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Clozapine Drug-Drug Interactions: A Review of the Literature

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 HUMAN PSYCHOPHARMACOLOGY, VOL. 12, 5±20 (1997)

REVIEW

Clozapine Drug±Drug Interactions: A Review of

the Literature
STACY C. EDGE1 , JOHN S. MARKOWITZ2 * and C. LINDSAY DEVANE3
1
Psychopharmacy, 2 Department of Pharmacy Practice, 3 Department of Psychiatry and Behavioral Sciences, Institute
of Psychiatry, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina, 29465, USA

Clozapine is often used in combination with other medications. To date, there has been no comprehensive review of
drug±drug interactions involving clozapine. This review summarizes published reports of suspected drug±drug
interactions, and assesses their clinical signi®cance. A computerized search was conducted using MEDLINE (1975±
1996) to retrieve all reports of adverse events associated with the concurrent use of clozapine and other agents.
Forty-three reports involving 19 di€erent drugs were evaluated. Clozapine appeared to be involved in pharmaco-
kinetic and pharmacodynamic interactions when prescribed concurrently with most major classes of therapeutic
agents. In general, the addition of other medications with similar pharmacological e€ects or side-e€ects to clozapine
may enhance these e€ects in an additive or possibly synergistic manner. The selective serotonin reuptake inhibitor
¯uvoxamine was involved in the most thoroughly documented pharmacokinetic interactions, while a number of
reports were found implicating various benzodiazepines in apparent pharmacodynamic interactions. No clozapine±
drug combination is absolutely contraindicated, but some members of a given therapeutic class may pose less risk
than others when used concurrently with clozapine.

KEY WORDS Ð clozapine; drug interaction; polypharmacy

INTRODUCTION status may be erroneously attributed to a single

It is common and accepted practice for patients
diagnosed with schizophrenia and other psychi-
atric disorders to be treated with several medica-
tions simultaneously. These agents may be other
psychotropic drugs employed adjunctively to treat
psychosis and antipsychotic-induced side-e€ects,
or pharmacotherapy targeted at symptoms asso-
ciated with concomitant mood disorders or anxiety
(Wolkowitz, 1993; Siris, 1993). Further, patients
may be receiving additional medications such as
cardiovascular, antimicrobial, hypoglycemic, anti-
in¯ammatory, and other agents on an acute or
chronic basis. Polypharmacy at some time during
psychoactive drug therapy is probably inevitable.
This situation leads to potential drug±drug inter-
actions. Most drug interactions are probably of
insucient magnitude to be of clinical signi®cance,
while others which do cause a change in clinical
*Author to whom correspondence should be addressed.
CCC 0885±6222/97/010005±16
# 1997 by John Wiley & Sons, Ltd.
agent. Clearly, the most de®nitive method to
establish causality in drug±drug interactions is to
re-challenge the patient with medications. When
pharmacokinetic interactions are suspected, appro-
priately timed drug levels can provide conclusive
evidence.
Drug interactions generally fall into three
categories: pharmaceutic, pharmacodynamic, and
pharmacokinetic. Since pharmaceutic interactions
typically involve problems with incompatibility of
parenteral products, they are rarely signi®cant in
psychiatric pharmacotherapy.
Pharmacodynamic interactions are those which
alter the pharmacologic activity of drugs resulting
in antagonistic, additive, or synergistic e€ects.
These interactions are not associated with changes
in plasma or tissue concentration of drug. For
example, patients receiving antihypertensive medi-
cations in combination with antipsychotics can
experience additive hypotensive drug e€ects
(Markowitz et al., 1995). Conversely, tricyclic
6 S. C. EDGE ET AL.
antidepressants can antagonize the therapeutic
e€ects of some antihypertensives (Briant and
Diamond, 1973).
Pharmacokinetic interactions may alter either
absorption, distribution, metabolism, or elimina-
tion of one or more involved drugs. Changes in
drug absorption may result when medications are
administered with food or antacids. For instance,
some antacids impair the absorption of chlorpro-
mazine (Fann et al., 1974). Interactions resulting in
changes of drug distribution typically involve
protein-binding displacement. Most psychotropic
medications are highly protein-bound, but the
signi®cance of displacement interactions among
antipsychotic drugs is unknown (Rolan, 1994).
Recently, it has become clear that plasma and
tissue drug concentrations of many hepatically-
cleared medications, including many psycho-
tropics, can be signi®cantly altered by induction
or inhibition of speci®c cytochrome P450 (CYP)
isozymes. Alteration in CYP activity has been
attributed to several factors, including co-adminis-
tered medications, food, and smoking behavior
(Pollock, 1994; Spatzenegger and Jaeger, 1995).
Clozapine (CLZ) is an atypical antipsychotic
agent distinguished clinically from other anti-
psychotics in its low incidence of extrapyramidal
symptoms and e€ectiveness in otherwise drug-
resistant schizophrenia and other psychotic dis-
orders (Kane et al., 1988; McElroy et al., 1991).
Wider use of this drug has been limited due to an
approximate 1% risk of drug-induced agranulo-
cytosis (Alvir et al., 1993). However, 60 000
patients in the US are currently being treated with
CLZ (personal communication from Sandoz
Pharmaceuticals, October, 1995). Further, CLZ
use is commonly associated with a variety of other
adverse events, including sedation, dizziness,
tachycardia, hypersalivation, dry mouth, consti-
pation, hypotension, transient fever, and seizures
(Lierberman and Sa€erman, 1992).
Clozapine is thought to exert its therapeutic
e€ects by antagonizing dopamine receptor sub-
types (D1 > D2) as well as serotonin receptor sub-
types (5HT2). Additionally, other receptors
including adrenergic (1 and 2), muscarinic, and
histamine type 1 (H1) are antagonized resulting in
an array of side-e€ects (Lieberman and Sa€erman,
1992; Sandoz product information, 1996).
Clozapine is extensively metabolized by the liver.
Its major metabolites include norclozapine
(NORCLZ) (Ereshefsky et al., 1989; Baldessarini
and Frankenburg, 1991), which may exceed
concentrations of the parent drug, (Gauch and
Michaelis, 1971; Bondesson and Lindstrom, 1988)
and clozapine-N-oxide (CLZNO), which can be
reduced back to the parent compound (Jann et al.,
1994). NORCLOZ appears to have D2 and 5-HT2
receptor anity similar to that of the parent
compound (Kuoppamaki et al., 1993). Addition-
ally, Gerson et al. (1994) reported that NORCLOZ
was toxic to haemopoietic precursors. CLZNO
appears to be inactive at either serotonin or
dopamine receptors (Kuoppamaki et al., 1993).
