Clozapine is an antipsychotic that is uniquely effective in treating treatment-resistant schizophrenia. It is a second-generation antipsychotic or an atypical antipsychotic. Clozapine is distinctively effective against ‘negative’ symptoms of schizophrenia. It is reserved for patients whose condition remains inadequately controlled despite previous use of two or more antipsychotic drugs, of which at least one is a second-generation drug (Ritter, et al., 2020, p. 602). Clozapine restores the balance of the neurotransmitters (naturally occurring chemicals in the brain) dopamine and serotonin and helps in thinking better, have an upbeat mood, and behave appropriately (College of Psychiatric and Neurologic Pharmacists, 2016). Clozapine can have numerous side effects: risk of decreased white blood cell count (agranulocytosis), weight gain, seizures, sudden drop in BP upon standing up too quickly (orthostatic hypotension), sedation, severe constipation (Brunton, 2018, p. 282).
Uses of Clozapine
Clozapine (Clozaril) is used to treat refractory schizophrenia and refractory mania (Brunton, 2018, p. 299). In treatment-refractory schizophrenia, response rates are 0% for typical antipsychotic agents, less than 10% for newer agents, but consistently about 60% for clozapine (Brunton, 2018, p. 282).
Clozapine can be beneficial in patients with refractory mania as adjunctive therapy and as monotherapy (Brunton, 2018, p. 294).
Clozapine is also FDA approved to reduce the risk of recurrent suicidal behavior in people with schizophrenia or schizoaffective disorder (College of Psychiatric and Neurologic Pharmacists, 2016).
It may take a few weeks before the full benefit of this drug takes effect (WebMD, n.d.).
Dose of Clozapine
- Clozapine is usually taken 1 or 2 times per day with or without food. You begin at a low dose and the dose is increased slowly over several weeks. The range is from 25 mg to 900 mg. Only your doctor can determine the correct dose for you.
- Hallucinations, disorganized thinking, and delusions may improve in the first 1-2 weeks.
- Sometimes these symptoms do not completely go away.
- Motivation and desire to socialize can take at least 1-2 weeks to improve.
- It may take 2-3 months before you get the full benefit of clozapine (College of Psychiatric and Neurologic Pharmacists, 2016).
The following doses are for adults unless otherwise specified.
Dose for Refractory Schizophrenia
Clozapine is begun at 12.5 mg orally once daily or every 12 hours initially; increased daily in steps of 25-50 mg/day, to achieve target dosage of 300-450 mg/day by end of 2 weeks. Sometimes, it may have to be increased to 600-900 mg/day to obtain an acceptable response. Generally, patients who respond should continue maintenance treatment on their effective dose even after the acute episode (Cunha, n.d.).
Acute psychosis, 1st episode – 200–600 mg/day
Acute psychosis, chronic – 400–900 mg/day
Maintenance, 1st episode – 200–600 mg/day
Maintenance, chronic – 300–900 mg/day (Brunton, 2018, p. 283)
Schizophrenia requires long-term treatment. You should not stop taking clozapine on your own, even if you are feeling better – you should do so only in consultation with your doctor. If you miss doses of clozapine you face an increased risk for a relapse in your symptoms (College of Psychiatric and Neurologic Pharmacists, 2016).
Dose for Refractory Mania in Bipolar Disorder
Clozapine can be a good option for resistant mania. Clozapine is started with 25 mg at night and titrated up to 100 mg daily in divided doses within one week. Treatment is continued with clozapine 100 mg daily in divided doses and 1500 mg valproate preparations. Remission can happen within 2 weeks of starting clozapine (Arafat, et al., 2016).
What if I miss a dose?
Take the missed dose as soon as you remember, unless it is close to the time of your next scheduled dose. Do not double your next dose to make up for the missed dose or take more than what is prescribed. If you miss more than 2 days of medication, contact your doctor because an adjustment of your dose may be needed (College of Psychiatric and Neurologic Pharmacists, 2016).
What if I overdose?
The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, increased heart rate, low BP, trouble breathing and excess salivation. Seek emergency medical help if these symptoms occur. Generally, doses above 2500 mg are fatal. However, some people have recovered from overdoses in excess of 4 g.
Clozapine REMS Program
Since there is a risk of neutropenia (decreased white blood cells) with clozapine, it is only available through a restricted program called the Clozapine REMS Program. Main requirements of the Clozapine REMS Program include (RxList, 2019):
- Only those doctors who are certified with the program by enrolling and completing training are allowed to prescribe Clozaril
- Patients receiving Clozaril should be enrolled in the program and comply with the ANC testing and monitoring requirements
- Pharmacies dispensing Clozaril must be certified with the program by enrolling and completing training and must only dispense to patients who are eligible to receive Clozaril
Clozaril Side Effects (College of Psychiatric and Neurologic Pharmacists, 2016) (Cunha, n.d.)
Common Side Effects
- Increased heart rate
- Low blood pressure
- Significant Constipation. Routine use of stool softeners and repeated inquiry into bowel habits are necessary to prevent serious intestinal obstruction from undetected constipation (Brunton, 2018, p. 292).
