Lithium Prescribing and Monitoring Guidelines

When using this document please ensure that the version you are using is the most up to date either by checking on the Trust intranet or if the review date has passed, please contact the author.

‘Out of date policy documents must not be relied upon’

These guidelines have been adapted with kind permission from the guidelines developed by the Dorset HealthCare University NHS Foundation Trust

Approval Version Issue Date Review Document Author Committee Date D&TC 1 Dec 2010 Dec 2012 Dr James Stallard Consultant in Liaison Psychiatry Jacqui Bowden Clinical Pharmacy Manager D&TC 2 Oct 2013 Oct 2016 Dr James Stallard Laura Dollery, Risk Pharmacist

Version Control

Version Date Author Section Principle Amendment Changes 2 October Laura Dollery, Reviewed, no changes. 2013 Risk Pharmacist Amended to comply with Document Control

Medicines Policy Page 1 of 14 October, 2013 Lithium prescribing & monitoring Version 2 Lithium Prescribing and Monitoring Guidelines

Contents

1. Introduction 2. Indications 3. Initiation 4. Blood monitoring, prescribing, supply and administration 5. Lithium in the Acute Hospital Setting 5.1 Acutely unwell patients 5.2 Adverse effects 5.3 Lithium toxicity 5.4 Management of lithium toxicity 5.5 Renal impairment 5.6 Fluid balance 5.7 Surgery 6. Maintenance 7. Stopping lithium 8. Monitoring summary 9. References Appendix A Drug Interactions with Lithium

1.0 INTRODUCTION Medicines Policy Page 2 of 14 October, 2013 Lithium prescribing & monitoring Version 2

1.1 These guidelines have been developed to ensure that the management of Lithium therapy is safe, effective, evidence based, and in line with current NICE Guidance: NICE Clinical Guideline 38 – Bipolar Disorder; July 2006; NICE Clinical Guideline 23 – Depression amended April 2007. They were reviewed in July 2010 to ensure that the standards stated in the NPSA report Safer Lithium Therapy NPSA/2009/PSA005 are being met.

1.2 Lithium is classified as ‘amber’ according to the DHFT Mental Health Formulary and Bournemouth Health Community Joint Formulary. This means that treatment is initiated by a specialist (usually in secondary care), and responsibility remains with the specialist until the patient is stabilised on the optimum dose. Prescribing responsibility may be transferred to primary care if agreed. There is an associated shared care guideline.

1.3 This Guideline does not provide detail on dosage, side-effects, interactions or contra-indications. Please refer to the latest SPC for this information or contact the Pharmacy Department.

2.0 INDICATIONS

Bipolar

2.1 Lithium, is an option that should be considered for long-term treatment of bipolar disorder. The choice should depend on: – response to previous treatments – the relative risk, and known precipitants, of manic versus depressive relapse – physical risk factors, particularly renal disease, obesity and diabetes – the patient’s preference and history of adherence – gender (valproate should preferably not be prescribed for women of child-bearing potential) – a brief assessment of cognitive state (such as the Mini-Mental State Examination) if appropriate, for example, for older people, (NICE CG 38 – Bipolar Disorder; July 2006).

Depression

2.2 Treatment resistant depression: consider a trial of lithium augmentation for patients whose depression has failed to respond to several antidepressants in adequate doses for adequate periods of time, and who are prepared to tolerate the burdens associated with its use, (NICE CG 23– Depression amended April 2007).

2.3 Recurrent depression and relapse prevention: patients who have had multiple episodes of depression, and who have had a good response to treatment with an antidepressant and lithium augmentation, should remain on the combination for at least 6 months, (NICE CG 23– Depression amended April 2007).

2.4 When patients are taking an antidepressant with lithium augmentation, if one drug is to be discontinued, this should be lithium in preference to the antidepressant, (NICE CG 23– Depression amended April 2007).

Medicines Policy Page 3 of 14 October, 2013 Lithium prescribing & monitoring Version 2 2.5 Lithium augmentation should be routinely initiated only by specialist mental healthcare professionals (including General Practitioners with a Special Interest in Mental Health), (NICE CG 23– Depression amended April 2007).

3.0 INITIATION

It is rare that it would be necessary to start lithium treatment in an acute general hospital. Lithium should only be initiated by specialist mental healthcare professionals.

3.1 The benefits, risks and side-effects of treatment with lithium should be discussed with the patient. This should include the need for compliance and long-term commitment to the treatment, and the risk of stopping abruptly. This discussion with the patient should be documented in the healthcare record.

