15 - Notes

Notes

768 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Notes ■ ■Monitor decline in renal function over a considerable period as a 30% change over 2 years is associated with a fivefold increase in risk of end stage renal disease. Chronic kidney disease (CKD) progression is often non-­linear.1 ■ ■Monitor risk of moving from CKD stage 3–5 (eGFR 10–59) to dialysis/­transplantation using the Tangri score at https://qxmd.com/calculate/calculator_125/kidney-­failure-­ risk-­equation-­8-­variable. The four (age, sex, eGFR, urine albumin : creatinine ratio) and eight (previous four items plus serum calcium, phosphorus, bicarbonate, ­albumin) variable equations accurately predict the 2-­ and 5-­year probability of treated kidney failure (dialysis or transplantation) for a potential patient with CKD stage 3–5.3 ■ ■In general, renal function significantly affects overall drug elimination so the amount of drug excreted unchanged in urine should be 30% or more of the dose.4 ■ ■Older adults (>65 years) should be assumed to have at least mild renal impairment. Their serum creatinine may not be raised because they have a smaller muscle mass. ■ ■Avoid drugs that are nephrotoxic (e.g. lithium, non-­steroidal anti-­inflammatory drugs) where renal reserve is limited. ■ ■Be cautious when using drugs that are extensively renally cleared (e.g. sulpiride, ­amisulpride, lithium). ■ ■Elimination of drugs metabolised hepatically can be reduced in kidney disease ­possibly by inhibition of enzymatic activity caused by uraemia.5 ■ ■Start at a low dose and increase slowly because, in renal impairment, the half-­life of a drug and the time for it to reach steady state (amount absorbed is the same as cleared when the drug is given continuously) are often prolonged. Plasma level monitoring may be useful for some drugs. ■ ■Try to avoid long-­acting drugs (e.g. depot preparations). Their dose and frequency cannot be easily adjusted should renal function change. ■ ■Prescribe as few drugs as possible. Patients with renal failure take many medications requiring regular review. Interactions and adverse effects can be avoided if fewer drugs are used. ■ ■Monitor patient for adverse effects. Patients with renal impairment are more likely to experience adverse effects and they may take longer to develop than in healthy patients. Adverse effects such as sedation, confusion and postural hypotension can be more common. ■ ■Be cautious when using drugs with anticholinergic effects, since they may cause ­urinary retention. ■ ■There are few clinical studies of the use of psychotropic drugs in people with renal impairment. Advice about drug use in renal impairment is often based on knowledge of the drug’s pharmacokinetics in healthy patients. ■ ■The effect of renal replacement therapies (e.g. dialysis) on drugs is difficult to predict. See Tables 8.8–8.14. Seek specialist advice. ■ ■Try to avoid drugs known to prolong the QTc interval. In established renal failure electrolyte changes are common so it is probably best to avoid antipsychotics with the greatest risk of QTc prolongation (see section on ECG changes – QT prolongation in Chapter 1). ■ ■Monitor weight carefully. Weight gain predisposes to diabetes which can contribute to rhabdomyolysis6 and renal failure. Psychotropic medications commonly cause weight gain.

Prescribing in hepatic and renal impairment CHAPTER 8 ■ ■Be vigilant for serotonin syndrome with antidepressants, dystonias and neuroleptic malignant syndrome (NMS) with antipsychotics. The resulting rhabdomyolysis can cause renal failure. There are case reports of rhabdomyolysis occurring with antipsychotics without other symptoms of NMS.7–9 ■ ■Depression is common in CKD but evidence for effectiveness of antidepressants in this condition is lacking.10,11 In CKD starting some antidepressants at a higher versus lower dose reduces mortality risk.12 Depression is poorly treated in patients on haemodialysis.13 In common with other chronic physical illnesses, depression in end stage renal disease may be associated with increased mortality,14–16 and the degree of risk may be linked to the severity of the depression.17 Non-­drug treatment such as cognitive behavioural therapy, exercise or relaxation techniques probably reduces depressive symptoms for adults on dialysis.18 SSRIs are associated with hip fracture in patients on haemodialysis (adjusted odds ratio 1.25; 95% confidence interval [CI] 1.17, 1.35).19 ■ ■Both schizophrenia and bipolar disorder are associated with an increased risk of CKD.20,21 ■ ■Antipsychotics (e.g. olanzapine, quetiapine) may be associated with acute kidney injury22 possibly via their effects on blood pressure and urinary retention but studies are conflicting.23 ■ ■Mood-­stabilising anticonvulsants used in bipolar disorder are associated with an increased rate of CKD.21 Table 8.8  Antipsychotic medications in renal impairment. Drug Comments Amisulpride24–27 Primarily renally excreted. 