Other elimination products include methiolated,
hydroxylated (Stock et al., 1977), and glucuroni-
dated (Markowitz and Patrick, 1993; Luo et al.,
1994) metabolites. Clozapine appears to be meta-
bolized predominantly by hepatic CYP 1A2 and
CYP2D6 isoenzymes (Fisher et al., 1992; Dahl
et al., 1994; Jerling et al., 1994).
There are accumulating reports of adverse events
associated with concomitant administration of
clozapine and other medications. While case
reports obviously lack the rigour of formal con-
trolled studies, it is generally post-marketing
reports of adverse events which lead to the recog-
nition of clinically signi®cant drug±drug inter-
actions and contraindication. A comprehensive
review of the drug interactions involving CLZ has
not been previously published.
METHODS
Accordingly, we have reviewed case reports and
studies of both pharmacodynamic and pharmaco-
kinetic interactions involving clozapine. A compu-
terized literature search using MEDLINE (January
1975±April 1996) was conducted to retrieve all
pertinent studies, reviews, and case reports. Cross-
referencing of published bibliographies yielded
additional reports. Drug interaction reports were
divided into two main categories, pharmaco-
dynamic and pharmacokinetic. In some instances
the mechanism of interaction was unclear. Assess-
ments of clinical signi®cance and the degree in
which causality was established were also made.
Reports were categorized as `clinically signi®cant'
when signi®cant adverse e€ects or loss of thera-
peutic ecacy occurred which was clearly linked
to combination drug therapy. A designation of
`possible' clinical signi®cance was made when
there were no clinically signi®cant e€ects yet
clear evidence that a drug interaction took place
(i.e. elevated drug levels), or when the magnitude of
the interaction although not clinically signi®cant,
 CLOZAPINE DRUG±DRUG INTERACTIONS: A REVIEW
might have the potential to be so. When neither of
the aforementioned criteria were met a designation
of `no clinical signi®cance' was made. With regard
to establishment of causality, when there was a
preponderance of evidence that a drug±drug
interaction had occurred rather than a singular
drug e€ect, a conclusion was made that causality
had been established. When there was some
reasonable question as to whether an adverse event
was associated with a single agent or instances
when there were con¯icting reports, an assessment
of `unclear' was made. When the adverse event
could be explained by known pharmacological
e€ects of either agent administered or when both
agents were initiated simultaneously, an assess-
ment was made that no causality had been
established.
RESULTS
A total of 42 reports of clozapine drug interactions
involving 19 di€erent drugs as well as smoking
behaviour were found. Many of the reports
involved several cases. Agents from nearly all
therapeutic drug classes were implicated. A sum-
mary of ®ndings is found in Table 1 along with an
assessment of the clinical signi®cance and degree
that causality of the drug interaction could be
established in each case.
Interactions with the selective serotonin
reuptake inhibitor ¯uvoxamine appeared to be
the most thoroughly described in terms of both
frequency and documentation through therapeutic
drug monitoring. Adverse events associated with
concomitant use of benzodiazepines was also well
documented. Lithium use in combination with
CLZ was also associated with a number of adverse
events. A discussion of the individual cases follows.
Pharmacodynamic interactions
Benzodiazepines. A number of cases have been
reported in which an apparent pharmacodynamic
interaction between CLZ and benzodiazepines has
occurred. Adverse drug reactions experienced with
concomitant administration of CLZ and benzo-
diazepines include: delirium, ataxia, hypersaliva-
tion, confusion, sedation, and slurred speech.
Adverse e€ects have been reported when benzo-
diazepines were added to an existing CLZ regimen,
when CLZ was added to an existing benzo-
diazepine regimen, and when both CLZ and the
benzodiazepine were initiated simultaneously.
7
Adverse reactions were associated with single
benzodiazepine doses as low as lorazepam 2 mg.
Cobb et al. (1991) reported two cases of a
possible interaction in which patients had had
lorazepam added to an existing CLZ regimen.
They developed marked sedation, sialorrhea, and
ataxia. It was noted that both patients had received
lorazepam previously while taking tri¯uoperazine
and haloperidol, respectively, without adverse
consequences.
Grohman et al. (1989), in a post-marketing drug
surveillance programme, reported four cases of a
severe adverse reaction associated with the com-
bination of CLZ and a benzodiazepine. In three of
the four cases, severe hypotension, respiratory
depression, and loss of consciousness occurred.
One patient experienced collapse and loss of
consciousness. Diazepam was implicated in two
cases, lorazepam in a third case, and diazepam,
clobazam, and lormetazepam in the fourth.
Jackson et al. (1995) reported two cases of similar
adverse events of disorientation, confusion, sialor-
rhea, and delirium in patients receiving either CLZ
and lorazepam or CLZ with clonazepam. One
patient was re-challenged with the combination of
CLZ and lorazepam, with a return of adverse
e€ects, thereby establishing causality in the CLZ±
benzodiazepine interaction. In all cases the
patients sensorium cleared with benzodiazepine
discontinuation and they were able to continue
CLZ treatment.
Sassim and Grohman (1988) reported two cases
of respiratory collapse in patients receiving a
combination of CLZ and a benzodiazepine. One
patient received a combination of CLZ 25 mg/day,
and diazepam 20 mg/day, while the other
received CLZ 12.5 mg/day and diazepam 5 mg/day,
along with ¯urazepam 30 mg/day 1 day prior to
the adverse event. Both patients were in the
early stages of CLZ titration. These occurr-
ences prompted a retrospective chart review of
39 patients who had been treated with CLZ with
and without a benzodiazepine. The review indi-
cated that three (7.7%) of the patients experienced
collapse with the combination and only one (2.6%)
on CLZ alone. Further, there were signi®cantly
higher rates of sedation and dizziness among the
patients receiving combination treatment.
Klimke and Klieser (1994) reported a case
of death secondary to respiratory arrest in a
CLZ-treated patient following the administration
of three doses of intravenous lorazepam 2 mg
within 9 h. The patient had been receiving CLZ
 8
Table 1. Drug interactions with clozapine
Agent N Postulated mechanism Results of interaction Clinical Causality References
signi®cance established
Benzodiazepines
Lorazepam 2 Pharmacodynamic Delirium, sedation, Yes Yes Cobb et al. (1991)
1 interaction ataxia, slurred speech, Grohman et al. (1989)
2 hypersalivation Jackson et al. (1995)
1 Pharmacodynamic interaction Respiratory arrest, death Yes No Klimke and Klieser (1994)
Clonazepam 1 Pharmacodynamic interaction Delirium, ataxia, sedation Yes Yes Jackson et al. (1995)
Diazepam 2 Pharmacodynamic interaction Respiratory collapse Yes No Sassim and Grohman (1988)
Antihypertensives
Enalapril 2 Pharmacodynamic interaction Synergistic or additive Yes Yes Arnowitz et al. (1994)
hypotensive e€ect, syncope
Propranolol 1 Unclear Coma Yes No Vetter and Proppe (1992)
Miscellaneous
Lithium 4 Pharmacodynamic interaction Symptoms of neurotoxicity Yes No Blake et al. (1992)
1 Yes Unclear Hellwig et al. (1996)
1 Diabetic ketoacidosis Yes Unclear Peterson and Byrd (1996)
1 Pharmacodynamic interaction Neuroleptic malignant Yes No Pope et al. (1986)
syndrome (NMS)
