Therapeutic Drug Monitoring (Clozapine)

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When to carry out a plasma level

Clozapine therapeutic drug monitoring can be useful in certain circumstances, but is not required for routine management, for example:

  • If the patient’s smoking status changes
  • To monitor compliance
  • In poor responders after an adequate trial especially prior to consideration of augmentation strategies
  • If dose reduction is being contemplated
  • To diagnose dose-related side effects
  • If a drug interaction is suspected
  • Non-urgent investigation of suspected overdose
  • Measuring baseline levels during successful treatment to use as a reference point
  • For patients on long term high dose who have no evidence of previous levels being assessed

Side effects that are thought to be dose-related include; sedation, dizziness, hypersalivation, tachycardia, postural hypotension, constipation and seizures. Often these can be avoided/minimised by careful and slow dose escalation or alleviated by reducing the dose.

As a rule, treat the patient – not the level

 

Requesting a plasma level

Clozapine plasma levels are not performed by local GGC labs. All clozapine manufacturers and monitoring services have a service level agreement with an external laboratory to perform clozapine plasma levels. GG&C will use Magnalabs.

Packs and forms for measuring clozapine levels are available from Magnalabs, who can be contacted on 01989 763333. An assay request form is included in each pack and should be completed in full in order to aid interpretation of the results. A minimum of 2ml of venous blood is required to perform the assay. The sample and request form should be sent directly to the correct external laboratory for analysis.

Paper copies of the results are sent to the patient’s named consultant psychiatrist, usually within a week of the sample being taken. In addition, MH pharmacy services have access to clozapine plasma level results online. The current cost for analysis of each clozapine level is approximately £15.00 plus VAT.

Interpretation of plasma levels

Trough sample

Suggested action

0mg/L

Review patient – if dose >50mg/day suggest no clozapine taken for up to a week before sampling

<0.35mg/L

If response good maintain current dose

If response poor or incomplete, review and address issue of compliance. If compliance OK, consider cautious dose increase and repeat assay after 1 week.

0.35 - 0.6mg/l

If response good maintain current dose. If side effects present and are serious or persistent consider cautious dose reduction.

If response poor and there has been an adequate trial consider cautious dose increase or augmentation

0.6 – 1.0mg/L

If response good review current dose and consider cautious dose reduction if mental state allows

If response poor cautiously reduce dose to bring level down below 0.6mg/L. Monitor mental state and repeat level at least 1 week after dose reduction.

1.1  – 1.9mg/L*

 

If response good with no signs of toxicity review dose and consider cautious dose reduction to bring level below 1 and possibly below 0.6mg/L.

If response poor cautiously reduce dose to bring level down below 1 and possibly below 0.6mg/L. Monitor mental state and repeat level at least 1 week after dose reduction.

2mg/L & above*

If response good with no signs of toxicity URGENT REVIEW and consider cautious dose reduction to bring level below 1 and possibly below 0.6mg/L if mental state allows

If response poor URGENT REVIEW, withhold for 24 hours and dose reduction.

If patient in the community consider admitting. Stop clozapine for 24 hours and re-start at 75% of last dose and reduce dose by 25mg per week to bring plasma clozapine below 1 and possibly below 0.6mg/L. Monitor mental state and repeat level at least 1 week after dose reduction.

With levels >1mg/L, plasma clozapine may continue to rise in the short term even after dose reduction is commenced.

* Seizure risk is increased significantly with levels greater than 1mg/L. Serious consideration must be given to the pros and cons of using seizure prophylaxis. For further information see section below.

Interpretation of plasma level- practical guidance
  1. Consider the norclozapine level as well as the clozapine level
    • The clozapine/norclozapine ratio (mean 1.3) can be an indicator of compliance or saturated metabolism. If plasma levels are within the recommended range and the patient is responding well with minimal side effects it should not be used as an indicator for dose adjustment.
    • Norclozapine is usually around 70% of clozapine level
    • Is the clozapine level much more (>3 fold) than the norclozapine level? (ratio >3)
      • It may not be a true ‘trough’ sample. Attempt to confirm if it is a trough sample before taking any further actions
      • Clozapine N-demethylation may have become saturated. If saturation is suspected, consider cautious dose reduction, but be aware that the level may take some time to decrease
    • Is norclozapine level greater than clozapine level? (ratio <1)
      • May suggest poor adherence over 24 hours prior to assay (i.e. clozapine level decreases, but norclozapine with longer half-life remains high) 
  2. Is the result unexpected? – consider repeating before acting on result
    • Is it incompatible with the clinical picture?
    • Is it markedly different from previous result(s) at constant dose with no other external factors implicated?
  3. The use of clozapine suspension may result in variable dosing (especially if not shaken before use)
  4. Treat the patient NOT the level
    • Clozapine TDM is an aid to clinical decision making, it should not dictate practice. 
  5. Contact MH pharmacy services for advice in interpreting plasma clozapine levels
External factors that may influence levels

