Elevated Clozapine Level by harry206

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                    Elevated Clozapine Levels
                                      Dr. Harvinder Singh
                                   Email: drharvinder206@gmail.com




Clozapine Kinetics:
Studies9 indicate that 300 mg/day of clozapine produces serum levels between 200 and 600 ng/mL (611 to
1834 nM/L) at steady state.
Two major metabolites are produced, N-oxide and N-desmethyl (norclozapine) derivatives. Apparently
derivatives have lower pharmacological activity and toxicity compared to the parent compound.
Studies10 indicate that the desmethyl derivative is correlated to the serum clozapine level (77%) and
increases with duration of treatment and age.



Low serum Clozapine levels
May be due to an inadequate dosage, poor absorption or rapid metabolism.
Factors that contribute to this effect include age, gender, weight and smoking pattern.
Women can have higher serum clozapine levels than men.
Agents that induce the CYP1A2 metabolic pathway such as Carbamazepine and cigarette smoking
decrease serum clozapine levels.
Rifampin (?)


High serum Clozapine levels
Selective Serotonin Reuptake Inhibitors (Fluvoxamine and Fluoxetine)
Citalopram12
Antibiotics such as Erythromycin, Ciprofloxacin
Conflicting reports are available for the addition of Valproic acid to clozapine
Lamotrigine (caution required)
Cimetidine
Omeprazole (3 reports found)
Amiodarone (1 report found)
Smoking Cessation
Lithium (?)




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                        Case Reports of Elevated Clozapine Levels
                           (Literature search from 1999-2011)

Elevated Clozapine level after Fluvoxamine Initiation (Am J Psychiatry 153:6,
June 1996)1-

Case 1:
45 year old female
15 year history of Schizophrenia
Maintained on regimen of Clozapine (900 mg/day) for 22 months
Only modest benefit- she remained delusional & withdrawn
Serum Clozapine level= 396 ng/ml; Norclozapine level= not done
Fluvoxamine (25 mg/day) added to augment Clozapine response
20 days later: Serum Clozapine level= 1462 ng/ml
Clozapine dose lowered to 500 mg/day
17 days later: Serum Clozapine level= 1034 ng/ml
Patient demonstrated no adverse event or clinical benefit from this combination

Case 2:
41 year old male
25 year history of Schizophrenia
Maintained for several months on Clozapine (500 mg/day)
Fluvoxamine added to treat obsessive compulsive symptoms
Serum Clozapine level not obtained before starting Fluvoxamine
Fluvoxamine titrated to 300 mg/day in 3 weeks
1 month later: Serum Clozapine level= >1000 ng/ml; and Somnolence, slurred speech, ataxic gait, &
hypotension emerged
Clozapine dose lowered to 400 mg/day; no change in Fluvoxamine dosage
1 week later: Serum Clozapine level= 1830 ng/ml
Clozapine dose further reduced to 350 mg/day- Serum Clozapine level= 1382 ng/ml
Aforementioned side effects abated at reduced Clozapine dose
Combined therapy not associated with clinical improvement

Silver et al (Am J Psychiatry 1995; 152: 1098)2 demonstrated the clinical benefit of Fluvoxamine
augmentation in Clozapine resistant Schizophrenia.
Case2:
45 year old male
Institutionalized for 4 years for paranoid Schizophrenia.
Treated with antipsychotics (Haloperidol, Sulpiride and Levomepromazine) was ineffective.
Fluvoxamine (200 mg/day) was also ineffective. (Note: Clozapine was not added yet).
Clozapine (600 mg/day) started for 10 month, but ineffective (Note: this is without Fluvoxamine)
Now Fluvoxamine (25 mg/day) added to Clozapine regimen
2 weeks later: he became more interested in surrounding, initiated social contacts, participated more in
ward activities, sleep improved & preoccupation with delusions decreased.
2 weeks after the initiation of Fluvoxamine:- dose was increased to 50 mg/day
1 week later: patient complaints of dizziness, nausea, unsteadiness while walking, & became more
troubled by his thoughts. Physical and lab results were normal.
Fluvoxamine reduced to 25 mg/day and led to improvements within days.



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Note: Clozapine levels were not obtained, so side effect profile can be attributed to raised Clozapine level
secondary to increasing Fluvoxamine dosage to 50 mg/day.

Mechanism: Clozapine metabolized by CYP450 2D6 & 1A2 isoenzyme system, and Fluvoxamine
competes for these latter metabolic sites. This results in raised Clozapine level and is responsible for both
clinical improvement and adverse event profile.
Note the substantial risk of anticholinergic & anti-alpha adrenergic side effects, in addition to greater
seizure risk, so Clozapine levels should be closely monitored.

