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{{BioPsy}}
 
{{BioPsy}}
{| border="1" cellpadding="3" cellspacing="0" width="250px" align="right" style="border-collapse: collapse; margin: 0 0 0 0.5em"
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{{Drugbox|
|-
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| IUPAC_name = 8-chloro-11-(4-methyl-1-piperazinyl)-<br />5''H''-dibenzo(b,e)(1,4)diazepine
| bgcolor="#ffffff" align="center" colspan="2" |
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| image = Clozapine.svg
[[Image:{{PAGENAME}}.png|{{PAGENAME}} chemical structure]]<br/>
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| image2 = Clozapine-3D-vdW.png
''{{PAGENAME}}''
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| CAS_number = 5786-21-0
|-
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| ATC_prefix = N05
| align="center" colspan="2" | ''[[IUPAC nomenclature|IUPAC chemical name]]''
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| ATC_suffix = AH02
|-
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| PubChem = 2818
| '''[[CAS number]]'''
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| DrugBank = APRD00470
|5786-21-0
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| C=18 | H=19 | Cl=1 | N=4
|-
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| molecular_weight = 326.823 g/mol
{{PubChem Row|2818}}
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| melting_point = 183
|- style="border-bottom: 3px solid gray"
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| solubility = 0
| '''[[ATC code]]'''
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| bioavailability = 60 to 70%
| [[ATC code N05|N05]]AH02
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| metabolism = [[Liver|Hepatic]], by several [[Cytochrome P450|CYP]] [[isozyme]]s
|-
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| elimination_half-life = 6 to 26 hours (mean value 14.2 hours in steady state conditions)
| bgcolor="#eeeeee" | [[Chemical formula]]
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| excretion = 80% in metabolized state: 30% biliary and 50% [[kidney|renal]]
| bgcolor="#ddeeff" | {{carbon}}<sub>18</sub>{{hydrogen}}<sub>19</sub>{{chlorine}}{{nitrogen}}<sub>4</sub>
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| pregnancy_category = B
|-
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| legal_status = [[Prescription drug|Prescription only]], special restrictions imposed in many countries
| bgcolor="#eeeeee" | [[SMILES]]
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| routes_of_administration = Oral
| bgcolor="#ddeeff" | CN1CCN(CC1)C2=C3C=CC=<br>CC3=NC4=C(N2)C=C(C=C4)Cl
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}}
|-
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'''Clozapine''' (sold as '''Clozaril''', '''Leponex''', '''Fazaclo''', '''Froidir'''; '''Gen-Clozapine''' in Canada, '''Klozapol''' in Poland) was the first of the [[atypical antipsychotic]]s to be developed. It was approved by the United States [[Food and Drug Administration]] (FDA) in 1989 and is the only FDA-approved medication indicated for treatment-resistant [[schizophrenia]] and for reducing the risk of [[suicidal behaviour]] in patients with schizophrenia. {{dubious}}
| bgcolor="#eeeeee" | [[Molecular weight]]
 
| bgcolor="#ddeeff" | 326.823 g/mol
 
|-
 
| bgcolor="#eeeeee" | [[Bioavailability]]
 
| bgcolor="#ddeeff" | 60 to 70%
 
|-
 
| bgcolor="#eeeeee" | Metabolism
 
| bgcolor="#ddeeff" | hepatic by different CYP-enzyme subtypes
 
|-
 
| bgcolor="#eeeeee" | [[Elimination half-life]]
 
| bgcolor="#ddeeff" | 6 to 26 hours (mean value 14.2 hours in steady state conditions)
 
|-
 
| bgcolor="#eeeeee" | [[Excretion]]
 
| bgcolor="#ddeeff" | 80% in metabolized state: 30% biliar und 50% in urine
 
|-
 
| bgcolor="#eeeeee" | [[Pregnancy category (pharmaceutical)|Pregnancy category]]
 
| bgcolor="#ddeeff" | B
 
|-
 
| bgcolor="#eeeeee" | [[Regulation of therapeutic goods|Legal status]]
 
| bgcolor="#ddeeff" | Rx-only/special restrictions are imposed in many countries
 
|-
 
| bgcolor="#eeeeee" | Routes of administration
 
| bgcolor="#ddeeff" | 50-60%
 
|}
 
'''Clozapine''' (sold as '''Clozaril'''®, '''Leponex'''®, '''Fazaclo'''®) was the first of the [[atypical antipsychotic]]s to be developed. It was approved by the United States [[FDA]] in 1989 and is the only FDA-approved medication indicated for treatment-resistant [[schizophrenia]] and for reducing the risk of [[suicidal behaviour]] in patients with schizophrenia.
 
   
==History and main uses==
+
Clozapine has been shown to be superior in efficacy in treating schizophrenia. Were it not for its [[adverse drug reaction|side effect]]s it would be first line treatment; however the rare but potentially lethal side effects of [[agranulocytosis]] and [[myocarditis]] relegate it to third-line use. Furthermore it may rarely lower seizure threshold, [[Leukocyte#Medications_causing_leukopenia|cause leukopenia]], cause hepatic dysfunction, weight gain and be associated with [[Diabetes mellitus type 2|type II]] [[Diabetes mellitus|diabetes]]. More common side effects are predominantly [[anticholinergic]] in nature, with dry mouth, sedation and constipation. It is also a strong antagonist at different subtypes of [[adrenergic receptor|adrenergic]], [[muscarinic acetylcholine receptor|cholinergic]], [[histamine receptor|histaminergic]] and [[serotonin receptor|serotonergic]] receptors.
Clozapine was developed by [[Sandoz]] in [[1961]], and introduced in [[Europe]] ten years later. In [[1975]], after reports of [[agranulocytosis]] leading to death in some clozapine-treated patients, Clozapine was voluntarily withdrawn by the manufacturer. Clozapine fell out of favor for more than a decade. However, when studies demonstrated that clozapine was more effective against treatment-resistant schizophrenia than other antipsychotics, the FDA and health authorities in most other countries approved its use only for treatment-resistant schizophrenia, and required regular haematological monitoring to detect [[granulocytopenia]], before [[agranulocytosis]] develops. In December of 2002, Clozapine was also approved for reducing the risk of suicide in schizophrenic or schizoaffective patients judged to be at chronic risk for suicidal behavior.
 
