Clozapine oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations containing clozapine.
Drugs List
Therapeutic Indications
Uses
Psychotic disorders in Parkinson's disease where standard treatment failed
Schizophrenia - resistant to other treatment
Dosage
Treatment resistance is defined as a lack of satisfactory clinical improvement despite the use of adequate doses of at least two different antipsychotic agents for adequate duration.
Initiation of clozapine treatment must be by a specialist and is restricted to those patients with a white blood cell count above 3.5 x 10 to the power 9 per litre, an absolute neutrophil count above 2.0 x 10 to the power of 9 litre and a normal differential blood count.
To protect patient safety, at any one time patients should only be prescribed one brand of clozapine and only registered with the monitoring service connected to that brand. Prescribers and pharmacists should adhere to brand prescribing and dispensing, in order to limit the disruption to effective haematological monitoring that may be caused when patients switch brands.
The dosage must be adjusted individually and the lowest effective dose should be used.
Adults
Treatment-resistant schizophrenic patients
Initial dose:
12.5mg once or twice on the first day, then 25mg once or twice a day on the second day. Dosage may be slowly increased in increments of 25mg to 50mg daily achieving a dose level of up to 300mg per day in divided doses within 2 to 3 weeks.
Thereafter, if required daily dose may be increased in increments of 50mg to 100mg at half weekly or preferably weekly intervals.
Maximum dose 900mg per day. Adverse reactions may increase at doses over 450mg per day, in particular seizures.
Therapeutic dose:
200mg to 450mg a day, in divided doses. Total daily dose may be divided unevenly, with the larger portion at bedtime (up to 200mg may be taken as a single dose at bedtime).
Maintenance:
Patients may be maintained on lowest possible dose, once maximum therapeutic benefit has been achieved. It is recommended to carefully titrate dose downwards.
If the daily dose is 200mg or less, give as a single dose, preferably in the evening, for a duration of at least 6 months.
Ending therapy:
If termination is planned, it is recommended a gradual reduction in dose over at least a one to two week period. If abrupt discontinuation is necessary the patient should be carefully observed, particularly in view of the return of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting and diarrhoea.
Restarting therapy:
If the interval since the last dose exceeds 48 hours, clozapine should be re-started with 12.5mg once or twice on first day. If well tolerated, dose titration to therapeutic level may be quicker than for initial treatment, but use caution if cardiac or respiratory arrest occurred with previous dosing.
Psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failed
Initial dose:
12.5mg once a day, taken in the evening. Dosage may be slowly increased in increments of 12.5mg increments, with a maximum of two increments a week, up to a maximum of 50mg a day (a dose that cannot be reached until the end of the second week). It is preferred if the total daily dosage is given as a single dose.
Therapeutic dose:
25mg to 37.5mg once a day. Dosage may be slowly increased in increments of 12.5mg a week. Maximum daily dose should not exceed 50mg, unless considered necessary in exceptional cases. Maximum daily dose of 100mg must never be exceeded. Dose increases should be limited or deferred if orthostatic hypotension, excessive sedation or confusion occurs. Blood pressure should be monitored during the first weeks of treatment.
Maintenance:
An increase in anti-parkinsonian medication is possible if indicated on the basis of motor status, when there has been a complete remission of psychotic symptoms for at least 2 weeks.
If this results in the recurrence of psychotic symptoms, clozapine dosage may be increased in increments of 12.5mg a week. Dose should not exceed a maximum of 100mg a day, in one or two divided doses.
Ending therapy:
Reduce gradually by steps of 12.5mg over a period of at least one to two weeks.
Discontinue treatment immediately in the event of neutropenia or agranulocytosis and monitor patient for psychiatric signs and symptoms.
Elderly
Treatment should be initiated at a particularly low dose (12.5mg given once on first day) and restrict subsequent dose increments to 25mg per day.
Children
Treatment-resistant schizophrenic patients
Unlicensed in children under 16 years
Children 12 to 18 years
12.5mg once or twice on the first day, then 25mg to 50mg on the second day. Dosage may be slowly increased in increments of 25mg to 50mg, over a period of 14 to 21 days, up to 300mg a day in divided doses (larger dose at night, up to 200mg daily may be taken as a single dose at bedtime).