50% excreted unchanged in urine. Limited experience in renal disease, one study in Chinese patients showing more than twofold increase in AUC, trough and peak plasma concentrations with GFR 30mL/min.28 Manufacturer states no data with doses of >50mg but recommends following dosing: 50% of dose if GFR 30–60mL/min; 33% of dose if GFR is 10–30mL/min; no recommendations for GFR <10mL/min so best avoided in established renal failure. Aripiprazole24,25,27,29–32 Less than 1% of unchanged aripiprazole renally excreted. Manufacturer states no dose adjustment required in renal failure as pharmacokinetics are similar in healthy and severely renally diseased patients. There is one case report of safe use of oral aripiprazole 5mg in an 83-­year-­old man having haemodialysis. Avoid depot formulation where possible although there is a case report of aripiprazole 400mg depot use in a 64-­year-­old man on haemodialysis. Asenapine25,27,33 Extensively hepatically metabolised. Manufacturer states no dose adjustment required for patients with renal impairment but no experience with use if GFR <15mL/min. A 5mg single-dose study suggests that no dose adjustment is needed with any degree of renal impairment. Chlorpromazine24,27,34–36 Less than 1% excreted unchanged in urine. Caution required in severe impairment because of the risk of accumulation. No dose adjustment required for GFR >10mL/ min. For GFR <10mL/min, start with small doses and monitor for anticholinergic, sedative and hypotensive adverse effects. (Continued )

770 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Table 8.8  (Continued) Drug Comments Clozapine25,27,37–41 Contraindicated by manufacturer in severe renal disease, but only trace amounts of unchanged clozapine are excreted in urine. No dose adjustment required in GFR

10mL/min, titrate cautiously in very severe impairment. Nocturnal enuresis and urinary retention are common adverse effects. Anticholinergic, sedative and hypotensive adverse effects are more frequent in patients with renal disease. May cause and aggravate diabetes, a common cause of renal disease. Rare case reports of interstitial nephritis and acute renal failure, but also successful continuation after renal transplantation.42 Flupentixol24,25,27 Negligible renal excretion of unchanged flupentixol. Dosing: GFR 10–50mL/min dose as in normal renal function; GFR <10mL/min start with quarter to half of normal dose and titrate slowly. May cause hypotension and sedation in renal impairment and can accumulate. Manufacturer advises caution in renal failure because of increased cerebral sensitivity to antipsychotics. Avoid depot preparations in renal impairment. Haloperidol8,24,25,27,43,44 Less than 1% excreted unchanged in the urine. Manufacturer advises caution in renal failure. Dosing: GFR 10–50mL/min dose as in normal renal function; GFR <10mL/min start with a lower dose as can accumulate with repeated dosing. A case report of haloperidol use in renal failure suggests starting at a low dose and increasing slowly. Has been used to treat uraemia-associated nausea in renal failure. Avoid depot preparations in renal impairment. Lumateperone45,46 <1% excreted unchanged in urine. Manufacturer advises no dose adjustment needed in renal impairment. Lurasidone24 9% excreted unchanged in the urine. Serum concentrations are increased by 1.5-­, 1.9-­ and 2.0-­fold in mild, moderate and severe impairment, respectively. Manufacturer advises a starting dose of 18.75mg (20mg) and maximum dose of 74mg (80mg) per day if GFR <50mL/min. Avoid in GFR <15mL/min unless benefits outweigh risks (no data to support use). Renal failure has been reported rarely. Olanzapine7,25,27,34,44,47 57% of olanzapine is excreted mainly as metabolites (7% excreted unchanged) in urine. Dosing: UK manufacturers recommend GFR <50mL/min initially 5mg daily and titrate as necessary. Avoid long-­acting preparations in renal impairment unless the oral dose is well tolerated and effective. UK manufacturer recommends a lower long-­acting injection starting dose of 150mg, 4-­weekly in patients with renal impairment. US manufacturers state that no dose adjustment is required for oral or depot preparation. May cause and aggravate diabetes, a common cause of renal disease. Hypothermia has been reported when used in renal failure. Paliperidone25,27,34 Paliperidone is a metabolite of risperidone. 59% excreted unchanged in urine. Dosing: GFR 50–80mL/min, 3mg daily and increase according to response to max. of 6mg daily; GFR 10–50mL/min, 3mg alternate days (or 1.5mg daily) increasing to 3mg daily according to response. Use with caution as clearance is reduced by 71% in severe kidney disease. Manufacturer contraindicates oral form if GFR <10mL/min due to lack of experience, and monthly, 3-­monthly and 6-­monthly depot preparations if GFR <50mL/min (reduced loading and maintenance doses if GFR >50mL/min). Two case reports of successful paliperidone monthly injection use in patients with renal failure undergoing haemodialysis.48,49