   
==Commonly approved indications==
+
Safer use of clozapine requires weekly [[full blood count|blood monitoring]] for around five months followed by four weekly testing thereafter. [[Echocardiogram]]s are recommended every 6 months to exclude cardiac damage.
* Treatment-resistant schizophrenia, if the required hematologic monitoring is adhered to
 
* Reducing the risk of suicide in schizophrenic or schizoaffective patients judged to belong to a high risk group with chronic risk for suicidal behavior. Clozapine was shown to prolong the time to suicidal attempt significantly greater than Olanzapine (Zyprexa®).
 
   
Clozapine works equally well against positive (e.g. delusions, hallucinations) and negative (e.g. emotional and social withdrawal) symptoms of schizophrenia. It has no dyscognitive effect often seen with other psychoactive drugs and is even able to increase the capabilities of the patient to react to this environment and thereby fosters social rehabilitation.
+
==History==
  +
Clozapine was developed by [[Sandoz]] in [[1961]], and introduced in [[Europe]] ten years later. In [[1975]], after reports of [[agranulocytosis]] leading to death in some clozapine-treated patients, clozapine was voluntarily withdrawn by the manufacturer. Clozapine fell out of favor for more than a decade. However, when studies demonstrated that clozapine was more effective against treatment-resistant [[schizophrenia]] than other [[antipsychotics]], the [[FDA]] and health authorities in most other countries approved its use only for treatment-resistant schizophrenia, and required regular [[hematological]] monitoring to detect [[granulocytopenia]], before [[agranulocytosis]] develops. In December of 2002, clozapine was also approved for reducing the risk of suicide in schizophrenic or [[schizoaffective]] patients judged to be at chronic risk for suicidal behavior.
   
==Off-label and investigational drug use==
+
==Indications==
  +
Clozapine is used principally in treating treatment-resistant schizophrenia,<ref name ="Wahlbecko7">{{cite journal | author = Wahlbeck K, Cheine MV, Essali A | title = Clozapine versus typical neuroleptic medication for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = | issue = 2 | pages = | publisher = John Wiley and Sons, Ltd. | date = 2007 | url = http://www.cochrane.org/reviews/en/ab000059.html (abstract) | doi = 10.1002/14651858.CD000059 | id = ISSN 1464-780X}}</ref> a term generally used for the failure of symptoms to respond satisfactorily to at least two different antipsychotics;<ref>{{cite journal | author = Meltzer HY | title = Treatment-resistant schizophrenia--the role of clozapine. | journal = Current Medical Research and Opinion | volume = 14 | issue = 1 | pages = 1-20 | date = 1997 | url = http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=9524789&dopt=Abstract (Abstract) | doi = }}</ref> It clearly has been shown to be more effective in reducing symptoms of schizophrenia than the older [[typical antipsychotics]], with maximal effects in those who have responded poorly to other medication; though the relapse rate is lower and patient acceptability better, this has not translated to significant observed benefits in global functioning.<ref name ="Wahlbecko7"/>
  +
  +
It is also used for reducing the risk of suicide in patients judged to belong to a high risk group with chronic risk for suicidal behavior. Clozapine was shown to prolong the time to suicidal attempt significantly greater than [[olanzapine]].
  +
  +
Clozapine works well against positive (e.g. delusions, hallucinations) and negative (e.g. emotional and social withdrawal) symptoms of schizophrenia. It has no [[dyscognitive]] effect often seen with other psychoactive drugs and is even able to increase the capabilities of the patient to react to this environment and thereby fosters social rehabilitation.
  +
  +
===Off-label and investigational drug use===
 
* Treatment of psychosis in L-Dopa treated patients (25 to 50 mg at bedtime is often sufficient); this indication is currently approved in Switzerland
 
* Treatment of psychosis in L-Dopa treated patients (25 to 50 mg at bedtime is often sufficient); this indication is currently approved in Switzerland
* Treatment of otherwise resistant acute episodes of [[mania]]
+
* Treatment of psychotic symptoms occurring in patients with [[dementia]] of the Lewy-body-type
* Treatment of psychotic symptoms occurring in patients with [[dementia]] of the Levy-body-type
+
* Treatment of otherwise resistant acute episodes of [[mania]]
* Treatment of severe cases of obsessive compulsive disorder
+
* Treatment of intractable chronic [[insomnia]], if all other measures have failed
* Treatment of intractable chronic [[insomnia]], if all other measurements have failed
+
* Treatment of [[schizoid personality disorder]]
   
Though much research has been done evaluating the benefit of clozapine in treating the aforementioned conditions, it is too early to come to a conclusive result. If you contemplate clozapine as drug for these conditions, weigh carefully benefits and risks and inform the patients fully, if possible, about the advantages and risks of clozapine treatment, before a joint decision is made. If the patient is not able to make own decisions, parents or guardians or the competent court must give their consent.
+
Though much research has been done evaluating the benefit of clozapine in treating the aforementioned conditions, results have been inconclusive regarding its actual efficacy in treating those conditions.
   
