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Dorset Medicines Advisory Group

SHARED CARE GUIDELINES FOR THE USE OF MONOAMINE OXIDASE INHIBITORS (MAOIs) – and

INDICATION

Monoamine Oxidase Inhibitors (MAOIs) are licensed for the treatment of depressive illness especially where other trials of have failed. This shared care guideline recommends that MAOIs are initiated under specialist supervision due to their tolerability, significant dietary and pharmacological interactions. Once a patient’s condition has stabilised, it should be considered the MAOI can be prescribed by the patients GP under this shared care agreement.

NICE CG90 Depression in Adults: recognition and management recommends that when reviewing drug treatment for a person with depression whose symptoms have not adequately responded to initial pharmacological interventions: • check adherence to, and side effects from, initial treatment, increase the frequency of appointments using outcome monitoring with a validated outcome measure, • be aware that using a single rather than combination medication or augmentation is usually associated with a lower side-effect burden, • consider reintroducing previous treatments that have been inadequately delivered or adhered to, including increasing the dose, • consider switching to an alternative antidepressant. When switching to another antidepressant consider switching to: o initially a different SSRI or a better tolerated newer-generation antidepressant, o subsequently, an antidepressant of a different pharmacological class that may be less well tolerated, for example , a or an Monoamine-oxidase inhibitor. Due to the a more favourable side effect profile, less interactions and acquisition costs, phenelzine should be considered the first line MAOI of choice.

AREAS OF RESPONSIBILITY FOR SHARED CARE This shared care agreement outlines suggested ways in which the responsibilities for managing the prescribing of MAOIs can be shared between the specialist setting and the patient’s GP (if different). GPs are invited to participate. If the GP is not confident to undertake these roles, then he or she is under no obligation to do so. In such an event, the total clinical responsibility for the patient for the diagnosed condition remains with the specialist. If a specialist asks the GP to prescribe this drug, the GP should reply to this request as soon as practicable. Sharing of care assumes communication. The intention to share care is usually explained to the patient by the doctor initiating treatment. It is important that patients are consulted about treatment and are in agreement with it. The doctor who prescribes the medication legally assumes clinical responsibility for the drug and the consequences of its use. REFERRAL AND INITIATION

Monoamine oxidase inhibitors should only be initiated under specialist supervision. Phenelzine should be considered first line MAOI of choice.

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Specialist Responsibilities 1 Prescribing until maintenance regime established. 2 Discussion of risks and benefits with patients and carers in particular the dietary restrictions and interactions with medication, including OTC. Specialist Responsibilities 3 Provision of written information on use, side effects and dietary restrictions 4 Provide details of concurrent medication prescribed via psychiatric secondary care to GP. 5 Provide details of patient follow up including care plan. 6 Inform GP of any identified problems e.g. compliance with treatment. 7 Provide details of mental health key worker if appropriate. 8 Provide details of concurrent medication prescribed via psychiatric secondary care to GP. 9 Provide support to GP in response to queries about switching antidepressants

General Practitioner Responsibilities 1 Provide details of any concurrent medication, coexisting health problems and compliance issues to the specialist 2 Continued discussion of risks and benefits of medication with patients and carers as required. 3 Prescribing once maintenance doses established. Switching or discontinuation should only be done through the specialist 4 Continued monitoring as agreed with secondary care and referral back to secondary care if patient becomes non-compliant and/or if mental state 5 Continued discussion of risks and benefits of medication with patients and carers as required. 6 Prescribing once maintenance doses established. Switching or discontinuation should only be done through the specialist deteriorates 7 Respond to adverse reactions and advise on concomitant medication. 8 Update specialist on any changes in medical condition or prescribed concomitant medication until discharged from specialist services 9 Seek support from specialist when considering switching antidepressants

Patient's role (or that of carer)

1 Take medication as prescribed

2 Follow instructions re diet

3 Report any side effects

4 Report worsening of depressive symptoms

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SUPPORTING INFORMATION

Monitoring Regular blood pressure measurement is recommended during initiation and routine checks should be made during maintenance. Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Dosage and Administration Tranylcypramine Initially 10mg twice daily not later than 3pm, increasing the 2nd dose to 20mg after 1 week if necessary. Doses above 30mg daily under close supervision only; usual maintenance dose 10mg daily.