Thereafter, if required daily dose may be increased in increments of 50mg to 100mg at twice weekly or preferably weekly intervals. Usual dosage is 200mg to 450mg a day.
Maximum dose 900mg per day. Adverse reactions may increase at doses over 450mg per day, in particular seizures.
Patients with Renal Impairment
The Renal Drug Handbook gives the following dosage recommendations:
GFR 10 to 50ml per minute: Dose as in normal renal function. Use with caution.
GFR less than 10ml per minute: Start with a low dose and titrate slowly.
Additional Dosage Information
Switching from previous antipsychotic therapy
Clozapine should not generally be used in combination with other antipsychotics. It is recommended that the dose of the previous antipsychotics is discontinued gradually before clozapine treatment is started.
Contraindications
Children under 12 years
Drug intoxication
Patients unable to undergo regular blood tests
Alcohol-induced psychosis
Bone marrow aplasia
Breastfeeding
Cardiomyopathy
Central nervous system depression
Circulatory failure
Coma
Hepatic disorder
History of clozapine induced agranulocytosis
History of idiosyncratic agranulocytosis
History of myeloproliferative disorder
Hypokalaemia
Long QT syndrome
Myelosuppression
Myocarditis
Paralytic ileus
Progressive hepatic disorder
Severe cardiac dysfunction
Severe cardiac failure
Severe renal impairment
Torsade de pointes
Toxic psychosis
Uncontrolled epileptic disorder
Precautions and Warnings
Children aged 12 to 16 years
Elderly
Family history of long QT syndrome
History of lower abdominal surgery
Patients over 60 years
Predisposition to venous thromboembolism
Tobacco smoking
Benign ethnic neutropenia
Benign prostatic hyperplasia
Cardiovascular disorder
Dementia
Diabetes mellitus
Epileptic disorder
Galactosaemia
Glucose-galactose malabsorption syndrome
Hepatic impairment
Hereditary fructose intolerance
History of bone marrow aplasia
History of cardiac disorder
History of colonic disorder
History of paralytic ileus
Lactose intolerance
Narrow angle glaucoma
Pregnancy
Renal impairment
Correct electrolyte disorders before treatment
Some formulations contain aspartame - caution in phenylketonuria
Advise ability to drive/operate machinery may be affected by side effects
History of bone marrow disorders - review by a haematologist before therapy
Pre-treatment medical history and clinical examination
Prescribe by brand to limit disruption to haematological monitoring
Presentations with sorbitol unsuitable in hereditary fructose intolerance
Some formulations contain lactose
Supply restriction: physicians and pharmacists registered with CPMS/DCMS
Ensure normal differential white cell counts before starting treatment
Actively treat constipation, potential complications can have a rapid onset
Advise patient to report constipation
Clozapine may cause agranulocytosis - see manufacturers information
Consider myocarditis if new or worsening cardiac signs or symptoms occur
If stable neutrophil count for 1 year, blood monitoring may be 4-weekly
Investigate for myocarditis if tachycardia with heart failure develops
Monitor blood counts during therapy and for four weeks after discontinuing
Monitor blood glucose closely in patients with diabetes mellitus
Monitor blood pressure during 1st weeks of treatment in Parkinsons patients
Monitor ECG in patients at risk of QT prolongation
Monitor ECG prior to and during treatment in existing cardiac abnormalities
Monitor for signs of blood dyscrasias eg fever, sore throat, malaise etc
Monitor for signs of haematological and non-haematological toxicity
Monitor hepatic function in patients with hepatic impairment
Monitor leucocyte count weekly for 18 weeks then 2-weekly for first year
Monitor periodically for signs or symptoms of hyperglycaemia
Risk of cerebrovascular events
Advise patient to report symptoms of infection immediately
Avoid immobilisation-treatment may cause increased risk of thromboembolism
Discontinue if thrombocytopenia occurs
First dose and/or rapid dose escalation may cause profound hypotension
Increased risk for venous thromboembolism - take preventive measures
May cause postural hypotension
Withdraw if neutrophil count falls below 1.5 X 10 to the power of 9/L
Withdraw if white blood cell count falls below 3 X 10 to the power of 9/L
Withdraw drug gradually over 1-2 weeks unless for neutropenia
Consider disc'g treatment when medical management of hyperglycaemia failed
Discontinue if cholestatic jaundice occurs
Discontinue if diagnosis of myocarditis is confirmed
Discontinue if eosinophilia occurs
Discontinue if hepatic enzymes exceed 3 x ULN
Discontinue if patient develops neuroleptic malignant syndrome
Changes in caffeine intake may require dosage adjustment
Dose adjustment required if patient starts/stops smoking during therapy
Advise patient to avoid alcohol during treatment
Female: Ensure adequate contraception during treatment
Patients, prescribers and pharmacists must register with the CPMS/DCMS/ZTAS
Blood clozapine monitoring is recommended for patients who stop smoking or switch to e-cigarettes, when reduced clozapine metabolism is suspected, when a patient has pheumonia or a serious infection and upon the appearance of toxicity symptoms.
