This is interim advice pertaining to the period of the COVID-19 pandemic. This advice is additional to, but does not replace existing NSWH, LHD/SHN, and local policy, guidance and protocols.

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This interim guideline applies to clozapine management in NSW Health Services, including clozapine General Practitioner (GP) shared care. 

This advice aims to support clinicians and consumers in achieving safe care during the COVID-19 pandemic. The advice recognises the need for a balance between patient and public health safety and ensuring the special care needs of vulnerable people receiving clozapine therapy are met. The COVID-19 pandemic is a period during which this group of consumers may require increased monitoring and clinical review. Clinicians will be making decisions about how much of this can be provided virtually or by telephone contact and when a face-to-face contact is indicated and necessary.

Implications for the medical management of clozapine during COVID-19

Infection with COVID-19 presents several additional threats to people being treated with clozapine.

These threats include:

  • the effects of the virus itself 
  • factors associated with clozapine 
  • the interaction of the virus, the medical illness resultant from COVID-19 and clozapine 
  • the complex biopsychosocial environment of a person being treated with clozapine for a serious mental illness.

Clozapine is the most effective antipsychotic available for treatment resistant schizophrenia. However, concerns about its adverse effect profile may lead to overly hasty cessation of the medication. This should not occur unless the person’s physical state mandates this, rather a reduction in the dose of clozapine may be appropriate. Reduction or cessation of clozapine in hospital should be closely monitored by the Psychiatry team.

Reduction or cessation of clozapine in hospital should be closely monitored by the Psychiatry team. Butler M et al (2020). Clozapine prescribing in COVID-19 positive medical inpatients: a case series. Therapeutic Advances in Psychopharmacology 10: 1-9.

Risks of interaction between COVID-19 and the biopsychosocial environment of people treated with clozapine

People treated with clozapine for severe mental illness may be exposed to a significant range of factors that could impact upon their physical and mental health.

These factors include:

  • The indications/need to continue with clozapine.
  • Balancing self-isolation and marginalisation. The control of COVID-19 requires social isolation, however in those with serious and persisting mental illness this may risk exacerbating their existing marginalisation. Fear of infection and lack of social connectedness combine to reduce contact. Mental Health Services need to be mindful of this and increase observation and contact, even when face-to-face contact needs to be reduced, by using alternate means of communication. 
  • Loss of contact or reduced access to psychosocial treatments. The self-isolation caused by COVID-19 has interrupted the provision of psychological and social treatments. The provision of these treatments via alternate means or the adoption of internet-based treatment is encouraged. 
  • Clinicians should be mindful of the overlap between COVID-19 symptoms and cold and flu like symptoms associated with clozapine induced neutropenia and myocarditis.

Additional threats due to infection with COVID-19

Infection with COVID-19 over and above the multitude of other factors dealt with in this guideline is noted to be associated with:

  • neutropenia
  • increased clozapine levels
  • fluctuation in blood glucose levels
  • increased rate of myocarditis
  • increased rate of thrombosis.

Additional threats due to clozapine

Clozapine itself causes adverse effects that increase the risk of adverse outcomes in a COVID-19 infection. These include:

  • hypersalivation which increases the risk of pneumonia
  • diabetes mellitus and poor glucose control
  • obesity
  • reduction in White Cell Count (WCC).

COVID-19 vaccination for people being treated with clozapine

Are people taking clozapine at greater risk of either myocarditis/pericarditis or thrombosis with thrombocytopenia syndrome (TTS)?

There were no cases or reports identified in the literature as of March 2022. The advice from clinical experts is that people taking clozapine should be prioritised for COVID-19 vaccination because they have an increased risk of COVID-19 morbidity and mortality.

Recent systematic reviews emphasise the increased risk of COVID-19 morbidity and mortality for people with mental disorders.

There has been one case report that indicated administration of mRNA COVID-19 vaccine, Pfizer-BioNTech, could elevate clozapine levels due to a complex mix of inflammatory and metabolic effects. As COVID-19 vaccination may elevate clozapine levels, close monitoring for clozapine toxicity is advised.

