Clozapin, Clozaril®

Brand name

  • Clozaril®

Drug Class

  • Atypical Antipsychotic Agent

Preparations

  • Tablets 25 mg
  • Tablets 100 mg

Indications

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.

Pharmacology

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

Metabolism

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

Dosing

  • 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.

Monitoring

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)

Drug Interactions

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

Adverse Effects

Greater than 5%

  1. Tachycardia:
    1. occurs  in approximately 25 percent of patients
    2. Tolerance  generally develops  within 4 to 6 weeks
  2. Orthostatic Hypotension.    
    1. Approximately  9 percent of patients receiving clozapine experience orthostatic hypotension  (Safferman et al. 1991)
    2. Is caused predominantly  by the antiadrenergic properties of  clozapine.
    3. Patients gradually develop tolerance, usually within 4 to 6 weeks of treatment (Marinkovic  et al. 1994)
    4. Patients with orthostatic hypotension secondary to clozapine may describe dizziness  or lightheadedness and are prone to syncope
    5. In  rare  cases (1/3,000),  orthostatic hypotension has  been associated with collapse  and respiratory and/or cardiac arrest  (Sandoz Pharmaceuticals Company 1995)
    6. It can be minimized if patients  are advised to rise slowly from a sitting or  lying position, especially in the morning and after  meals.
    7. Increased fluid and salt intake may help by increasing blood  volume.
    8. If these steps are ineffective, support stockings can be tried.
    9. Tilting the head of the bed  slightly upward at night may produce some relief by reducing renal artery pressure and increasing  renin production
    10. Fludrocortisone,  a potent mineralocorticoid,  has been used to treat clozapine-related  hypotension (Testani 1994). Fludrocortisone works by increasing sodium  retention and potassium excretion in the kidney. The usual starting dose is 0.1 mg/day  and can be increased by increments of 0.1 mg every 5 to 7 days. Maintenance doses range  from 0.1 to 1.0 mg/day. 
    11. The alpha-adrenergic agonist ephedrine has also been  used to treat orthostatic hypotension (Patterson 1992); the typical dose ranges from 25 to 150 mg/day.
    12. Dihydroergotamine, at doses of  10 mg/day, has been shown in a double-blind, placebo-controlled study to prevent orthostatic hypotension in patients treated with psychotropic  medications (Thulesius and Berlin 1986).
  3. Constipation.     
    1. Occurs in 14% of patients
    2. Three deaths  from severe ileus and obstipation  have been reported (Hayes and Gibler 1995).
    3. It is most likely due to the  anticholinergic properties of clozapine, and other medications with anticholinergic  properties may exacerbate it.
  4. Nausea: 
    • Reported in 11% of patients  (Marinkovic et al. 1994)
    • Metoclopramide  has been used with some success (Lieberman et al. 1989).
    • Other treatments that  have been successfully used include antacids and H2 blockers (Lieberman and Safferman   1992).
    • Cimetidine should be avoided because it inhibits the hepatic microsomal P-450 system and can  raise the blood level of clozapine (Jann et al. 1993).
  5. Seizure:
    1. Risk increased over time
    2. Risk is higher during titration or if the dose is higher than 600 mg
    3. Patients  with a prior  history of seizures  or head trauma are at increased  risk (Haller and  Binder 1990).
    4. Other  drugs that  lower the seizure threshold  may increase the risk of clozapine-induced seizure.  
    5. Drugs  such as  benzodiazepines  that raise the seizure  threshold may also increase  the risk of seizure if discontinued during clozapine treatment  
    6. Drinking alcohol may increase the risk of seizure.
    7. If a seizure occurs,
      1. an EEG and  a neurology consultation should  be considered.
      2. Clozapine should be temporarily  held and reinstituted at a dose approximately 50 percent  of that at which the seizure occurred (Lieberman et al. 1989).
      3. If clozapine is held for  more than a few days, treatment should be restarted at initial doses because patients lose their  tolerance to the adverse effects.
      4. The dose should be increased more slowly and a reduction in target dose should be considered.
      5. clozapine blood level may help the clinician determine the lowest possible effective dose (Simpson and Cooper 1978)
  6. Enuresis
    1. Estimates  of the incidence  of urinary incontinence  have ranged from 0.23 percent  (Aronowitz et al. 1995) to 30 percent  (Konicki et al. 1995).
    2. This wide variation may be due  to underreporting of this symptom
    3. The mechanism of enuresis is  unknown, but suggestions include excessively deep sleep related to  clozapine’s sedating properties, and urinary retention with subsequent  over-flow related to clozapine’s anticholinergic properties (Aronowitz et  al. 1995).
    4. The alpha-adrenergic antagonist properties of clozapine have also  been implicated (Konicki et al. 1995).
    5. Patients can be told to avoid fluids in the evening and to  void before going to bed. Scheduled middle-of-the-night  awakenings to empty the bladder can be practiced. If necessary, an enuresis alarm can be used.
    6. Desmopressin  intranasal spray, 20 to 40 meg before  sleep has also reportedly  been used to successfully  treat clozapine-related enuresis  (Steingard 1994). 
    7. Caution is recommended because there are case reports  of seizures secondary to desmopressin-related water intoxication  (Beach et al. 1992)
    8. Oxybutynin,  an anticholinergic  agent with antispasmodic  properties, used at doses  of 5 to 15 mg/day, has been reported to help in both enuresis and urinary urgency (Frankenburg et al.  1996)
  7. Akathisia.    
    • Akathisia  has been reported  in 6% (Marinkovic et al.  1994) to 39% (Cohen et al. 1991) of  patients
  8. Fever
  9. Neuroleptic malignant syndrome
  10. Drowsiness/dizziness/Sedation
  11. 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
  12. Anticholinergic Activity: caution in BPH
    1. Narrow angle glaucoma
    2. Constipation
    3. Fecal impaction
    4. Paralytic illus
  13. Fatigue, flu-like symptoms
  14. Weight gain
  15. Hyperglycemia
  16. Dyslipidemia
  17. Headache
  18. Tremor
  19. Vertigo

