1

2 differences to these drugs. 2 Pharmacokinetics Lurasidone is rapidly absorbed, with a time to maximum concentration of 1 to 3 hours and a mean half-life of 18 hours for a 40 mg dose. 1 However, lurasidone has poor bioavailability (approximately 20%), in part, due to extensive first pass metabolism by CYP3A4. 2, 5 Food increases the AUC of a 20mg dose threefold. 5 Lurasidone should be administered with a meal of at least 350 calories, regardless of fat content, to ensure maximum absorption. 2 Lurasidone is 99.8% protein bound with affinity to albumin and α 1-glycoprotein. 5 Lurasidone is eliminated by hepatic metabolism, primarily by CYP3A4. 2 Two of the metabolites are active but have low affinity for the human D 2 and 5-HT receptors. Two other metabolites have similar binding affinities to lurasidone but the clinical significance of these is not clear. 2, 6 The elimination half-life has been reported as being between 12.2 and 18.3 hours 2, 6 but this reflects results from single dose studies. At steady state, the half-life has been reported to increase to 36 hours. 5 This difference may explain the statement made in the product information: Steady- state concentrations of lurasidone are reached within 7 days of starting lurasidone. Following administration of 40 mg the mean elimination half-life was 18 hours. 6 It is widely accepted that steady state is reached in approximately 5 half-lives. If steady state is achieved in 7 days then the elimination half-life would have to be 33.6 hours. Renal and Hepatic Impairment No dosage adjustment is required with mild renal or hepatic impairment. In patients with moderate renal or hepatic impairment (CrCL 30 to 50 ml/min, Child-Pugh class B), the recommended starting dose is 20mg and the maximum dose should not exceed 80mg once daily. Lurasidone is not recommended in severe renal or hepatic impairment. 6 Interactions Caution is advised when combining with alcohol or CNS active medications, and medicines known to cause QT prolongation. 6 Lurasidone is mainly metabolised by CYP 3A4. The Australian, European and USA product information lists concomitant use of strong CYP 3A4 inhibitors and inducers as a contraindication. 6, 9, 10 As this is a predictable drug interaction, to include it among the strongest prohibitions seems overly cautious. The UK product information also mentions P- gp and BCRP inhibitors and gives dabigatran as an example 11 The European product information advises that lurasidone is an in vitro inhibitor of P-gp and BCRP but the clinical significance of this is unknown. 9 Lurasidone is a substrate of P-gp and BCRP in vitro but the in vivo relevance of this is unclear. Coadministration of lurasidone with P-gp and BCRP inhibitors increase exposure to lurasidone. 6, 9 Coadministration of lurasidone with digoxin (a P-gp substrate) did not increase the exposure to digoxin and only slightly increased C max (1.3 fold) and therefore, it is considered that lurasidone can be coadministered with digoxin. 6 Although the manufacturer does not recommend additional digoxin monitoring, given the narrow therapeutic index of digoxin, it may be prudent to monitor digoxin concentrations after the initiation of lurasidone. 12 Concomitant administration of the P-gp substrate dabigatran etexilate may result in increased dabigatran plasma concentrations. 9 Adverse Effects The various location versions of product information (PI) for Latuda contain much the same information in greater or lesser detail. The adverse events can be grouped into those which are mentioned in the PI but have little supporting evidence and those that are mentioned and have evidence indicating they are likely to occur. Graylands Hospital Drug Bulletin April 2016 Vol 23 No.1 Page 2

3 Adverse Events with Little Supporting Evidence Leucopenia, neutropenia and agranulocytosis The product information carries a warning against these blood dyscrasias but refers to reports during treatment with antipsychotic agents and other agents in the same class. 6 Conversation and correspondence with the Servier drug information service did not reveal any case reports of lurasidone being associated with blood dyscrasias and Servier ultimately referred questions on this topic back to the product information. Based on this, it seems that the warning is based on class effects alone and there appears to be no particular concern with lurasidone having the tendency to cause leucopenia, neutropenia or agranulocytosis. QTc Prolongation Phase II studies indicate lurasidone causes no significant QTc prolongation. 5 The product information, however, recommends caution when LATUDA is prescribed in patients with known cardiovascular disease or family history of QT prolongation, hypokalaemia, and in concomitant use with other medicinal products thought to prolong the QT interval. 6 A review article comparing 15 antipsychotics also found that lurasidone was the only antipsychotic with less QTc prolongation than placebo. 13 Seizure Frequency A warning to use lurasidone cautiously in patients with seizures is present in the product information. 