Clozapine (Blood)

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Auckland Te Toka Tumai

Test Guide

Clozapine (Blood)

Testing Laboratory

Auckland Te Toka Tumai | Auckland Hospital

Department

Chemical Pathology

Delphic Registration Code (Alpha Code)

CLOZ

Test Code (Numeric Code)

0852

Laboratory Handling

Separating

Centrifuge and separate blood as soon as possible after collection

Laboratory

LabPLUS High Performance Liquid Chromatography

Sample Stability

If temperature during shipping is likely to exceed 24°C then results may not always be reliable.

Synonyms

Clozapine
Clopine
Clozaril
Norclozapine
Desmethylclozapine

Turnaround Time

3 days

Turn around time is based on working days (Monday-Friday).

Specimen Type

Serum

Specimen Requirements

Tube/Container Type:

Preferred

Plain (Red Top)

Acceptable

Lithium Heparin - Non-gel (Green Cap)

Preferred Sample Volume (ml)

Paediatric Specimen Requirements

Tube/Container Type:

Preferred

Plain(Microtainer)

Pre-testing Requirements

Pre-dose trough (12 hours since previous dose) recommended.

A Clozapine level is not required as part of routine monitoring (LabPlus policy):

"Repeat" request forms will not be accepted. A new form must be completed for each request for a clozapine level.

The name of the requestor must be clearly written, along with a contact telephone number and signature.

The clinical information for the test must be clearly written on the request form. "Routine monitoring" or "on clozapine" will not be accepted. If clinical information is not provided, or does not provide sufficient justification for the test, the test may be declined.

If a test is declined, the specimen will be held for a reasonable period (usually 3 weeks but dependant on the stability of the sample). Medical practitioners seeking approval for a declined test should email the on-call Chemical Pathologist, giving the patient's name and NHI number and the clinical justification for the test. If unable to email, call the on-call Chemical Pathologist via Lablink and identify yourself as a doctor.

Additional Specimen Information

IMPORTANT: Serum or plasma separator tubes (SST or PST) with gel are not acceptable for the testing of drugs at LabPlus. Significant adsoprtion of clozapine and it metabolites occur in these tubes.

URGENT requests:

Urgent requests must go through a Chemical Pathologist at chemicalpathologist@adhb.govt.nz or through LabLINK (Auckland Hospital ext, 22000). An email, or a writing "urgent" on the request form is not sufficient.

Clozapine analysis is time-consuming and technically difficult. Urgent analysis cannot always be guaranteed. If urgent analysis is agreed to, samples must be in the lab by mid-morning to be resulted same day.

Urgent requests will only be accepted:
• from a psychiatrist or a psychiatry registrar specifically authorised by a psychiatrist consultant
• admission to ACH with clozapine related complications, or
• medical needs that could be compromised if they deteriorate in mental state

Diagnostic Use

Clozapine testing may be performed to monitor levels when the dosage is being change, adherence is in question or symptoms suggest undertreatment or toxicity. Possible toxic effects of clozapine include agranulocytosis, myocarditis and cardiomyopathy, constipation, intestinal obstruction, drowsiness and seizures.

Although clozapine levels can vary between individuals and are affected by factors such as gender, age, smoking status and weight (2), routine measurement of clozapine levels is not indicated in every day practice for the following reasons:
1. A significant proportion of patients (approximately 1/5 th ) respond to clozapine treatment even if the serum concentration is below the therapeutic interval quoted above (1) .
2. Following a change in dose, patients with poor initial response at 6 weeks may respond by 4-6 months.
3. There is no agreed toxic threshold for clozapine related CNS toxicity. Seizures can occur at or even below the therapeutic interval in some patients. The risk of toxicity is increased at clozapine concentrations > 3000 nmol/L.
4. Haematological and cardiac side effects (e.g. agranulocytosis, myocarditis and myopathy) are not dose related. A full blood count should be checked on regular basis and if signs of infection are present. Patients should be regularly assessed for symptoms and signs of heart failure. Please review your local DHB guidelines with regards to routine monitoring and frequency of blood tests.