2 Pharmacodynamic interaction Seizures Yes Yes Garcia et al. (1994)
1 Pharmacodynamic interaction Agranulocytosis Yes No Valevski et al. (1993)
S. C. EDGE ET AL.

Methazolamide 1 Pharmacodynamic interaction Decrease in WBC, Yes No Burke and Ranno (1994)
possibly additive
Meclizine 1 Pharmacodynamic interaction Urinary retention, possible Yes No Cohen (1994)
additive anticholinergic e€ects
Ca€eine 1 Pharmacodynamic interaction Exacerbation of psychosis Yes Unclear Vainer and Chouinard (1994)
1 Pharmacokinetic; inhibition Increased CLZ levels, Yes Yes Odum-White and de Leon
of CYP1A2 sedation, sialorrhea (1996)
Smoking 148 Pharmacodynamic; Lower average CLZ Possible Unclear Haring et al. (1989)
Pharmacokinetic; concentration
1 Induction of CYP1A2 McCarthy (1994)
Cimetidine 1 Pharmacokinetic; inhibition Increase in CLZ Yes Yes Szymanski et al. (1991)
of CYP1A2 and/or CYP2D6 concentration leading to
dizziness, diaphoresis,
weakness, vomiting
Erythromycin 1 Pharmacokinetic; inhibition of Increased CLZ Yes Ues Funderburg et al. (1994)
concentration, seizure
1 CYP3A4 Increased CLZ concentration, Yes Yes Cohen et al. (1996)
toxicity, leucocytosis
Ampicillin 1 Unclear Increased sedation, Possibly No Csik and Molner (1994)
hypersalivation
Antidepressants
Nortriptyline 1 Pharmacokinetic; inhibition Elevated nortriptyline Yes Yes Smith and Risken (1994)
of CYP2D6 concentration
Fluvoxamine 2 Pharmacokinetic; inhibition Elevated CLZ concentration Yes Yes Weigmann et al. (1993)
3 of CYP1A2 Hiemke et al. (1994)
1 Szegedi et al. (1995)
3 Dumortier et al. (1996)
2 Dequardo and Roberts (1996)
Fluoxetine 4 Pharmacokinetic; inhibition Reported to both increase No Unclear* Centorrino et al. (1994)
1 of CYP2D6 or have no e€ect on CLZ Eggert et al. (1994)
concentration
14 Pharmacokinetic; inhibition Patients exhibited higher Possibly Yes Centorrino et al. (1996)
of CYP2D6, 3A4 average CLZ concentrations
than matched controls
Paroxetine 16 Pharmacokinetic; inhibition Patients exhibited higher Possibly Yes Centorrino et al. (1996)
of CYP2D6 average CLZ concentrations
than matched controls
Sertraline 10 Pharmacokinetic; inhibition Patients exhibited higher Possibly Yes Centorrino et al. (1996)
of CYP2D6, 3A4 and 1A2 average CLZ concentrations
than matched controls
Anticonvulsants
Valproic acid 11 Unclear Reported to both decrease Possibly Unclear* Centorrino et al. (1994)
4 and increase CLZ Finley and Warner (1994)
concentration Costello and Suppes (1995)
Carbamazepine 2 Pharmacokinetic; induction Decrease in CLZ Yes Yes Raitasuo et al. (1993)
8 of CYP450 concentration Shroder and Calabrese (1995)
6 Tiihonen et al. (1994)
1 Pharmacodynamic interaction Possibly additive/synergistic Yes Unclear Junghan et al. (1993)
Phenytoin 2 Pharmacokinetic; induction to cause Decrease in CLZ Yes Yes Miller (1991)
of CYP450 concentration
CLOZAPINE DRUG±DRUG INTERACTIONS: A REVIEW

Neuroleptics
Risperidone 1 Pharmacokinetic; competitive Increase in CLZ Possibly Yes Tyson et al. (1995)
inhibition concentration
1 CYP2D6 Koreen et al. (1995)
1 Pharmacodynamic/ Possibly additive/synergistic Yes No Godleski and Sernyak (1996)
Pharmacokinetic to cause agranulocytosis
*Con¯icting reports.
9
10 S. C. EDGE ET AL.
400 mg/day, but had refused the medication 35 h
prior to the adverse event. The patient died 12 h
following the last lorazepam dose. It was dicult in
this case to implicate the drug combination rather
than lorazepam alone in inducing respiratory
arrest.
Antihypertensives.
Enalapril
Two cases of syncope and hypotension in patients
taking enalapril treated with concomitant CLZ
were reported by Aronowitz et al. (1994). In both
cases CLZ was added to an existing antihyperten-
sive regimen resulting in the adverse event. In one
case the patient was able to continue both medi-
cations after reducing the enalapril dosage, while in
the other case the patient was maintained on CLZ
alone thereafter. The combination of enalapril and
CLZ resulted in an apparent pharmacodynamic
drug interaction. An additive or synergistic e€ect
may have occurred through adrenergically-
mediated vasodilatation and enhanced the risk of
prolonged hypotension and syncope.
Propranolol
Propranolol, a beta adrenergic antagonist, is
sometimes used to treat CLZ-induced tachycardia.
Vetter and Proppe (1992) reported the occurrence
of coma in a 45-year-old woman 1.5±2 h following
the addition of a single dose of 150 mg clozapine to
an existing regimen of propranolol 40 mg/day. The
patient fully recovered and was subsequently
slowly titrated to clozapine to 100 mg/day with
continuation of propranolol without additional
side-e€ects.
Propranolol has been reported to elevate the
concentrations of neuroleptics such as chlorpro-
mazine and thioridazine (Peet et al., 1980; Green-
dyke and Kanter, 1987). Formal studies on the
interaction between CLZ and propranolol have
not been done but a possible pharmacokinetic
interaction may have occurred. In this case, the
single beginning dose of 150 mg of CLZ is higher
than usually recommended, and de®nitive evidence
of a drug interaction is lacking.
Miscellaneous.
Lithium
There have been eight reported cases of possible
pharmacodynamic interactions with lithium and
CLZ combinations. One author theorized that the
serotonergic e€ects of both medications may be a
possible mechanism for neurotoxicity reportedly
induced by the co-administration of these two
agents.
Blake et al. (1992) reported neurologic symp-
toms such as myoclonic jerks, gait disturbances,
facial spasms, and confusion in four patients (ages
27±34 years) following the addition of lithium to
CLZ therapy. None of the patients' lithium
concentrations were found to be in toxic ranges,
and all improved after lithium discontinuation.