Prescribing in hepatic and renal impairment CHAPTER 8 Drug Comments Pimavanserin45,50 <1% excreted unchanged in urine. Manufacturer states no dose adjustment needed in GFR ≥30mL/min but advises to avoid if GFR <30mL/min due to lack of data. Pimozide24,25,27 <1% of pimozide excreted unchanged in the urine; dose reductions not usually needed in renal impairment. Dosing: GFR 10–50mL/min dose as in normal renal function; GFR <10mL/min start at a low dose and increase according to response. Manufacturer cautions in renal failure. Quetiapine24,25,27,51–53 <5% of quetiapine excreted unchanged in the urine. Plasma clearance reduced by an average of 25% in patients with a GFR <30mL/min but manufacturer states no dose adjustment is necessary. Case reports (thrombotic thrombocytopenic purpura, DRESS and non-­NMS rhabdomyolysis) resulting in acute renal failure with quetiapine have been published. Risperidone24,25,27,44,54–57 Clearance of risperidone and the active metabolite of risperidone (9-­OH-­) is reduced by 60% in patients with moderate to severe renal disease. Dosing: GFR <50mL/min 0.5mg twice daily for at least 1 week then increasing by 0.5mg twice daily to 1–2mg bd. The long-­acting injection should only be used after titration with oral risperidone as described above. If 2mg orally is tolerated, 25mg intramuscularly every 2 weeks (Risperdal Consta®) can be administered. Manufacturers of the Okedi® monthly injection do not recommend use in GFR <60mL/min. Risvan® 75mg monthly or PerserisTM (subcutaneous) 90mg monthly can be used if 3mg oral is tolerated. UzedyTM can be given 50mg monthly if 2mg oral is tolerated. There are two case reports of successful use of risperidone long-­acting injection in haemodialysis at a dose of 50mg 2 weekly in one patient and 37.5mg then 25mg in an older adult. Another describes the successful use of risperidone in a child with steroid-­induced psychosis and nephrotic syndrome. Sulpiride6,24,25,27,58 Almost totally renally excreted, with 95% excreted in urine and faeces as unchanged sulpiride. Dosing regimen: GFR 30–60mL/min give 70% of normal dose; GFR 10–30mL/min give 50% of normal dose; GFR <10mL/min give 34% of normal dose. Alternately, the dosing interval can be prolonged by a factor of 1.5, 2 and 3, respectively. There is a case report of renal failure with sulpiride due to diabetic coma and rhabdomyolysis. Probably best avoided in renal impairment. Trifluoperazine27 Less than 1% excreted unchanged in the urine. Dose GFR <10–­50mL/min as for normal renal function – start with a low dose. Very limited data. Ziprasidone24,44,59,60 <1% renally excreted unchanged. No dose adjustment needed for GFR >10mL/min but care needed with using the injection as it contains a renally eliminated excipient (cyclodextrin sodium). Case report of 80mg twice daily dose used in a patient on haemodialysis who then developed agranulocytosis.61 Zuclopenthixol24,27 10–20% of unchanged drug and metabolites excreted unchanged in urine. Manufacturer cautions use in renal disease as can accumulate. Dosing: 10–50mL/min dose as in normal renal function; GFR <10mL/min start with 50% of the dose and titrate slowly. Avoid both intramuscular preparations (acetate and decanoate) in renal impairment. If use is essential, follow the same dosing guidance as for oral. AUC, area under the curve; bd, twice a day; DRESS, drug reaction with eosinophilia and systemic symptoms; GFR, ­glomerular filtration rate. Table 8.8  (Continued)

772 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Table 8.9  Antidepressants in renal impairment.10 Drug Comments Agomelatine25 Negligible renal excretion of unchanged agomelatine. No data on use in renal disease. Manufacturer says pharmacokinetics unchanged in small study of 25mg dose in severe renal impairment but cautions use in moderate or severe renal disease. A growing number of studies demonstrate nephroprotective effects in rats. Amitriptyline24,25,27,36,44,62–64 <2% excreted unchanged in urine; no dose adjustment needed in renal failure. Dose as in normal renal function but start at a low dose and increase slowly. Monitor patient for urinary retention, confusion, sedation and postural hypotension. Has been used to treat pain in those with renal disease. Associated with acute kidney injury.64 Brexanolone45,65 <1% excreted unchanged in urine. Manufacturer states no dosage adjustment is recommended in patients with GFR 15–60mL/min; avoid use in patients with GFR of <15mL/min because of the potential accumulation of the injection solubilising agent, betadex sulfobutyl ether sodium. Bupropion24,25,27,36,44,66–68 (amfebutamone) 0.5% excreted unchanged in urine but in patients with renal impairment, plasma concentrations are higher, elimination half-­life is longer and oral clearance is significantly lower. Metabolites may accumulate, increasing the risk of seizures. In renal impairment, reduce dose to 150mg once daily and/or reduce frequency of dosing. A single-dose study in haemodialysis patients (stage 5 disease) recommended a dose of 150mg every 3 days. Has been used to treat sexual dysfunction in mild to moderately depressed patients with chronic kidney disease. Citalopram24,25,27,44,69–75 <13% of citalopram excreted unchanged in