Continuing Education Activity

Clozapine is an FDA-approved atypical antipsychotic medication for treatment-resistant schizophrenia. Clozapine is not the first-line drug of choice due to its range of adverse effects, making compliance an issue for many patients. However, it also has some advantages, including lowering the risk of suicide and tardive dyskinesia and fewer relapses. Regarding suicide risk, clozapine has been demonstrated to reduce suicidal behavior even in non-treatment-resistant schizophrenia and schizoaffective disorder patients. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of clozapine pertinent for members of the interprofessional team where this agent is indicated.

Objectives:

• Identify the mechanism of action of clozapine.
• Review the indications for initiating clozapine therapy.
• Describe the adverse effects associated with clozapine.
• Explain the importance of improving care coordination among interprofessional team members to improve outcomes for patients receiving therapy with clozapine.

Indications

Clozapine is an FDA-approved atypical antipsychotic drug for treatment-resistant schizophrenia.[1] The definition of treatment-resistant schizophrenia is persistent or moderate delusions or hallucinations after failing two trials of antipsychotic medicines.[2] Since its creation, it has been the drug of choice for treatment-resistant schizophrenia, even though it has many adverse effects.[3] Clozapine is not the first-line drug of choice due to its range of adverse effects, making compliance an issue for many patients.[3]

Clozapine was first synthesized in 1956 in many European countries like Switzerland, Austria, West Germany, and Finland.[1][2] Concurrent studies in the United States led to reports of death due to cases of agranulocytosis, taking clozapine off the market for a long time.[1] A pivotal study known as the US Clozaril Study showed the efficacy of clozapine over chlorpromazine in a 6-week trial of patients who failed to respond to three previous antipsychotic drugs.[2] The study results ultimately led to the FDA approval for treatment-resistant schizophrenia.[2] A meta-analysis done in 2018 showed that clozapine might be more effective than other antipsychotics even when used as a first- or second line of treatment.[4]

Other Advantages[2]

• Lower risk of suicide (clozapine has been shown to reduce suicidal behavior even in patients with non-treatment-resistant schizophrenia and schizoaffective disorder.)
• Lower risk for tardive dyskinesia
• Improvement of cognition which leads to improved quality of life
• Decreased relapse

Mechanism of Action

Clozapine is part of a group of drugs known as second-generation antipsychotics or atypical antipsychotics. Antipsychotic drugs are vital in treating the core symptoms of schizophrenia: hallucinations and delusions.[5] As an atypical antipsychotic, clozapine acts an antagonist to both dopamine and serotonin receptors. It binds to the dopamine D4 with a higher affinity than the dopamine D2 receptor, contributing to decreased adverse events and extrapyramidal symptoms. Clozapine is a partial 5-HT1A agonist, contributing to reducing negative symptoms and extrapyramidal symptoms, and a muscarinic M1, M2, M3, M5, histamine, and alpha-1 adrenergic-receptor antagonist. Norclozapine, the metabolite of clozapine, actively works on the M1 and M4 receptors.[1]

Administration

Healthcare Providers must apply and receive certification in the Clozapine REMS program to prescribe clozapine for outpatient use. To receive treatment, a patient must be enrolled in the clozapine REMS registry by a certified clinician. In addition, pharmacies and pharmacists must obtain certification through Clozapine REMS to receive clozapine and dispense it to patients. All of these actions can be done online through the website www.clozapineREMS.com.

Clozapine is available as oral tablets, oral disintegrating tablets, and oral suspension in the following strength. Choice of dosage form depends on patient acceptability and tolerability.

• Oral tablet dosages of 25 mg, 50 mg, 100 mg, and 200 mg
• Orally disintegrating tablet dosages of 12.5 mg, 25 mg, 100 mg, 150 mg, and 200 mg
• Oral suspension dosage of 50 mg/mL (100 mL)

According to the FDA, clozapine's maximum recommended dosage is up to 900 mg per day. The average dose is 300 mg per day for women and 400 mg per day for men. Slow titration is essential for reducing many side effects associated with clozapine.[6] With the persistent partial response, clozapine may be augmented with ECT to increase the drug's efficacy.[6][7] Other methods of augmentation include lamotrigine and other antipsychotics.[6]

Clozapine is metabolized to norclozapine and other metabolites by the cytochrome P450 enzymes (CYP1A2, CYP3A4, CYP2C19, with some influence from CYP2C9 and CYP2D6).[3] Clozapine has a short plasma half-life of 12 to 16 hours.[8]

Specific Population

Hepatic Impairment: The manufacturer's labeling provides no dosage adjustment recommendation; however, it suggests dose reductions in patients with significant hepatic impairment.