3.2 All patients commencing on lithium therapy should be given a copy of the purple NPSA pack comprising the patient information booklet, a lithium alert card and record book for tracking lithium plasma level results. The patient should be advised that the results record needs to be available for the dispensing pharmacist to allow dispensing of lithium in community. This should also be recorded in the healthcare record

3.3 Baseline monitoring should be performed before prescribing commences, see section 4 for further detail. If the results do not fall within the normal range, then the decision to commence prescribing lithium should be reviewed if appropriate or the starting dose reconsidered.

3.4 Women of child bearing age: exclude pregnancy (test if appropriate) and advise to use suitable contraception. (If patient becomes pregnant, refer to the Perinatal Care Pathway (available at St Ann’s) and/or current specialist advice).

3.5 Advise patient with regard to adequate fluid balance and sodium intake and interactions with medication that can be bought over the counter such as NSAIDs.

3.6 The brand of lithium predominantly prescribed within the Trust is Priadel®. Different preparations may vary in bioavailability, so the same brand of lithium should always be prescribed. Care should be taken, including additional monitoring, of changing between brands or between tablets and liquid. The tablets contain lithium carbonate, and the liquid contains lithium citrate. Doses are usually prescribed as lithium carbonate. To reduce the risk of medication errors, the Trust Pharmacy only stocks one strength of liquid: 10.8mmol/5ml. 5ml is equivalent to one 400mg lithium carbonate tablet. All inpatient charts are endorsed by pharmacy to ensure that it is clear what quantity should be administered.

3.7 The time of first sample to check the lithium plasma concentration is 5 to 7 days, (if a patient is over 65 years old and/or has impaired renal function the sample should be taken after 7 days), following initiation or changing dose. The blood sample should be taken 12 hours post dose. Any deviation from this timing must be recorded in a progress note (and notified to the lab on the Medicines Policy Page 4 of 14 October, 2013 Lithium prescribing & monitoring Version 2 Sample Request Form) and considered when interpreting the results. Repeat every 5 to 7 days (depending on age/renal function) until the required level is reached, thereafter monitor every 3 months. If the patient is taking lithium liquid, it is usually given as a twice daily dose. Monitor 2 hours post dose for the peak concentration. See section 4.

3.8 Usually, the full dose is given in a modified-release form as a single daily dose at bedtime. The starting dose is normally 400mg (200mg in the elderly).

3.9 Check for interactions with other current medication. Common interactions include ACE inhibitors, diuretics and angiotensin-II receptor antagonists. There are other less common interactions and the prescriber should refer to Appendix A, the current edition of the BNF and the SPC for further information.

4.0 BLOOD MONITORING, PRESCRIBING, SUPPLY AND ADMINISTRATION

4.1 Prior to prescribing, dispensing or administering lithium, Trust medical, pharmacy and nursing staff should ensure that there is a recent lithium level available. Guidance for appropriate levels of monitoring is as follows: -

• Any patient known to be taking lithium at the time of admission to inpatient care should have lithium levels done as soon as possible to ascertain the current level. This may also give some indication of recent compliance.

• It is important to consider that patients admitted as an emergency may not have taken their lithium doses as normal, and therefore doses should not be increased above the patient’s maintenance dose based on a low lithium level unless compliance can be assured. It would be safer to prescribe the patient’s usual dose and then recheck levels after 5 to 7 days.

• Patients initiating on lithium or having dose changes should have levels done 5 days after starting or dose change unless they have impaired renal function or are older than 60 years in which case it should be 7 days.

• Serum lithium levels should be repeated weekly until the target dose is reached.

• Once stabilised, routine serum lithium levels should be done every 3 months.

• Serum lithium levels should be checked prior to prescribing, monitoring, supply or administration and if there is no lithium level found within the last 3 months for maintenance patients, bloods should be urgently arranged. Unless the patient is clinically lithium toxic, lithium should not be stopped due to lack of a blood test.

• It is recommended that for inpatients serum lithium levels are documented on the current drug chart on the day the blood sample was drawn and that all patients have the levels section of their purple book completed.

5.0 LITHIUM IN THE ACUTE HOSPITAL SETTING

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5.1 Acutely Unwell Patients NICE guidelines recommend that lithium should be stopped for up to 7 days in patients that become acutely and severely unwell with a metabolic or respiratory disturbance from whatever cause.

5.2 Adverse effects The following table outlines the main early medium term and late adverse effects of lithium which are not associated with toxicity.