Less than 5%

  1. Agranulocytosis: granulocyte count <0.5 x 109/L -)
      • is  defined as a granulocyte count of< 500/mm3
      • leucopenia is defined as a  white bloodcell (WBC) count of  < 3500/mm3.  
      • The risk of agranulocytosis is highest in the first 3 months of clozapine treatment, and  95% of the cases occur within the first 6 months (Lieberman and Safferman 1992)
      • Weekly WBC and diff. is indicated
      • Patient’s condition should be monitored closely
      • If any WBC count falls below 2,000/mm3  or if the ANC falls below  1,000/mm3, treatment should be discontinued, daily WBC  counts should be obtained, and bone marrow aspiration should be considered (Sandoz Pharmaceuticals Company  1996).
  2. Myoclonus.    
    • Myoclonus occurs in approximately 2% of patients treated with clozapine 
    • In a series of five cases, these episodes were described as primarily  orofacial, alternating between both sides of the face, and were sometimes associated with weakness of the extremities 
    • Because myoclonus can herald the onset of tonic-clonic seizures,  a reduction of clozapine dose or addition of an anticonvulsant may be indicated.
    • Both valproate and carbamazepine have been reported to be effective
  3. Thrombocytopenia
  4. Sialorrhea.    
      • The pathophysiology of sialorrhea is not clear.
      • Instruction in swallowing two or three times without inhaling (by compression of nostrils) alleviated the sensation  of choking without affecting the sialorrhea.
      • Patients can be encouraged to chew sugar-free gum during the day so that the  frequent need to swallow will be less noticeable (Bourgeois et al. 1991).
      • A towel placed on the pillow at night can be used to absorb excess saliva.
      • The use of anticholinergic  drugs has been reported to be effective in reducing sialorrhea. Amitriptyline at doses of 75 to 100 mg/day (Copp et al. 1991) and benztropine at 1 to 2 mg/day (Bourgeois et  al. 1991) have been used. However, anticholinergic drugs increase the already potent anticholinergic properties of clozapine and are not generally recommended (Lieberman et al.  1989).
      • The alpha 2 -adrenergic agonist clonidine has been effective
      • A clonidine patch,  0.1 to 0.2 mg/day applied weekly, has been recommended to allow a more sustained delivery of the drug (Grabowski 1992).
      • Clozapine, a potent alpha- adrenergic antagonist, tends to block the  antiphypertensive effect of clonidine, a potent alpha-adrenergic agonist (Markowitz et al. 1995). Nonetheless, patients’ blood pressure should be monitored carefully when initiating this combination.
  5. Eosinophilia: (eosinophil count > 3.0 x 109/L)
  6. Granulocytopenia: (granulocyte count <1.5 x 109/L-)
  7. Cardiovascular toxicity:
    1. Chest pain
    2. Myocardial infarction and sudden death
    3. DVT and PE
    4. Arrhythmia
  8. Respiratory arrest
  9. Tardive dyskinesia, parkinsonism, irritability: Dopamin turnover in the Mesolimbic > Nigrostriatal system compared with other atypical antipsychotics = Lower extrapyramidal side effects
  10. Delirium: caused  by the anticholinergic  properties of clozapine (Schuster  et al. 1977)
  11. Little or no prolactin elevation. (In contrast to conventional antipsychotics)

 

Contraindications

  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

Pregnancy and Breastfeeding

  • 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.

 

Precautions

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

Note

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.

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