Clozapin, Clozaril®

• Clozaril®

• Atypical Antipsychotic Agent

• Tablets 25 mg
• Tablets 100 mg

1. Resistant schizophrenia.

2. Non-responsive schizophrenia.

3. Improve both positive and negative symptoms. (Controlled clinical trials).

4. Potent exert aggressive activity against isolation – induced fighting behavior.

Mechanism of Action:

• A di-benzodiazepine derivative
• Dopamine- D1, D2, D3 D4 (highly potent for this receptor) and D5-receptor blocker
• Serotoninergic (S2-5-HTP) receptor blocker
• Alpha-adrenergic receptor blocker
• Histaminergic (H1) receptor blocker
• Cholinergic receptor blocker

Pharmacokinetics:

1. Absorption:

• Orally
• Food does not affect.
• First-pass effect metabolism, bioavailability: 50 to 60%.

2. Distribution:

• Plasma concentrations peak: 2.5 hours after dosing.
• 95% bound to plasma proteins.

3. Biotransformation/Metabolism:

• Almost completely metabolized prior to excretion.
• Is a substrate for many CYP 450 isoenzymes
• Converted to Norclozapine (Desmethyl clozapine), and clozapine-N-oxide.
• Significant correlation between clozapine plasma levels and clinical response.
• In patients who responded to treatment, plasma clozapine levels reached at least 350 to 370 ng/ml.

4. Elimination:

• Mean half-life: 12 hours
• Only trace amounts of unchanged drug are detected in the urine and feces. (Excreted Urin>feces)

5. Carcinogenicity:

• No increased incidence of tumors in treated animals.

6. Mutagenicity:

• No evidence of mutagenic effects

• Therapeutic Dose Range: 300-600 mg/day in divided doses.
• Maximum Dose: 900 mg/day.
• Maintenance Dose: 150-300 mg/day in divided doses.
• Patients 60 years of age and older: Low dose (12.5 mg given once on the first day) + subsequent dose increments restricted to 25 mg/day.
• Pediatrics and adolescents (< 18 years of age): No studies have been performed.

At baseline: 

• Troponin, CRP & Echocardiography

Follow ups: 

• Troponin, CRP, on days 7, 14, 21, 28
• Vital signs daily

Discontinue Clozapine if: 

1. Troponin > 2 x ULN or
2. CRP > 100 mg/L

Continue Clozapine with daily Troponin & CRP if:

1. Symptoms of infections or
2. HR > 120 bpm or rise > 30 bpm or
3. CRP 50-100 mg/L or
4. Mild Tropnonin elevation (<2 ULN)

1. Enhance the CNS effects of:

• Alcohol
• MAO inhibitors
• Narcotics
• Antihistamines
• Benzodiazepines
• Anticholinergic
• Antihypertensive agents

2. Increasing effect of Norepinephrine

3. Decrease the effect of Epinephrine

4. Should not be used with:

• Carbamazepine (Potential Bone Marrow Suppression)
• Medications potential to suppress bone marrow function

5. Enzyme Inhibitor Effect-Increase Plasma levels: (Should NOT be used simultaneously):

• Valproic acid
• Azole Anti-Mycotics and Protease Inhibitors (however, no interactions have been reported to date.)
• Fluvoxamine
• Ciprofloxacin
• Oral contraceptives
• SSRIs (paroxetine, sertraline, fluoxetine, citalopram)
• Caffeine
• Sudden smoking cessation

6. Enzyme Inducer Effect-Decreased Plasma levels: (Should NOT be used simultaneously):

• Carbamazepine
• Phenytoin
• Rifampicin
• Omeprazole
• Tobacco smoking

Greater than 5%

1. Seizure: Risk increased over time
2. Fever
3. Neuroleptic malignant syndrome
4. Drowsiness/dizziness/Sedation
5. Cardiovasculartoxicity:
   1. Myocarditis (promptly discontinued)
   2. Pericarditis
   3. Cardiomyopathy (promptly discontinued)
   4. Tachypnea
   5. Respiratory rate > 20/min
   6. Fever > 38.0
   7. QT interval prolongation
   8. Orthostatic hypotension
   9. Increased Troponin
   10. Increased CRP
6. Anticholinergic Activity: caution in BPH
   1. Narrow angle glaucoma
   2. Constipation
   3. Fecal impaction
   4. Paralytic illus
7. Fatigue, flu-like symptoms
8. Weight gain
9. Hyperglycemia
10. Dyslipidemia
11. Headache
12. Tremor
13. Vertigo

