Clozapine should not be given to patients with uncontrolled epilepsy, alcoholic or toxic psychoses, drug intoxication, or a history of circulatory collapse. It should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold. It is contra-indicated in patients with bone-marrow suppression, myeloproliferative disorders, or any abnormalities of white blood cell count or differential blood count. It is also contra-indicated in patients with a history of drug-induced neutropenia or agranulocytosis with the exception of that due to chemotherapy. It should not be used with drugs that carry a high risk of bone-marrow suppression (see Interactions, below).
Clozapine is contra-indicated in patients with severe renal impairment caution is required in mild to moderate renal impairment. It should be used with caution in hepatic impairment and avoided in symptomatic or progressive liver disease or hepatic failure. Patients with a history of cardiac impairment or abnormal cardiac findings on examination should be referred to a specialist for further evaluation, which may include an ECG treatment with clozapine should only then be started if the potential benefits clearly outweigh any risk. Clozapine should not be used in severe heart failure.
Clozapine possesses antimuscarinic properties and consequently it is contra-indicated in patients with paralytic ileus it should also be used with caution in benign prostatic hyperplasia and angle-closure glaucoma.
Clinical monitoring for hyperglycaemia has been recommended, especially in patients with or at risk of developing diabetes (see Effects on Carbohydrate Metabolism, above).
Monitoring the white blood cell and absolute neu-trophil counts is mandatory during clozapine treatment and should be carried out in accordance with official recommendations these may vary between countries. Patients or their carers should report the development of any infection or signs such as fever, sore throat, or flu-like symptoms which suggest infection.
Patients who develop tachycardia at rest, dyspnoea, arrhythmias, chest pain, or other signs and symptoms of heart failure should be investigated immediately and clozapine treatment stopped if a diagnosis of myocarditis or cardiomyopathy is suspected.
Because of an increased risk of collapse due to ortho-static hypotension associated with rapid dose escalation during initial titration of clozapine dosage, it is recommended that treatment should be begun under close medical supervision. In addition, patients with Parkinson’s disease should have their blood pressure monitored for the first weeks of treatment.
On planned withdrawal, the dose of clozapine should be reduced gradually over at least a 1- to 2-week period in order to avoid the risk of rebound psychosis and other withdrawal symptoms (see above). If abrupt withdrawal is necessary then patients should be observed carefully.
Clozapine may affect the performance of skilled tasks such as driving.
The American Academy of Pediatrics considers that, although the effect of clozapine on breast-fed infants is unknown, its use by mothers during breast feeding may be of concern since antipsychotic drugs do appear in breast milk and thus could conceivably alter CNS function in the infant both in the short and long term.
Clozapine appears to be distributed into breast milk in relatively high concentrations. Concentrations in a patient given 50 mg daily were 63.5 nanograms/mL in breast milk and 14.7 nanograms/mL in plasma at 100 mg daily they were 115.6 nanograms/mL and 41.4 nanograms/mL, respectively.
The manufacturers have also stated that studies in animals suggest that clozapine is excreted into breast milk and has an effect on nursing infants they recommend that mothers receiving clozapine should not breast feed.
The FDA has issued advice against the use of atypical antipsychotics, including clozapine, in the treatment of behavioural problems in elderly patients with dementia after analysis of placebo-controlled studies showed an increased risk of mortality with certain drugs in this class. See under Risperidone.
White Cell Counts.
A white blood cell count and a differential blood count must be performed before starting clozapine therapy and regularly throughout treatment. Treatment should not be started if the white blood cell count is less than 3500 cells/mm and the absolute neutrophil count (ANC) is less than 2000 cells/mm, or if there is an abnormal differential count. Monitoring should continue throughout therapy and for 4 weeks after withdrawal.
In the EU, including the UK, monitoring is performed at weekly intervals for the first 18 weeks and then at least every 2 weeks between weeks 18 and 52 after 1 year of treatment with stable neutrophil counts, patients may be monitored at least every 4 weeks.
If during therapy the white blood cell count falls to between 3000 and 3500 cells/mm or the ANC falls to between 1500 and 2000 cells/mm then monitoring should be performed twice weekly until values stabilise or increase.
Clozapine should be withdrawn immediately if the white blood cell count falls below 3000 cells/mm or the ANC drops below 1500 cells/mm counts should be monitored daily until they return to normal. Clozapine should not be restarted in these patients.
In the USA, white blood cell and ANC are monitored weekly for the first 6 months and then every 2 weeks thereafter after 1 year of therapy, patients may be monitored every 4 weeks.