Lithium has a narrow therapeutic index and a number of adverse effects that can affect adherence to treatment. In the initial phase of treatment, thirst, abdominal discomfort, nausea, diarrhoea, gustatory disturbance, muscle weakness and fatigue may be troublesome. These symptoms occur more frequently at higher lithium levels. They tend to be transitory.

Lithium also has problematic longer term effects such as tremor, diabetes insipidus, renal impairment and hypothyroidism.

Early Medium term Late (1 to 14 days) (14 to 365 days) (more than 365 days) Related to high Lithium level GI: vomiting dry mouth. Cognitive: slow reaction (greater than 0.8 mmols per times, impaired memory. litre) Renal: polyuria, nephrogenic diabetes insipidus Renal: impairment. GI: anorexia, bad taste in mouth, diarrhoea. Neurological: tremor Neurological: myopathy, ataxia. Cardiac: T-wave inversion

Dermatological: worsening of skin diseases, e.g. psoriasis . Not related to high Lithium Thyroid: non toxic goitre, Metabolic: weight increase. level. hyperthyroidism (rare).

Thyroid: reduced T4 GI: Persistent mild diarrhoea. (transient). Haematological: leucocytosis

Neurological: weakness.

5.3 Lithium toxicity

Lithium toxicity can occur in individuals recently commenced on lithium or after a long uneventful course of treatment. It can occur at therapeutic serum levels and can arise following a change of dose of lithium, changes to other medicines such as initiation, withdrawal or dose changes. It may also occur as a result of physiological change unrelated to medication changes which occur as a result for instance of the ageing process eg declining renal function. It can develop insidiously.

Mild toxicity is characterised by nausea, diarrhoea, blurred vision, polyuria, dizziness, a fine resting tremor, muscle weakness or drowsiness. Cerebellar signs are a core feature of lithium neurotoxicity. Medicines Policy Page 6 of 14 October, 2013 Lithium prescribing & monitoring Version 2

Parkinson’s and Chorea may occur indicating basal ganglia involvement. Confusion, blackouts, hyper-reflexia, incontinence and hypernatraemia may develop. Impaired consciousness, seizures and coma may progress to death.

ECG changes include sinus and junctional bradycardia and heart block. Risk factors for lithium toxicity include nephrogenic diabetes insipidus and impaired renal function. Drug interactions predisposing to toxicity include medications such as NSAIDs, furosemide, thiazide diuretics, ACE inhibitors and some antidepressants (see Appendix A).

5.4 Management of lithium toxicity

Patients with suspected lithium toxicity should be observed for at least 24 hours. Depending on the serum levels and the severity of the symptoms. lithium should be withheld for 24 to 48 hours or continued as a reduced dose. Lithium levels should be monitored immediately and then every six to twelve hours. The diagnosis of toxicity is made on clinical grounds.

In mild cases, attention to hydration, electrolyte balance and ECG monitoring is necessary. In more severe cases haemodialysis should be considered. It should be instituted when serum lithium levels are greater than 3 mmols/L or when conservative measures have failed.

Clinical improvement may take up to 3 weeks.

5.5 Renal impairment

Lithium therapy may result in renal impairment through its effects on tubular or glomerular functions. Renal tubular dysfunction results in diabetes insipidus characterised by polyuria and polydipsia. In mild, reversible cases lithium dose reduction may be adequate. In severe cases of acute diabetes insipidus marked dehydration may occur and the priority is restoration of water and electrolyte balance.

Patients in acute renal failure should have lithium plasma levels monitored closely. Doses may need adjusting; it is advised to seek advice from a renal specialist and a clinician with expertise in the management of bipolar disorder.

Suggested doses in renal impairment are as follows; • calculated creatinine clearance > 50ml/min = no dosage reduction • calculated creatinine clearance 10 - 50ml/min = 50 - 70% of normal dose • calculated creatinine clearance < 10ml/min = 25 - 50% of normal dose

Lithium doses should be adjusted to achieve plasma concentrations of 0.6- 0.8mmol/L but a therapeutic response may be seen at 0.4mmol/L (lower end of the range for maintenance in the elderly).

