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1 Document name: Focus on paroxetine Portfolio Document type: Medicines Management Communication Staff group to whom it applies: All prescribers, pharmacy and clinical staff within the Trust Distribution: The whole of the Trust How to access: Issue date: Next review: Approved by: Developed by: Director leads: Intranet Ward folders Date of issue March 2006 Reviewed November 2008 November 2010 September 2011 Date of review September 2014 Drug and Therapeutics Sub- Committee Kate Dewhirst Senior Clinical Pharmacist, North Kirklees on behalf of the Drug and Therapeutics Sub-Committee Medical Director Contact for advice: Medicines Information

2 South West Yorkshire Partnership NHS Foundation Trust Drug and Therapeutics Committee Communication Focus on Paroxetine Introduction Paroxetine is a selective serotonin re-uptake inhibitor (SSRI) and is licensed for the treatment of a wide variety of mental health disorders. It has been the focus of many media campaigns and Committee on Safety of Medicines (CSM) investigations and alerts. This document attempts to bring these alerts together and support safe prescribing of paroxetine in South West Yorkshire Partnership NHS Foundation Trust. Always refer to the summary of product characteristics before prescribing and for full details of all adverse effects, contra-indications and precautions ( The South West Yorkshire Mental Health NHS Trust prescribing guidelines for the pharmacological treatment of depression recommend that paroxetine is no longer prescribed for new patients. Dosage and administration Paroxetine is given orally, once daily in the morning with food. Tablets should be swallowed rather than chewed or crushed and for the liquid, shake the bottle. The maximum recommended dose in the elderly should not exceed 40mg for any indication. CSM advice (paroxetine dosage). The recommended dose for the treatment of depression, social anxiety disorder, generalised anxiety disorder, and post-traumatic stress disorder is 20mg and for obsessive-compulsive disorder and panic disorder it is 40mg daily. There is no evidence that higher doses are more effective. Indication Initial dose Recommended treatment dose Major depressive disorder Obsessive compulsive disorder Panic disorder, with or without agoraphobia Social anxiety disorders/social phobia Generalised anxiety disorder Post Traumatic stress disorder Increments 20mg daily 40mg daily After three to 10mg daily 40mg daily After three to Licensed maximum (see CSM advice ) but not recommended by CSM 60mg daily 60mg daily Length of treatment At least six months May be several months or longer May be several months or longer Evaluate regularly At least 6 months, up to one year Evaluate regularly Contra indications Paroxetine is contra-indicated in combination with monoamine oxidase inhibitors (MAOIs)

3 Adverse events and special precautions Withdrawal symptoms seen on discontinuation of paroxetine Stopping antidepressants abruptly can cause discontinuation/withdrawal symptoms. To minimize the risk of the dose should be reduced gradually over at least four weeks and possibly longer. Symptoms are usually mild and self-limiting but can occasionally be severe especially if the antidepressant is stopped abruptly. Some commonly experience withdrawal symptoms Flu-like symptoms (chills, aches, sweating) Nausea and vomiting Dizziness Numbness and tingling (electric shock sensations) Irritability Anxiety Insomnia Excessive (vivid) dreams The perception of symptoms may be made worse if no prior warning is given. Paroxetine is associated with the greatest number of spontaneous reports of withdrawal reactions (CSM 2000). This may be due in part to reports in the media and articles in medical publications prior to other SSRIs being available. The recommended tapering regimen is a 10mg reduction at weekly intervals. If intolerable symptoms occur the resumption of the previously prescribed dose may be considered and a more gradual decrease subsequently attempted. Children and adolescents Paroxetine should not be used in children under 7 years, as safety and efficacy have not been established. Paroxetine should not be used in children and adolescents (ages 7 to 17 years) as controlled clinical trials have found paroxetine to be associated with an increased risk of suicidal behaviour and hostility. Efficacy has not been adequately demonstrated CSM advice (SSRIs for major depressive disorder in children and adolescents). Following a review of the safety and efficacy of SSRIs for the treatment of depression in children and adolescents the CSM has advised (December 2003) that the SSRIs citalopram, escitalopram, paroxetine and sertraline and the related antidepressant venlafaxine are contra-indicated in those under 18 years; fluvoxamine should also not be used to treat depression in these individuals because there is insufficient information on safety and efficacy. Suicide/suicidal ideation A CSM Expert Working Group communication on the safety of SSRIs concluded that there was no evidence to suggest that SSRIs increase the risk of suicide to a greater extent than other antidepressants. However depression and other psychiatric conditions for which paroxetine are licensed can be associated with an increased risk of suicide behaviour, which persists until significant remission occurs. It is general clinical experience with all antidepressant therapies that the risk of suicide may increase in the early stages of recovery. There is a possibility this risk may be higher in young adults ages All patients started on paroxetine should be closely monitored during all stages of treatment but this is especially important in the early stages of treatment, after dose increases, in those with a recent or past history of suicidal attempts or thoughts and young adults. NICE recommend weekly monitoring for the first month. Akathesia The use of paroxetine has been associated with the development of akathesia. This is most likely to occur within the first few weeks of treatment. If these symptoms develop increasing the dose may be detrimental. CSM advice Extra-pyramidal reactions (including orofacial dystonias) are reported to the CSM more commonly with Paroxetine than with other SSRIs Serotonin syndrome In common with other SSRIs, Serotonin syndrome (and neuroleptic malignant syndrome like events have been reported rarely with paroxetine on its own or in combination with other serotonergic agents. In common with other SSRIs and other classes of antidepressant, paroxetine has been associated with Altered glycaemic control in diabetes Precipitation of seizures or worsening of epilepsy