Elderly (over 65 years) Use with great caution and at reduced dose.

Children Not recommended. Refer to manufacturer‘s advice on concurrent electroconvulsive therapy and doses. Phenelzine One 15mg tablet three times a day. A response is usually seen within the first week. If no response is evident after two weeks, the dosage may be increased to a maximum of one 15mg tablet four times a day. Doses of up to two 15mg tablets three times a day may be used in hospitals. The effectiveness of the drug may not become apparent in less than 4 weeks therapy. After a satisfactory response has been achieved, the dosage may be reduced very gradually to a suitable maintenance level. This may be as low as one 15mg tablet every other day. Elderly (over 65 years): As for adults. Isocarboxazid A daily dose of 30mg, in single or divided doses, should be given until improvement is obtained. The maximal effect is only observed after a period varying from 1 - 4 weeks. If no improvement has been seen by 4 weeks, doses up to 60mg may be tried, according to the patient's tolerance, for no longer than 4 - 6 weeks, provided the patient is closely monitored because of the increased risk of adverse reactions occurring. Once the optimal effect is achieved, the dose should be reduced to the lowest possible amount sufficient to maintain the improvement. Clinical experience has shown this to be usually 10 - 20mg daily but up to 40mg daily may be required in some cases. The elderly The elderly are more likely to experience adverse reactions such as agitation, confusion and postural hypotension. Half the normal maintenance dose may be sufficient to produce a satisfactory clinical response.

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Duration of treatment NICE guidance recommends that people with depression who benefit from treatment with antidepressants are advised to continue with treatment for at least 6 months after remission, extending to at least 2 years for people at risk of relapse. Contraindications Common to all MAOIs Cerebrovascular disease, severe cardiovascular disease, actual or suspected phaeochromocytoma, impairment, blood dyscrasias, hyperthyroidism. MAOIs are not indicated in manic phase.

Selective inhibitors (SSRIs): Cases of serious and sometimes fatal reactions () have been reported in patients receiving monoamine oxidase inhibitors (MAOIs) in combination with SSRIs, and in patients who have recently discontinued an SSRI and have been started on a MAOI. Treatment with SSRIs should only be started 2 weeks after discontinuation of Isocarboxazid. Conversely, treatment with should not be started until at least a week after stopping a SSRI or related anti-depressant (at least 5 weeks for ). Use of MAOIs with or after has been reported to produce a serotonin syndrome, sometimes fatal.

Avoid use with other MAOIs, as symptoms of overdose are possible; or with , since increased blood pressure may occur. Due to risk of hypertensive crisis or severe convulsive seizures avoid for at least 2 weeks after stopping previous MAOI (for e.g. furazolidone, isocarboxazid, pargyline HCl and procarbazine HCl) and then start at a reduced dose. Similarly, at least a week should elapse between the discontinuance of tranylcypromine and the administration of another MAOI, or the re- administration of tranylcypromine. Tranylcypromine. Reports of hyperactivity, hypertonicity, hyperpyrexia, coma and death have been associated with the use of tranylcypromine in combination with tricyclic antidepressants; Tetracyclic antidepressants should also be avoided. The use of in patients already on tranylcypromine may be particularly hazardous.

Phenelzine should not be used in combination with , , or with CNS depressants such as and narcotic . Death has been reported in patients receiving a single dose of . It is suggested that MAOIs are not administered at the same time as antiepileptics, altretamine, doxapram, , oxypertine or . Phenelzine should be withdrawn two weeks before elective surgery/dentistry. Phenelzine should not be given with or local anaesthesia containing sympathomimetic vasoconstrictors, possible combined hypotensive effects of phenelzine and spinal anaesthesia should be considered.

