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Patients who have low WBC counts because of
benign ethnic neutropenia should be given special consideration and
may be started on Apo-Clozapine after agreement of a hematologist.
During Apo-Clozapine therapy, patients may experience transient
temperature elevations above 38°C with the peak incidence within
the first 3 weeks of treatment.
This fever is generally benign and self-limiting; however, on
occasion there may be an associated increase or decrease in the
white blood cell count. Patients
should be carefully evaluated to rule out the possibility of an
underlying infectious process or the development of blood dyscrasia.
In the presence of high fever, the possibility of neuroleptic
malignant syndrome must be considered (see Warnings).
Fever that is otherwise unexplained can accompany myocarditis
(see Warnings).
Because of the potential for initial sedation, Apo-Clozapine may
impair mental and/or physical abilities especially during the first
few days of therapy. The
recommendation for gradual dose escalation should be carefully
adhered to and patients should be cautioned about activities
requiring alertness (e.g., driving, operating machinery, swimming,
climbing, etc.) (see Dosage and Administration).
Apo-Clozapine may enhance the central effects of alcohol, MAO
inhibitors, CNS depressants including narcotics, antihistamines and
benzodiazepines, as well as the effects of anticholinergic and
antihypertensive agents.
Caution is advised with patients who are
receiving (or have recently received) benzodiazepines or other
psychotropic drugs, as these patients may have an increased risk of
circulatory collapse accompanied by respiratory and/or cardiac
arrest.
Owing to its anti-a-adrenergic properties,
Apo-Clozapine may reduce the blood pressure increasing effect of
norepinephrine or other predominantly a-adrenergic agents and
reverse the pressor effect of epinephrine.
Apo-Clozapine should not be used with other
agents, such as carbamazepine, having a known potential to suppress
bone marrow function. In
particular, the concomitant use of long-acting depot antipsychotic
drugs should be avoided because these medications, which may have
the potential to be myelosuppressive, cannot be rapidly removed from
the body.
Concomitant use of valproic acid with
Apo-Clozapine may alter the plasma levels of clozapine.
Rare but serious reports of seizures, including onset of
seizures in non-epileptic patients, and isolated cases of delirium
where clozapine was co-administered with valproic acid have been
reported. These effects
are possibly due to a pharmacodynamic interaction, the mechanism of
which has not been determined.
Clozapine is a substrate for many CYP 450
isoenzymes, in particular 1A2 and 3A4.
Caution is called for in patients receiving concomitant
treatment with other drugs which are either inhibitors or inducers
of these enzymes.
Concomitant administration of drugs known to
inhibit the activity of cytochrome P450 isozymes may increase the
plasma levels of clozapine:
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Drugs known to inhibit the activity of the
major isozymes involved in the metabolism of clozapine and with
reported interactions include, cimetidine (2D6, 3A4), and
erythromycin (3A4). Other
potent inhibitors of CYP3A, such as azole antimycotics and
protease inhibitors, could potentially also increase clozapine
plasma concentrations; however, no interactions have been
reported to date.
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Substantial elevation of the plasma
concentration of clozapine has been reported in patients
receiving the drug in combination with fluvoxamine (1A2).
Smaller elevations in clozapine plasma concentrations
have also been reported in patients receiving the drug in
combination with other selective serotonin re-uptake inhibitors
(SSRIs) such as paroxetine, sertraline and fluoxetine.
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The plasma concentration of clozapine is
increased by caffeine (1A2) intake and decreased by nearly 50%
following a 5-day caffeine-free period.
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No clinically relevant interactions have
been observed thus far with tricyclic antidepressants,
phenothiazines and type Ic anti-arrhythmics, known to bind to
cytochrome P450 2D6.
Concomitant administration of drugs known to
induce cytochrome P450 enzymes may decrease the plasma levels of
clozapine:
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Drugs known to induce the activity of 3A4
and with reported interactions with clozapine include, for
instance, carbamazepine, phenytoin and rifampicin.
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Known inducers of 1A2 include, for
instance, omeprazole and cigarette smoking.
In cases of sudden smoking cessation, the plasma
clozapine concentration may be increased, thus leading to an
increase in adverse effects.
Interactions with omeprazole have not been reported to
date.