==Chemistry==
+
==Contraindications==
Clozapine is yellow crystalline solid with [[melting point]] 183-184 °C. It is insoluble in water, soluble in [[acetone]], very well soluble in [[chloroform]].
+
Clozapine is [[contraindicated]] in individuals with uncontrolled [[epilepsy]], [[myeloproliferative disease]], or [[agranulocytosis]] with prior clozapine treatment.
Chemical name is <8-chloro-11-(4-methyl-1-piperazinyl)-5''H''-dibenzo[''b'',''e''][1,4]diazepine>.
 
   
Molecular weight is 326.83
+
Many other (relative) contraindications (e.g. preexisting cardiovascular or liver damage, epilepsy) also exist.
   
==Pharmacology==
+
==Adverse effects==
Clozapine is classified as an 'atypical' antipsychotic drug because its profile of binding to dopamine receptors and its effects on various dopamine mediated behaviors differ from those exhibited by more typical antipsychotics. In particular, clozapine interferes to a lower extend with the binding of dopamine at D1, D2, D3 and D5 receptors, and has a high affinity for the D4 receptor, but it does not induce catalepsy nor inhibit apomorphine-induced stereotypy in animal models as is seen with 'conventional' neuroleptics. This evidence suggests clozapine is preferentially more active at limbic than at striatal dopamine receptors and may explain the relative freedom of clozapine from extrapyramidal side effects together with stong anticholinergic activity.
+
The use of clozapine is associated with a fair number of side effects, many minor though some serious and potentially fatal: the more common include [[constipation]], [[drooling]], [[muscle]] stiffness, [[sedation]], [[tremor]]s, [[orthostasis]], [[hyperglycemia]], and [[weight gain]]. The risks of [[extrapyramidal symptom]]s such as [[tardive dyskinesia]] are much less with clozapine when compared to the [[typical antipsychotics]]; this may be due to clozapine's anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine.{{Fact|date=June 2007}}
   
Clozapine also is a strong antagonist at different subtypes of adrenergic, cholinergic, histaminergic and serotonergic receptors.
+
Clozapine may have a synergistic effect with the sedating action of other drugs such as [[benzodiazepines]], and thus respiratory depression may result with concomitant use. Care should be taken, especially if the latter drugs are given parenterally.
   
It has approximately the same potency as chlorpromazine.
+
Many [[male]] patients have experienced ceasure of [[ejaculation]] during [[orgasm]] as a side effect of Clozapine though this is not documented in official drug guides{{Fact|date=February 2007}}.
   
==Pharmacokinetics==
+
===Agranulocytosis===
The absorption of clozapine is almost complete, but the oral bioavailability is only 60 to 70% due to fist pass metabolization. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to effect the bioavailability of clozapine.
+
Clozapine carries a [[black box warning]] for drug-induced [[agranulocytosis]]. Without monitoring, agranulocytosis occurs in about 1% of patients who take clozapine during the first few months of treatment;<ref name="GoodmanGilman">{{cite book |last=Baldessarini |first=Ross J. |coauthors=Frank I. Tarazi |editor=Laurence Brunton, John Lazo, Keith Parker (eds.) |title=[[Goodman & Gilman's The Pharmacological Basis of Therapeutics]] |edition=11<sup>th</sup> ed. |year=2006 |publisher=[[McGraw-Hill]] |location=New York |isbn=978-0071422802|pages= |chapter=Pharmacotherapy of Psychosis and Mania}}</ref> the risk of developing it is highest about three months into treatment, and decreases substantially thereafter, to less than 0.01% after one year.<ref name="Alvir1993">{{cite journal |author=Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA |title=Clozapine-induced agranulocytosis. Incidence and risk factors in the United States |journal=[[New England Journal of Medicine|N Engl J Med]] |volume=329 |issue=3 |pages=162–7 |year=1993 |pmid=8515788 |doi=}} [http://content.nejm.org/cgi/content/full/329/3/162 Free full text with registration]</ref> Patients who have experienced agranulocytosis with prior treatment of clozapine should not receive it again. Clozapine also carries black box warnings for [[seizures]], [[myocarditis]], and "other adverse [[cardiovascular]] and [[Respiration (physiology)|respiratory]] effects." Lowering of the [[seizure threshold]] may be dose related and slow initial titration of dose may decrease the risk for precipitating seizures. Slow titration of dosing may also decrease the risk for [[orthostatic hypotension]] and other adverse cardiovascular side effects.
The elimination half-life of clozapine is about 14 hours at steady state conditions (varying with daily dose). Clozapine is extensively hepatically metabolized involving many CYP-450 isoenzymes and eliminated in the urine and feces.
 
   
==Metabolism==
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===Cardiac toxicity===
Clozapine is metabolized via the [[cytochrome P450]] system in humans to polar metabolites suitable for elimination. The cytochrome P450 isoenzyme 1A2 is primarily responsible for clozapine metabolism, but 2C, 2D6, 2E1 and 3A3/4 appear to play roles as well. Agents which induce (e.g. cigarette smoke) or inhibit (e.g. theophylline, ciprofloxacin, fluvoxamine) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine.
+
A more recently identified and sometimes fatal side effect is that of [[myocarditis]] which usually develops within the first month of commencement and presents with signs of [[cardiac failure]] and cardiac arrhythmias.<ref>{{cite journal | author = Haas SJ, Hill R, Krum H | title = Clozapine-associated myocarditis | journal = Drug Safety | volume = 30 | pages = 47–57 | date = 2007 | doi = }}</ref> [[Cardiomyopathy]] is another potentially fatal cardiac condition which may arise less acutely.
   