- Increased salivation
- Dry mouth
- Feeling drowsy or dizzy
- Blurred vision
- Increased appetite
- Weight gain
- Increased sweating
- Inflammation of heart muscle (myocarditis)
Rare/Serious Side Effects
- Severely low blood pressure
- Urinary incontinence
- Slurred speech
- Decreased white blood cells (agranulocytosis): It has an incidence of 1-2%; the highest risk occurs during the initial 6 months of treatment, peaking at months 2–3 and diminishing rapidly thereafter. The mechanism is immune-mediated(Brunton, 2018, p. 293). The blood count is monitored weekly for the first 18 weeks, and less frequently thereafter (Ritter, et al., 2020, p. 602). Provided the drug is stopped at the first sign of leukopenia or anemia, the effect is reversible. Agranulocytosis is rare but life-threatening (Ritter, et al., 2020, p. 601).
- Metabolic syndrome: weight gain, high blood sugar, and high cholesterol. Weight gain is a significant problem during long-term use and represents a major barrier to medication adherence, as well as a significant threat to the physical and emotional health of the patient. Appetite stimulation is the primary mechanism involved, with little evidence to suggest that decreased activity (due to sedation) is the main contributor to antipsychotic-related weight gain(Brunton, 2018, p. 292).
- Higher risk of death, strokes, and transient ischemic attacks (TIAs) in elderly people with behavior problems due to dementia.
- Sudden cardiac death due to arrhythmia (irregular heartbeat). To minimize this risk, take the smallest effective dose when the benefits outweigh the risks. ECG may be needed to monitor for an irregular heartbeat.
- Allergic reaction: Symptoms include swollen, pale red bumps or wheals on the skin that appear suddenly, and cause itching and burning sensation; difficulty in breathing; swelling of face, lips, tongue, or throat. Get emergency medical help.
- Extrapyramidal symptoms at high doses:
- Acute dystonias: involuntary movements (restlessness, muscle spasms, protruding tongue, fixed upward gaze, neck muscle spasm). They occur commonly in the first few weeks, often declining with time, and are reversible on stopping drug treatment.
- Tardive dyskinesia: It develops after months or years of treatment. It consists of involuntary movements, often of the face and tongue, but also of trunk and limbs.
- Neuroleptic malignant syndrome: Symptoms of high fever, muscle stiffness or pain or weakness, severe tiredness, severe confusion, sweating, fast/irregular heartbeat, dark urine, change in the amount of urine. These may be symptoms of a rare and serious condition that can lead to death. Contact emergency medical services immediately.
Precautions and Warnings with Clozapine (WebMD, n.d.)
Clozaril can cause a serious decrease in a certain type of white blood cells (agranulocytosis or neutropenia). Blood tests should be done before starting and while you are taking clozapine. Neutropenia may lower your ability to fight infections. Get medical help right away if you have any signs of severe neutropenia or infection (such as sore throat that doesn’t go away, fever, swollen lymph nodes, unusual tiredness, weakness).
Clozapine can also cause seizures in higher doses. Inform your doctor if you have ever had seizures. While taking this medication, avoid driving or other activities which require alertness (e.g., operating heavy machinery, swimming).
This medication may rarely cause an inflammation of the heart muscle or heart failure. Get medical help immediately if you develop chest pain, fast/irregular heartbeat, shortness of breath, swelling of ankles/feet, unusual tiredness, or unusual/sudden weight gain.
Clozapine can cause low BP or a slow heartbeat when you stand up suddenly (postural hypotension), leading to dizziness or fainting. Get up slowly when rising from a sitting or lying position.
There may be a slightly increased risk of serious, possibly fatal side effects when this medication is used by older adults with dementia. It is not approved for the treatment of dementia-related behavior problems in the elderly. Discuss the risks and benefits of this and other effective and possibly safer treatments available for dementia-related behavior problems, with your doctor.
Use during Pregnancy and Lactation
Clozapine use during pregnancy may be acceptable. Neonates exposed to antipsychotic drugs such as clozapine during the last three months of pregnancy are at risk for extrapyramidal symptoms (EPS) or withdrawal symptoms after delivery; these complications vary in severity, with some being self-limited and others requiring ICU support and prolonged hospitalization.
Clozapine enters breast milk; so, its use is not recommended while breastfeeding.
Interactions of Clozaril (WebMD, n.d.)
A product that may interact with this drug is metoclopramide. Other medications that can affect the excretion of clozapine include fluvoxamine, rifamycins, St. John’s wort, drugs used to treat seizures, etc.
Drugs that can increase the effects of drowsiness and sedation that occur with clozapine are opioid pain or cough relievers, alcohol, marijuana, drugs used to treat insomnia or anxiety, muscle relaxants, or antihistamines.
Arafat, Y. et al., 2016. Clozapine Can Be the Good Option in Resistant Mania. Case Rep Psychiatry, Vol 2016, Article ID 3081704, 3 pages, https://doi.org/10.1155/2016/3081704.
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