COVID-19 vaccination and clozapine initiation

Clozapine induced myocarditis typically presents within 14-21 days of commencement. There is a small increased risk of myocarditis post administration of mRNA COVID-19 vaccines which includes Comirnaty (Pfizer) and Spikevax (Moderna). Symptoms typically occur within 1-5 days with most cases have being identified within 14 days of vaccination.

Delaying clozapine initiation to after 21 days post second (or subsequent) vaccination may allow clarity as to which agent is likely responsible if myocarditis does occur.

Patients should be asked to report any adverse effects or new physical symptoms in the post vaccination period (for up to 4 weeks).

General recommendations for people treated with clozapine

  • address hypersalivation
  • vaccinate for influenza and pneumococcal disease
  • Help people to stop smoking. Note that changes in cigarette smoking will have a feedback effect on clozapine levels.
  • As part of COVID-19 preparedness, clozapine services should liaise with their local emergency department and develop escalation pathways for consumers who become unwell, but do not have symptoms or risk factors for COVID-19
  • Where no symptoms or risk factors of COVID-19 are identified, complete recommended routine physical assessments and screening.
  • Consider pre-existing and/or metabolic conditions and consumer preferences when completing assessments.
  • Be aware of early indicators of myocarditis, regardless of cause, including: CRP >50mg/L, fever above 38oC and troponin rise 2x upper limit of normal. Tachycardia may be a sign of myocarditis however this may also be due to benign tachycardia. Relative increases in heart rate should be monitored. 

If symptoms or risk factors for COVID-19 are present

  1. Discuss the consumer’s presentation with the team’s medical staff or in their absence,
  2. Seek the advice of the team/clinical leader, or
  3. Contact your District/Network COVID-19 hotline and 
  4. Support the consumer to attend their nearest fever/COVID-19 clinic for assessment,
  5. Consider directing the consumer to Emergency Department if their condition suggests they may need more comprehensive assessment and testing (Note: the differential diagnoses may include clozapine myocarditis or neutropenia) .

The symptoms of COVID-19 infection include

  • respiratory symptoms: runny nose, cough, sore throat, loss of smell or taste, shortness of breath
  • systemic symptoms: fever, chills, fatigue, headache, myalgia
  • gastrointestinal symptoms: vomiting, diarrhea
  • as the illness worsens shortness of breath, chest pain and signs and symptoms of a more general physical illness
  • delirium and other neuropsychiatric presentations.

When a person must self-isolate

Isolation during COVID-19 infection is to reduce the risk of onward transmission. Guidance from both the Commonwealth and NSW Health about isolation periods has changed over the past year see CDNA Coronavirus COVID-19 Guidelines , NSW COVID-19 Guidance and Support and NSW Management and Support if tested COVID +ve.

NSW Health recommends anyone with respiratory symptoms or unexplained fever should be tested for COVID-19. A low threshold should be used for testing for COVID-19 in people being treated with clozapine.

Pharmacy prescription management

Local services should consider their arrangements for providing scripts and medication dispensing. Ideally these should occur with the least amount of waiting time thereby reducing consumers’ risk of exposure to COVID-19. For example, faxing, e-mailing or e-prescribing prescriptions to pharmacies.

Medication delivery is recommended for socially isolated consumers who have symptoms risk factors for COVID-19 or suspected or confirmed positive for COVID-19. Consumers may be eligible for the Australian Government funded COVID-19 Home Medication Service, where they can order their clozapine remotely and have it delivered to their home.

Monitoring recommendations and considerations in consumers taking clozapine during the COVID-19 pandemic

Cardiac Monitoring

It is recommended that routine ECGs and echocardiograms be maintained in line with local LHD guidelines or policy.

NSW Health (2022). GL2022_011 Monitoring Clozapine-induced Myocarditis. Sydney, Mental Health Branch NSW Health: 1-13. 


There should be no change in the frequency of haematological monitoring for people on clozapine. Dispensations that include extended blood monitoring are not recommended due to serious complications associated with clozapine therapy in consumers with COVID-19. Additional medication only dispensations may be considered for example, to support discharge planning.