6 However, lurasidone was not associated with increased seizure frequency in Phase II trials, nor was there any reported significant change in EEG. 5 Metabolic Profile Lurasidone has been reported to have little metabolic effects with negligible weight gain, dyslipidaemia and changes to glucose control. 5 A pooled analysis of lurasidone effects on weight and BMI changes showed that lurasidone has a lower liability for long term weight gain than other atypical antipsychotics. 14 Orthostatic Hypotension A warning that lurasidone may cause orthostatic hypotension is present in the product information. 6, 10 However, these statements combine dizziness, tachycardia and orthostatic hypotension. Macaluso et al in a review state that Supporting evidence for adrenergic blockade can be extrapolated from the fact that cases of orthostatic hypotension were reported in the clinical trials of lurasidone. 2 but they do not reference supporting evidence. Most literature does not mention orthostatic hypotension as a reported adverse effect and two papers reported dizziness but no 24, 25 hypotension. It appears that dizziness does occur in a small proportion of patients but this seems unrelated to orthostatic hypotension. Adverse Effects Likely to Occur The most common adverse events reported for patients taking lurasidone (greater than 5% and at least twice the rate of placebo) were akathisia, nausea, parkinsonism, and 7, 12 somnolence. Dose-related adverse effects are akathisia, somnolence, and parkinsonism with doses higher than 80 mg associated with an increase in akathisia, parkinsonism, somnolence, and prolactin elevations without additional statistically significant clinical benefit. 12 Hyperprolactinaemia While lurasidone does cause prolactin elevation in significantly more patients than placebo, 7 a comparative study ranked this effect well below that caused by risperidone, paliperidone and haloperidol. 13 Extrapyramidal Side Effects Lurasidone shows a higher risk for akathisia compared to risperidone, olanzapine, and quetiapine. Lurasidone also appears to increase the risk of anxiety but not agitation. 26 Somnolence Despite its lack of H 1 effects, somnolence appears to be reported by patients. Lurasidone has been ranked amongst the least sedating antipsychotics but still more sedating than aripiprazole, iloperidone, sertindole, paliperidone and amisulpride. In Graylands Hospital Drug Bulletin April 2016 Vol 23 No.1 Page 3

4 terms of sedation it is comparable to risperidone, haloperidol and asenapine. 13 Patient Reviews Although highly unreliable, it can sometimes be instructive to scan comments made by patients on websites about new drugs. Most of the side effects discussed by patients are the usual akathisia, parkinsonism and sedation. However, a repeated theme is discussion of effects that appear to be aggression, irritability, activation or even a manic switch. This should not be surprising since the recent direction of research has been towards the antidepressant effects of lurasidone. Prescribers should be mindful of the risks of prescribing an antipsychotic that can have antidepressant effects to patients at risk of activation. Pregnancy and Lactation Lurasidone is a category B1 drug in pregnancy i.e. no foetal toxicities have been observed in animal studies. 27 However exposure to lurasidone in the third trimester has been reported to increase the incidence of extrapyramidal and withdrawal symptoms in newborns. 27 Lurasidone does partition into breast milk of rats, therefore, lurasidone is not recommended to be used during breastfeeding. 27 Dosage The efficacy of lurasidone has been established at doses of 40, 80, 120 and 160 mg/day. The recommended starting dose is 40 mg once daily. Initial dose titration is not required. Patients should be treated with the lowest effective dose that provides optimal clinical response and tolerability, which is expected to be 40 mg or 80 mg once daily for most patients. Dose increases should be based on physician judgement and observed clinical response. In the six week controlled trials, there was no suggestion of added benefit with the 120 mg/day dose compared to 40 and 80 mg/day. In the pooled analyses, no added benefit occurred at 160 mg/day compared to lower doses. Doses above 80 mg may be considered for certain patients based on individual clinical judgement. The maximum recommended dose is 160 mg/day. 2 It is possible that evening dose administration is associated with more favourable tolerability overall relative to morning dosing. 19 Efficacy There is now a considerable body of evidence demonstrating superiority over placebo of lurasidone in the treatment of schizophrenia and depression in bipolar disorder. Non-inferiority has also been demonstrated against most of the current treatments. Placebo controlled trials have demonstrated efficacy for lurasidone in the treatment of schizophrenia 15, 28 Lurasidone has also been shown to be as effective as olanzapine 29 and quetiapine. 