Renal Impairment: The manufacturer's labeling provides no dosage adjustment recommendation; however, it suggests dose reductions in patients with significant renal impairment.

Pregnancy: Women between 18 to 45 years of age and exposed to clozapine during pregnancy should be enrolled in the Atypical Antipsychotics Pregnancy Registry by their health care providers. (website  womensmentalhealth.org/pregnancyregistry). Clozapine is an FDA pregnancy category B medicine.[9]

Breastfeeding Women: Since clozapine use is not studied during breastfeeding, and some case reports of sedation and adverse hematologic effects in breastfed infants in literature, alternative medicine is advised. If the infant is exposed to clozapine via breastfeeding, closely monitor the infant for excessive sedation and white blood cell count. Some expert panel recommends against breastfeeding if women require clozapine while lactating.[10]

Adverse Effects

Agranulocytosis

The risk of developing agranulocytosis is around 1% in patients who take clozapine, which may be independent of dosing.[2][3] Most cases occur early in the treatment, within six weeks to six months, and require extensive monitoring of blood absolute neutrophil counts.[2] The definition of neutropenia is an ANC level below 1500/mm, and agranulocytosis is an ANC level below 500/mm. Many have tried to explain the link between clozapine and agranulocytosis by attributing this adverse effect to drug interactions with the immune system and genetic predisposition.[3] A study in 2015 looked into the benefits of pharmacogenetic testing and how it may affect monitoring in patients at risk for clozapine-induced agranulocytosis.[11] The study suggested that patients with a lower genetic risk may benefit from a more relaxed hematological monitoring schedule.[11] Risk factors include old age, female, genetics, and concurrent treatment with other drugs known to cause agranulocytosis.[3] Clinicians must place patients taking clozapine on a national registry.[2] Granulocyte colony-stimulating factor may be an option to increase levels of white blood cells.[6]

Myocarditis

Clozapine-induced myocarditis is a rare complication, affecting less than 3% of patients. This lethal dose-independent side effect appears more frequently during the first four weeks of treatment. In these patients, signs and symptoms of myocarditis may vary from having a flu-like illness to respiratory and cardiovascular symptoms.[3] Some clozapine-induced myocarditis cases may even present atypically without any symptoms leading to higher fatality rates. Risk factors include rapid titration of the drug, metabolic side effects of clozapine, concurrent use of selective serotonin reuptake inhibitors, and illicit substances.[3] Treatment includes immediate clozapine cessation, which may resolve the case.[3]

Metabolic Syndrome

Clozapine is associated with significant weight gain, diabetes type 2, diabetic ketoacidosis, and increased lipid levels-all due to increased insulin resistance.[2] Both clozapine and olanzapine have higher metabolic side effects than the other atypical and typical antipsychotics due to their high affinity for serotonin 5-HT2C receptors.[2][5] It is important to note that other factors, including poor diet and a sedentary lifestyle, may contribute to the development of metabolic syndrome.[3] The American Heart Association defines metabolic syndrome as increased weight, dyslipidemia, increased blood pressure, increased glucose intolerance, increased proinflammatory, and prothrombic states.[5] The development of DKA is one of the serious side effects of clozapine, having a higher mortality rate than agranulocytosis.[3] Recommendations include counseling the patient on proper diet, exercise, and other drugs like metformin and orlistat to reduce the metabolic effects of clozapine.[3][2]

Seizures

Clozapine may lower the seizure threshold in both patients with epilepsy and normal patients. The risk is usually dose-dependent, around 1% to  6%, especially with rapid titration, and might be more prevalent in younger patients. This side effect may appear at any stage of treatment. Patients who experience a seizure while on clozapine may benefit from the addition of an anti-epileptic like valproic acid.[3]

Excessive Salivation

Sialorrhea is a dose-dependent and benign condition that may be bothersome to some patients.[3] One risk of excessive salivation is aspiration pneumonia.[12]

Pulmonary Embolism

A recent study comparing clozapine to several other antipsychotics showed it to be the only drug to increase platelet adhesion and aggregation.[3] The risk seems to be higher in elderly patients and pregnant women taking high doses.[3] Many studies have found this link to be dose-independent, highly lethal, and demonstrate early onset.[13]

Constipation

Cholinergic and serotonergic properties of clozapine may affect the gastrointestinal system and lead to constipation or even ileus. Constipation affects anywhere from 15% to 60% of all patients taking clozapine and is dose-dependent, making it one of the most common side effects. In severe cases, constipation can progress to ileus, leading to bowel obstruction and bowel ischemia.[3] One study suggests these cholinergic effects may even lead to dysphagia, which can progress to aspiration pneumonia, meaning gastric hypomotility may not be limited to just the bowel.[12] Management includes adequate fluid intake, laxative or docusate use, and dose reduction.[3]

Other

Other side effects may include orthostatic hypotension, sedation, tachycardia, sexual dysfunction, and urinary retention.[3]

Contraindications

Clozapine is contraindicated in patients with serious hypersensitivity reactions to clozapine or any component of the formulation.