Blood monitoring should be carried out in accordance with national specific recommendations. Patients must be able to undergo regular blood tests. A white blood cell count and differential count are mandatory. WBC and differential blood counts must be performed within 10 days prior to initiating clozapine to ensure only patients with a WBC greater than or equal to 3.5 x 10 to the power 9 per litre and ANC greater than or equal to 2.0 x 10 to the power 9 per litre receive clozapine.
If the white blood cell count falls below to between 3.5 and 3.0 x 10 to the power 9 per litre and or the absolute neutrophil count falls to between 2.0 and 1.5 x 10 to the power 9 per litre, monitor haematological parameters at least twice weekly until the values stabilise within these ranges or higher.
Discontinue immediately if white blood cell count falls below 3.0 x 10 to the power 9 per litre and or the absolute neutrophil count falls below 1.5 x 10 to the power 9 per litre. Patients should have whole and differential blood counts performed daily and they should be monitored for influenza-like symptoms. Confirmation of the haematological value is required by performing two blood counts on two consecutive days. However, clozapine should be discontinued after the first blood count. Following discontinuation, haematological evaluation is required until recovery has occurred.
If clozapine has been withdrawn and either a further drop in the whole blood counts to below 2.0 x 10 to the power of 9 per litre occurs, or the absolute neutrophil count falls to below 1.0 x 10 to the power of 9 per litre. Further treatment must be guided by an experienced haematologist.
If clozapine treatment is interrupted for other reasons, additional haematological monitoring is required. Patients who have been on clozapine for more than 18 weeks and had treatment disrupted for more than 3 days but less than 4 weeks should have white blood cells and absolute neutrophil count monitored weekly for an additional 6 weeks. If no abnormality occurs, monitoring at intervals not exceeding 4 weeks may be resumed. If treatment has been interrupted for 4 weeks or more, weekly monitoring is required for the next 18 weeks and the dose should be re-titrated.
Clozapine should be discontinued in the event of eosinophilia, that is if the eosinophil count rises above 3.0 x 10 to the power of 9 per litre. Therapy should only restarted after the eosinophil count has fallen below 1.0 x 10 to the power of 9 per litre. Discontinue treatment in the event of thrombocytopenia, that is if the platelet count falls below 50 x 10 to the power of 9 per litre.
Patients in whom clozapine has been discontinued as a result of either white blood cell count or absolute neutrophil count deficiencies must not be re-exposed to clozapine.
Due to the anticholinergic properties of clozapine, intestinal peristalsis may be affected. Constipation is a common effect however intestinal obstruction, faecal impaction and paralytic ileus have occurred, including in some cases a fatal outcome. Caution is advised in patients aged over 60 years, with a history of colonic disease or lower abdominal surgery and in patients taking other medication known to cause constipation (particularly those with anticholinergic properties). Constipation must be recognised early and actively treated as complications may have a fast onset.
Pregnancy and Lactation
Pregnancy
Use clozapine with caution in pregnancy.
There is limited information available for clozapine in pregnancy. The manufacturer recommends monitoring newborns carefully, neonates exposed to antipsychotics during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress or feeding disorder.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.
Schaefer concludes that treatment is the same as for non pregnant patients but that disturbances have been seen in newborns exposed to antipsychotic drugs and should be monitored. There have been no reports of increased malformations. Clozapine has been associated with weight gain, hyperglycaemia and glucose intolerance in pregnant women.