urine. Single-­dose studies in mild and moderate renal impairment show no change in the pharmacokinetics of citalopram. Dosing is as for normal renal function; however, use with caution if GFR <10mL/min due to reduced clearance. The manufacturer does not advise use if GFR <20mL/min. Renal failure has been reported with citalopram overdose. Citalopram can treat depression in chronic renal failure and improve quality of life but use of citalopram (or escitalopram) is associated with a higher risk of sudden cardiac death vs other SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline) when used in patients on haemodialysis (adjusted hazard ratio 1.18; 95%CI 1.05, 1.31). Concurrent PPI use may increase the risk in haemodialysis;76 minimising the serum-­to-­dialystate potassium gradient may attenuate it.77 A case report of hyponatraemia has been reported in a renal transplant patient on citalopram. Clomipramine25,27,34,36,78 2% of unchanged clomipramine excreted in urine. Dosing: GFR 20–50mL/min dose as for normal renal function; GFR <20mL/min, effects unknown, start at a low dose and monitor patient for urinary retention, confusion, sedation and postural hypotension as accumulation can occur. There is a case report of clomipramine-­ induced interstitial nephritis and reversible acute renal failure. Desvenlafaxine10,34,79,80 45% of desvenlafaxine excreted unchanged in urine. Manufacturer recommends GFR 30–50mL/min 50mg/day; GFR <30mL/min 25mg/day or 50mg on alternate days. Half-­life is prolonged and desvenlafaxine accumulates as GFR decreases. Urinary retention, delay when starting to pass urine and proteinuria have been reported as adverse effects. Dosulepin27,34,81 (dothiepin) 56% of mainly active metabolites renally excreted. They have a long half-­life and may accumulate, resulting in excessive sedation. Dosing: GFR 20–50mL/min dose as for normal renal function; GFR <20mL/min start with a small dose and titrate to response. Monitor patient for urinary retention, confusion, sedation and postural hypotension. Doxepin25,27,34,36,82 <1% excreted unchanged in urine. Dosing: GFR 10–50mL/min as in normal renal function but monitor patient for urinary retention, confusion, sedation and postural hypotension; GFR <10mL/min start with a small dose and increase slowly. Manufacturer advises using with caution. Haemolytic anaemia with renal failure has been reported with doxepin. Used topically to treat pruritis in chronic renal failure.

Prescribing in hepatic and renal impairment CHAPTER 8 Drug Comments Duloxetine27,34,83–85 <1% excreted unchanged in urine. Manufacturer states no dose adjustment is necessary for GFR >30mL/min; however, starting at a low dose and increasing slowly are advised. Duloxetine is contraindicated in patients with a GFR <30mL/min as it can accumulate in chronic kidney disease. Two case reports of acute renal failure with duloxetine have been reported. Serotonin syndrome was reported in a patient with chronic kidney disease on trazodone and duloxetine.86 Escitalopram27,34,75,87–89 8% excreted unchanged in urine. The manufacturer states dosage adjustment is not necessary in patients with mild or moderate renal impairment, but caution is advised if GFR <30mL/min so start with a low dose and increase slowly. A case study of reversible renal tubular defects and another of renal failure have been reported with escitalopram. One study says effective vs placebo in end stage renal disease. Use of escitalopram (or citalopram) is associated with a higher risk of sudden cardiac death vs other SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline) when used in patients on haemodialysis (adjusted hazard ratio 1.18; 95%CI 1.05, 1.31). Concurrent PPI use may increase the risk in haemodialysis;76 minimising the serum-­to-­dialystate potassium gradient may attenuate it.77 Fluoxetine11,25,27,34,36,44,90–93 2.5–5% of fluoxetine and 10% of the active metabolite norfluoxetine are excreted unchanged in urine. Dosing: GFR 20–50mL/min dose as normal renal function; GFR <20mL/min consider using a low dose or on alternate days and increase according to response. Plasma levels after 2 months’ treatment with 20mg (in patients on dialysis with GFR <10mL/min) are similar to those with normal renal function. Efficacy studies of fluoxetine in depression and renal disease are conflicting. One small placebo-­controlled study of fluoxetine in patients on chronic dialysis found no significant differences in depression scores between the two groups after 8 weeks of treatment. Another found fluoxetine effective. A case series (n = 4) of once-­weekly fluoxetine 90mg or 180mg use in depressed patients on haemodialysis describes efficacious use with better tolerability at 90mg dose. Fluvoxamine27,34,36,44,94 2% excreted unchanged in urine. Renal impairment does not appear to affect the pharmacokinetics of fluvoxamine, but the UK manufacturer recommends starting at a low dose. Acute renal failure has been reported. Variations in albumin levels might affect serum concentrations of fluvoxamine in haemodialysis. Imipramine25,27,34,36,62 <5% excreted unchanged in urine. No specific dose adjustment necessary in renal impairment. Monitor patient for urinary retention, confusion, sedation and postural hypotension. Renal impairment with imipramine has been reported and manufacturer advises caution in severe renal impairment. Renal damage reported rarely. Lofepramine25,27,34,95 There is little information about the use of lofepramine in renal impairment. <5% excreted unchanged in urine. Dosing: GFR 10–50mL/min dose as in normal renal function; GFR <10mL/min start with a small dose and titrate slowly. Manufacturer contraindicates in severe renal impairment. Mirtazapine25,27,34,96 75% excreted unchanged in urine. Clearance is reduced by 30% in patients with GFR of 11–39mL/min and by 50% in patients with GFR <10mL/min. Dosing advice: GFR 10–40mL/min dose as for normal renal function but monitor for adverse effects; GFR <10mL/min start at a low dose and monitor closely. Mirtazapine has been used to treat pruritis caused by renal failure97 and appetite loss in chronic kidney disease.98,99 Rarely associated with kidney calculus formation. Moclobemide25,27,34,100,101 <1% of parent drug excreted unchanged in urine; an active metabolite was found to be raised in patients with renal impairment but this does not appear to be clinically significant. Dose adjustments are not required in renal impairment. Table 8.9  (Continued) (Continued )

774 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Drug Comments Nortriptyline27,34,36,44,62,102 <5% excreted unchanged in urine. If GFR 10–50mL/min dose as in normal renal function; if GFR <10mL/min start at a low dose. Plasma level monitoring recommended at doses of >100mg/day, as plasma concentrations of active metabolites are raised in renal impairment. Worsening of GFR in elderly patients has also been reported. Paroxetine25,27,34,36,103–106 <2% of oral dose excreted unchanged in urine. Single-­dose studies show increased plasma concentrations of paroxetine when GFR <30mL/min. Dosing advice differs: GFR 30–50mL/min dose as normal renal function; GFR <10–30mL/min start at 10mg/ day (other source says start at 20mg) and increase dose according to response in 10mg increments/week, max. dose 40mg/day. Extended release paroxetine should be started at 12.5mg/day in severe renal impairment, max. dose 50mg/day in depression or panic disorder, 37.5mg/day in social anxiety disorder. Paroxetine 10mg daily has been used to treat depression in patients on haemodialysis. Rarely associated with Fanconi syndrome and acute renal failure. Phenelzine27,34 Approximately 1% excreted unchanged in urine. No dose adjustment required in renal failure. Reboxetine25,27,34,107,108 Approximately 10% of unchanged drug excreted unchanged in urine. Dosing: GFR <80mL/min, 2mg twice daily, adjusting dose according to response. Half-­life is prolonged and plasma concentration increased as renal function decreases. Sertraline25,27,34,36,109–113 <0.2% of unchanged sertraline excreted in urine. Pharmacokinetics in renal impairment are unchanged in single-­dose studies but no published data on multiple dosing. Dosing is as for normal renal function. Sertraline has been used to treat dialysis-­associated hypotension114 and uraemic pruritis;115 however acute renal failure has been reported so it should be used with caution. Overall, studies of sertraline in patients with depression and chronic kidney disease fail to show efficacy. The CAST study, an RCT of sertraline (median dose 150mg) vs placebo in chronic non-­dialysis-­ dependent kidney disease, found no difference in change in depressive symptoms.113 The ASCEND trial of sertraline vs CBT in patients on haemodialysis with depression found no significant differences between sertraline (to 200mg) and CBT in response and remission rates but QIDS-­C depression scores at 12 weeks were lower for sertraline than CBT.116 Another small RCT (ASSertID study) in patients with depression on haemodialysis reported no difference between sertraline and placebo.117 Has been associated with serotonin syndrome when used in patents on haemodialysis. Case report of neutropenia when used in end stage renal disease.118 May reduce CRP in patients on haemodialysis with depression119 and a high CRP may predict response to sertraline (not placebo) in depression with chronic kidney disease.120 Trazodone25,27,34,121 <5% excreted unchanged in urine but care needed as approximately 70% of active metabolite also excreted. Dosing: GFR 20–50mL/min dose as normal renal function; GFR <20mL/min start with small dose and increase gradually; serotonin syndrome reported in a patient with chronic kidney disease on trazodone and duloxetine.86 Has been trialled (unsuccessfully) for insomnia in haemodialysis, incidence of adverse events was higher with trazodone vs placebo.122 Long-­term use may be associated with an increased risk of chronic kidney disease.123 Trimipramine27,34,36,62,124,125 No dose reduction required in renal impairment; however, elevated urea, acute renal failure and interstitial nephritis have been reported. As with all tricyclic antidepressants in renal impairment, monitor patient for urinary retention, confusion, sedation and postural hypotension. Table 8.9  (Continued)