FDA states the following Black Box warnings:

• Neutropenia (due to the risk of agranulocytosis)
• Orthostatic hypotension
• Seizures
• Myocarditis
• Dementia (risk of a cardiovascular event)

Drugs that may inhibit cytochrome CYP1A2 leading to increased levels of clozapine include but are not limited to antifungals, oral contraceptives, fluvoxamine, ciprofloxacin, caffeine disulfiram. Drugs that may induce CYP1A2 include but are not limited to omeprazole, rifampicin, tobacco, phenytoin, and phenobarbital. Other drugs that induce (carbamazepine and rifampicin) and inhibit (cimetidine and erythromycin, among others) CYP3A4 may also affect clozapine drug levels.[3]

Tobacco may affect clozapine metabolism through CYP1A2; therefore, it is important to understand the blood levels and efficacy of clozapine when a patient smokes or when they abruptly stop.[3]

Monitoring

Serious adverse effects that require monitoring include but are not limited to: 

Agranulocytosis

Weekly complete blood count (CBC) to measure ANC levels. ANC levels less than 1500/mm indicate neutropenia. Levels less than 500/mm indicate agranulocytosis.[3] A complete blood count should be taken weekly for the first six months, then every other week for the next six months.[1] A national registry is in place to monitor for safe use.[2]

Metabolic Syndrome

Diet and exercise, blood glucose levels[3]

Cardiovascular

Baseline troponin I or T levels, high sensitivity CRP levels, echocardiography, and BNP levels, as well as vitals and weekly laboratory testing of troponins, CRP, and BNP levels[3]

Seizure

EEG and clozapine blood levels[3]

Toxicity

A 36-year-old male experienced rhabdomyolysis following an overdose of clozapine 125 mg tablets. The patient was discharged from the hospital after five days of stay when the creatinine kinase levels returned within normal range Monitor creatinine kinase levels to diagnose possible rhabdomyolysis.[14] Another acute overdose in a 60-year-old male reported venous thromboembolic event and pulmonary embolism event; therefore, it is essential to monitor patients initiated on clozapine who may be at an increased risk of thromboembolic events.[15]

The common adverse events associated with clozapine overdose are hypersalivation, tachycardia, hypotension, sedation, delirium, coma, respiratory depression, or failure. There are few reports of cardiac arrhythmias, aspiration pneumonia, and seizure. Fatality is reported at doses above 2500 mg, and on the contrary, some patients recovered after ingestion of 4000 mg clozapine.

Management

There is a lack of a specific antidote to an overdose of clozapine. Monitor and maintain an airway, ventilation, cardiac status, vital signs, and provide symptomatic and supportive measures. Consider the possibility of multiple-drug overdose and contact Poison Control Center to report and get information on additional management (1-800-222-1222).

Enhancing Healthcare Team Outcomes

Clozapine, due to its many lethal adverse reactions, has become a drug that many clinicians are afraid to prescribe due to fear of patient safety. One of the most significant concerns for clozapine is the adverse effect of agranulocytosis and requires cessation of therapy and hematology consultation. The FDA has mandated a national registry to monitor weekly white blood cell count levels for anyone prescribed clozapine. There are many limitations for clozapine use, described in a systematic review looking at barriers to its use. There are three levels this study uses to describe the barriers; these are the patient, the clinician, and health-system-related barriers. Some patient barriers include non-compliance to weekly blood draws, tolerating clozapine adverse effects, and patients prescribed multiple drugs. From the clinician’s perspective, some barriers are inadequate experience and knowledge of prescribing clozapine, fear of side effects, lack of adherence to guidelines, need for intense monitoring, and perception of patient non-compliance. Some systemic problems include insufficient resources, including staffing and nurses, shortage of beds, and service fragmentation. Point-of-care devices, educational interventions for clinicians and patients, and shared decision-making involving patients are crucial to tackling these barriers. These solutions need evaluation using controlled study designs.[16] [Level 4]

Coordination of clozapine treatment is best through the national registry, which helps identify the patient and collaborate the care by interprofessional health care team members consisting of prescribers, nurses, physician assistants, specialists, psychiatrists, and pharmacists.