==Contraindications==
+
===Central nervous system===
Clozapine is [[contraindicated]] in individuals with uncontrolled epilepsy, myeloproliferative disease, or agranulocytosis with prior clozapine treatment.
+
Psychotic symptoms can worsen while under influence and following the discontinuation especially after long-term use.<ref>[http://www.rxlist.com/cgi/generic/clozapine_ad.htm rxlist.com / Clozapine side effects]</ref>
   
Many other (relative) contraindications (e.g. preexisting cardiovascular or liver damage, epilepsy) also exist.
+
===Weight gain and diabetes===
  +
The FDA requires the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and [[diabetes]] with these medications. Indeed, there are case reports of clozapine-induced hyperglycemia and diabetes; additionally, there are case reports of clozapine-induced diabetic [[ketoacidosis]]. There is data showing that clozapine can decrease insulin sensitivity. Clozapine should be used with caution in patients who are diagnosed with diabetes or in patients at risk for developing diabetes. All patients receiving clozapine should have their fasting blood glucose monitored.
   
==Side effects==
+
In addition to [[hyperglycemia]], significant weight gain is frequently experienced by patients treated with clozapine.<ref>Wirshing DA, Wirshing WC, Kysar L, Berisford MA. (1999) Novel antipsychotics: comparison of weight gain liabilities. ''Journal of Clinical Psychology'' '''60''' 358-63 </ref> Impaired glucose metabolism and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease. The data suggests that clozapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics.{{Fact|2007|date=November 2007}} Research has indicated that clozapine may cause a deficiency of [[selenium]].<ref>{{cite journal |author=Vaddadi KS, Soosai E, Vaddadi G |title=Low blood selenium concentrations in schizophrenic patients on clozapine |journal=British journal of clinical pharmacology |volume=55 |issue=3 |pages=307-9 |year=2003 |pmid=12630982 |doi=}}</ref>
Clozapine carries a [[black box warning]] for drug induced [[agranulocytosis]]. Agranulocytosis occurs in about 1% of patients who take clozapine during the first 6 months of treatment, and decreases to about 0.01% thereafter. Patients who have experienced agranulocytosis with prior treatment of clozapine should not receive clozapine again. Clozapine also carries black box warnings for [[seizures]], [[myocarditis]], and "other adverse [[cardiovascular]] and [[Respiration (physiology)|respiratory]] effects." Lowering of the [[seizure threshold]] may be dose related and slow initial titration of dose may decrease the risk for precipitating seizures. Slow titration of dosing may also decrease the risk for [[orthostasis]] and other adverse cardiovascular side effects.
 
   
Common side effects with clozapine treatment include: [[constipation]], [[drooling]], [[muscle]]-stiffness, [[sedation]], [[tremor]]s, [[orthostasis]],[[hyperglycemia]] and [[weight]]-gain. The risks of [[extrapyramidal symptom]]s and [[tardive dyskinesias]] are much less with clozapine when compared to the [[typical antipsychotics]] (also known as conventional antipsychotics or conventional neuroleptics).
+
In 2007, a pharmacogenetic test was introduced to measure the probability of developing agranulocytosis.<!--
   
Central depression is increased, if other drugs with the same actions are given concomittantly. With benzodiazepines, given by i.v.-route, severe intoxications sometimes leading to respiratory and cardiac arrest have been seen. Benzodiazepines should be given in moderate oral doses and not as i.v.-injection.
+
--><ref name="Pgxhealth_2007_site">[http://www.pgxhealth.com/genetictests/clozapine/ PGxPredict:CLOZAPINE] - a page about the agranulocytosis risk test.</ref><ref name="Forbes_pr_2007_test"> [http://www.forbes.com/businesswire/feeds/businesswire/2007/01/23/businesswire20070123005298r1.html Clinical Data Launches Pharmacogenetic Test for Clozapine-Induced Agranulocytosis on Schedule] - press release at the Forbes site.</ref><!--
   
Recently the FDA required the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and [[diabetes]] with atypical antipsychotics. Indeed, there are case reports of clozapine-induced hyperglycemia and diabetes. Additionally there are case reports of clozapine-induced diabetic [[ketoacidosis]]. There is data showing that clozapine can decrease insulin sensitivity. Clozapine should be used with caution in patients who are diagnosed with diabetes or in patients at risk for developing diabetes. All patients receiving clozapine should have their fasting blood glucose monitored.
+
--><!--
   
