Clozapine 43961 225499431 2008-07-14T00:44:43Z Rjwilmsi 203434 no 'of' between a month and a year per [[Wikipedia:Manual_of_Style_%28dates_and_numbers%29#Longer_periods|MOS]] using [[Project:AutoWikiBrowser|AWB]] {{Drugbox| | IUPAC_name = 8-chloro-11-(4-methyl-1-piperazinyl)-<br />5''H''-dibenzo(b,e)(1,4)diazepine | image = Clozapine.svg | image2 = Clozapine-3D-vdW.png | CAS_number = 5786-21-0 | ATC_prefix = N05 | ATC_suffix = AH02 | PubChem = 2818 | DrugBank = APRD00470 | C=18 | H=19 | Cl=1 | N=4 | molecular_weight = 326.823 g/mol | melting_point = 183 | solubility = 0 | bioavailability = 60 to 70% | metabolism = [[Liver|Hepatic]], by several [[Cytochrome P450|CYP]] [[isozyme]]s | 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% [[kidney|renal]] | pregnancy_category = B | legal_status = [[Prescription drug|Prescription only]], special restrictions imposed in many countries | routes_of_administration = Oral }} '''Clozapine''' (sold as '''Clozaril''', '''Leponex''', '''Fazaclo''', '''Froidir'''; '''Gen-Clozapine''' in Canada; '''Clozaril''', '''Denzapine''', '''Zaponex''' in the UK; '''Klozapol''' in Poland) is an [[antipsychotic]] medication used in the treatment of [[schizophrenia]]. The first of the [[atypical antipsychotic]]s to be developed, it was first introduced in Europe in 1971, but was voluntarily withdrawn by the manufacturer in 1975 after it was shown to cause [[agranulocytosis]] that led to death in some clozapine-treated patients. In 1989, after studies demonstrated that it was more effective than any other antipsychotic for treating schizophrenia, the FDA approved clozapine's use but only for treatment-resistant schizophrenia. The FDA requires weekly blood testing for patients taking clozapine.[http://www.time.com/time/magazine/article/0,9171,975910-5,00.html] The FDA also requires clozapine to carry five [[black box]] warnings for [[agranulocytosis]], seizures, myocarditis, for "other adverse cardiovascular and respiratory effects", and for "increased mortality in elderly patients with dementia-related psychosis." [http://www.rxlist.com/cgi/generic/clozapine.htm] In 2002 the FDA approved clozapine for reducing the risk of [[suicidal behavior]] but only for patients with schizophrenia. Clozapine has been shown to be the most effective drug in treating schizophrenia but due to its potential to cause many severe [[adverse drug reaction|side effect]]s, it is relegated to third-line use. Clozapine is only used in patients after other anti-psychotics have failed. Safer use of clozapine requires weekly [[full blood count|blood monitoring]] for around five months followed by four weekly testing thereafter. ==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.<ref>{{cite book |author=Healy, David |title=The Creation of Psychopharmacology |publisher=Harvard University Press |location=Cambridge |year=2004 |pages=238-42 |isbn=0-674-01599-1 |url=http://books.google.co.uk/books?id=6O2rPJnyhj0C&}}</ref> 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 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,<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 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]], [[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 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. 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{{Fact|date=February 2007}}. ===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;<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 previous treatment of clozapine should not receive it again. In 2007, a pharmacogenetic test was introduced to measure the probability of developing agranulocytosis.<!-- --><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><!-- --> 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. 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. Patients are advised to inform their [[physician|doctor]] if they develop a [[sore throat]], or [[fever]]. If the number of white blood-cells drops notably then referral to a [[hematology|hematologist]] is undertaken. 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 [[Challenge-dechallenge-rechallenge|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. ===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.<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 = 10.2165/00002018-200730010-00005 <!--Retrieved from CrossRef by DOI bot-->}}</ref> [[Cardiomyopathy]] is another potentially fatal cardiac condition which may arise less acutely. More recently, a regular six-monthly [[echocardiogram]] is also recommended to detect [[myocarditis]]. ===Central nervous system=== 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> ===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.<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 = 10.1046/j.1365-2125.2003.01773.x <!--Retrieved from CrossRef by DOI bot-->}}</ref> ==Chemistry== It is insoluble in water, soluble in [[acetone]], and very 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 <ref> {{Citation | last = Novartis Pharmaceuticals | author-link = Novartis | title = Prescribing Information | url=http://www.novartis.ca/downloads/en/products/clozaril_scrip_e.pdf | accessdate = 2007-06-29 | date = April 2006 | year = 2006 | publisher = Novartis Pharmaceuticals | pages = p36 }} </ref> ==Mechanism of action== 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. Smoking increases the metabolism of Clozapine to the extent that approximately double the dose is required in heavy smokers compared to non-smokers. 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> ==Dosage== Due to risk of serious side effects, clozapine treatment is commenced at a very low dose and increased slowly until a therapeutic dose 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><ref name=bnf>{{cite book |title=[[British National Formulary]] |edition=55 |date=March 2008 |chapter=4.2.1 Antipsychotic drugs |pages=p195}}</ref> In severely ill and/or younger patients higher doses may be needed, while in the elderly much lower doses may be sufficient. 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.<ref name=bnf /> 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== *[[DHA-clozapine]] == Notes == {{Reflist}} == References == * 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== * [http://www.clozaril.com Clozaril] - [[Novartis]] * [http://www.mentalhealth.com/drug/p30-c02.html Clozapine] * [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] * [http://www.fazaclo.com/ Fazaclo] {{Antipsychotics}} [[Category:Atypical antipsychotics]] [[Category:Benzodiazepines]] [[Category:Piperazines]] [[de:Clozapin]] [[es:Clozapina]] [[fr:Clozapine]] [[it:Clozapina]] [[nl:Clozapine]] [[pl:Klozapina]] [[ru:Клозапин]] [[sv:Klozapin]]