Variable

Effect on plasma clozapine (with constant dose)

Age

Decreased in younger patients

Gender

Decreased in males

Ethnicity

Increased in several Asian ethnicities e.g. Chinese, Korean, Taiwanese

Liver disease

Possibly increased

Caffeine intake

Increased with significant caffeine intake

Infection (especially chest)

Increased

Cigarette smoking

Significantly decreased in smokers

(see Clozapine and smoking)  

Drug interactions

Increase plasma clozapine levels

Decrease plasma clozapine levels

Fluvoxamine (very significant)

Rifampicin

Other SSRIs (modest increases)

Phenytoin

Ciprofloxacin

Phenobarbital

Cimetidine*

Primidone (metabolised to phenobarbital)

Combined oral contraceptive with ethinyloestradiol*

Omeprazole*

Erythromycin*

St John’s wort*

Lamotrigine*

 

Modafinil*

 

Pregabalin*

 

Risperidone*

 

Sodium valproate in non-smokers**

Sodium valproate in smokers**

Ritonavir***

Carbamazepine***

This list only includes pharmacokinetic interactions and is not exhaustive, please refer to most recent      

Summary of Product Characteristics or Stockley’s Drug Interactions for comprehensive interaction information

*   These interactions have been demonstrated in a few case reports only and may be of less clinical significance

**   There are reports of sodium valproate both increasing and decreasing clozapine plasma levels which may be dependent on whether individual is a smoker or non-smoker.

*** The use of clozapine with either ritonavir or carbamazepine is contraindicated due to risk of haematological adverse effects.

Constipation and plasma levels
  • Constipation is a potentially severe dose-related side effect of clozapine.
  • Constipated patients may not absorb clozapine as expected and as a result, interpretation of plasma clozapine and norclozapine results may be unreliable.
  • Continued dosing of clozapine without addressing constipation can make matters worse and can have catastrophic results.
  • Severe constipation can lead to paralytic ileus or bowel obstruction, which is potentially fatal.

 

In a patient who develops high plasma levels unrelated to other external factors or drug interactions, the possibility of constipation (even if the patient is not complaining of this) should be considered and treated. For further advice on managing constipation, see MRG 25 Assessment & treatment of clozapine induced constipation or clozapine and constipation section.

Seizure risk and plasma levels
  • Seizure risk is increased significantly with levels greater than 1mg/L
  • Serious consideration must be given to the pros and cons of using seizure prophylaxis.
  • High clozapine plasma levels should be managed by careful dose reduction
  • For acute high levels not associated with definitive seizure activity the use of an anticonvulsant is not usually required, although each case must be managed individually based on the actual level, clinical picture and the patient’s medical history.
  • Consideration of short term benzodiazepine use may be advisable in managing seizure risk.
  • Where there is evidence of seizure activity, clozapine should be withheld for 24 hours, recommenced at half the original dose and an anticonvulsant commenced irrespective of the plasma level.
  • In the small subset of patients who are maintained at levels above the upper limit of the reference range consider seizure prophylaxis to manage the ongoing risk.
  • Sodium valproate is usually the treatment of choice when managing clozapine seizure risk with lamotrigrine as an alternative.

N.B Sodium valproate is contraindicated in women of child-bearing potential who are not subject to the pregnancy prevention programme and therefore commencing seizure prophylaxis in this population will take time to consider and ensure appropriate safeguards are in place. Lamotrigine requires a slow titration due to risk of serious skin reactions, therefore it takes time to titrate to a dose that would provide seizure prophylaxis.

Flowchart

Editorial Information

Last reviewed: 08 October 2019

Next review: 01 March 2022

Author(s): MHS Clozapine Review Group

Version: 1

Approved By: PMG-MH

Reviewer Name(s): Andrew Walker, Suzanne Burke