Interpretation

Interpretation for serum clozapine & desmethylclozapine levels (3,4):

Desmethylclozapine is the major metabolite of clozapine via CYP1A2 with some activity. It may help provide clues to the interpretation of the clozapine result.
There is considerable variation in the clozapine ratio between different people due to genetic variations in metabolism. Based on published articles (4,5,7) and in-house data review, clozapine/ desmethylclozapine ratios in adults are usually 1 – 3 in trough samples taken from compliant patients at steady state. Higher plasma clozapine concentration tends to have a higher clozapine/desmethylclozapine ratio as the major metabolic pathway for clozapine exhibits saturable kinetics.
The within-subject variation of clozapine is about 20% which means that the ratio will vary by up to +/- 41% from the mean on 95% of occasions in a stable patient on a same dose. A change of > 60% is needed between two trough levels to show there has been a significant difference.
The within-subject variation of desmethylclozapine is about 18% which means that the ratio will vary by up to +/-36% from the mean on 95% of occasions in a stable patient on a same dose. A change of > 53% is needed between two trough levels to show there has been a significant difference.
Serum levels should be interpreted with previous measurements where available.

Factors that may influence clozapine levels:

Dose
Irregular adherence to medications
Acute inflammatory states – may lead to an increase in clozapine levels (6)
Constipation – a common side effect of clozapine which can affect the degree and rate of clozapine absorption. The GI hypomotility caused by clozapine can result in delayed absorption. Once the bowel moves after a period of constipation, some of the retained but not yet absorbed clozapine in the gut may only get absorbed then. Thus, it is crucial to beware of the cumulative dose of clozapine when the bowel movement pattern changes.
Liver disease
Co-prescription with CYP450 medications:
- Increased clozapine levels: e.g. caffeine, ciprofloxacin, erythromycin, fluoxetine
- Decreased clozapine levels: e.g. carbamazepine, phenobarbitone, phenytoin, rifampicin
Smoking – aromatic hydrocarbons in cigarette smoke (not nicotine) are an inducer of CYP1A2, leading to faster clozapine metabolism (e.g. can lower serum clozapine level). Therefore sudden smoking cessation can cause a large increase in serum levels. Nicotine replacement therapy (e.g. nicotine patches) use does not affect clozapine levels.
Older patients (> 65 years) – may be more likely to show toxic effects despite levels within the reference interval, and may have effective treatment control below this interval.
Renal impairment – lower doses usually recommended.

Possible causes for a rise in clozapine/desmethylclozapine ratio

Not a trough sample – absorption of clozapine from the last dose has not been completed at the time of sampling
Enzyme saturation – clozapine metabolism is saturated with a high clozapine level (usually >3000nmol/L)
Addition of an enzyme inhibitor e.g. fluvoxamine
Stopping smoking

Possible causes for a drop in clozapine/desmethylclozapine ratio

Poor adherence in preceding days
Addition of enzyme inducer, e.g. starting smoking

Reference Intervals

Units: nmol/L

Clozapine: nmol/L = ug/L x 3.06

Desmethylclozapine: nmol/L = ug/L x 3.20

Therapeutic range: Clozapine: 1050 to 1800 nmol/L

Therapeutic control can be achieved at levels less than 1000 nmol/L in some patients.

Reference intervals stated are for trough (pre-dose) levels. They are only a guide, and there is significant variability in both clinical response and likelihood of side effects. Some side effects, e.g. cardiac and haematological, are not dose related (see below).

Metabolism: Clozapine is extensively metabolized by cytochrome P450 system into Clozapine N-oxide and N-desmethylclozapine. The major contributions to this metabolism include CYP1A2, and CYP3A4. Other contributory CYP enzymes include CYP2C19 and CYP2D6.