In patients on haemodialysis a maintenance dose should be given after dialysis. Serum lithium concentrations following dialysis can be useful as a dosing guideline. Patients on dialysis should have their lithium dose adjusted to 25-50% of the normal dose. Medicines Policy Page 7 of 14 October, 2013 Lithium prescribing & monitoring Version 2 5.6 Fluid balance

Lithium is contra-indicated in patients with low body sodium levels. Therefore sodium intake needs careful management, in patients where it is restricted sodium levels should be stabilised and the lithium dose carefully titrated to avoid an increase in serum lithium concentrations. Patients taking lithium should be carefully instructed to avoid dehydration and to report polyuria and any prolonged vomiting, diarrhoea or fever. Patients should maintain a fluid intake of 2.5-3 L/day; where fever, vomiting or diarrhoea has occurred this should be supplemented so as not to cause dehydration. In these patients it may be necessary to temporarily reduce or stop lithium.

5.7 Surgery

Lithium should be withheld 24 hours prior to major surgery due to the risk of lithium accumulation, as anaesthesia can cause a reduction in renal clearance. In patients undergoing minor surgery, it is not necessary to stop lithium therapy if fluid and electrolytes are carefully monitored.

6.0 MAINTENANCE

6.1 To comply with the NPSA report, it is important that the physical monitoring described in the Monitoring Summary below is completed and up to date. This is the responsibility of the prescriber and constitutes part of the shared care agreement between primary and secondary care.

6.2 The following monitoring areas are recorded the healthcare record

• Height • Weight • Physical health check • Mental state

• Urea and electrolytes • Creatinine and renal • Thyroid • ECG • Full blood count • Lithium levels

7.0 STOPPING TREATMENT

Abrupt discontinuation of lithium may precipitate early recurrence of mania and depressive episodes (the rebound phenomenon). Gradual discontinuation carries a lower risk of rebound phenomena.

7.1 Tell patients that erratic compliance or stopping the drug suddenly may increase the risk of relapse. Record guidance given in the healthcare record.

Medicines Policy Page 8 of 14 October, 2013 Lithium prescribing & monitoring Version 2 7.2 Continue a trial for at least 6 months to establish effectiveness.

7.3 Reduce the dose gradually over at least 4 weeks, and preferably over up to 3 months (even if the patient is taking another antimanic agent).

7.4 If lithium treatment is stopped or is about to be stopped abruptly, consider changing to an atypical antipsychotic or valproate, and monitor closely for early signs of mania and depression.

Medicines Policy Page 9 of 14 October, 2013 Lithium prescribing & monitoring Version 2

8.0 MONITORING SUMMARY 9 Routine essential monitoring

Baseline Initiation Monitoring Height 9 Weight 9 Especially in patients with rapid weight gain. Urea & 9 If urea and creatinine levels rise see below. electrolytes Serum 9 9 6 monthly creatinine/ (more often if evidence of impaired renal function or if the patient starts taking drugs such renal function as ACE inhibitors, diuretics or NSAIDs).

If urea and creatinine levels rise, monitor lithium dose and blood levels more closely and assess the rate of deterioration of renal function. The decision on whether to continue the drug depends on clinical efficacy and the degree of renal impairment. Consider consulting a renal physician. Thyroid 9 9 6 monthly function tests (more often if evidence of deterioration). ECG 9 Good practice. Essential for patients with cardiovascular disease, or risk factors for it. Full blood 9 9 Annually count and as clinically required. Lithium levels 5-7 days after starting, 9 Every 3 months. and 5-7 days after every dose change, and until Normally, 0.6–0.8 mmol/litre, according to levels are stable. patient response. (A therapeutic response may be seen at a level of 0.4mmol/litre). Aim for the minimum dose to achieve a 0.8–1.0 mmol/litre if the patient has relapsed therapeutic response. previously on lithium or has sub-syndromal Usually in the range: 0.6 symptoms. to 0.8 mmol/litre (NICE) Also observe/inform patient to be aware of signs A therapeutic response of toxicity: blurred vision, GI disturbances, may be seen at a level muscle weakness, drowsiness, etc. These of 0.4mmol/litre. usually occur at levels >1.5mmol/litre, but can occur at lower levels. NB Monitoring should be done at 7 days post Monitor older adults more closely, as they are at change for older people greater risk of developing toxicity. Use lower because they take doses. They may develop symptoms of lithium longer to reach steady toxicity at standard therapeutic levels. state. Physical 9 Annually health check normally in primary care for people with bipolar disorder (NICE): –lipid levels, including cholesterol in all patients over 40 even if there is no other indication of risk – plasma glucose levels – weight – smoking status and alcohol use – blood pressure. Patient’s 9 9 As needed. mental state. Regular reviews of mental state and personal and social functioning, to ensure that symptoms (including sub-threshold symptoms) are treated if they significantly impair social functioning. Medicines Policy Page 10 of 14 October, 2013 Lithium prescribing & monitoring Version 2 9.0 REFERENCES