Cautions Common to all MAOIs Diabetes mellitus, cardiovascular disease, epilepsy, blood disorders, concurrent electroconvulsive therapy; elderly (dose reduction is required ) monitor blood pressure (risk of postural hypotension and hypertensive responses—discontinue if palpitations or frequent headaches); if possible avoid abrupt withdrawal; severe hypertensive reactions to certain drugs and foods (see interactions); avoid in restless or agitated patients; acute porphyria. Patients should be specifically asked if they are taking any other medication because of the possibility of drug interactions.

Tranylcypramine Due to potential for interaction with analgesics; caution should be exercised in prescribing tranylcypromine for patients with a previous history of dependence on drugs or alcohol Tranylcypromine should not be used with indirectly acting sympathomimetic amines such as , or similar anti-obesity agents, ephedrine or phenylpropanolamine (certain cold cures may contain such agents) or with levodopa or , as severe hypertensive reactions may result. All patients taking tranylcypromine should be warned against self-medication

4 Dorset Medicines Advisory Group with proprietary 'cold- cure' preparations and nasal decongestants and advised of the dietary restriction (see interactions). Tranylcypromine should not be used in pregnancy, unless considered essential by the physician. Evidence for safety in human pregnancy is lacking, nor is there evidence from animal work that it is free from hazard. As it is excreted in human milk then a risk cannot be excluded. A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from tranylcypromine therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Use tranylcypromine with great caution in elderly patients; in those with cardiovascular disease in whom physical activity should be regulated, as the drug may suppress anginal pain. Tranylcypromine should preferably be withdrawn at least two weeks before elective surgery because of possible hazardous drug interactions with certain anaesthetics

Side effects Common to all MAOIs Commonly postural hypotension (especially in elderly) which may be temporary and dizziness,. If hypotension persists, then the manufacturers recommend discontinuation. Less common sideeffects include drowsiness, insomnia, headache, weakness and fatigue, dry mouth, constipation and other gastro-intestinal disturbances, oedema, myoclonic movement, hyperreflexia, elevated liver enzymes; agitation and tremors, nervousness, euphoria, arrhythmias, blurred vision, nystagmus, difficulty in micturition, sweating, convulsions, rashes, purpura, leucopenia, sexual disturbances, sleep disturbances and weight gain with inappropriate appetite may also occur; psychotic episodes with hypomanic behaviour, confusion, and may be induced in susceptible persons; suicidal behaviour; jaundice has been reported and, on rare occasions, fatal progressive hepatocellular necrosis; paraesthesia, peripheral neuritis, peripheral neuropathy may be due to pyridoxine deficiency; hyponatraemia, blood dyscrasias, hypertensive crisis with throbbing headache requiring discontinuation of treatment as it may be an early warning of hypertensive crisis

Other rare severe side-effects reported include: ataxia, shock-like coma, toxic delirium, neuroleptic malignant syndrome (occasionally fatal), manic reaction, acute anxiety reaction, precipitation of schizophrenia, transient respiratory and cardiovascular depression following ECT, fatal progressive necrotising hepatocellular damage, reversible jaundice, hypermetabolic syndrome, oedema of the glottis and fever associated with increased muscle tone. Hyponatraemia should be considered in all patients who develop drowsiness, confusion or convulsions

Severe hypertensive reactions may occur, notably in association with foods containing tyramine (see interactions). On occasions these have been fatal. Symptoms may be pain and stiffness in the neck, multiple extrasystoles, often with substernal pain, sweating, and pallor, sometimes followed by flushing, mydriasis and photophobia.

Tranylcypromine may aggravate some co-existing symptoms in depression such as anxiety and agitation. Overstimulation, including anxiety and agitation, developing rarely into hypomanias has also been observed. Mild dependence as amphetamine-like structure. Insomnia is the most frequent side effect; manufacturers advise it may usually be overcome by giving the last dose of the day not later than 3 p.m., by reducing dosage, or by prescribing a mild hypnotic. Dependence on tranylcypromine with tolerance to high doses has been reported rarely and can occur in patients without past history of drug dependence.