Prescribing in hepatic and renal impairment CHAPTER 8 Drug Comments Venlafaxine25,34,36,126–128 1–10% excreted unchanged in urine (30% as the active metabolite). Clearance is decreased and half-­life prolonged in renal impairment. Dosing: GFR 30–90mL/min reduce by 25–50%; GFR <30mL/min reduce dose by at least 50%, consider alternate day dosing. Rhabdomyolyisis129 and renal failure have been reported rarely with venlafaxine. Has been used to treat peripheral diabetic neuropathy in haemodialysis patients. High doses may cause hypertension. Vortioxetine25,130 Negligible amounts are excreted unchanged in urine. Manufacturer advises that no dose adjustment is needed in renal impairment and end stage disease but advises caution due to a lack of data. CBT, cognitive behavioural therapy; CRP, C-­reactive protein; GFR, glomerular filtration rate; PPIs, proton pump inhibitors. Table 8.9  (Continued) Table 8.10  Mood stabilisers in renal impairment. Drug Comments Carbamazepine25,27,34,131–134 2–3% of dose excreted unchanged in urine. Dose reduction not necessary in renal disease, although cases of renal failure, tubular necrosis and tubulointerstitial nephritis have been reported rarely and metabolites may accumulate. Can cause Stevens–Johnson syndrome and toxic epidermal necrolysis, which may result in acute renal failure. Maintenance therapy in bipolar disorder is associated with an increased rate of chronic kidney disease.21 Lamotrigine25,27,34,135–139 <10% of lamotrigine excreted unchanged in urine. Single-­dose studies in renal failure show pharmacokinetics are little affected; however, inactive metabolites can accumulate (effects unknown) and half-­life can be prolonged. Renal failure and interstitial nephritis have also been reported. Dosing: GFR <10–50mL/min use cautiously, start with a low dose, increase slowly and monitor closely. One source suggests in GFR <10mL/min use 100mg every other day. Lithium25,27,34,36,140,141 Lithium is nephrotoxic and contraindicated in severe renal impairment; 95% excreted unchanged in urine. Long-­term treatment may result in impaired renal function in about a quarter of patients142 (‘creatinine creep’), permanent changes in kidney histology, microcysts, oncocytoma and collecting duct renal carcinoma, nephrogenic diabetes insipidus, nephrotic syndrome and both reversible and irreversible kidney damage.143,144 However shorter studies in younger populations do not show declining GFR145 or the development of end stage renal disease.21,146,147 These differences may be due to methodology, improved monitoring and targeting recommended maintenance serum levels (0.6–0.8mmol/L in BPAD). Prevent nephrotoxicity by using once daily dosing, tightly adhering to recommended plasma levels, avoiding intoxication, assertively treating comorbidities and actively monitoring kidney function. Collaboration is vital between psychiatrist, nephrologist and patient in decision-making if chronic kidney disease occurs.148 Risk factors for lithium-­induced nephrotoxicity include increasing age, duration of treatment, cumulative dose, lower initial eGFR, female gender, hypertension and diabetes, concomitant nephrotoxic drugs, nephrogenic diabetes insipidus and previous lithium toxicity.149 If lithium is used in renal impairment, toxicity is more likely and lithium toxicity increases the risk of renal impairment. Renal damage is more likely with chronic toxicity than acute. The manufacturer contraindicates lithium in severe renal impairment. Dosing: GFR 10–50mL/min avoid or reduce dose (50–75% of normal dose) and monitor levels; GFR <10mL/min avoid if possible, however if used it is essential to reduce dose (25–50% of normal dose). Lithium can be used successfully during haemodialysis.150 (Continued )

776 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Table 8.11  Anxiolytics and hypnotics in renal impairment. Drug Comments Buspirone25,27,34,36 <1% excreted unchanged; however, active metabolite is renally excreted. Dosing advice contradictory, suggests GFR 20–50mL/min start at a low dose and give twice daily; GFR <20mL/min avoid if possible due to accumulation of active metabolites; if essential, reduce dose by 25–50% if patient is anuric. Manufacturer contraindicates in severe renal impairment (GFR <20mL/min). Chlordiazepoxide25,27,36 1–2% excreted unchanged but chlordiazepoxide has a long-­acting active metabolite that can accumulate. Dosing: GFR 10–50mL/min dose as normal renal function; GFR <10mL/min reduce dose by 50%. Monitor for excessive sedation. Manufacturer cautions in chronic renal disease. Long-­term use may be associated with an increased risk of CKD.123 Clomethiazole25,27,34,160 (chlormethiazole) 0.1–5% of drug excreted unchanged in urine. Dose as in normal renal function but monitor for excessive sedation. Manufacturer recommends caution in renal disease. Clonazepam25,27,34,161 <0.5% of clonazepam