Both clozapine and desmethylclozapine (the major metabolite) are reported.

Elimination half-life: Plasma level peaks typically after 1-3 hours and half-life is usually 8-16 hours at steady state (1).

Test Method

Liquid Chromatography Mass Spectrometry

Limitations / Interference

Co-prescription with CYP450 medications (as listed above)
Smoking status changes
Acute inflammatory states
Constipation affecting absorption
Liver disease
Renal impairment
Non‑trough samples
Enzyme saturation
Lifestyle changes affecting metabolism (e.g. smoking habits)

Uncertainty of Measurement

12%

References:
1. Byerly MJ, DeVane CL. Pharmacokinetics of Clozapine and Risperidone: A Review of Recent Literature. Journal of Clinical Psychopharmacology. 1996;16(2):177-87.
2. Rostami-Hodjegan A, Amin AM, Spencer EP, Lennard MS, Tucker GT, Flanagan RJ. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol. 2004;24(1):70-8.
3. Schoretsanitis G, Kane JM, Ruan CJ, Spina E, Hiemke C, de Leon J. A comprehensive review of the clinical utility of and a combined analysis of the clozapine/norclozapine ratio in therapeutic drug monitoring for adult patients. Expert Rev Clin Pharmacol. 2019;12(7):603-621.
4. Couchman L, Morgan PE, Spencer EP, Flanagan RJ. Plasma clozapine, norclozapine, and the clozapine:norclozapine ratio in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1993-2007. Therapeutic drug monitoring. 2010;32(4):438-47.
5. Pfuhlmann B, Hiemke C, Unterecker S, Burger R, Schmidtke A, Riederer P, et al. Toxic clozapine serum levels during inflammatory reactions. J Clin Psychopharmacol. 2009;29(4):392-4.
6. Patteet L, Maudens KE, Vermeulen Z, Dockx G, De Doncker M, Morrens , et al. Retrospective evaluation of therapeutic drug monitoring of clozapine and norclozapine in Belgium using a multidrug UHPLC-MS/MS method. Clin Biochem. 2014 ;47(18):336-9.
7. Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, et al. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.
8. Medsafe. 2015. Clozapine - Close Monitoring Required. Prescriber Update 36(2): 18 -21. URL: https://www.medsafe.govt.nz/Profs/PUArticles/June2015/June2015Clozapine.htm (accessed 26 July 2019).
9. Bryant, L. (2015). The dangers of smoking cessation? and medicines. Journal of Primary Health Care , 7 (4), 345?347. https://doi.org/10.1071/HC15345
10. McKean, A. (2014). Safer prescribing of high-risk medicines?: Best Practice Journal , (62), 46?49. Retrieved from http://www.bpac.org.nz/BPJ/2014/July/safer-prescribing.aspx
11. Winckel, K., & Siskind, D. (2017). Clozapine in primary care. Australian Prescriber , 40 (6), 231?236. https://doi.org/10.18773/austprescr.2017.067

Last updated: 25/08/2026

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Clozapine (Blood)

Overview

Testing Laboratory

Department

Delphic Registration Code (Alpha Code)

Test Code (Numeric Code)

Laboratory Handling

Separating

Laboratory

Sample Stability

Synonyms

Turnaround Time

Specimen

Specimen Type

Specimen Requirements

Tube/Container Type:

Preferred

Acceptable

Preferred Sample Volume (ml)

Paediatric Specimen Requirements

Tube/Container Type:

Preferred

Pre-testing Requirements

Additional Specimen Information

Referral

Aliquot Instructions

Sample Type

Transport to Lab

Additional Referral/Aliquot Information

Clinical Information/Test Method

Diagnostic Use

Interpretation

Reference Intervals

Test Method

Limitations / Interference

Uncertainty of Measurement

Additional Information

Contact Information

Contact Information

Enquiry Form

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