The White Cell Count can be suppressed in a viral illness such as COVID-19. In that context an ANC ≥ 2.0 x 109/L (or ≥ 1.5 x 109/L if they have a history of benign ethnic neutropenia) is of more immediate importance than a marginally reduced WCC (i.e. slightly under 3.0 x 109/L). The decision to stop clozapine due to a reduced WCC alone should be taken in discussion with the clozapine monitoring system haematologist and in the context of the person’s clinical state.

Monitoring of consumers with a stable mental state

While taking into account the risks of reduced social support and contact, it may be appropriate to consider a decrease in the frequency of face-to-face assessment for signs and symptoms of infection and mental state examination to once every eight weeks.

Consider in a consumer who:

  • is clinically well
  • has taken clozapine continuously for at least 12 months
  • has not had an Absolute Neutrophil Count (ANC) < 2.0 x 109/L (or < 1.5 x 109/L, if they have a history of benign ethnic neutropenia); and
  • has been adherent with monitoring requirements (pathology, cardiology and medical review).

Monitoring and assessment via the telephone or via approved NSW Health video conferencing should occur on alternate months.

For all other consumers, face to face assessment should continue as normal every 7 days or 28 days.

Frequency of monitoring

Where increased frequency of monitoring is required due to a break in therapy (> 3 days, less than 4 weeks), weekly haematological monitoring as per the relevant clozapine monitoring system protocol should continue. For the recommencement of clozapine, comply with the relevant clozapine monitoring system protocol.

When increased monitoring is required

(see Table 2: Guide to levels of intervention for people treated with clozapine with possible symptoms of COVID-19)

If symptomatic or testing positive to COVID-19 then check:

  • FBC  possible increased incidence of neutropenia 
  • Troponins – myocarditis
  • CRP, D-dimer – measure of pro-inflammatory effects of infection
  • LFT – increased rate of hepatic dysfunction
  • Clozapine level – may be elevated (clozapine trough level should be taken 12 hours post dosing)
  • ECG – QTc prolongation
  • If available: Oxygen saturation.

Other investigations may be warranted due to physical state.

Special considerations

COVID-19 illness in a patient taking clozapine

Where signs and symptoms of infection are present, it may be necessary to consider reducing the clozapine dose to as much as half. Clozapine levels may increase due to infection or reduced smoking. The reduced dose should continue for approximately 3 days after the fever has ceased and titrated back up in stages depending upon the clinical condition of the patient and clozapine levels if available. In the presence of physical deterioration reduction and/or cessation of clozapine should be considered and discussed with the Psychiatry team.

Clozapine initiation

Initiating clozapine in a patient who has or is at risk of contracting COVID-19 is potentially complicated by an overlap of COVID-19 symptoms and clozapine side effects. It is recommended that the treating team carefully considers the risk of harms versus potential benefits of initiating clozapine, especially for the first time. See advice above in relation to COVID-19 vaccination and clozapine initiation.

Mental health assessment and support

The psychological impact of the COVID-19 pandemic should be considered as part of the mental health assessment whenever a consumer is reviewed.  Clinicians should be mindful that consumers who are prescribed clozapine may have greater vulnerability to social anxieties, including concerns about contact with others. Enhanced support from mental health clinicians may be required during this time. 

Transfer of care

Where a consumer transfers between clozapine centres, is discharged from hospital or is transferred to GP shared care, the inclusion of COVID-19 information must be considered in the transfer of care. For example, if a consumer has been in contact with someone who is COVID-19 positive, receiving clinicians must be informed. Consideration of COVID-19 information for consumers should be a part of care planning for the receiving care team.

Home visits or transporting of consumers

There are times when clinicians may need to visit a consumer in their home or transport a consumer in a vehicle. For essential face to face consumer contact, screening for COVID-19 must be completed over the phone prior to each scheduled face to face appointment. Screening must be extended to all other people who will be in attendance. Additional PPE and equipment for screening such as a thermometer should be made available to clinicians. 

