Clozapine

CLINICAL USE

Atypical antipsychotic:Schizophrenia Psychosis in Parkinson’s disease

DOSE IN NORMAL RENAL FUNCTION

Schizophrenia: 200–450 mg daily in divided doses, maximum 900 mg dailyPsychosis in Parkinson’s disease: 25– 37.5 mg daily at night, maximum 100 mg daily in 1–2 divided doses

PHARMACOKINETICS

Molecular weight &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp :326.8

%Protein binding &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp :95–97

%Excreted unchanged in urine &nbsp &nbsp : Minimal (50% as metabolites)

Volume of distribution (L/kg) &nbsp &nbsp &nbsp :1.6–6

half-life – normal/ESRD (hrs)&nbsp &nbsp &nbsp :6–26

DOSE IN RENAL IMPAIRMENT

GFR (mL/MIN)

20 to 50 &nbsp &nbsp : Dose as in normal renal function; use with caution

10 to 20 &nbsp &nbsp : Dose as in normal renal function; use with caution

<10 &nbsp &nbsp &nbsp &nbsp &nbsp : Start with a low dose and titrate slowly

DOSE IN PATIENTS UNDERGOING RENAL REPLACEMENT THERAPIES

CAPD &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp:Unlikely to be dialysed. Dose as in GFR <10 mL/min

HD &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp &nbsp :Unlikely to be dialysed. Dose as in GFR <10 mL/min

HDF/high flux &nbsp :Unknown dialysability. Dose as in GFR <10 mL/min

CAV/VVHD &nbsp &nbsp &nbsp:Unknown dialysability. Dose as in GFR 10 to 20 mL/min

IMPORTANT DRUG INTERACTIONS

Potentially hazardous interactions with other drugsAnaesthetics: enhanced hypotensive effect Analgesics: avoid concomitant use with azapropazone; increased risk of convulsions with tramadol; enhanced hypotensive and sedative effects with opioidsAnti-arrhythmics: increased risk of ventricular arrhythmias with anti-arrhythmics that prolong the QT interval; increased risk of arrhythmias with flecainideAntibacterials: concentration possibly increased by erythromycin (possible increased risk of convulsions); concentration increased by ciprofloxacin; concentration possibly reduced by rifampicin; avoid concomitant use with chloramphenicol and sulphonamides (increased risk of agranulocytosis)Antidepressants: concentration possibly increased by citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine (increased risk of toxicity); possibly increased CNS effects of MAOIs; possibly increased antimuscarinic effects with tricyclics; increased plasma level of tricyclicsAnti-epileptics: antagonises anticonvulsant effect; metabolism accelerated by carbamazepine and phenytoin; avoid concomitant use with drugs known to cause agranulocytosisAntimalarials: avoid concomitant use with artemether/lumefantrineAntipsychotics: avoid concomitant use with depot formulations (cannot be withdrawn quickly if neutropenia occurs)Antivirals: concentration possibly increased by amprenavir; concentration increased by ritonavir – avoid concomitant useAnxiolytics and hypnotics: increased sedative effectsCytotoxics: increased risk of agranulocytosis – avoid concomitant useLithium: increased risk of extrapyramidal side effects and possibly neurotoxicityPenicillamine: increased risk of agranulocytosis –avoid concomitant useSibutramine: increased risk of CNS toxicity – avoid concomitant use Ulcer-healing drugs: effects possibly enhanced by cimetidine; concentration possibly reduced by omeprazole.

ADMINISTRATION

Reconstition

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Route

Oral

Rate of Administration

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Comments

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OTHER INFORMATION

Patient must be registered with appropriate company monitoring schemeAssociated with myocarditis (increased risk in the first 2 months) and cardiomyopathyPotentially fatal agranulocytosis and neutropenia have been reported. WCC has to be monitored at least weekly for the first 18 weeks then 2 weekly for weeks 18–52 and then at least 4 weeklyIncreased risk of side effects especially seizures in doses above 450 mg dailyRarely interstitial nephritis has been reported with clozapineDose in severe renal impairment taken from personal experience.

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