Phenelzine may cause excessive stimulation in schizophrenic patients; in manic-depressive states it may result in a swing from a depressive to a manic phase. Due to the possibility of patients undergoing ―Withdrawal Syndrome‖ abrupt withdrawal of phenelzine should be avoided where possible. Withdrawal may be associated with nausea, vomiting and malaise. An uncommon withdrawal

5 Dorset Medicines Advisory Group syndrome following abrupt withdrawal of phenelzine has been infrequently reported. Signs and symptoms of this syndrome generally commence 24 to 72 hours after drug discontinuation and may vary from vivid nightmares and agitation to frank psychosis and convulsions. This syndrome generally responds to reinstitution of low-dose phenelzine followed by cautious downward titration and discontinuation.

Interactions BNF currently lists 933 interactions with MAOIs. The following table highlights the interactions with other classes of medication. For a full list of interactions, the BNF online can be accessed here.

Drug/drug group Nature of interaction ACE Inhibitors MAOIs possibly enhance hypotensive effect of ACE inhibitors Adrenergic Enhanced hypotensive effect when MAOIs given with adrenergic neurone Neurone Blockers blockers MAOIs interact with tyramine found in some beverages containing alcohol and some dealcoholised beverages (hypertensive crisis)—if no tyramine, Alcohol enhanced hypotensive effect. Additive central effects including sedation are predicted. Alpha-blockers enhanced hypotensive effect when MAOIs given with alpha-blockers Preferably withdraw at least two weeks before elective surgery because of possible drug interaction. Patients taking MAOIs should not undergo surgery requiring general anaesthesia. Also, they should not be given cocaine or local Anaesthetics anaesthesia containing vasoconstrictors. The possible combined hypotensive effects of MAOIs and spinal anaesthesia should be kept in mind. Discontinue MAOI therapy two weeks before surgery because of the possible hazardous interaction with certain anaesthetics Avoid narcotic analgesics , because of possible potentiation. Avoid concurrent use with pethidine and closely related narcotic analgesics, Analgesics and nefopam, as potentiation may occur; a similar reaction has been reported with dextromethorphan. Angiotensin-II MAOIs possibly enhance hypotensive effect of angiotensin-II receptor Receptor antagonists Antagonists Antidepressants, MAOIs increase CNS effects of SSRIs (risk of serious toxicity) SSRI Increased risk of hypertension and CNS excitation when MAOIs given with tricyclics, tricyclics should not be started until 2 weeks after stopping MAOIs Antidepressants, (3 weeks if starting clomipramine or ), also MAOIs should not be Tricyclic started for at least 1–2 weeks after stopping tricyclics (3 weeks in the case of clomipramine or imipramine) After stopping MAOIs do not start tricyclic-related antidepressants for 2 Antidepressants, weeks, also MAOIs should not be started until at least 1–2 weeks after Tricyclic (related) stopping tricyclic-related antidepressants MAOIs possibly enhance hypoglycaemic effect of antidiabetics including Antidiabetics insulin. MAOIs possibly antagonise anticonvulsant effect of antiepileptics (convulsive Antiepileptics threshold lowered)