30 Comparable efficacy rates have been seen with risperidone although in one study all-cause discontinuation rates were higher with lurasidone. 25 Lurasidone significantly improved depressive symptoms compared with placebo in patients with major depressive disorder associated with subthreshold hypomanic symptoms 18, 24 (mixed features). An open-label, uncontrolled extension study demonstrated the safety and tolerability of lurasidone during 6 months of treatment for bipolar disorder, both as monotherapy and adjunctive with lithium or valproate. 16 Treatment with lurasidone has been associated with sustained improvement in depressive symptoms, and in patient-rated measures of quality of life and functioning. Lurasidone monotherapy has been shown to be comparable in terms of efficacy to the combination of olanzapine and fluoxetine, and superior to quetiapine, lithium or lamotrigine. 31 Cognitive enhancement from lurasidone has been linked with its strong affinity to 5-HT 7 32, 33 receptors. It has also been suggested that the concomitant inhibition of dopamine D2 and D4 receptors could induce cognitive impairment, and the lack of dopamine D4 receptor antagonism by lurasidone may contribute to its cognitive-enhancing effect. 34 Graylands Hospital Drug Bulletin April 2016 Vol 23 No.1 Page 4

5 Place in Therapy From the data published so far, lurasidone appears to be as effective as currently available antipsychotics in the treatment of schizophrenia with some advantages in side effect profile. It appears less likely to cause metabolic and cardiac effects but more likely to cause EPSE compared to other second generation antipsychotics. Although it is only licenced in Australia for the treatment of schizophrenia, lurasidone has been shown to be effective in the acute phase of depressive disorders associated with bipolar disorder, including depressive disorders with mixed features. Unlike most other antipsychotics, cognitive enhancement and antidepressant effects have been attributed to lurasidone. TGA changes to medication names The Therapeutic Goods Administration (TGA) has announced changes to the names of some medicines in Australia, occurring from April The intent is to better align with names used internationally. A complete list of medicines affected is available on the TGA website. Other countries such as the United Kingdom and New Zealand have already updated these names. There will be a four year transition period in which these changes will occur. The labelling and packaging of existing products will need to change over this period. The changes to psychotropic drugs are summarised below: Old Name New Name Overdose Two case reports of overdose with lurasidone were found, one patient ingesting 560mg and the other 1360mg. In both cases the patients recovered without any significant medical sequelae. The larger overdose was associated with mild hypertension and a single raised TSH result. 35 Availability Latuda film-coated tablets are intended for oral administration only. In Australia lurasidone is available in 40 mg (equivalent to mg lurasidone), or 80 mg (equivalent to mg lurasidone). In other countries a 20mg tablet is also available. 6 Conversations with Servier indicate that the tablets are recommended to be swallowed whole to mask the bitter taste. This Drug Bulletin was written by Darren Schwartz and was reviewed by Dr Joseph Lee and the Graylands Pharmacy Department Benzhexol Dothiepin Phenobarbitone Phenobarbitone sodium Benztropine mesylate Dexamphetamine sulfate Flupenthixol decanoate Pericyazine trihexyphenidyl (benzhexol) dosulepin (dothiepin) phenobarbital (phenobarbitone) phenobarbital (phenobarbitone) sodium benzatropine mesilate dexamfetamine sulfate flupentixol decanoate periciazine Comments are welcome at the address: DrugInformation.Graylands@health.wa.gov.au Graylands Hospital Drug Bulletin April 2016 Vol 23 No.1 Page 5

6 References 1. Citrome L. Lurasidone for schizophrenia: a brief review of a new second-generation antipsychotic. Clinical schizophrenia & related psychoses 2011 Jan;4(4): Macaluso M, Kazanchi H, Preskorn SH. How the pharmacokinetics and receptorbinding profile of lurasidone affect the clinical utility and safety of the drug in the treatment of schizophrenia. Expert opinion on drug metabolism & toxicology 2015;11(8): Potkin SG, Keator DB, Kesler-West ML, et al. D2 receptor occupancy following lurasidone treatment in patients with schizophrenia or schizoaffective disorder. CNS spectrums 2014 Apr;19(2): Ishibashi T, Horisawa T, Tokuda K, et al. Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5- hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity. The Journal of pharmacology and experimental therapeutics 2010 Jul;334(1): Meyer JM, Loebel AD, Schweizer E. Lurasidone: a new drug in development for schizophrenia. Expert opinion on investigational drugs 2009 Nov;18(11): Lurasidone Product Information. In: Laboratories S, ed. Version 4c ed; Citrome L. Lurasidone for schizophrenia: a review of the efficacy and safety profile for this newly approved secondgeneration antipsychotic. International journal of clinical practice 2011 Feb;65(2): Ishiyama T, Tokuda K, Ishibashi T, Ito A, Toma S, Ohno Y. Lurasidone (SM ), a novel atypical antipsychotic drug, reverses MK-801-induced impairment of learning and memory in the rat passive-avoidance test. Eur J Pharmacol 2007 Oct 31;572(2-3): Latuda, INN-lurasidone - Europa. European Medicines Agency; Lurasidone US Approval. 