In addition to hyperglycemia, weight gain may be experienced by patients treated with clozapine. Impaired glucose metabolism and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease. The data suggests that clozapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics. Research has indicated that clozapine may cause a deficiency of [[selenium]].
+
--> The test has two gradations - Higher and Lower risk, with a relative agranulocytosis risk of 2.5 and 0.5 compared to general level. The company states that the test is based on two [[Single nucleotide polymorphism|SNP]]s of the [[Human leukocyte antigen|HLA]]-DQB1 gene.
  +
  +
==Chemistry==
  +
It is insoluble in water, soluble in [[acetone]], very well soluble in [[chloroform]].
  +
  +
Its solubility in water is 11.8 mg/L (25 C)
  +
  +
The manufacturer Novartis claim a solubility of <0.01% in water
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<ref>
  +
{{Citation
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| last = Novartis Pharmaceuticals
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| author-link = Novartis
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| title = Prescribing Information
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| url=http://www.novartis.ca/downloads/en/products/clozaril_scrip_e.pdf
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| accessdate = 2007-06-29
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| date = April 2006
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| year = 2006
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| publisher = Novartis Pharmaceuticals
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| pages = p36 }}
  +
</ref>
  +
==Pharmacology==
  +
Clozapine is classified as an [[atypical antipsychotic]] drug because its profile of binding to [[serotonin receptor|serotonergic]] as well as [[dopamine]] receptors;<ref name ="Nahgre01">{{cite journal |author=Naheed M, Green B. |year=2001|title=Focus on clozapine|journal= |volume=17 |issue=3 |pages=223-9 |pmid=11900316 |url=http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11900316 (abstract) |accessdate= 2007-07-02}}</ref> its effects on various dopamine mediated behaviors also differ from those exhibited by more typical antipsychotics. In particular, clozapine interferes to a lower extent with the binding of dopamine at D<sub>1</sub>, D<sub>2</sub>, D<sub>3</sub> and D<sub>5</sub> receptors, and has a high affinity for the D<sub>4</sub> receptor, but it does not induce [[catalepsy]] nor inhibit [[apomorphine]]-induced [[Stereotypy (psychiatry)|stereotypy]] in animal models as is seen with [[typical antipsychotic|'conventional' neuroleptics]]. This evidence suggests clozapine is preferentially more active at limbic than at striatal dopamine receptors and may explain the relative freedom of clozapine from [[extrapyramidal]] side effects together with strong [[anticholinergic]] activity.
  +
  +
Clozapine is also partial agonists at the 5-HT1A receptor, putatively improving depression, anxiety, and negative/cognitive symptoms.
  +
  +
Clozapine also is a strong antagonist at different subtypes of [[adrenergic receptor|adrenergic]], [[muscarinic acetylcholine receptor|cholinergic]] and [[histamine receptor|histaminergic]] receptors, the last two being predominantly responsible for its side effect profile.
  +
  +
It has approximately the same potency as [[chlorpromazine]].
  +
  +
===Pharmacokinetics===
  +
The absorption of clozapine is almost complete, but the oral [[bioavailability]] is only 60 to 70% due to [[first-pass metabolism]]. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to affect the bioavailability of clozapine.
  +
The [[elimination half-life]] of clozapine is about 14 hours at [[steady state]] conditions (varying with daily dose).
  +
  +
Clozapine is extensively metabolized in the liver, via the [[cytochrome P450]] system, to [[Chemical polarity|polar]] metabolites suitable for elimination in the urine and faeces. The major metabolite, ''norclozapine'' ([[demethylation|desmethyl]]-clozapine), is pharmacologically active. The cytochrome P450 [[isoenzyme]] [[CYP1A2|1A2]] is primarily responsible for clozapine metabolism, but 2C, [[CYP2D6|2D6]], [[CYP2E1|2E1]] and [[CYP3A4|3A3/4]] appear to play roles as well. Agents which [[enzyme induction and inhibition|induce]] (e.g. cigarette smoke) or [[enzyme inhibitor|inhibit]] (e.g. [[theophylline]], [[ciprofloxacin]], [[fluvoxamine]]) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine.
   
 
==Monitoring==
 
==Monitoring==
Patients who take clozapine are advised to have a [[blood cell count]] every week, for the first 6 months of therapy. After this they should continue to conduct said count every 2 weeks. If the number of white blood-cells drops notably, one should consult with a [[hematology|hematologist]]. If you are using clozapine and have a [[sore throat]], or [[fever]], then you should inform your [[physician|doctor]].
+
In the USA, patients who take clozapine are required to have a [[blood cell count]] every week, for the first six months of therapy. After this, they are required to have a blood cell count every other week for the second six months after therapy. After twelve months, blood cell counts need be performed every four weeks.
   
More recently, a regular [[echocardiogram]] is also recommended to detect [[myocarditis]].
+
If the number of white blood-cells drops notably, one should consult with a [[hematology|hematologist]]. If you are using clozapine and have a [[sore throat]], or [[fever]], then you should inform your [[physician|doctor]].
  +
  +
Clozapine and norclozapine plasma levels may also be monitored, though they show a significant degree of variation and are higher in women and increase with age.<ref>{{cite journal |author= Lane HY, Chang YC, Chang WH, Lin SK, Tseng YT, Jann MW. |year=1999 |month=January |title=Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics |journal=J Clin Psychiatry |volume=60 |issue=1 |pages=36-40 |pmid=10074876 |url=http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_uids=10074876&dopt=Abstract (abstract) |accessdate=2007-06-24}}</ref>
  +
  +
More recently, a regular six-monthly [[echocardiogram]] is also recommended to detect [[myocarditis]].
   
 
The manufacturers of both the brand and generic clozapine are required by the FDA to track white blood cells counts for patients receiving clozapine, and pharmacies are required to obtain a copy of the [[Full blood count|CBC]] prior to dispensing the medication to the patient. The purpose of the monitoring system is to prevent rechallenge with clozapine in patients with a history of clozapine-induced agranulocytosis and to detect [[leukopenia|leukopenic]] events among patients taking clozapine. In other countries (e.g. in Europe), restrictions have been eased.
 
The manufacturers of both the brand and generic clozapine are required by the FDA to track white blood cells counts for patients receiving clozapine, and pharmacies are required to obtain a copy of the [[Full blood count|CBC]] prior to dispensing the medication to the patient. The purpose of the monitoring system is to prevent rechallenge with clozapine in patients with a history of clozapine-induced agranulocytosis and to detect [[leukopenia|leukopenic]] events among patients taking clozapine. In other countries (e.g. in Europe), restrictions have been eased.
   