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Drug/drug group Nature of interaction Increased antimuscarinic and sedative effects when MAOIs given with Antihistamines Note: Sedative interactions apply to a lesser extent to the non-sedating antihistamines. Interactions do not generally apply to antihistamines used for topical action (including inhalation) Increased risk of antimuscarinic side-effects when MAOIs given with antimuscarinics Note: Many drugs have antimuscarinic effects; concomitant use of two or Antimuscarinics more such drugs can increase side-effects such as dry mouth, retention, and constipation; concomitant use can also lead to confusion in the elderly. Interactions do not generally apply to antimuscarinics used by inhalation Contra-indication with levodopa or dopamine, as severe hypertensive Antiparkison‘s reactions may result; In combination with anticholinergic anti-parkinsonism agents drugs potentiation has been reported. Antiparkinsonism drugs should be used with caution in patients receiving MAOIs. Enhanced hypotensive effect when MAOIs given with beta-blockers Note: Since systemic absorption may follow topical application of beta- Beta -blockers blockers to the eye the possibility of interactions, in particular, with drugs such as should be borne in mind Calcium-channel Enhanced hypotensive effect when MAOIs given with calcium-channel Blockers blockers Matured cheeses, hydrolysed protein extracts such as Marmite or Bovril, Food and beverages alcoholic drinks, particularly red wines such as chianti, non-alcoholic beer and with a high lager, and protein foods that are not fresh or whose preparation involved tyramine content hydrolysis, fermentation, pickling or hanging, also broad bean pods which contain levodopa and banana skins may also present a hazard. Insulin MAOIs enhance hypoglycaemic effect of insulin MAOIs can cause increased risk of hypertension and CNS excitation when given with other MAOIs (avoid for at least 2 weeks after stopping previous MAOIs and then start at a reduced dose) MAOIs Note: For interactions of reversible MAO-A inhibitors (RIMAs) see Moclobemide, and for interactions of MAO-B inhibitors see Rasagiline and Selegiline; the antibacterial Linezolid is a reversible, non-selective MAO inhibitor Possible CNS excitation or depression (hypertension or hypotension) when MAOIs given with analgesics and nefopam, as potentiation may occur. Opioid Analgesics A similar reaction has been reported with dextromethorphan avoid concomitant use and for 2 weeks after stopping MAOIs before starting treatment with opioid analgesics. Risk of hypertensive crisis when MAOIs given with sympathomimetics. Avoid use with indirectly acting sympathomimetic amines such as Sympathomimetics amphetamine, fenfluramine or similar anti-obesity agents, ephedrine or phenylpropanolamine (certain cold cures may contain such agents) Possible increased serotonergic effects and increased risk of convulsions when MAOIs given with tramadol—some manufacturers advise avoid concomitant use and for 2 weeks after stopping MAOIs

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Other antidepressants should not be started for 2 weeks after treatment with MAOIs has been stopped (3 weeks with clomipramine or imipramine). Only experienced psychiatrists should use selected tricyclics in conjunction with MAOIs as this is potentially fatal. There is no evidence that the combination is more effective than when either constituent is used alone. The combination of tranylcypromine with clomipramine is particularly dangerous. Conversely, MAOIs should not be started until at least 7–14 days after a tricyclic or related antidepressant (3 weeks in the case of clomipramine or imipramine) has been stopped. In addition, MAOIs should not be started for at least 2 weeks after a previous MAOI has been stopped (then started at a reduced dose). Drugs with a very long half-life (such as fluoxetine), it may be advisable to extend this interval (see interactions) This list is not exhaustive. The manufacturer’s summary of product characteristics (SPC) and the most current edition of the British National Formulary should be consulted for full information on contra-indications, warnings, side-effects and drug interactions.

Information to patient Verbal information along with the patient information leaflet from the Choice & Medication website will be provided. It is essential that the patient has a good understanding of the food restrictions and is able to adhere to these. Information on these food risks will be given to the patient prior to starting treatment.

Drug costs: Monthly Maximum MAOI Pack size Dosage form Price maximum daily dose drug cost Phenelzine 100 15mg tablet £22.50 90mg £22.50 Tranylcypromine 28 10mg tablet £239.94 30mg £719.82 Isocarboxazid 56 10mg tablet £217.75 60mg £653.25

References 1. Summary of Product Characterisics for tranylcypromine, Phenelzine and Isocaboxazid. Accessed online Feb 2018 2. NICE CG90 Depression last updated April 2016 https://www.nice.org.uk/guidance/cg90 Accessed Feb 20118 3. NICE CG91 Depression in adults with a chronic physical health problem: recognition and management Oct 2009 https://www.nice.org.uk/guidance/cg91 Accessed Feb 2018 4. The Maudsley Prescribing Guidelines in Psychiatry 12th Edition 5. Psychotropic Drug Directory 2016. Bazire, S. LRP LLC

Written by Medicines Management Mental Health February 2018 Group, Dorset Healthcare Approved by Dorset Medicines Advisory Group March 2018 Date of next review Feb 2020 or before, in light of new evidence or information.

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