excreted unchanged in urine. Dose adjustment not required in impaired renal function; however with long-­term administration, active metabolites may accumulate so start at a low dose and increase according to response. Monitor for excessive sedation. Has been used for insomnia in patients on haemodialysis. Long-­term use may be associated with an increased risk of CKD.123 Diazepam27,34,36,162 <0.5% is excreted unchanged. Dosing: GFR 20–50mL/min dose as in normal renal function; GFR <20mL/min use small doses and titrate to response. Long-­acting, active metabolites accumulate in renal impairment; monitor patients for excessive sedation and encephalopathy. One case of interstitial nephritis with diazepam has been reported in a patient with chronic renal failure. Long-­term use may be associated with an increased risk of CKD.123 Eszopiclone163 <10% excreted unchanged in urine. No dose adjustment is needed in renal impairment. Gabapentin 100% excreted unchanged in urine, clearance is reduced in renal impairment resulting in higher plasma concentrations and longer elimination half-­lives.164 As expected this may result in toxicity in renal impairment if doses are not reduced.165 Acute renal failure has been reported,166 as has myoclonus,167 altered mental status, fall and fracture when used in patients on haemodialysis for restless legs, itch and neuropathic pain.168,169 Has been used to treat pruritis, muscle cramps and restless legs syndrome in haemodialysis patients in RCTs.170–172 Dosing advice differs: GFR 15–60mL/min start low and increase according to response; GFR <15mL/min 300mg alternate days36,166 or 100mg at night then increase according to tolerability27,173 but check for toxicity as described above. Manufacturer has table of very specific dosing in renal impairment in SMPC.166 Drug Comments Valproate25,27,34,151–155 Approximately 2% excreted unchanged. Dose adjustment usually not required in renal impairment; however free valproate levels may be increased. Renal impairment, interstitial nephritis, Fanconi syndrome, renal tubular acidosis and renal failure have been reported. Risk factors for renal tubular dysfunction include being bedbound and low serum carnitine and phosphorus levels.156 Dose as in normal renal function, however in severe impairment (GFR <10mL/min) it may be necessary to alter doses according to free (unbound) valproate levels. Possibly less likely than lithum to cause chronic kidney disease in patients with bipolar disorder157,158 but data are conflicting.159 BPAD, bipolar affective disorder; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate. Table 8.10  (Continued)

Prescribing in hepatic and renal impairment CHAPTER 8 Drug Comments Lemborexant,45,174 suvorexant, daridorexant <1% excreted unchanged in urine. Manufacturers state no dose adjustment needed in renal impairment. Exposure to lemborexant may increase during severe renal impairment with a potential increased risk of somnolence.175 Lorazepam25,27,34,36,176–181 <1% excreted unchanged in urine, dose as in normal renal function but carefully according to response as some may need lower doses. Monitor for excessive sedation. Impaired elimination reported in two patients with severe renal impairment and also reports of propylene glycol in lorazepam injection causing renal impairment and acute tubular necrosis. However, lorazepam injection has been successfully used to treat catatonia in two patients with renal failure, and it is the drug of choice in status epilepticus for patients with renal disease.182 Melatonin <1% excreted unchanged in urine. Manufacturers state limited information on use in renal impairment, but numerous studies suggest melatonin may be renoprotective in acute kidney injury and chronic renal disease183,184 and beneficial for sleep in haemodialysis patients.185,186 Dose as for normal renal function but monitor for oversedation in severe impairment. Nitrazepam25,27 <5% excreted unchanged in urine. Dosing: GFR 10–50mL/min dose as in normal renal function; GFR <10mL/min start with small dose and increase slowly. Manufacturer advises reducing dose in renal impairment. Monitor patient for sedation and unsteadiness. Long-­term use may be associated with an increased risk of CKD.123 Pregabalin Up to 99% excreted unchanged in urine. Acute renal failure reported.187 Associated with altered mental status and falls when used in patients on haemodialysis168 and myoclonus.188 Case report of seizure on abrupt cessation in patient with CKD.189 Used to treat uraemic pruritis and neuropathic pain in patients on haemodialysis190–192 and restless legs syndrome in CKD.193 Dosing advice differs; titrate dosing by tolerability and response for all GFRs; initial dose for GFR 30–60mL/min 75mg daily and max. 300mg daily; GFR 15–30mL/min 25–50mg daily and max. 150mg daily; GFR <15mL/min 25mg daily and max. 75mg daily. Manufacturer has table of very specific dosing in renal impairment in SMPC.187 Oxazepam27,34,36,194 <1% excreted unchanged in urine. Dose adjustment may be needed in severe renal impairment. Oxazepam