 
==Dosage==
 
==Dosage==
Start with 12.5 mg bedtime dose (6.25 mg in outpatients). The dose might then by increased cautiously by 25mg daily. The usual effective dose is 150 mg to 450 mg. In severely ill and/or younger patients up to 900 mg may be needed. In the elderly much lower doses may be sufficient (25 to 100 mg). The greater part or all of the daily dose may be given at bedtime, once maintenance dose has been determined, in order to minimize daytime sedation and orthostatic problems.
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Due to risk of serious side effects, clozapine treatment is commenced at a very low dose (25&nbsp;mg daily) and increased slowly until a therapeutic dose (300–600&nbsp;mg daily) is reached.<ref>{{cite web | author = Novartis Pharmaceuticals | authorlink = | title = Clozaril Dosing Guide | publisher = Novartis Pharmaceuticals | date = | url = http://www.clozaril.com/hcp/tools/dosing_guide.jsp | accessdate = 2007-06-29}}</ref> In severely ill and/or younger patients up to 900 mg may be needed. In the elderly, much lower doses may be sufficient (25 to 100 mg). Once the patient is stabilized and the maintenance dose has been determined, the greater part or all of the daily dose may be given at bedtime. This will ameliorate daytime sedation and orthostatic problems; most people benefit from the sedation to get to sleep anyway. Furthermore, compliance on medication taken more frequently than once daily drops off dramatically.
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==See also==
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*[[DHA-clozapine]]
   
 
== References ==
 
== References ==
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=== Notes ===
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{{Reflist}}
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  +
=== Sources ===
 
* Benkert, Hippius: Kompendium der Psychiatrischen Pharmakotherapie (German), 4th. ed., Springer Verlag
 
* Benkert, Hippius: Kompendium der Psychiatrischen Pharmakotherapie (German), 4th. ed., Springer Verlag
* B. Bandelow, S. Bleich, and S. Kropp: Handbuch Psychopharmaka (German), 2nd. ed. Hogrefe
+
* B. Bandelow, S. Bleich, and S. Kropp: Handbuch Psychopharmaka (German), 2nd. ed. Hogrefe
  +
* Crilly JF (2007) ''The history of clozapine and its emergence in the US Market: A review and Analysis.'' History of Psychiatry, 18(1): 39-60. {{doi|10.1177/0957154X07070335}}
   
 
==External links==
 
==External links==
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* [http://www.pharma.us.novartis.com/product/pi/pdf/Clozaril.pdf US Clozaril Package Insert] (PDF)
 
* [http://www.pharma.us.novartis.com/product/pi/pdf/Clozaril.pdf US Clozaril Package Insert] (PDF)
 
* [https://www.clozarilregistry.com/care/Splash.jsp Clozaril Registry Website]
 
* [https://www.clozarilregistry.com/care/Splash.jsp Clozaril Registry Website]
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Clozapine chemical structure
Clozapine

8-chloro-11-(4-methyl-1-piperazinyl)-
5H-dibenzo(b,e)(1,4)diazepine
IUPAC name
CAS number
5786-21-0
ATC code

N05AH02

PubChem
2818
DrugBank
APRD00470
Chemical formula {{{chemical_formula}}}
Molecular weight 326.823 g/mol
Bioavailability 60 to 70%
Metabolism Hepatic, by several CYP isozymes
Elimination half-life 6 to 26 hours (mean value 14.2 hours in steady state conditions)
Excretion 80% in metabolized state: 30% biliary and 50% renal
Pregnancy category B
Legal status Prescription only, special restrictions imposed in many countries
Routes of administration Oral

Clozapine (sold as Clozaril, Leponex, Fazaclo, Froidir; Gen-Clozapine in Canada, Klozapol in Poland) was the first of the atypical antipsychotics to be developed. It was approved by the United States Food and Drug Administration (FDA) in 1989 and is the only FDA-approved medication indicated for treatment-resistant schizophrenia and for reducing the risk of suicidal behaviour in patients with schizophrenia. [dubious]

Clozapine has been shown to be superior in efficacy in treating schizophrenia. Were it not for its side effects it would be first line treatment; however the rare but potentially lethal side effects of agranulocytosis and myocarditis relegate it to third-line use. Furthermore it may rarely lower seizure threshold, cause leukopenia, cause hepatic dysfunction, weight gain and be associated with type II diabetes. More common side effects are predominantly anticholinergic in nature, with dry mouth, sedation and constipation. It is also a strong antagonist at different subtypes of adrenergic, cholinergic, histaminergic and serotonergic receptors.

Safer use of clozapine requires weekly blood monitoring for around five months followed by four weekly testing thereafter. Echocardiograms are recommended every 6 months to exclude cardiac damage.

History

Clozapine was developed by Sandoz in 1961, and introduced in Europe ten years later. In 1975, after reports of agranulocytosis leading to death in some clozapine-treated patients, clozapine was voluntarily withdrawn by the manufacturer. Clozapine fell out of favor for more than a decade. However, when studies demonstrated that clozapine was more effective against treatment-resistant schizophrenia than other antipsychotics, the FDA and health authorities in most other countries approved its use only for treatment-resistant schizophrenia, and required regular hematological monitoring to detect granulocytopenia, before agranulocytosis develops. In December of 2002, clozapine was also approved for reducing the risk of suicide in schizophrenic or schizoaffective patients judged to be at chronic risk for suicidal behavior.