Elevated Clozapine Serum Level After Treatment With Amiodarone5
(Psychosomatics 49:3, May-June 2008)
Case:
75 year old male (non smoker)
Long history of Schizophrenia
Managed on Clozapine (300 mg/day) and Divalproex Sodium (1000 mg/day)- no side effect reported
Medical Problems: HTN, COPD, Dilated Cardiomyopathy, h/o Vent Tachycardia (received AICD)
4 months after placement of AICD, developed pericardial effusion without tamponade, AICD removed.
Within 48 hour of this procedure developed VT, received magnesium and IV Amiodarone (150 mg).
Patient remained stable and discharged (on hospital day 22) on Amiodarone (400 mg/day), and his
preadmission doses of clozapine and divalproex sodium. His other medications included ipratropium,
albuterol, metoprolol, pantoprazole, magnesium gluconate, and iron supplements.
Returned to Clozapine clinic, Serum Clozapine level= 1580 ng/ml (combined Clozapine and
Norclozapine= 1786)- compared to pre-hospital level= 242 ng/ml
Patient denies sedation or dizziness; but found to be more tangential and disorganized by his outpatient
psychiatrist.
Clozapine dose reduced to 150 mg/day
2 weeks later, Serum Clozapine level= 355 ng/ml

Mechanism: Clozapine is primarily metabolized through CYP 1A2, but numerous secondary pathways
(including 2C9/19, 2D6, and 3A3/4) are also involved.
Although amiodarone primarily inhibits CYP 3A4, its major active metabolite, desethylamiodarone, is a
potent inhibitor of 1A1/2, 2B6, and 2D6.

Elevated Clozapine Plasma Level With Lamotrigine (Am J Psychiatry 158:11,
November 2001)3
Although Durson et al.4 reported substantial improvement in six patients when Lamotrigine, an
anticonvulsant and mood stabilizer, was added to clozapine therapy in a dose of 125–250 mg/day.

Kossen et al3 found the tripling of the patient’s clozapine plasma level during his use of lamotrigine,
associated with side effects and no clinical improvements.
Case:
35 year old male
On Clozapine 400 mg/day for 3 years, with partial response
Plasma Clozapine level (in 6 assays over 3 year; measured 12 hr after dose is taken): were stable
(300=500 μg/liter)
Lamotrigine treatment began (Clozapine level= 350 μg/liter)
Lamotrigine titrate up to 100 mg/day (in steps of 25 mg every 2 weeks)
After pt was on Lamotrigine 100mg/day for 2 weeks:- complaints of dizziness & sedation
Plasma Clozapine level= 1020 μg/liter; no clinical improvement was seen
Lamotrigine dose tapered over period of 2 weeks, and Clozapine level at end =450 μg/liter

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No explanation found, but clinicians should be aware of this combinations.
One reason may be the high dosage of Clozapine by Kossen et al.


Cimetidine induced Clozapine toxicity6 (J Clin Psychiatry. 1991 Jan;52(1):21-
2)
Cimetidine (another broad CYP inhibitor) induced clozapine toxicity occurred with coadministration of
Clozapine (900 mg/day) and Cimetidine (400 mg tid).
Within 3 days, the patient complained of diaphoresis, vomiting, lightheadedness, and generalized
weakness, in the context of an elevated clozapine level (1,559 ng/ml).


Omeprazole May Elevate Clozapine Levels
(Source: http://www.medsafe.govt.nz/profs/PUarticles/ClozOmep.htm)
Three reports have been received in the Intensive Medicines Monitoring Programme (IMMP) of problems
associated with the combined use of clozapine and Omeprazole. The dose of Omeprazole was unknown
in each case. The reports are summarized as follows:

    1. A man aged 73 was well stabilised after titration of clozapine to 200mg daily. At 150mg daily,
       he had a blood level of clozapine of 570 nmol/L. Omeprazole was added to his therapy and about
       two months later his clozapine blood level was 2700 nmol/L. This rose to 6420 nmol/L after a
       further six days (usual therapeutic range 1-2000 nmol/L). No adverse effects were reported. The
       dose of clozapine was reduced and plasma levels fell quite quickly.
    2. A man aged 32 had remained well on clozapine 475mg daily, for three years. Some time after
       commencing omeprazole, he was found unconscious after a probable seizure. A high clozapine
       plasma level (8216 nmol/L) was noted. Clozapine was withdrawn for four days to reduce plasma
       levels, and the patient recovered.
    3. Another man aged 44 had been well controlled on clozapine 600mg daily for two years, and was
       then prescribed omeprazole for peptic ulceration and oesophagitis. Two weeks later he suffered a
       generalised seizure and had a plasma clozapine level of 1790 nmol/L. No previous values were
       available. The omeprazole was discontinued and the clozapine dose reduced to 300mg daily.
       There were no further problems.
These reports suggest that the addition of omeprazole to therapy with clozapine may cause elevated
clozapine plasma levels and dose-related adverse effects. There is no clearly recognisable mechanism for
this interaction. Clozapine and omeprazole have multiple metabolism sites but are both substrates for the
CYP 3A4 hepatic enzyme, which may be more important for metabolism in some patients. In these
circumstances, competitive inhibition may come into play.