Table 1: Possible interactions between clozapine and medications that may be used in patients with COVID-19

Class / Medicine 

COVID-19 oral antivirals:

Nirmatrelvir and ritonavir (PaxlovidTM)

​Mild to moderate
COVID-19 infection.
​Increased clozapine levels leading to potentially serious and/or life-threatening reactions such as cardiac arrhythmias.


Seek specialist advice regarding treatment options for COVID-19 infection.

PaxlovidTM Drug Guideline including drug interaction table.

Molnupiravir may be a suitable alternative oral antiviral. See Drug Guideline.


Opioids e.g. morphine, oxycodone, fentanyl

Moderate to severe pain.

Increased risk of CNS depression.

Exacerbation of clozapine associated constipation.

Carefully monitor patient and adjust opioid dose as required.


  • Ciprofloxacin
  • Macrolides (azithromycin, erythromycin, clarithromycin)

Treatment of bacterial infections, particularly those of the respiratory tract.
  • Increased clozapine levels and risk of toxicity.
  • Effect is most marked with ciprofloxacin.
  • Increased QTc.
  • Avoid if possible.
  • If required, the clozapine dose may need reducing.


  • Midazolam
  • Lorazepam
  • Diazepam
  • Sedation.
  • Induction of anaesthesia.

Increased risk of CNS depression.

Carefully monitor patient and adjust benzodiazepine dose as required.


Smoking decreases clozapine levels. Cessation of smoking likely to increase clozapine levels.

Clozapine dose may need to be adjusted if patient stops smoking (the dose may need to be adjusted by 50%).

For more information on specific drug interactions refer to The University of Liverpool COVID-19 Drug Interactions Checker.

Table 2: Guide to levels of intervention for people treated with clozapine with possible symptoms of COVID-19

COVID-19 Infection Prevention and Control measures including PPE guidance are available in the COVID-19 Prevention and Infection Control Manual.

The level of COVID-19 infection prevention and control measures required will vary according to the COVID-19 Risk Monitoring Dashboard – Healthcare settings.

No symptoms or risk factors for COVID-19#
  • COVID-19 status: no symptoms or risk factors for COVID-19 *
  • Medical & MH assessment: no change to routine care, treatment or assessment.
  • Monitor: usual clozapine investigations.
Symptoms or risk factors for COVID-19#
  • COVID-19 status - presence of symptoms or risk factors for COVID-19. This could include acute illnesses such as URTIs or gastroenteritis.
  • Medical assessment: fever/COVID-19 clinic and/or GP involvement.
  • Increased frequency of contact.
  • Infection prevention & control: COVID-19 testing. Patient to self-isolate until results available.
  • Monitor: immune status, clozapine level, significant adverse effects, comorbid illnesses e.g. diabetes.

COVID-19 positive

  • COVID-19 status: confirmed COVID-19+, with mild illness. Can be managed at home.
  • Medical assessment: GP review or ED if GP not available.
  • Increased frequency of contact.
  • Infection prevention & control: patient needs to self-isolate.
  • Monitor: immune status, clozapine level, comorbid illnesses, severity of COVID-19. Integrate care with GP involvement.
COVID-19 positive
Moderate - severe
  • COVID-19 status: COVID-19+, with moderate to severe illness.
  • Medical assessment: ED assessment.
  • MH assessment: record mental state including cognition. Transfer to ED. Inform medical team about psychiatric and medication history.
  • Monitor: transfer care to medical setting. Monitor vital signs.
  • * A risk assessment should be made by the health care worker prior to a consumer presenting to the CHC or before home visits, this includes asking screening questions.
  • # If visiting a consumer in their home consideration will also need to be made regarding the health and COVID-19 status of household members.

References and important support documents


Important support documents

Document information

Developed by

Mental health community of practice - Clozapine Working Group.


  • Clinical Directors of Mental Health

Endorsed by

Deb Willcox, Deputy Secretary, Health System Strategy and Planning, NSW Ministry of Health.

For use by

NSW Local Health Districts / Specialty Health Networks.

Current as at: Thursday 24 November 2022
Contact page owner: Health Protection NSW