11. UK Prescribing information LATUDA. In: Pharmaceuticals S, ed. Europe; Risbood V, Lee JR, Roche-Desilets J, Fuller MA. Lurasidone: an atypical antipsychotic for schizophrenia. The Annals of pharmacotherapy 2012 Jul- Aug;46(7-8): Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013 Sep 14;382(9896): Meyer JM, Mao Y, Pikalov A, Cucchiaro J, Loebel A. Weight change during longterm treatment with lurasidone: pooled analysis of studies in patients with schizophrenia. International clinical psychopharmacology 2015 Nov;30(6): Tandon R, Cucchiaro J, Phillips D, et al. A double-blind, placebo-controlled, randomized withdrawal study of lurasidone for the maintenance of efficacy in patients with schizophrenia. Journal of psychopharmacology 2016 Jan;30(1): Ketter TA, Sarma K, Silva R, Kroger H, Cucchiaro J, Loebel A. LURASIDONE IN THE LONG TERM TREATMENT OF PATIENTS WITH BIPOLAR DISORDER: A 24 WEEK OPEN LABEL EXTENSION STUDY. Depression and anxiety Sanford M, Dhillon S. Lurasidone: a review of its use in adult patients with bipolar I depression. CNS drugs 2015 Mar;29(3): McIntyre RS, Cucchiaro J, Pikalov A, Kroger H, Loebel A. Lurasidone in the treatment of bipolar depression with mixed (subsyndromal hypomanic) features: post hoc analysis of a randomized placebo-controlled trial. The Journal of clinical psychiatry 2015 Apr;76(4): Harvey PD. The clinical utility of lurasidone in schizophrenia: patient considerations. Neuropsychiatric disease and treatment 2015;11: Franklin R, Zorowitz S, Corse AK, Widge AS, Deckersbach T. Lurasidone for the treatment of bipolar depression: an evidence-based review. Neuropsychiatric disease and treatment 2015;11: Findlay LJ, El-Mallakh P, El-Mallakh RS. Management of bipolar I depression: clinical utility of lurasidone. Therapeutics and clinical risk management 2015;11: Bobo WV. Asenapine, iloperidone and lurasidone: critical appraisal of the most recently approved pharmacotherapies for schizophrenia in adults. Expert review of clinical pharmacology 2013 Jan;6(1): Caccia S, Pasina L, Nobili A. Critical appraisal of lurasidone in the management of schizophrenia. Neuropsychiatric disease and treatment 2012;8: Graylands Hospital Drug Bulletin April 2016 Vol 23 No.1 Page 6

7 24. Suppes T, Silva R, Cucchiaro J, et al. Lurasidone for the Treatment of Major Depressive Disorder With Mixed Features: A Randomized, Double-Blind, Placebo-Controlled Study. The American journal of psychiatry 2015 Nov 10:appiajp Citrome L, Cucchiaro J, Sarma K, et al. Long-term safety and tolerability of lurasidone in schizophrenia: a 12-month, double-blind, active-controlled study. International clinical psychopharmacology 2012 May;27(3): Thomas JE, Caballero J, Harrington CA. The Incidence of Akathisia in the Treatment of Schizophrenia with Aripiprazole, Asenapine and Lurasidone: A Meta-Analysis. Curr Neuropharmacol 2015;13(5): Team APW. Lurasidone Loebel A, Cucchiaro J, Silva R, et al. Efficacy of lurasidone across five symptom dimensions of schizophrenia: pooled analysis of short-term, placebocontrolled studies. European psychiatry : the journal of the Association of European Psychiatrists 2015 Jan;30(1): Meltzer HY, Cucchiaro J, Silva R, et al. Lurasidone in the treatment of schizophrenia: a randomized, doubleblind, placebo- and olanzapine-controlled study. The American journal of psychiatry 2011 Sep;168(9): Loebel A, Cucchiaro J, Sarma K, et al. Efficacy and safety of lurasidone 80 mg/day and 160 mg/day in the treatment of schizophrenia: a randomized, doubleblind, placebo- and active-controlled trial. Schizophrenia research 2013 Apr;145(1-3): Taylor DM, Cornelius V, Smith L, Young AH. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments metaanalysis. Acta psychiatrica Scandinavica 2014 Dec;130(6): Sumiyoshi T, Higuchi Y, Uehara T. Neural basis for the ability of atypical antipsychotic drugs to improve cognition in schizophrenia. Frontiers in behavioral neuroscience 2013;7: Meltzer HY, Rajagopal L, Huang M, Oyamada Y, Kwon S, Horiguchi M. Translating the N-methyl-D-aspartate receptor antagonist model of schizophrenia to treatments for cognitive impairment in schizophrenia. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum 2013 Nov;16(10): Murai T, Nakako T, Ikeda K, Ikejiri M, Ishiyama T, Taiji M. Lack of dopamine D4 receptor affinity contributes to the procognitive effect of lurasidone. Behavioural brain research 2014 Mar 15;261: Molnar GP, Grimsich LC, Catalano G, Catalano MC. Acute lurasidone overdose. Journal of clinical psychopharmacology 2014 Dec;34(6): Graylands Hospital Drug Bulletin April 2016 Vol 23 No.1 Page 7