When two of the patients were re-challenged with
the combination, one experienced a recurrence of
symptoms. It was not stated whether any of the
patients had previously tolerated lithium treatment
alone or in combination with other agents. Thus it
was unclear if this was a result of the combination,
or lithium alone.
Garcia et al. (1994) reported two patients who
experienced seizures when lithium was added to
existing CLZ treatment. Neither patient had
elevated lithium concentrations, and both were
able to tolerate CLZ treatment without further
seizures after the lithium was discontinued.
Valevski et al. (1993) reported that CLZ and
lithium combined treatment of a 50-year-old
schizoa€ective female patient resulted in an
episode of agranulocytosis lasting 27 days. The
patient required treatment with granulocyte±
macrophage colony-stimulating factor 300 mg
SQ, followed by interleukin-3 300 mg/day SQ
which resulted in complete recovery. In this case,
clozapine was added to an existing lithium regimen
and it was not clear if the adverse event was
attributable to the combination or to clozapine
alone. The authors suggested that the lithium could
have possibly masked an earlier myelosuppressive
e€ect of CLZ through its myelostimulatory e€ect.
Hellwig et al. (1996) reported a patient who
developed an acute organic psychosis presumably
due to neurotoxicity of lithium after discontinuing
long-term CLZ therapy. The patient, a 33-year-old
man with schizoa€ective disorder, was receiving
lithium 2700 mg/day, CLZ 600 mg/day, and
valproic acid (VPA), up to 3000 mg/day. Second-
ary to inadequate response, CLZ was discontinued
and haloperidol was started. Four days later, the
patient developed an acute organic psychosis with
delusions and visual hallucinations. The serum
lithium concentration was found to be 1.5 mEq/l,
nearly twice the value measured repeatedly during
the co-administration of CLZ. Lithium was
discontinued and the patient recovered completely.
The mechanism by which CLZ might decrease
lithium concentrations is unclear. It is possible that
 CLOZAPINE DRUG±DRUG INTERACTIONS: A REVIEW
the described neurotoxicity could have been caused
by the haloperidol±lithium combination as such
reactions ®nd support in the literature. However,
the authors reported that the patient had been
treated with this combination previously without
incident.
Pope et al. (1986) reported the development of
neuroleptic malignant syndrome (NMS) in a
lithium-treated patient 16 days following the addi-
tion of CLZ. The syndrome resolved in 24±48 h
following the discontinuation of CLZ. The patient
had a previous history of NMS with ¯uphenazine,
and there was no evidence that lithium was
contributory.
Peterson and Byrd (1996) reported the develop-
ment of diabetic ketoacidosis secondary to cloza-
pine and lithium treatment. The patient, previously
treated with lithium and a standard antipsychotic,
developed diabetic ketoacidosis 5 weeks after the
initiation of clozapine. The patient declined reinsti-
tution of clozapine treatment. In this case, it is not
clear that the adverse e€ect was due to the addition
of clozapine.
Methozolamide
Burke and Ranno (1994) reported a case of
neutropenia associated with concomitant use of
CLZ and methozolamide. An 86-year-old woman
who was maintained on CLZ 125 mg, alternating
with 18.75 mg every other night for over a year,
was started on methazolamide, 50 mg twice daily,
for treatment of glaucoma. Seven days later, her
WBC count was 1900 with 37% (703) neutrophils.
One week before, the WBC count had been 5600
with 73% (4088) neutrophils. CLZ and methazo-
lamide were discontinued. The WBC gradually
recovered and CLZ was restarted. The patient was
able to maintain a WBC count in the previous
range.
Carbonic anhydrase inhibitors have signi®cant
potential to cause bone marrow toxicity on their
own. A pharmacodynamic interaction may be
possible due to a potential synergistic e€ect
between these two drugs enhancing the possibility
of agranulocytosis. However, methozolamide alone
may have accounted for the e€ect in this case as
methazolamide was never administered singularly.
Meclizine
Cohen (1994) reported a case of a 38-year-old man
with treatment-refractory paranoid schizophrenia,
who was treated with CLZ, 200 mg b.i.d. with
improvement. His medication regimen upon
11
admission included meclizine, 12.5 mg t.i.d. and
slow release verapamil 180 mg/day. Six months
after CLZ treatment was initiated, he began to
experience nocturnal enuresis, frequency of urina-
tion, and abdominal bloating. The symptoms
increased in severity over the 7-month course of
CLZ therapy. He eventually became unable to void
and was subsequently diagnosed with bladder
atony. CLZ and meclizine were discontinued. He
was treated with bethanechol 25 mg t.i.d. with
improvement in symptoms.
Clozapine is known to cause enuresis and
urinary retention. The co-administration of mecli-
zine which is also anticholinergic could have
potentiated the anticholinergic e€ects of CLZ.
Although the e€ects of the two drugs could have
been additive, either agent alone may have been
responsible.
Ca€eine
Vainer and Chouinard (1994) reported a potential
interaction between clozapine and ca€eine. A
39-year-old man with refractory schizophrenia
and a habit of consuming 5±10 cups of co€ee per
day was placed on CLZ. The patient was started on
CLZ at a dose of 75 mg/day with improvement
noted. Six months after initiation, at a dosage of
150 mg/day, the patient displayed a reaction not
previously seen while he received haloperidol.
Each time the patient took CLZ with two cups
of co€ee or ca€einated soda, he experienced a
short-lasting acute psychotic exacerbation. These
reactions were prevented when the CLZ was taken
with water.
The authors suggested that the e€ects derived
from this CLZ and ca€eine interaction were due to
a pharmacodynamic adenosine A2a receptor±
dopamine D2 receptor mechanism in postsynaptic
striatal membranes. In response, Carrillo et al.
(1995) suggested that in addition to the above
pharmacodynamic interaction theorized by Vainer,
there may be a pharmacokinetic explanation as
well. The interaction between CLZ and ca€eine
may be due to an inhibition of cytochrome
P4501A2, which could increase the concentration
of one or both drugs. Odum-White and de Leon
(1996) in a report supporting this theory, described
a patient receiving CLZ 550 mg/day for 5 months
who was also taking ca€eine 200 mg tablets and
drinking approximately a litre of ca€einated tea
daily to combat sedation. Plasma CLZ and
NORCLZ were measured at 1500 ng/ml and
630 ng/ml respectively. The patient was advised
12 S. C. EDGE ET AL.
to discontinue the ca€eine and tea. One week later,
while continuing to receive CLZ 550 mg/day, a
second blood sample revealed a concentration of
CLZ 630 ng/ml and NORCLZ 330 ng/ml. The
signi®cance of this interaction probably warrants
further investigation, particularly in light of
suggestions to add or increase the consumption
of ca€einated beverages as a means of managing
CLZ-associated sedation (Clozaril Patient Man-
agement Handbook, Sandoz, 1995).