If during therapy the white blood cell count falls to between 3000 and 3500 cells/mm and the ANC is above 1500 cells/mm then monitoring should be performed twice weekly.
If the white blood cell count falls below 3000 cells/mm or the ANC is below 1500 cells/mm then clozapine treatment should be interrupted and counts performed daily. Clozapine may be restarted if the white blood cell count recovers to above 3500 cells/mm and the ANC to above 2000 cells/mm. After recovery, weekly monitoring is recommended for the next 12 months before reducing to every 2 weeks for 6 months, and then every 4 weeks thereafter.
Clozapine should be withdrawn if the white blood cell count falls below 2000 cells/mm or the ANC drops below 1000 cells/mm counts should be monitored daily until they return to normal. Clozapine should not be restarted in these patients.
In patients with decreased white blood cell or ANC it is especially important that they or their carers report the development of any infection or signs such as fever, sore throat, or flu-like symptoms which suggest infection.
In the EU, clozapine should be withdrawn if the eosinophil count is greater than 3000 cells/mm it should only be restarted once the count has fallen to below 1000 cells/mm.
Similar advice is given in the USA although the values differ: clozapine should be withdrawn if the eosinophil count is above 4000 cells/mm and restarted once the count has fallen to below 3000 cells/mm.
European licensing information states that clozapine should be stopped if the platelet count falls below 50 000 cells/mm.
If treatment with clozapine is interrupted for reasons other than abnormal haematological values then more frequent monitoring may be required following resumption of therapy.
In the EU, patients who have taken clozapine for at least 18 weeks and stopped therapy for more than 3 days but less than 4 weeks should resume weekly monitoring for the next 6 weeks before reducing to at least every 4 weeks if the counts are stable a break of 4 weeks or more would require weekly monitoring for the next 18 weeks.
US licensed product information recommends resuming weekly monitoring for 6 months in patients whose therapy has been interrupted for more than 1 month frequency of monitoring is then reduced as described in White Cell Counts, see above. Those who have taken clozapine for at least 6 months and stopped therapy for more than 3 days but less than 4 weeks should resume weekly monitoring for the next 6 weeks before reducing to at least every 2 weeks for 6 months if the counts are stable those on clozapine for over 1 year may be monitored every 4 weeks after initial weekly monitoring for 6 weeks.
A review of the literature between 1993 and April 2004 suggested that clozapine and olanzapine do not appear to increase the risk of fetal teratogenicity literature regarding aripiprazole, quetiapine, risperidone, and ziprasidone was incomplete or not available. The rate of spontaneous abortions in pregnant women exposed to clozapine or olanzapine was not found to be higher than that of the general population however, these 2 drugs increased the risk of hyperglycaemia in pregnant women. A prospective comparative study of pregnancy outcomes in women taking clozapine, olanzapine, quetiapine, and risperidone also concluded that atypicals do not appear to be associated with an increased risk for maj or malformations when compared to the baseline risk in the general population. The authors recommended that benefits and risks be weighed carefully in each case and optimal control of the psychiatric disorder be maintained throughout pregnancy and postpartum together with careful monitoring.
Clozapine may enhance the central effects of MAOIs and CNS depressants including alcohol, antihistamines, benzodiazepines, and opioid analgesics.
Clozapine should not be used with drugs that carry a high risk of bone-marrow suppression including carbamazepine, cotrimoxazole, chloramphenicol, penicillamine, sulfonamides, antineoplastics, or pyrazolo-ne analgesics such as azapropazone. Long-acting depot antipsychotics have myelosuppressive potential and should not be used with clozapine as they cannot be withdrawn rapidly should neutropenia occur. Additive effects may occur when clozapine is given with drugs that possess antimuscarinic, hypotensive, or respiratory depressant effects. Clozapine may reduce the effects of alpha-adrenoceptor agonists such as noradrenaline.
The metabolism of clozapine is mediated mainly by the cytochrome P450 isoenzyme CYP1A2. Use with drugs that inhibit or act as a substrate to this isoenzyme may affect plasma concentrations of clozapine and the dose of clozapine may need to be altered. Increased plasma-clozapine concentrations, with an increased risk of adverse effects, may be seen in patients who suddenly stop smoking. Use with phenytoin or other enzyme-inducing drugs may accelerate the metabolism of clozapine and reduce its plasma concentrations.
A patient with schizophrenia controlled with clozapine therapy had a tonic-clonic seizure 7 days after starting treatment with erythromycin. It appeared that erythromycin had inhibited the metabolism of clozapine and raised its serum concentrations. Increased drowsiness and hypersalivation have been seen in a patient receiving clozapine and ampicillin he recovered when ampicillin was replaced with doxycycline.