Prescribers should be aware of the possibility of this interaction and check clozapine levels if
concomitant therapy with omeprazole is required.


Clozapine toxicity associated with smoking cessation7 (Am J Ther. 2005 Sep-
Oct;12(5):469-71)
young woman smoker who abruptly discontinued heavy daily cigarette-smoking while on clozapine (450
mg/day).


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Within several days, she developed dry mouth, dizziness, blurred vision with dilated pupils, sedation, and
confusion.
Clozapine level was markedly elevated (1,615 ng/ml) in comparison to her baseline levels.
Combined serum concentration of clozapine + norclozapine was 2.5 μg/mL, compared with levels of
about 600 ng/mL at daily doses of 350 mg at other times while smoking.
Reducing the dose of clozapine led to rapid alleviation of these symptoms.

Note: it is also important to recall that the discontinuation of a CYP-inducer (e.g., tobacco smoke) can
also lead to increased concentrations of substrates. Polyaromatic compounds in cigarette smoke, as
opposed to compounds in nicotine itself, can induce CYP 1A2 and thereby affect the metabolic clearance
of clozapine.


Serum Clozapine levels and therapeutic effect

A review by Greenwood-Smith and associates8 concluded that although the literature does not advocate
routine serum testing for patients on clozapine, there is evidence for the usefulness of therapeutic drug-
monitoring in specific clinical situations (e.g., when there are signs of toxicity, when the smoking status
of the patient changes, and when the physical health of the patient is impaired).

Perry et al11: identified an optimum clozapine concentration of 350 ng/ml (1070 nM/L).
64% of the patients with clozapine plasma concentrations greater than 350 ng/ml responded, whereas only
22% of the patients with concentrations less than 350 ng/ml responded. Use of clozapine blood levels as a
predictor for treatment response in treatment-refractory schizophrenic patients appears worthwhile.


Reference:
1. Dequardo JR, Roberts M. Elevated clozapine levels after Fluvoxamine initiation. Am J Psychiatry. 1996
Jun;153(6):840-1. PubMed PMID: 8633707.
2. Silver H, Kaplan A, Jahjah N. Fluvoxamine augmentation for clozapine-resistant schizophrenia. Am J Psychiatry.
1995 Jul;152(7):1098. PubMed PMID: 7793452.
3. Kossen M, Selten JP, Kahn RS. Elevated clozapine plasma level with lamotrigine. Am J Psychiatry. 2001
Nov;158(11):1930. PubMed PMID: 11691709.
4. Dursun SM, McIntosh D, Milliken H: Clozapine plus lamotrigine in treatment-resistant schizophrenia (letter).
Arch Gen Psychiatry 1999; 56:950
5. Stevens JR, Freudenreich O, Stern TA. Elevated clozapine serum level after treatment with amiodarone.
Psychosomatics. 2008 May-Jun;49(3):255-7. PubMed PMID: 18448783.
6. Szymanski S, Lieberman JA, Picou D, et al: A case report of cimetidine-induced clozapine toxicity. J Clin
Psychiatry 1991; 52: 21–22
7. Derenne JL, Baldessarini RJ: Clozapine toxicity associated with smoking cessation: case report. Am J
Therapeutics 2005; 12:469–471
8. Greenwood-Smith C, Lubman DI, Castle DJ: Serum clozapine levels: a review of their clinical utility. J
Psychopharmacol 2003;17:234–238
9. Sandoz, Inc. Pharmacokinetic characteristics of clozapine following single oral administration of 50 mg of 14C-
clozapine in healthy volunteers, East Hanover, NJ: 1984 Apr
10. Olesen OV, Thomsen K, Jensen PN et al. Clozapine serum levels and side effects during steady state treatment
of schizophrenic patients: a cross-sectional study. Psychopharmacology 1995; 117:371-378
11. Perry PJ et al. Clozapine and Norclozapine Plasma Concentrations and Clinical Response of Treatment
Refractory Schizophrenic Patients. Am J Psychiatry 1991; 148:231-235
12. Borba CP, Henderson DC. Citalopram and clozapine: potential drug interaction. J Clin Psychiatry. 2000
Apr;61(4):301-2. PubMed PMID: 10830154.



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