• Monitor patient’s mental status (orientation, mood, behavior) before and periodically during therapy. Titrate slowly and monitor closely; may cause orthostatic hypotension, bradycardia, syncope, and cardiac arrest.
• Monitor BP (sitting, standing, lying) and pulse rate before and frequently during initial dose titration.
• Assess weight and BMI initially and periodically during therapy. Refer as appropriate for nutritional/weight management and medical management.
• Observe patient carefully when administering medication to ensure that medication is actually taken and not hoarded or cheeked.
• Monitor for signs of myocarditis (unexplained fatigue, dyspnea, tachypnea, fever, chest pain, palpitations, other signs and symptoms of heart failure, ECG changes, such as ST-T wave abnormalities, arrhythmias, or tachycardia during first mo of therapy). If these occur, clozapine should be discontinued and not restarted.
• Monitor patient for onset of akathisia (restlessness or desire to keep moving) and extrapyramidal side effects (parkinsonian: difficulty speaking or swallowing, loss of balance control, pill-rolling motion of hands, mask-like face, shuffling gait, rigidity, tremors and dystonic muscle spasms, twisting motions, twitching, inability to move eyes, weakness of arms or legs) every 2 mo during therapy and 8–12 wk after therapy has been discontinued. Notify health care professional if these symptoms occur; reduction in dose or discontinuation of medication may be necessary. Trihexyphenidyl or benzotropine may be used to control these symptoms.
• Monitor for possible tardive dyskinesia (uncontrolled rhythmic movement of mouth, face, and extremities; lip smacking or puckering; puffing of cheeks; uncontrolled chewing; rapid or worm-like movements of tongue). Report these symptoms immediately; may be irreversible.
• Monitor frequency and consistency of bowel movements and assess for symptoms of hypomotility (nausea, vomiting, abdominal distension, abdominal pain). Symptoms range from constipation to paralytic ileus; risk increased with use of other anticholinergic medications. Increasing bulk and fluids in the diet, and laxatives may help to minimize constipation. Prophylactic laxatives may be used for high-risk patients.
• Clozapine lowers the seizure threshold. Institute seizure precautions for patients with history of seizure disorder.
• Transient fevers may occur, especially during first 3 wk of therapy. Fever is usually self-limiting but may require discontinuation of medication. Also, monitor for development of neuroleptic malignant syndrome (fever, respiratory distress, tachycardia, seizures, diaphoresis, hypertension or hypotension, pallor, tiredness). Notify health care professional immediately if these symptoms occur.
• Assess respiratory status during therapy. If deep-vein thrombosis, acute dyspnea, chest pain, or other respiratory signs and symptoms occur, consider pulmonary embolism.
• Assess for falls risk. Drowsiness, orthostatic hypotension, and motor and sensory instability increase risk. Institute prevention if indicated.
• Monitor for signs and symptoms of hepatotoxicity (fatigue, malaise, anorexia, nausea, jaundice, hyperbilirubinemia, coagulopathy, hepatic encephalopathy). May require permanent discontinuation if combined with elevated transaminases.

Lab Test Considerations:

• Monitor WBC, absolute neutrophil count (ANC), and differential count before starting therapy. ANC must be ≥1500/mm³ for the general population and ≥1000/mm³ for patients with documented Benign Ethnic Neutropenia (BEN) for patient to begin therapy. Monitor ANC weekly for the first 6 mo, then biweekly for the second 6 mo, then, if maintained within acceptable parameters, monthly after 12 mo. If mild neutropenia (ANC 1000–1499/mm³) occurs, continue therapy and monitor ANC 3 times/wk until ANC ≥1500/mm³. Once ANC ≥1500/mm³, return to patient's last ANC monitoring interval. If moderate neutropenia (ANC 500–999/mm³) occurs, recommend hematology consultation. Interrupt therapy for suspected clozapine-induced neutropenia. Resume therapy once ANC ≥1000/mm³. Monitor ANC daily until ANC ≥1000/mm³ then 3 times/wk until ANC ≥1500/mm³. Once ANC ≥1500/mm³, check ANC weekly for 4 wk, then return to patient's last ANC monitoring interval. If severe neutropenia (<500/mm³) occurs, recommend hematology consultation. Interrupt therapy for suspected clozapine-induced neutropenia. Do not rechallenge unless benefit outweighs risk. Monitor ANC daily until ANC ≥1000/mm³, then 3 times/wk until ANC ≥1500/mm³. If patient rechallenged, resume therapy as a new patient using normal monitoring once ANC ≥1500/mm³. For patients with Benign Ethnic Neutropenia (BEN), obtain at least 2 baseline ANC levels before starting therapy. Monitor ANC weekly for the first 6 mo, then biweekly for the second 6 mo, then, if maintained within acceptable parameters, monthly after 12 mo. If neutropenia (ANC 500–999/mm³) occurs, recommend hematology consultation and continue therapy. Monitor ANC 3 times/wk until ANC ≥1000/mm³ or at patient's known baseline. Once ANC ≥1000/mm³, check ANC weekly for 4 wk, then return to patient's last ANC monitoring interval. If severe neutropenia (<500/mm³) occurs, recommend hematology consultation. Interrupt therapy for suspected clozapine-induced neutropenia. Do not rechallenge. Monitor ANC daily until ANC ≥500/mm³, then 3 times/wk until ANC ≥patient's baseline. If patient rechallenged, resume therapy as a new patient using normal monitoring once ANC ≥1000/mm³ or at patient's baseline.
  • Assess fasting blood glucose and cholesterol levels initially and throughout therapy.
  • Monitor liver function tests periodically during therapy or if clinical signs of hepatotoxicity occur.

Toxicity and Overdose:

• Overdose is treated with activated charcoal and supportive therapy. Monitor patient for several days because of risk of delayed effects.
  • Avoid use of epinephrine and its derivatives when treating hypotension, and avoid quinidine and procainamide when treating arrhythmias.