Less than 5%

1. Agranulocytosis: granulocyte count <0.5 x 109/L -)
2. Thrombocytopenia
3. Eosinophilia: (eosinophil count > 3.0 x 109/L)
4. Granulocytopenia: (granulocyte count <1.5 x 109/L-)
5. Cardiovascular toxicity:
   1. Chest pain
   2. Myocardial infarction and sudden death
   3. DVT and PE
   4. Arrhythmia
6. Respiratory arrest
7. Tardive dyskinesia, parkinsonism, irritability: Dopamin turnover in the Mesolimbic > Nigrostriatal system compared with other atypical antipsychotics = Lower extrapyramidal side effects
8. Little or no prolactin elevation. (In contrast to conventional antipsychotics)

1. Hypersensitivity
2. Myeloproliferative disorders
3. Granulocytopenia/ agranulocytosis from previous chemotherapy
4. Bone Marrow failure
5. Active/progressive liver disease
6. Unable to undergo blood tests.
7. Severe CNS depression
8. Severe renal/cardiac disease
9. Uncontrolled epilepsy
10. Paralytic ileus

• Caution: Category B. Antipsychotic drugs, including CLOZARIL, should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus
• Lactation: Not recommended in nursing mother.

1. Hematologic:

• First 26 weeks: Weekly CBC
• Second 26 weeks: CBC once every two weeks- in case of WBC ≥3500/mm3 +ANC ≥2000/mm3+ acceptable patient’s clinical condition.
• Third 26 weeks and after: CBC every four weeks if WBC ≥3500/mm3 +ANC ≥2000/mm3+ acceptable patient’s clinical condition.

• Previous Hematologic dx: history of primary bone marrow disorders = treated only if the benefit outweighs the risk.
• Eosinophilia: If the eosinophil count > 3.0 x 109/L = Discontinue
• Caution: If both eosinophilia + clozapine-induced myocarditis = should not be re-exposed to clozapine.
• Thrombocytopenia: If Plt< 0 x 109/L = Discontinue
  • Monitoring MUST continue AS LONG AS patient is on Clozapin
  • Poor compliance patients = Do not prescribe
  • In Neutropenia ANC<1.5 x 109/L or severe leukopenia (WBC <2.0 x 109/L) = Must Discontinue
• Re-start therapy: If the eosinophil count < 1.0 x 109/L

2. Dementia: Elderly patients + dementia = Not indicated

3. Pediatrics (< 18 years of age): No studies have been performed.

4. In case of lethargy, weakness, fever, sore throat, flu-like complaints or any other signs of infection: Contact your physician immediately.

5. Fever:

• Above 38°C (100.4°F)- transient temperature elevations aka Benign self limiting Fever- in first three weeks.
• Caution: If Fever + WBC rose = carefully evaluate the patient!
• If high grade fever = R/O Neuroleptic Malignant Syndrome = discontinue Clozapin

6. Activities requiring alertness: cautioned: (e.g., driving, operating machinery, swimming, climbing, etc.)

7. Rebound, withdrawal effects: Abrupt discontinuation for any reason = observe the patient carefully for Psychotic + cholinergic effects like: profuse sweating, headache, nausea, vomiting+ diarrhea.

8. Discontinuation of Therapy:

• In planned termination of Clozapin: Gradual dose reduction over 1-2 weeks = observe the patient carefully for Psychotic + cholinergic effects like: profuse sweating, headache, nausea, vomiting+ diarrhea.

9. Cardiovascular and/or pulmonary disease:

• Cautioned: Gradual titration needed
• Clozapine-induced myocarditis = Must discontinue
• Caution for: risk of orthostatic hypotension = during the initial dose titration.

10. Tardive Dyskinesia:

• Highest among the elderly, especially elderly women
• Lowest incidence of extrapyramidal and Tardive dyskinesia compare to other antipsycotics. (Very Rare)
• Improve patient’s condition with Tardive dyskinesia. (The only anti-psychotic agent)

11. Dyslipidemia: Clinical Monitoring + baseline periodic monitoring = mandatory

12. Hepatic impairment:

• Pre-existing liver disorders = check LFT before start
• If Jaundice, abnormal LFT, Nausea, Vomiting = must be discontinued.
• Restart = Normal LFT

13. Renal impairment: Dose adjustment needed

14. Vascular Disease: Cautioned in Stroke or PMHx of Stroke

15. Concomitant use with Alcohol/OTCs: Notify your physician

16. Missed Dose:

• < Two hours = take the dose right away
• > Tow hours = Skip and continue your regular dose
• Do Not Take Double Dose
• If stopped taking > 2 days = Do Not Restart, Contact your physician

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.