Pharmacokinetic interactions
Smoking. Smoking is a known inducer of hepatic
enzymes, mainly cytochrome P4501A2 through the
action of nicotine and other polyaromatic hydro-
carbons in tobacco smoke. Induction of the
metabolism of chlorpromazine, haloperidol, and
¯uphenazine secondary to smoking has been
previously demonstrated. The e€ects of smoking
on CLZ plasma concentrations are less clear. Some
studies report that smoking is associated with
lower plasma CLZ concentration in men, but not
women while other studies found no such e€ect in
either group (Haring et al., 1990; Hasegawa et al.,
1993). Haring et al. (1989) found that plasma
concentration at a given dose was lower in smokers
compared to non-smokers overall; however, only a
statistically signi®cant di€erence was found in the
plasma concentration in males. The male smoking
patients had a CLZ plasma concentration which
was 67:9% of the concentration found in non-
smoking female patients.
Conversely, the discontinuation of an enzyme
inducer such as tobacco smoke would potentially
lead to increased concentrations of the substrate
compound. McCarthy (1994) reported a case of a
25-year-old male smoker (1.5 ppd65 years) taking
450 mg/day of CLZ titrated over 5 weeks. He
stopped smoking 36 weeks into therapy and at
39 weeks a myclonic seizure was noted and CLZ
was decreased to 350 mg/day with the subsequent
elimination of symptoms. Two weeks later, the
patient experienced a grand mal seizure 3 h after
the bedtime dose of CLZ and was stabilized with
the discontinuation of medications. This case
suggests the removal of an enzyme inducer
(i.e. nicotine, polyaromatic hydrocarbons con-
tained in tobacco smoke) may have resulted in an
increase of plasma concentrations of the substrate
compound; however, the case is complicated as
other medications were administered which under-
go hepatic metabolism: clozapine, ¯uoxetine, and
pindolol. No CLZ plasma concentration data were
obtained from the patient.
Tricyclic antidepressants.
Nortriptyline
Smith and Riskin (1994) reported a case of a
38-year-old male with schizoa€ective disorder who
was started on CLZ after years of poor response to
various medications. The patient was taking
nortriptyline 100 mg/day for depression with a
plasma concentration on admission of 93 ng/ml.
CLZ was titrated to a dose of 225 mg/day. On day
15 of the trial, the patient complained of extreme
fatigue and was noted to have slurred speech and
tangential thinking. Two days later, he was
delirious, displaying extreme emotional lability,
intermittent religious preoccupation, confusion,
and memory loss. The nortriptyline concentration
at this time was 185 ng/ml. All medications were
withheld resulting in clearing of the sensorium.
CLZ alone was reinstituted, with the dose in-
creased to 300 mg/day over the next week without
further diculties. This suspected pharmacokinetic
interaction may have occurred through competi-
tive inhibition of the CYP2D6 isoenzyme which is
responsible for nortriptyline metabolism.
Selective serotonin reuptake inhibitors (SSRIs). All
of the SSRIs currently marketed in the US;
¯uvoxamine (FLUV), ¯uoxetine (FLX), sertraline,
and paroxetine have been implicated in drug±drug
interactions leading to elevations of plasma CLZ
concentration. Centorrino et al. (1996) reported
that serum concentrations of CLZ and NORCLZ
were on average 43% higher in 40 patients co-
medicated with ¯uoxetine, sertraline, or paroxetine
when compared to age- and CLZ dose-matched
controls. Further, there was a 25% greater risk of
attaining concentrations greater than 1000 ng/ml in
these patients. Only minor di€erences were found
between the individual SSRIs. At present, the most
substantial evidence for a CLZ-SSRI interaction
has been documented for FLUV.
Fluvoxamine
Weigmann et al. (1993) reported two cases in which
CLZ levels increased markedly following FLUV
addition to an existing CLZ regimen. Additionally,
laboratory monitoring provided evidence that
FLUV inhibits N-demethylation and N-oxidation
of CLZ.
Hiemke et al. (1994) demonstrated that when
FLUV, 100 mg/day was added to a CLZ regimen
 CLOZAPINE DRUG±DRUG INTERACTIONS: A REVIEW
of 400 mg/day in a 36-year-old male, a marked
increase in CLZ concentration occurred (260 ng/ml
to > 2000 ng/ml). The mean ratios of N-demethyl-
ation and N-oxidation decreased from 0.58 to 0.28
and from 0.48 to 0.04, respectively during the co-
administration of FLUV. Both drug doses were
lowered which resulted in acceptable levels of CLZ
and metabolites.
Szegedi et al. (1995) reported a case of a 34-year-
old man su€ering from chronic schizophrenia who
received CLZ, up to 400 mg/day for 2 years.
During this time, the concentration of CLZ ranged
between 77 and 197 ng/ml. A dose increase to
500 mg/day achieved a plasma concentration of
200 ng/ml. FLUV 50 mg/day was added to treat
the negative symptoms, which resulted in a plasma
CLZ concentration increase to 956 ng/ml.
Jerling et al. (1994) utilized a therapeutic drug
monitoring service for CLZ to study interactions
with other drugs. They noted that the addition of
FLUV to the CLZ regimen of four patients
increased the plasma concentration of CLZ by a
factor of 5±10 in three of the patients.
Dumortier et al. (1996) reported three cases in
which the combination of a ¯uvoxamine and CLZ
regimen resulted in substantial elevations in CLZ
plasma concentration. The ®rst patient main-
tained on CLZ 800 mg/day had a plasma
concentration of 820 ng/ml 2 days prior to the
addition of FLUV 200 mg/day and 2715 ng/ml
33 days after. The second patient, treated with
CLZ 500 mg/day had a plasma concentration of
200 ng/ml prior to the addition of FLUV 100 mg/
day, and 1765 ng/ml 29 days after. The third
patient, treated with CLZ 500 mg/day and
¯uvoxamine 150 mg/day for 1 year had CLZ
and NORCLZ concentrations measured at 3300
and 650 ng/ml respectively. Seventeen days after
¯uvoxamine was withdrawn, plasma concentra-
tions fell to 435 and 250 ng/ml respectively. None
of the patients experienced any signi®cant side-
e€ects from the drug combination.
Dequardo and Roberts (1996) reported two
cases of elevated CLZ concentration following
the addition of FLUV to an existing CLZ regimen.
The ®rst patient, treated with CLZ 900 mg/day,
had a serum CLZ concentration of 396 ng/ml.