Indications

Clozapine is used principally in treating treatment-resistant schizophrenia,[1] a term generally used for the failure of symptoms to respond satisfactorily to at least two different antipsychotics;[2] It clearly has been shown to be more effective in reducing symptoms of schizophrenia than the older typical antipsychotics, with maximal effects in those who have responded poorly to other medication; though the relapse rate is lower and patient acceptability better, this has not translated to significant observed benefits in global functioning.[1]

It is also used for reducing the risk of suicide in patients judged to belong to a high risk group with chronic risk for suicidal behavior. Clozapine was shown to prolong the time to suicidal attempt significantly greater than olanzapine.

Clozapine works well against positive (e.g. delusions, hallucinations) and negative (e.g. emotional and social withdrawal) symptoms of schizophrenia. It has no dyscognitive effect often seen with other psychoactive drugs and is even able to increase the capabilities of the patient to react to this environment and thereby fosters social rehabilitation.

Off-label and investigational drug use

  • Treatment of psychosis in L-Dopa treated patients (25 to 50 mg at bedtime is often sufficient); this indication is currently approved in Switzerland
  • Treatment of psychotic symptoms occurring in patients with dementia of the Lewy-body-type
  • Treatment of otherwise resistant acute episodes of mania
  • Treatment of intractable chronic insomnia, if all other measures have failed
  • Treatment of schizoid personality disorder

Though much research has been done evaluating the benefit of clozapine in treating the aforementioned conditions, results have been inconclusive regarding its actual efficacy in treating those conditions.

Contraindications

Clozapine is contraindicated in individuals with uncontrolled epilepsy, myeloproliferative disease, or agranulocytosis with prior clozapine treatment.

Many other (relative) contraindications (e.g. preexisting cardiovascular or liver damage, epilepsy) also exist.

Adverse effects

The use of clozapine is associated with a fair number of side effects, many minor though some serious and potentially fatal: the more common include constipation, drooling, muscle stiffness, sedation, tremors, orthostasis, hyperglycemia, and weight gain. The risks of extrapyramidal symptoms such as tardive dyskinesia are much less with clozapine when compared to the typical antipsychotics; this may be due to clozapine's anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine.[How to reference and link to summary or text]

Clozapine may have a synergistic effect with the sedating action of other drugs such as benzodiazepines, and thus respiratory depression may result with concomitant use. Care should be taken, especially if the latter drugs are given parenterally.

Many male patients have experienced ceasure of ejaculation during orgasm as a side effect of Clozapine though this is not documented in official drug guides[How to reference and link to summary or text].

Agranulocytosis

Clozapine carries a black box warning for drug-induced agranulocytosis. Without monitoring, agranulocytosis occurs in about 1% of patients who take clozapine during the first few months of treatment;[3] the risk of developing it is highest about three months into treatment, and decreases substantially thereafter, to less than 0.01% after one year.[4] Patients who have experienced agranulocytosis with prior treatment of clozapine should not receive it again. Clozapine also carries black box warnings for seizures, myocarditis, and "other adverse cardiovascular and respiratory effects." Lowering of the seizure threshold may be dose related and slow initial titration of dose may decrease the risk for precipitating seizures. Slow titration of dosing may also decrease the risk for orthostatic hypotension and other adverse cardiovascular side effects.

Cardiac toxicity

A more recently identified and sometimes fatal side effect is that of myocarditis which usually develops within the first month of commencement and presents with signs of cardiac failure and cardiac arrhythmias.[5] Cardiomyopathy is another potentially fatal cardiac condition which may arise less acutely.

Central nervous system

Psychotic symptoms can worsen while under influence and following the discontinuation especially after long-term use.[6]

Weight gain and diabetes

The FDA requires the manufacturers of all atypical antipsychotics to include a warning about the risk of hyperglycemia and diabetes with these medications. Indeed, there are case reports of clozapine-induced hyperglycemia and diabetes; additionally, there are case reports of clozapine-induced diabetic ketoacidosis. There is data showing that clozapine can decrease insulin sensitivity. Clozapine should be used with caution in patients who are diagnosed with diabetes or in patients at risk for developing diabetes. All patients receiving clozapine should have their fasting blood glucose monitored.

In addition to hyperglycemia, significant weight gain is frequently experienced by patients treated with clozapine.[7] Impaired glucose metabolism and obesity have been shown to be constituents of the metabolic syndrome and may increase the risk of cardiovascular disease. The data suggests that clozapine may be more likely to cause adverse metabolic effects than some of the other atypical antipsychotics.[How to reference and link to summary or text] Research has indicated that clozapine may cause a deficiency of selenium.[8]

In 2007, a pharmacogenetic test was introduced to measure the probability of developing agranulocytosis.[9][10] The test has two gradations - Higher and Lower risk, with a relative agranulocytosis risk of 2.5 and 0.5 compared to general level. The company states that the test is based on two SNPs of the HLA-DQB1 gene.

Chemistry

It is insoluble in water, soluble in acetone, very well soluble in chloroform.

Its solubility in water is 11.8 mg/L (25 C)

The manufacturer Novartis claim a solubility of <0.01% in water [11]

Pharmacology

Clozapine is classified as an atypical antipsychotic drug because its profile of binding to serotonergic as well as dopamine receptors;[12] its effects on various dopamine mediated behaviors also differ from those exhibited by more typical antipsychotics. In particular, clozapine interferes to a lower extent with the binding of dopamine at D1, D2, D3 and D5 receptors, and has a high affinity for the D4 receptor, but it does not induce catalepsy nor inhibit apomorphine-induced stereotypy in animal models as is seen with 'conventional' neuroleptics. This evidence suggests clozapine is preferentially more active at limbic than at striatal dopamine receptors and may explain the relative freedom of clozapine from extrapyramidal side effects together with strong anticholinergic activity.