may take longer to reach steady state in patients with renal impairment. Dosing: GFR 10–50mL/min dose as in normal renal function; GFR <10mL/min start at a low dose and increase according to response. Monitor for excessive sedation. Promethazine25,27,34,36,195 Dose reduction usually not necessary; however, promethazine has a long half-­life so monitor for excessive sedative effects in patients with renal impairment. Manufacturer advises caution in renal impairment. There is a case report of interstitial nephritis in a patient who was a poor metaboliser of promethazine. Temazepam25,27,34,36 <2% excreted unchanged in urine. In renal impairment the inactive metabolite can accumulate. Monitor for excessive sedative effects. Dosing: GFR 20–50mL/min dose as normal renal function; GFR <20mL/min dose as in normal renal function but start with 5mg. Zolpidem25,27,34,161,196 Clearance moderately reduced in renal impairment. No dose adjustment required in renal impairment. Zolpidem 1mg has been used to treat insomnia in patients on haemodialysis. One trial of use as a sleep aid in haemodialysis patients with pruritis.197 Associated with acute pyelonephritis in women.198 Long-­term use may be associated with an increased risk of CKD.123 Zopiclone25,27,34,199,200 <5% excreted unchanged in urine. Manufacturer states no accumulation of zopiclone in renal impairment but suggests starting at 3.75mg. Dosing: GFR <10mL/ min start with lower dose. Interstitial nephritis reported rarely. Long-­term use may be associated with an increased risk of CKD.123 CKD, chronic kidney disease; GFR, glomerular filtration rate; SMPC, summary of product characteristics. Table 8.11  (Continued)

778 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 8 Table 8.12  Anti-­dementia drugs in renal impairment. Drug Comments Donepezil25,27,201–203 17% excreted unchanged in urine. Dosing is as in normal renal function for GFR ≤10–50mL/min. Manufacturer states that clearance not affected by renal impairment. Single-­dose studies find similar pharmacokinetics in moderate and severe renal impairment compared with healthy controls. Has been used at a dose of 3mg/day in an elderly patient with Alzheimer’s dementia on dialysis. Single case of rhabdomyolysis causing acute renal failure204 and one of donepezil-­induced parkinsonism in end stage renal disease.205 Galantamine25,27 18–22% excreted unchanged in urine. Dose as in normal renal function for GFR 9–50mL/min and at GFR <9mL/min start at a low dose and increase slowly. Maximum 16mg/day in moderate impairment. Manufacturer contraindicates use in GFR <9mL/ min. Plasma levels may be increased in patients with moderate and severe renal impairment. Memantine25,34,206 Manufacturers recommend a 10mg immediate release dose if GFR 5–29mL/min; 10mg daily for 7 days then increased to 20mg daily if tolerated for GFR 30–49mL/min; no dose adjustment required for GFR >50mL/min. Extended release dose is 14mg daily for GFR 5–29mL/min. Renal tubular acidosis, severe urinary tract infections and alkalisation of urine (e.g. by drastic dietary changes, such as switching from carnivore to vegetarian diet) can increase plasma levels of memantine. Acute renal failure has been reported, and one case of encephalopathy in chronic kidney disease.207 Rivastigmine25,27 0% excreted unchanged in urine but manufacturer states caution is required for patients with renal disease because of an increased risk of adverse effects. Dosing advice for GFR <50mL/min start at a low dose and gradually increase. Steady-state plasma concentrations are not affected by renal function.208 GFR, glomerular filtration rate. Table 8.13  Other psychotropic drugs in renal impairment. Drug Comments Bremelanotide45,209 64.8% excreted unchanged in urine. Manufacturer states GFR 30–89mL/min no dosage adjustment necessary; caution for GFR <30mL/min as increased adverse effects (nausea and vomiting). Exposure is increased in renal impairment. Case report of Melotan II (bremelanotide is a variation of Melotan II) and rhabdomyolysis and renal dysfunction.210 Deutetrabenazine211 No clinical studies in renal impairment. Data limited, no specific dosing advice. Pitolisant45,212 <2% excreted unchanged in urine. Dosing: GFR 15–59mL/min 8.9mg daily, increase after 7 days to max. 17.8mg once daily;213 GFR <15mL/min not recommended.213 Peak concentrations and exposure increased in all stages of renal impairment. Solriamfetol45,214 95% excreted unchanged in urine. Dosing: GFR 60–89mL/min no dose adjustment is required; GFR 30–59mL/min 37.5mg once daily, increased to max. of 75mg once daily after 5 days; GFR 15–29mL/min 37.5mg once daily; GFR <15mL/min not recommended. In moderate or severe renal impairment risk of increased blood pressure and heart rate because of the prolonged half-­life. Increased exposure and t1/2 in all stages of renal impairment particularly end stage renal disease.215 Valbenazine45 <2% excreted unchanged in urine. No adjustment is necessary. Urinary retention reported as adverse effect in clinical trials. GFR, glomerular filtration rate.