PART 3 / CH 56
Clozapine
Roy Perlis and George Papakostas
A. Prior to initiating treatment
· check WBC with differential
· explain risks/side effects to patient; obtain signed consent
· contact Clozaril National Registry for rechallenge number:
1-800-448-5938
B. Dosing
· start 12.5hs day 1, 25hs on day 2, then increase by 25 qd until 150, then by 50qd up to 300.
· if more than 2d skipped, restart at low dose
· clearance: 50% renal, 20% hepatic. N-desmethyl metabolite is active.
· elimination t1/2 is 8-12 hours
C. Major side effect is agranulocytosis
· agranulocytosis = ANC<500
(ANC=%neutrophils x WBC)
· seen in 0.8% of patients on clozapine within 1 year,
most within 3 months; 95% within 6 months
· genetics: associated with HLA-B38, DR4, DQW3
· consequences: risk of sepsis, fatal in 0.03% of clozapine patients.
· benign neutropenia seen in up to 22% of patients
· eosinophilia (>500) seen in up to 32% of patients, hold clozapine until eos<3000.
·check WBC with differential weekly;
(if continuously treated for 6 months without WBC<3.5,
can check every other week)
| Result | Action |
|---|---|
| WBC<3.5k –or- WBC ¯3k in 3wk | begin biweekly WBC with diff. |
| WBC<3k –or- ANC<1.5k | Stop drug immediately Check WBC with diff. qd Monitor for infection May resume when WBC again >3k. |
| WBC<2k –or- ANC<1k | D/C drug forever Check WBC with diff. qd Consult hematologist |
C. Clozapine side effects
| Effect | Incidence | Management |
|---|---|---|
| CNS | ||
| Neutropenia Agranulocytosis Eosinophilia | 22% 0.8% 32% | see table |
| Seizure | <300: 1% <600: 3% >600: 5% | titrate slowly, prophylax at dose>550 (avoid carbamazepine) |
| Sedation Vertigo Tremor, HA | 40% 18% 5% | tolerance dose qhs or q7pm |
| OCD symptoms | up to 10% | ? decrease dose, add SSRI |
| Anticholinergic Delirium | Esp. older pts | decrease dose, eliminate other meds |
| CV | ||
| Tachycardia | 25% | tolerance |
| Orthostasis Hypotension/ syncope | 10% 5% | tolerance hydration, hs dosing |
GI
| Hypersalivation | 31% | towel on pillow, anticholinergics, prokinetic agents |
|---|---|---|
| Constipation | 15% | fluids, bowel regimen, avoid anticholinergics |
| Nausea | 10% | antiemetics |
| LFT | 30% | usually transient, benign. W/u jaundice |
| Other | ||
| Enuresis | up to 30% | avoid oversedation ditropan 5-15qd, or ddAVP 1 puff each nostril qhs, or tolterodine 2qd |
| Fever (<100F) | 5% | transient; if T>100, fever workup |
| Weight gain | >75% | Diet/exercise, follow for type 2 DM |
source: Young CR et al (1998) Schizophrenia Bull. 24:381-390.