4 Mydriasis and caution should be used in glaucoma Gastro-intestinal haemorrhage (SSRIs only) Mania Hyponatraemia Hyponatraemia (usually in the elderly and possibly due to inappropriate secretion of antidiuretic hormone) has been associated with all types of antidepressants however it has been reported more frequently with SSRIs than with other antidepressants. The CSM has advised that hyponatraemia should be considered in all patients who develop drowsiness, confusion or convulsions while taking an antidepressant. Pregnancy Paroxetine should only be used in pregnancy when strictly indicated. NICE Guideline for antenatal and postnatal mental health advises a woman taking paroxetine who is planning a pregnancy or has an unplanned pregnancy to stop the drug. However the MHRA recommends that paroxetine should not be stopped abruptly due to the risk of precipitating discontinuation symptoms and should be reviewed at the next appointment. A Drug Safety Update in June 2010 describes the increased risk of congenital cardiac malformations with regard to paroxetine and Fluoxetine. The absolute risk is about doubled from 1 in 100 to 2 in 100. If maternal use of paroxetine continues into later pregnancy, in particular the third trimester the neonate may show signs of withdrawal symptoms or serotonergic effects eg respiratory distress, vomiting, irritability, lethargy, tremor, constant crying. There may be an increased risk of side effects in some women as paroxetine may accumulate. There is a risk of persistant pulmonary hypertension, presenting as severe hypoxia when SSRIs are taken after 20 weeks gestation ( 5 cases per 1000 pregnancies compared to the background rate or 1-2 per 1000 pregnancies). Clinically relevant interactions Serotonergic agents Including MAOI s, tryptophan, triptans, tramadol, lithium, St. John s work and extracts Enzyme induction/inhibition CYP2D6 inhibition Oral anticoagulants NSAIDs and antiplatelet agents Common to all SSRIs Increase in serotonergic side effects such as nausea and anxiety Serotonin syndrome Concomitant use of MAOI s is contra-indicated The metabolism of paroxetine may be affected by the induction or inhibition of metabolising enzyme. If using with an enzyme inhibitor eg cimetidine consider maintaining the dose of paroxetine at the lower end of the range. With known enzyme inducers (eg carbamazepine, rifampicin phenytoin) adjust doses according to clinical response. As with other antidepressants including the SSRIs, paroxetine inhibits the hepatic cytochrome P450 enzyme CYP2D6. It is probably the most potent inhibitor compared to the other SSRIs and as such may have a higher incidence of interaction with medications metabolised by this enzyme. Eg metoprolol Certain antidepressants such as clomipramine Risperidone, clozapine, thioridazine, pimozide Antiarrhythmics propenafone, flecanide A pharmacodynamic interaction common to all SSRIs Increased anticoagulant activity and increased risk of haemorrhage A pharmacodynamic interaction common to all SSRIs Increased risk of haemorrhage Caution with other medication which may affect platelet function and in those with a history of bleeding disorders

5 Recommendations Paroxetine should not be considered for use as an antidepressant unless previous efficacy and tolerability have been established in an individual. Do not initiate in children, adolescents or women of childbearing age. The starting dose of paroxetine should be no more than 20mg (10mg in panic disorder) per day Increments should be in steps of no more than 10mg and occur only after several weeks and a full review and in accordance with the licensed maximum. Ensure service user and or carer is aware of potential serious adverse events and the signs and symptoms to be mindful of. This includes the increased risk of suicide in the early stages of treatment and initial increase in anxiety and irritability. Monitor closely during the early stages of treatment and after dose increments. In young adults and those with a history of self-harm monitor weekly for the first month. Ensure service user or carer is aware of the transient nausea and vomiting upon initiation of treatment and after dose increases. Ensure service user or carer is aware of the need for gradual reduction before discontinuation and the symptoms which may accompany dose reduction or abrupt discontinuation. Provide verbal and written information. Continually review efficacy and symptom control. Document this review Long-term use should be regularly evaluated. Review and discuss risks and benefits and discontinue if possible in pregnancy. References Summary of Product Characteristics; Seroxat; GlaxoSmithKline UK; October 2005 The Maudlsey Prescribing Guidelines 10t h Edition, South London and Maudsley NHS Trust, Oxleas NHS Trust Psychotropic Drug Directory, 2010; Bazire Findings of the Expert Working Group of the Committee of Safety of medicines, December 2004 CSM. Current Problems in Pharmacovigilance, Volume 26, September NICE Clinical Guidelines for Depression, Post-traumatic stress disorder, Anxiety, Antenatal and post natal mental health, Prepared by Kate Dewhirst for Drug and Therapeutics TAG Approved by Drug & Therapeutic TAG 7 th March 2006 Reviewed and amended Sept 2011 Next review Sept 2014