Twenty days after the addition of FLUV
25 mg/day, the concentration increased to
1462 ng/ml. The CLZ dose was then lowered to
500 mg/day and the serum concentration 17 days
later was 1034 ng/ml. No adverse e€ects were
reported. The second patient, receiving CLZ
13
500 mg/day, had FLUV 300 mg/day added to the
regimen over 3 weeks resulting in a serum CLZ
concentration of `over 1000 ng/ml' with accom-
panying somnolence, slurred speech, ataxia, and
hypotension. The CLZ dose was reduced to
400 mg/day and the serum concentration was
measured at 1830 ng/ml 1 week later. After further
reduction of CLZ to 350 mg/day, the serum
concentration decreased to 1382 ng/ml with abate-
ment of side-e€ects.
Fluoxetine
Centorrino et al. (1994) monitored serum concen-
trations of CLZ and its major metabolites with
regard to e€ects of co-treatment with FLX or
valproate. Eight patients were treated with the
combination of FLX and CLZ. The serum
clozapine level was increased signi®cantly
(by 76%) as was the level of NORCLZ (52%) in
four of the eight patients. This would appear to
implicate CYP2D6 inhibition in this interaction.
Conversely, Eggert et al. (1994) however,
reported a case in which a patient was on the
combination of FLX and CLZ without any
change in the plasma level of CLZ throughout
the duration of therapy.
Adding an SSRI to CLZ therapy has been
shown to improve therapeutic outcome (Centorri-
no et al., 1994; Szegedi et al., 1995). Recent clinical
studies suggest that the N-demethylated metabolite
of CLZ contributes to both ecacy and toxicity of
CLZ. The N-demethylated metabolite has higher
anities for 5-HT1C , 5-HT2 , and D2 receptors.
Further, NORCLZ exhibits di€erential myelotoxic
e€ects compared with the parent drug. Szegedi
et al. (1995) theorized that the manipulation of the
metabolism of CLZ might thus alter receptor
occupation and result in changes in ecacy and/or
adverse reactions.
Anticonvulsants. Several cases have been reported
showing a possible interaction between CLZ and
various anticonvulsant agents. We found 10 case
reports and two clinical trials with carbamazepine
(CBZ), one case report and two clinical trials with
valproic acid (VPA), and two case reports with
phenytoin (PHY).
There are con¯icting ®ndings regarding the e€ect
of VPA on CLZ concentrations. Wilson (1995)
performed a retrospective study of 100 patients.
Sixty-eight patients did not receive concurrent
anticonvulsant therapy while 20 received PHY,
CBZ, VPA, phenobarbital, or clonazepam in
14 S. C. EDGE ET AL.
conjunction with CLZ. Twelve patients were
excluded who had preexisting seizure disorders.
The anticonvulsant-treated patients showed less
improvement at 6 months than did the other
patients treated with CLZ alone. The author
suggested that anticonvulsants may hinder the
clinical response to CLZ through either pharmaco-
dynamic or pharmacokinetic interactions.
Valproic acid
Finley and Warner (1994) performed a pilot study
to examine the pharmacokinetic impact of VPA on
serum CLZ concentration over a 3-week period in
four patients previously stabilized on the anti-
psychotic. Initiation of VPA therapy was
associated with 41% mean decrease in CLZ con-
centration among the four patients studied. This
e€ect was not apparent until the second week of
combined drug treatment. The mechanism of
action is unclear. The authors stated that an
interaction may have occurred because of possible
protein binding displacement reaction. VPA is
generally characterized as a CYP enzyme inhibitor
rather than an inducer.
A case report by Costello and Suppes (1995)
described a 37-year-old man with a 13-year history
of schizoa€ective disorder, bipolar type, who was
treated with lithium, 1500 mg/day, and VPA,
1500 mg/day. When CLZ was initiated, the patient
experienced signi®cant sedation, confusion, and
slurred speech. At this time, the patient was thought
to be sensitive to CLZ and the symptoms were not
the result of a drug interaction. Eight weeks later
the VPA was discontinued with complete remission
of symptoms. Later the patient experienced a
grand mal seizure and was restarted on VPA,
1250 mg/day (serum concentration of 60 ng/ml).
Four days later, the patient had a recurrence of the
side-e€ects previously experienced. VPA was
stopped and PHY (300 mg/day) was initiated. A
prompt resolution of symptoms was again noted.
Centorrino et al. (1994) measured the serum
concentration of CLZ and its major metabolites
before and after VPA was added to the regimen. In
11 patients that received the combination of CLZ
and VPA, there were moderate increases in
concentration of CLZ (30%) and total analytes
(20%), and a small decrease in the NORCLZ
(23%). These ®ndings are not in agreement with
those reported by Finley and Warner (1994), in
which VPA decreased CLZ concentrations rather
than increasing them.
Carbamazepine
Carbamazepine (CBZ), an inducer of liver micro-
somal enzyme systems, is frequently combined
with neuroleptics. However, very little published
data on the possible drug interactions between
CBZ and neuroleptics other than haloperidol are
available (Jann et al., 1985). CBZ is not commonly
co-administered with CLZ due to concerns of
additive adverse haematological e€ects. There are
a number of reports of patients who received both
drugs in which an interaction was evidenced when
CLZ and CBZ were co-administered.
Raitasuo et al. (1993) reported that two patients
experienced a doubling in baseline plasma concen-
trations of CLZ after stopping the concomitant use
of CBZ. The increases occurred within 2 weeks.
Shroder and Calabrese (1995) reported eight
cases of CBZ and CLZ co-administration resulting
in signi®cantly lower CLZ concentrations in a
geriatric population.
A report by Jerling et al. (1994) used therapeutic
drug monitoring data for CLZ to study interac-
tions with other drugs. Patients on CBZ and CLZ
had a mean 50% lower CLZ concentration/dose
ratio than the CLZ alone group. Tiihonen et al.
(1994) demonstrated that CBZ decreased plasma
concentrations of CLZ in 12 patients while having
a less marked e€ect on thioridazine plasma
concentrations.
As mentioned previously, a potential problem
with the combination regimen of CBZ and CLZ is
the possible increased risk of haematological side-
e€ects. Junghan et al. (1993) reported a case of fatal
neutropenic sepsis occurring in a patient due to the
combined treatment with CLZ, CBZ, lithium,
benztropine and clonazepam. Patients who are
taking the combination of CBZ and CLZ may
increase the risk of agranulocytosis, a serious
complication associated with both drugs. The same
investigators retrospectively studied 147 patients in
their institution who were treated with CLZ alone
or with the combination. Fourteen patients were
treated with the combination. The overall incidence
of granulocytopenia was 5.4%, and agranulo-
cytosis did not occur. Granulocytopenia was seen
in 22% of patients receiving CLZ and CBZ, and
3.7% who were receiving CLZ alone.
Muller et al. (1988) described a case of NMS
following the addition of CLZ to an existing
CBZ regimen. Symptoms resolved upon discon-
tinuation of CLZ. Of note, the patient had a
previous history of NMS with bromperidol.
Evidence of a combination e€ect from these two
 CLOZAPINE DRUG±DRUG INTERACTIONS: A REVIEW 15

agents resulting in NMS rather than CLZ alone risperidone, 1 mg b.i.d., the CLZ concentration
is lacking. had increased to 398 ng/ml.