Lactation
Clozapine is contraindicated in breastfeeding.
Clozapine is concentrated in the breast milk. Because there is little published experience with clozapine during breastfeeding, and sedation and adverse haematological effects have been reported in breastfed infants, other agents are preferred. If breastfeeding is undertaken by a mother who is taking clozapine, close monitoring of the infant for excessive sedation and periodic monitoring of the infant's white blood count is advisable, although the risk of agranulocytosis is remote, considering the low dose to the infant via the breast milk.
Clozapine has a minimal effect on maternal prolactin levels, however a case of delayed galactorrhoea has been reported in a woman taking clozapine. The maternal prolactin level in a mother with established lactation may not affect her ability to breastfeed.
Animal studies suggest clozapine is excreted in breast milk and has an effect in the nursing infant, therefore, manufacturers advise mothers receiving clozapine should not breast feed.
Counselling
When the oral suspension is first dispensed or when there is visible settling of the suspension, the bottle should be shaken well for 90 seconds before being used. In all other instances the bottle should be shaken for 10 seconds before use.
The oral suspension should not be mixed with orange juice. If dilution is required it may be mixed with water but not with any other form of liquid.
At each consultation, a patient receiving clozapine must be reminded to contact the treating physician immediately if any kind of infection begins to develop. Particular attention should be paid to flu-like illness such as fever or sore throat and to other evidence of infection which may indicate neutropenia. Patients and care givers must be informed that if any of these symptoms present, they must have a blood test done immediately. Prescribers should keep a record of all blood results and take steps to prevent patients from accidentally being re challenged in the future.
Side Effects
Acute pancreatitis
Agitation
Agranulocytosis
Akathisia
Anaemia
Anorexia
Arrhythmias
Aspiration of ingested food
Benign hyperthermia
Blurred vision
Cardiac arrest
Cardiac failure
Cardiomyopathy
Chest pain
Cholestatic jaundice
Circulatory collapse
Compulsive disorders
Confusion
Constipation
Convulsions
Decrease of seizure threshold
Decreased glucose tolerance
Delirium
Diabetes mellitus
Disturbances in sweating
Dizziness
Drowsiness
Dry mouth
Dysarthria
Dysphagia
Dyspnoea
ECG changes
EEG changes
Eosinophilia
Exacerbation of diabetes
Extrapyramidal effects
Fatigue
Fever
Gastro-intestinal obstruction/impaction
Granulocytopenia
Headache
Hepatic necrosis
Hepatitis
Hypercholesterolaemia
Hyperglycaemia
Hyperosmolar non-ketotic coma
Hypersalivation
Hypertension
Hypertriglyceridaemia
Increase in creatine phosphokinase - rarely
Increases in hepatic enzymes
Influenza-like syndrome
Interference with temperature regulation
Interstitial nephritis
Inversion of T wave
Ketoacidosis
Leucocytosis
Leukopenia
Lower respiratory tract infection
Myocarditis
Myoclonic jerks
Nausea
Neuroleptic malignant syndrome
Neutropenia
Obstipation
Palpitations
Paralytic ileus
Parotid gland swelling
Pericardial effusion
Pericarditis
Pneumonia
Postural hypotension
Priapism
Prolongation of QT interval
Respiratory arrest
Respiratory depression
Restlessness
Rigidity
Sedation
Skin reactions
ST segment depression
Syncope
Tachycardia
Tachypnoea
Tardive dyskinesia
Thrombocythaemia
Thrombocytopenia
Thromboembolism
Torsades de pointes
Tremor
Urinary incontinence
Urinary retention
Venous thrombosis
Ventricular tachycardia
Vomiting
Weight gain
Withdrawal symptoms
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: June 2018
Reference Sources
Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 3nd edition (2015) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.
Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.
Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas.
Neonatal Formulary, 6th edition (2011) Blackwell Publishing, Oxford.
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Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
FDB Disclaimer : FDB Multilex is intended for the use of healthcare professionals and is provided on the basis that the healthcare professionals will retain FULL and SOLE responsibility for deciding what treatment to prescribe or dispense for any particular patient or circumstance.