Therapeutic Drug Monitoring (Clozapine)

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 as part of their annual physical review

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

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.

Email 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.

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

* Seizure risk is increased in levels >0.6mg/L and 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.

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. Is the patient on once daily dosing?
   • Levels can be up to 23% higher at 12 hours compared to those on twice daily dosing
   • Correcting for this may be appropriate, seek advice from pharmacy
4. The use of clozapine suspension may result in variable dosing (especially if not shaken before use)
5. Treat the patient NOT the level
   • Clozapine TDM is an aid to clinical decision making, it should not dictate practice. 
6. Contact MH pharmacy services for advice in interpreting plasma clozapine levels

*   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 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 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.

N.B Sodium valproate has restriction on use in both in women of child-bearing potential and men <55years-old, further guidance can be found here. 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.