Koreen et al. (1995) reported a similar case
Phenytoin during cross-tapering of CLZ and risperidone. The
patient, receiving CLZ 675 mg/day, had risper-
Two cases of a possible interaction between PHY
idone 2 mg/day, added. Steady-state CLZ and
and CLZ were reported by Miller (1991). The ®rst
NORCLZ plasma levels before risperidone treat-
case was a 29-year-old man with a 12-year history
ment was started were 829 ng/ml and 1384 ng/ml,
of schizophrenia who was treated with CLZ
respectively, and were 1800 ng/ml and 980 ng/ml
400 mg/day and achieved a plasma concentration
2 days after risperidone was started. The patient's
of 295 ng/ml. On day 14 of the 400 mg/day dose,
dose of CLZ was reduced to 500 mg/day. Her CLZ
the patient experienced a tonic-clonic seizure. The
and NORCLZ plasma concentrations after 5 days
dose of CLZ was decreased to 200 mg/day and
of CLZ at this dose were 1100 ng/ml and 760 ng/ml,
PHY (300 mg/day) was added to the treatment
respectively. No symptoms of toxicity were noted
regimen. Within 24±48 h, the patient's psychotic
during this cross-tapering period.
symptoms worsened acutely and the dose of CLZ
The interaction could have occurred because
was increased to 400 mg/day. His plasma CLZ
risperidone and CLZ are both partially metabol-
concentration was obtained 1 and 2 weeks after
ized by the hepatic microsomal cytochrome
CLZ 400 mg/day, was reinstated and was found to
P4502D6, thus a competitive metabolic inhibition
be 56.2 and 48.7 ng/ml, respectively. The CLZ dose
involving CYP2D6 could have occurred (DeVane,
was increased to 500 mg over 2 months yielding a
1996).
plasma concentration of 92.6 ng/ml with improved
Godleski and Sernyak (1996) reported the
clinical status.
occurrence of agranulocytosis in a CLZ-treated
In the second case, CLZ was started in a patient
patient (900 mg/day) 6 weeks after the addition
and titrated to a dose of 250 mg/day. After 7 days at
of risperidone 4±6 mg/day. Other medications
this dose, a plasma concentration was measured at
included lithium clonazepam, trihexyphenidyl and
940.5 ng/ml. On day 8 of the 250 mg/day dose, the
diphenhydramine. The patient had been treated
patient experienced a tonic-clonic seizure. The dose
with CLZ for 22 months without prior episodes of
was decreased to 150 mg/day and PHY was
neutropenia or leukopenia. Both CLZ and risper-
initiated with a loading dose of 1200 mg/day and
idone were stopped and the patient required
a maintenance dose of 300 mg/day. During the next
treatment with granulocyte stimulating factor with
week, psychotic symptoms worsened and the CLZ
eventual normalization of WBC count. Three
dose was increased to 250 mg/day. After 7 days,
months later risperidone 8 mg/day along with all
with a corresponding decrease in psychotic symp-
previous medications except trihexyphenidyl were
toms. The addition of PHY reduced the steady-
resumed without further incident. The authors
state plasma concentration of CLZ by 65±85%
suggest that the addition of risperidone may have
resulting in a deterioration in the patient's clinical
led to the development of agranulocytosis by
status requiring increases in dose. This interaction
a€ecting clozapine concentrations or the metabo-
between PHY and CLZ suggests that PHY, a well-
lism of toxic metabolites. No plasma concentration
known inducer of the CYP450 enzyme system, may
data was provided to support these hypotheses.
increase the rate of clearance of CLZ.
In this case, the adverse event occurred 6 weeks
after the addition of risperidone. Further, CLZ-
Antipsychotics. induced agranulocytosis does not appear to be
Risperidone dose-related. There appears to be no compelling
A case reported by Tyson et al. (1995) demon- evidence of a synergistic or additive in¯uence of
strated a possible pharmacokinetic interaction both drugs in this case to suggest that it was not
between CLZ and risperidone in a 32-year-old CLZ alone which accounted for the agranulo-
man. Risperidone was added to a CLZ regimen as cytosis.
an augmentation strategy. A CLZ plasma concen-
tration was obtained before and after the initiation Miscellaneous.
of risperidone therapy. After 5 months at a dose Ampicillin
of 300 mg b.i.d., the CLZ concentration was A case reported by Csik and Molner (1994)
344 ng/ml. After 2 weeks of augmentation with described a possible adverse interaction between
16 S. C. EDGE ET AL.
CLZ and ampicillin in a 17-year-old boy with a
diagnosis of schizophreniform disorder. CLZ was
initiated at a dose of 12.5 mg t.i.d. and increased to
50 mg t.i.d. During the ®rst 3 days, CLZ induced
some mild sedation. Over the course of 12 days, the
patient was showing signs of improvement. On day
15, the patient was prescribed ampicillin, 500 mg
q.i.d. On the second day of ampicillin treatment,
the patient was noted to be distractible, extremely
drowsy, and salivating excessively. There was no
evidence of confusion or delirium. The ampicillin
was discontinued and doxycycline was substituted.
The following day, the hypersalivation and other
symptoms had diminished. It is possible that the
adverse reaction may have been attributable to an
idiosyncratic reaction to ampicillin alone. No
plasma drug concentrations were reported in this
patient.
Erythromycin
Funderburg et al. (1994) reported a 32-year-old
man who experienced a tonic-clonic seizure after
the addition of erythromycin to his clozapine
therapy. The patient's dose of CLZ was
800 mg/day. He had been on the regimen for
3 weeks when he was prescribed erythromycin
250 mg q.i.d. after developing a sore throat and
fever. On day 7 of the antibiotic, the patient had a
single tonic-clonic seizure. His CLZ concentration
measured at this time was 1300 ng/ml. The
erythromycin was discontinued and CLZ stopped.
He was restarted on CLZ 2 days later, gradually
titrating to 800 mg/day. After several weeks at this
dose a plasma concentration of 700 ng/ml was
measured. The patient remained seizure free.
Cohen et al. (1996) reported increased plasma
CLZ concentration, leukocytosis, and signs of CLZ
toxicity including slurred speech, disorientation,
and diculty ambulating in a patient receiving CLZ
600 mg/day and erythromycin 333 mg t.i.d. A
steady-state CLZ plasma concentration at the time
of the adverse event was 1150 ng/ml. Other medi-
cations included propranolol 20 mg t.i.d., thiothix-
ene 10 mg t.i.d., and VPA 1000 mg t.i.d. All
symptoms resolved following the discontinuation
of CLZ and erythromycin. Clozapine was gradually
titrated to the previous 600 mg/day dose without
further adverse e€ects. A second steady-state CLZ
plasma concentration measurement was 385 ng/ml.
