# 15 - Notes

# Notes

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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 )

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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)

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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 )

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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 )

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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.