Apo-Clozapine has potent anticholinergic effects, which may produce
undesirable effects throughout the body. Great care should be exercised in using the drug in the
presence of prostatic enlargement, narrow-angle glaucoma or
paralytic ileus. Probably
on account of its anticholinergic properties, clozapine has been
associated with varying degrees of impairment of intestinal
peristalsis, ranging from constipation to intestinal obstruction,
faecal impaction and paralytic ileus.
On rare occasions, these cases have been fatal.
Deep vein thrombosis has been observed in association with
clozapine. Since
Apo-Clozapine may cause sedation and weight gain, thereby increasing
the risk of thromboembolism, immobilization of patients should be
avoided.
Whether pulmonary embolism can be attributed to
Apo-Clozapine or some characteristic(s) of its users is not clear. However, the possibility of pulmonary embolism should be
considered in patients receiving Apo-Clozapine who present with deep
vein thrombosis, acute dyspnea, chest pain, or other respiratory
symptoms.
In the event of eosinophilia, it is recommended to discontinue
Apo-Clozapine if the eosinophil count rises above 3.0 x 109/L, and
to re-start therapy only after the eosinophil count has fallen below
1.0 x 109/L. Eosinophilia
has been co-reported in some cases of myocarditis and thus such
cardiovascular adverse events associated with clozapine use may
represent hypersensitivity reactions to clozapine.
Patients with both eosinophilia and
clozapine-induced myocarditis should not be re-exposed to clozapine.
In the event of thrombocytopenia, it is recommended to discontinue
Apo-Clozapine therapy if the patient falls below 50.0
x 109/L.
Patients with stable pre-existing liver disorders may receive
Apo-Clozapine, but need regular liver function tests.
In patients in whom, during Apo-Clozapine treatment, symptoms
of possible liver dysfunction such as nausea, vomiting and/or
anorexia develop, liver function tests should be performed
immediately. If the
elevation of these values is clinically relevant or if symptoms of
jaundice occur, treatment with Apo-Clozapine must be discontinued.
It may be resumed only when the liver function tests have
returned to normal values. In
such cases, liver function should be closely monitored after the
re-introduction of the drug.
On rare occasions, severe hyperglycemia, sometimes leading to
ketoacidosis/hyperosmolar coma, has been reported during clozapine
treatment in patients with no prior history of hyperglycemia. While a casual relationship to clozapine
use has not been definitely established, glucose levels
returned to normal in most patients after discontinuation of
clozapine, and rechallenge produced a recurrence of hyperglycemia in
a few cases. The effect
of clozapine on glucose metabolism in patients with diabetes
mellitus has not been studied.
The possibility of impaired glucose tolerance should be
considered in patients receiving clozapine who develop symptoms of
hyperglycemia, such as polydipsia, polyuria, polyphagia or weakness.
In patients with significant treatment-emergent
hyperglycemia, discontinuation of clozapine
should be considered.
Clinical experience with clozapine in patients with concomitant
systemic diseases is limited. Nevertheless, caution is advised when
using Apo-Clozapine in patients with hepatic, renal or cardiac
disease. For severe
cases, see Contraindications.
Reproduction studies, performed in rats and rabbits at doses of
approximately 2 to 4 times the human dose, have revealed no evidence
of impaired fertility or harm to the fetus due to clozapine.
However, there have not been any adequate and well-controlled
studies in pregnant women. Because
animal reproduction studies are not always predictive of human
response and in view of the desirability of keeping the
administration of all drugs to a minimum during pregnancy,
Apo-Clozapine should be used only if the benefits clearly outweigh
the risks.
Animal studies suggest that clozapine may be excreted in breast milk
and have an effect on the nursing infant. Therefore, women receiving Apo-Clozapine should not
breast-feed.
Safety and efficacy in children below age 18 have not been
established.
Orthostatic hypotension can occur with Apo-Clozapine treatment
and there have been rare reports of tachycardia, which may be
sustained, in patients taking clozapine.
Elderly patients, particularly those with compromised
cardiovascular function, may be more susceptible to these effects.
Elderly patients may also be particularly
susceptible to the anticholinergic effects of
Apo-Clozapine, such as urinary retention and constipation.
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