ƒ NICE Clinical Guideline 38 – Bipolar Disorder; July 2006 ƒ NICE Clinical Guideline 23 – Depression amended April 2007 ƒ The Maudsley Prescribing Guidelines, 9th Edition ƒ Priadel SPC (Sanofi-Aventis) ƒ NPSA PSA 005 Safer Lithium Therapy Dec 2009 ƒ DRUGDEX® System: Authors: Monograph name (Drug Consult). In: Klasco RK (Ed): DRUGDEX® System (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA. Available by subscription at: http://www.thomsonhc.com/ (cited: 10/11/10). ƒ Ashley C, Currie A, editors. The Renal Drug Handbook. Third edition. Oxford: Radcliffe Publishing; 2009, p439 ƒ Summary of Product Characteristics – Camcolit; Lithium carbonate. Norgine limted. Accessed via http://emc.medicines.org.uk/ on 10/11/10. ƒ McEvoy GK, editor. Monograph name. In: AHFS Drug information. American society of health-system pharmacists, Bethesda, Maryland, USA. Accessed via www.medicinescomplete.com (cited: 10/11/10). ƒ Sweetman SC, editor. Monograph name. In: Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Accessed via www.medicinescomplete.com (cited: 10/11/10).

Medicines Policy Page 11 of 14 October, 2013 Lithium prescribing & monitoring Version 2 Drug Interactions with Lithium Appendix A

Drug Effect on lithium levels

NSAIDs including COX 2 Inhibitors May increase lithium levels by reducing renal clearance. Lithium levels may decrease when these treatments are withdrawn.

ACE Inhibitors May increase lithium levels by reducing renal clearance.

Angiotensin II receptor antagonists May increase lithium levels by reducing renal clearance.

Metronidazole May increase levels by reducing clearance.

Thiazide diuretics May increase lithium levels due to a paradoxical retention of fluid.

Steroids Alter electrolyte balance and may therefore adversely affect expected lithium levels.

Tetracyclines May increase lithium levels.

Xanthines (theophylline, caffeine) May decrease lithium levels.

Sodium bicarbonate containing May decrease lithium levels. products Diuretics (osmotic and carbonic May decrease lithium levels anhydrase inhibitors) Antipsychotics Higher doses in combination with lithium may cause neurotoxicity.

Serotonin enhancers May cause serotonin syndrome in combination with lithium.

Prescribers should be aware that this is not an exhaustive list of possible drug interactions with lithium and that the onus rests with them to establish whether lithium is safe to use under individual circumstances.

Medicines Policy Page 12 of 14 October, 2013 Lithium prescribing & monitoring Version 2 Consultation Process

Version Date Author Level of Consultation 1 Dec 2010 Dr James Stallard Senior Pharmacists, Dorset Consultant in Liaison Psychiatry Medicines Management Working Jacqui Bowden Group, D&TC Clinical Pharmacy Manager

Medicines Policy Page 13 of 14 October, 2013 Lithium prescribing & monitoring Version 2

EQUALITY IMPACT ASSESSMENT – SCREENING FORM

1. Title of document/service for assessment Lithium Prescribing and Monitoring Guidelines 2. Date of assessment October 2013 3. Date for review October 2016 4. Directorate/Service Trust-wide 5. Approval Committee D&TC

Yes/No Rationale 6. Does the document/service affect one group less or more favourably than another on the basis of: No • Race No • Gender (including transgender) No • Religion or belief No • Sexual orientation, to include heterosexual, lesbian, gay and bisexual people No • Age No • Disability – learning disabilities, physical disabilities, sensory impairment and mental health issues No • Marriage and Civil Partnership No • Pregnancy and Maternity 7. Does this document affect an No individual’s human rights? 8. If you have identified potential N/A discrimination, are the exceptions valid, legal and/or justified?

9. If the answers to any of the above questions is ‘yes’ Tick Rationale then: Demonstrate that such a disadvantage or advantage can be justified or is valid

Adjust the policy to remove disadvantage identified or better promote equality

If neither of the above possible, submit to Diversity Committee for review.

10. Screener(s)

Print name: Jacqui Bowden

11. Date Policy approved by Committee

12. Upon completion of the screening and approval by Committee, this document should be uploaded to papertrail.

Medicines Policy Page 14 of 14 October, 2013 Lithium prescribing & monitoring Version 2