These two cases suggest that inhibition of the
hepatic microsomal enzyme CYP3A4 was involved
resulting in an increased plasma concentration
of CLZ. Additionally, there is in vitro evidence
suggesting that known inhibitors of CYP3A4 such
as ketoconazole inhibit the metabolism of CLZ
(Pirmohamed et al., 1995). Interestingly, some
individuals with infections may have substantially
compromised CYP450 function e€ecting drug
disposition (Gillan et al., 1993).
Fluoroquinolones such as cipro¯oxacin are
potent inhibitors of CYP1A2 and would therefore
be expected to alter the disposition of CLZ (Gillan
et al., 1993). However, no such cases have been
reported to date.
Cimetidine
Szymanski et al. (1991) reported a case of apparent
cimetidine-induced CLZ toxicity. A 24-year-old
male treated with CLZ 900 mg/day and atenolol
50 mg/day was prescribed cimetidine 400 mg/day
t.i.d. Three days later the patient complained of
marked diaphoresis, dizziness, vomiting, general-
ized weakness and severe lightheadedness on
standing. Cimetidine was discontinued and the
CLZ dose was decreased to 200 mg/day resulting in
resolution of symptoms. The dose of CLZ was
then increased again to 900 mg/day over 1 week
without cimetidine. The patient continued to have
epigastric distress, and rantidine 150 mg b.i.d. was
started with relief of symptoms. CLZ serum con-
centrations obtained while the patient was treated
concomitantly with cimetidine at 800 mg/day had
increased signi®cantly from the concentration
obtained while the patient was treated with CLZ
alone (1559 ng/ml from 992 ng/ml). Rantidine, it
was noted, had no e€ect on plasma CLZ concen-
tration and was well tolerated by the patient.
Cimetidine (but not the other H2-antagonists)
broadly inhibits the activity of cytochrome P450
isozymes including CYP1A2 and CYP2D6. There
is evidence for the involvement of both of these
isozymes in the metabolism of CLZ.
CONCLUSION
Clozapine was reported to be involved in drug
interactions when prescribed concurrently with the
major classes of therapeutic agents. In general, the
addition of agents with similar pharmacological
e€ects or side-e€ects to CLZ such as hypotension
and cholinergic antagonism may potentially
enhance those e€ects in an additive or possibly
synergistic manner when co-administered. These
additive pharmacodynamic e€ects should be recog-
nized and discriminated from pharmacokinetic
drug interactions. For instance, drugs with known
 CLOZAPINE DRUG±DRUG INTERACTIONS: A REVIEW
myelosuppressive activity should clearly be avoided
when possible with CLZ treatment. There were
reports of both CLZ and methazolamide acting in
a possible synergistic or additive manner to cause
neutropenia. The SSRI FLUV appeared to be
involved in the most thoroughly documented
pharmacokinetic interactions with CLZ. FLUV
in¯uences the oxidative metabolism of CLZ by
inhibiting one or more cytochrome P450 isozymes.
Both drugs have been reported to be metabolized by
CYP2D6 in vitro, but FLUV has inhibitory e€ects
predominantly on CYP1A2. This is inconsistent
with a conclusion that CYP2D6 inhibition is
involved in vivo. A lack of association between
debrisoquine and S-mephenytoin hydroxylation
polymorphism and CLZ metabolism has been
reported (Dahl et al., 1994). Thus, it appears that
CYP1A2 is th predominant isoenzyme involved in
in vivo metabolism of CLZ (Crewe et al., 1992;
Jerling et al., 1994). During co-administration,
clozapine concentrations in plasma were elevated
by FLUV, whereas those for NORCLA and
CLZNO were not a€ected. In some case reports
CLZ concentrations were elevated 10-fold. While
the use of combined CLZ and FLUV is not
absolutely contraindicated, the potential magni-
tude of the interaction suggests that monitoring of
CLZ concentrations may be prudent if these agents
are used concurrently. The use of another SSRI
without CYP1A2 inhibitory activity may be desir-
able when close monitoring of CLZ concentration
is not practical. However, the increase in CLZ
concentration secondary to FLX, paroxetine and
sertraline reported by Centorrino et al. (1996)
suggests that all SSRIs should be used cautiously
with CLZ. It appears that the SSRIs sertraline and
paroxetine have the least documentation for
involvement in CLZ drug interactions. These SSRIs
and venlafaxine may have minimal inhibitory
activity on the cytochrome enzymes metabolizing
CLZ.
The benzodiazepines were implicated in a
number of probable pharmacodynamic inter-
actions in which patients became overly sedated,
had hypersalivation, confusion, and in some cases,
delirium. Lorazepam was the co-administered
agent most often reported in these cases. There
were also several instances of respiratory depres-
sion and collapse reported with various benzo-
diazepines. Since benzodiazepines are widely
co-prescribed with CLZ, the likely incidence of
serious side-e€ects, e.g. respiratory depression is
low. Nevertheless, benzodiazepines should be used
17
with caution in combination with CLZ and
administered in very low doses for as short a
duration as necessary.
There may be some risk of neurotoxicity and
development of seizures when CLZ-treated
patients are treated with lithium.
There were various ®ndings with concomitant
anticonvulsant use. The data regarding the e€ect of
co-administering VPA on CLZ concentrations is
con¯icting. One study showed a CLZ-lowering
e€ect while another showed a CLZ-increasing
e€ect. Carbamazepine was demonstrated in several
reports to decrease plasma CLZ concentrations
when used concurrently. Phenytoin was shown to
cause a reduction in CLZ concentrations in two
patients. The atypical antipsychotic risperidone
resulted in modest elevations in CLZ concentra-
tions in two patients without signs of toxicity. The
plasma concentration of the tricyclic antidepres-
sant nortriptyline was elevated in one patient
following the addition of CLZ which resulted
in adverse e€ects. The antibiotic erythromycin
resulted in elevated concentrations of CLZ and
seizure in one patient, and elevated CLZ concen-
trations and toxicity in another, possibly impli-
cating the CYP3A4 isozyme in CLZ metabolism. It
may be advisable to avoid erythromycin and other
macrolide antibiotics in CLZ-treated patients when
alternative agents are available. The H2-antagonist
cimetidine but not ranitidine resulted in elevated
CLZ concentrations suggesting that drugs such as
ranitidine or famotidine may be better alternatives
in CLZ-treated patients.
Certainly, the most de®nitive way to estab lish
causality in drug±drug interactions is by
re-exposure to the medications. However, risk
versus bene®t to the patient as well as medico-
legal issues must be carefully weighed prior to
drug re-challenge.
No CLZ-drug combination is absolutely contra-
indicated, but many present some risk to the
patient through either pharmacokinetic or
pharmacodynamic mechanisms. Further, it may
be assumed that some members of a given
therapeutic class may pose less risk than others in
combination with CLZ.
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