Clozapine is also partial agonists at the 5-HT1A receptor, putatively improving depression, anxiety, and negative/cognitive symptoms.

Clozapine also is a strong antagonist at different subtypes of adrenergic, cholinergic and histaminergic receptors, the last two being predominantly responsible for its side effect profile.

It has approximately the same potency as chlorpromazine.

Pharmacokinetics

The absorption of clozapine is almost complete, but the oral bioavailability is only 60 to 70% due to first-pass metabolism. The time to peak concentration after oral dosing is about 2.5 hours, and food does not appear to affect the bioavailability of clozapine. The elimination half-life of clozapine is about 14 hours at steady state conditions (varying with daily dose).

Clozapine is extensively metabolized in the liver, via the cytochrome P450 system, to polar metabolites suitable for elimination in the urine and faeces. The major metabolite, norclozapine (desmethyl-clozapine), is pharmacologically active. The cytochrome P450 isoenzyme 1A2 is primarily responsible for clozapine metabolism, but 2C, 2D6, 2E1 and 3A3/4 appear to play roles as well. Agents which induce (e.g. cigarette smoke) or inhibit (e.g. theophylline, ciprofloxacin, fluvoxamine) CYP1A2 may increase or decrease, respectively, the metabolism of clozapine.

Monitoring

In the USA, patients who take clozapine are required to have a blood cell count every week, for the first six months of therapy. After this, they are required to have a blood cell count every other week for the second six months after therapy. After twelve months, blood cell counts need be performed every four weeks.

If the number of white blood-cells drops notably, one should consult with a hematologist. If you are using clozapine and have a sore throat, or fever, then you should inform your doctor.

Clozapine and norclozapine plasma levels may also be monitored, though they show a significant degree of variation and are higher in women and increase with age.[13]

More recently, a regular six-monthly echocardiogram is also recommended to detect myocarditis.

The manufacturers of both the brand and generic clozapine are required by the FDA to track white blood cells counts for patients receiving clozapine, and pharmacies are required to obtain a copy of the CBC prior to dispensing the medication to the patient. The purpose of the monitoring system is to prevent rechallenge with clozapine in patients with a history of clozapine-induced agranulocytosis and to detect leukopenic events among patients taking clozapine. In other countries (e.g. in Europe), restrictions have been eased.

Dosage

Due to risk of serious side effects, clozapine treatment is commenced at a very low dose (25 mg daily) and increased slowly until a therapeutic dose (300–600 mg daily) is reached.[14] In severely ill and/or younger patients up to 900 mg may be needed. In the elderly, much lower doses may be sufficient (25 to 100 mg). Once the patient is stabilized and the maintenance dose has been determined, the greater part or all of the daily dose may be given at bedtime. This will ameliorate daytime sedation and orthostatic problems; most people benefit from the sedation to get to sleep anyway. Furthermore, compliance on medication taken more frequently than once daily drops off dramatically.


See also

References

Notes

  1. 1.0 1.1 Wahlbeck K, Cheine MV, Essali A (2007). (abstract) Clozapine versus typical neuroleptic medication for schizophrenia. The Cochrane Database of Systematic Reviews (2). ISSN 1464-780X.
  2. Meltzer HY (1997). (Abstract) Treatment-resistant schizophrenia--the role of clozapine.. Current Medical Research and Opinion 14 (1): 1-20.
  3. Baldessarini, Ross J.; Frank I. Tarazi (2006). "Pharmacotherapy of Psychosis and Mania" Laurence Brunton, John Lazo, Keith Parker (eds.) Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th ed., New York: McGraw-Hill.
  4. Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA (1993). Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med 329 (3): 162–7. Free full text with registration
  5. Haas SJ, Hill R, Krum H (2007). Clozapine-associated myocarditis. Drug Safety 30: 47–57.
  6. rxlist.com / Clozapine side effects
  7. Wirshing DA, Wirshing WC, Kysar L, Berisford MA. (1999) Novel antipsychotics: comparison of weight gain liabilities. Journal of Clinical Psychology 60 358-63
  8. Vaddadi KS, Soosai E, Vaddadi G (2003). Low blood selenium concentrations in schizophrenic patients on clozapine. British journal of clinical pharmacology 55 (3): 307-9.
  9. PGxPredict:CLOZAPINE - a page about the agranulocytosis risk test.
  10. Clinical Data Launches Pharmacogenetic Test for Clozapine-Induced Agranulocytosis on Schedule - press release at the Forbes site.
  11. Novartis Pharmaceuticals (April 2006), Prescribing Information, Novartis Pharmaceuticals, pp. p36, http://www.novartis.ca/downloads/en/products/clozaril_scrip_e.pdf, retrieved on 2007-06-29 
  12. Naheed M, Green B. (2001). (abstract) Focus on clozapine 17 (3): 223-9.
  13. Lane HY, Chang YC, Chang WH, Lin SK, Tseng YT, Jann MW. (January 1999). (abstract) Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics. J Clin Psychiatry 60 (1): 36-40.
  14. Novartis Pharmaceuticals. Clozaril Dosing Guide. Novartis Pharmaceuticals. URL accessed on 2007-06-29.

Sources

  • Benkert, Hippius: Kompendium der Psychiatrischen Pharmakotherapie (German), 4th. ed., Springer Verlag
  • B. Bandelow, S. Bleich, and S. Kropp: Handbuch Psychopharmaka (German), 2nd. ed. Hogrefe
  • Crilly JF (2007) The history of clozapine and its emergence in the US Market: A review and Analysis. History of Psychiatry, 18(1): 39-60. DOI:10.1177/0957154X07070335

External links


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