Giving clozapine with rifampicin has resulted in decreased clozapine concentrations with consequent return of paranoid thoughts in a patient with a complicated history of schizophrenia. An improvement was seen after rifampicin was replaced with ciprofloxacin. The interaction was thought to be due to the induction of cytochrome P450 isoenzymes, particularly CYP1A2, by rifampicin, resulting in the accelerated metabolism of clozapine.
Rises in serum concentrations of clozapine have been found in patients receiving clozapine after addition of fluoxetine or fluvoxamine to therapy. Increased serum concentrations of clozapine have also been reported when paroxetine or sertraline was added to therapy. A possible serotonin syndrome has been reported in a patient receiving clomipramine after clozapine was gradually withdrawn from the treatment regimen, although the symptoms were also similar to those of clozapine withdrawal (see above). There has been an isolated report of a patient who developed myoclonic jerks 79 days after fluoxetine was added to treatment with clozapine and lorazepam, although some doubt whether the effects were entirely due to an interaction. Giving clozapine with lithium may increase the risk of neuroleptic malignant syndrome. For reference to neurological reactions in patients receiving lithium with clozapine.
Use of phenytoin or other enzyme-inducing antiepileptics may accelerate the metabolism of clozapine and reduce its plasma concentrations. Studies have found that addition of sodium valproate to clozapine therapy may increase or decrease plasma concentrations of clozapine. Although no increase in clozapine-related adverse effects or loss of control of psychotic symptoms were reported in these studies, there has been a report of a patient who experienced sedation, confusion, slurring of speech and other functional impairment after valproate was given with clozapine. See also under Benzodiazepines, below.
Giving risperidone to a patient with schizoaffective disorder partially controlled by clozapine produced clinical improvement but was associated with a 74% rise in serum-clozapine concentrations over a 2-week period. Although no adverse effects occurred in this patient, the potential for serious adverse effects requires caution if these drugs are used together. Neuroleptic malignant syndrome associated with use of clozapine with haloperidol has been reported. See also under Chlorpromazine.
Although the UK manufacturers of ritonavir have stated that it may increase plasma concentrations of clozapine with a resultant increase in the risk of toxicity, there is evidence to suggest that, in fact, ritonavir may decrease the plasma concentrations of clozapine. Ritonavir has been noted to induce the cytochrome P450 isoenzyme CYP1A2 and hence, as clozapine is primarily metabolised via this isoenzyme, an acceleration of the metabolism of clozapine would be expected. US prescribing information has been amended accordingly.
Concern has been expressed over reports of cardiorespiratory collapse in patients taking both clozapine and benzodiazepines. In response, the manufacturers of clozapine outlined similar cases reported to them in the USA. Of 7 cases of respiratory arrest or depression only 2 involved recent use of a benzodiazepine among 26 cases of orthostatic hypotension with syncope reported during the first year the drug was marketed, only 8 included recent benzodiazepine use. The manufacturers concluded that an increased risk of such reactions in patients taking both drugs simultaneously was possible but not established, and advised caution when starting clozapine therapy in patients taking benzodiazepines.
Hypersalivation associated with clozapine and benzodiazepines may be exacerbated when these drugs are used together. A patient experienced increased hypersalivation, salivary thickening, and distension of the parotid glands when clonazepam was added to treatment with clozapine. Adverse effects reported in 5 other patients given clozapine and benzodiazepines together included hypersalivation, sedation, ataxia, and symptoms of delirium.
Potentially fatal gastrointestinal bleeding, accompanied by severe acidosis and hyperglycaemia, developed in a patient given buspirone with clozapine. The patient had previously been taking clozapine for over a year without adverse effect, and was subsequently maintained on clozapine alone without a recurrence of symptoms.
A patient stabilised on clozapine developed increased serum clozapine concentrations and signs of clozapine toxicity after starting treatment with cimetidine Cimetidine was withdrawn and ranitidine substituted without recurrence of toxicity.
A marked reduction in plasma-clozapine concentrations was seen in 2 smokers stabilised on the antipsychotic who began treatment with omeprazole, which is a known inducer of the cytochrome P450 isoenzyme CYP1A2. However, a small retrospective analysis of the effect of stopping omeprazole in 13 patients taking both drugs suggested that the effect of omeprazole was only significant in non-smokers, and the clozapine dose did not need to be adjusted in any of these patients.
Caffeine may inhibit the metabolism of clozapine. Care should be taken before stopping or starting caffeine-containing beverages in patients stabilised on clozapine treatment.