Clozapine
Systematic (IUPAC) name
8-chloro-11-(4-methyl-1-piperazinyl)- 5H-dibenzo(b,e)(1,4)diazepine
Identifiers
CAS number	5786-21-0
ATC code	N05AH02
PubChem	2818
DrugBank	APRD00470
Chemical data
Formula	C18H19N4Cl
Mol. weight	326.823 g/mol
Physical data
Melt. point	183 °C (361 °F)
Solubility in water	0 mg/mL (20 °C)
Pharmacokinetic data
Bioavailability	60 to 70%
Metabolism	hepatic by different CYP-enzyme subtypes
Half life	6 to 26 hours (mean value 14.2 hours in steady state conditions)
Excretion	80% in metabolized state: 30% biliar und 50% in urine
Therapeutic considerations
Pregnancy cat.	B Image File history File links Formula is drawn in bkchem and GIMP. File history Legend: (cur) = this is the current file, (del) = delete this old version, (rev) = revert to this old version. ... Image File history File links Download high-resolution version (1100x1026, 249 KB) File links The following pages on the English Wikipedia link to this file (pages on other projects are not listed): Clozapine ... IUPAC nomenclature is a systematic way of naming organic chemical compounds. ... CAS registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences and alloys. ... The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. ... A section of the Anatomical Therapeutic Chemical Classification System. ... PubChem is a database of chemical molecules . ... DrugBank is a database available at the University of Alberta that provides information about thousands of products. ... A chemical formula (also called molecular formula) is a concise way of expressing information about the atoms that constitute a particular chemical compound. ... General Name, Symbol, Number carbon, C, 6 Chemical series nonmetals Group, Period, Block 14, 2, p Appearance black (graphite) colorless (diamond) Atomic mass 12. ... General Name, Symbol, Number hydrogen, H, 1 Chemical series nonmetals Group, Period, Block 1, 1, s Appearance colorless Atomic mass 1. ... General Name, Symbol, Number nitrogen, N, 7 Chemical series nonmetals Group, Period, Block 15, 2, p Appearance colorless Atomic mass 14. ... General Name, Symbol, Number chlorine, Cl, 17 Chemical series halogens Group, Period, Block 17, 3, p Appearance yellowish green Atomic mass 35. ... The molecular mass of a substance (less accurately called molecular weight and abbreviated as MW) is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12). ... The melting point of a crystalline solid is the temperature at which it changes state from solid to liquid. ... It has been suggested that Solid solubility be merged into this article or section. ... This article describes water from a scientific and technical perspective. ... In pharmacology, bioavailability is used to describe the fraction of an administered dose of medication that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. ... Overview of the citric acid cycle The citric acid cycle, one of the central metabolic pathways in aerobic organisms. ... The elimination half-life of a drug (or any xenobiotic agent) refers to the timecourse necessary for the quantity of the xenobiotic agent in the body (or plasma concentration) to be reduced to half of its original level through various elimination processes. ... Excretion is the process of eliminating waste products of metabolism and other materials that are of no use. ... The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. ...
Legal status	Rx-only/special restrictions are imposed in many countries The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ...
Routes	oral

Clozapine (sold as Clozaril®, Leponex®, Fazaclo®) 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. In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body 1. ... The atypical antipsychotics (also known as second generation antipsychotics) are a class of prescription medications used to treat psychiatric conditions. ... The Food and Drug Administration (FDA) is an agency of the United States Department of Health and Human Services and is responsible for regulating food (humans and animal), dietary supplements, drugs (human and animal), cosmetics, medical devices (human and animal) and radiation emitting devices (including non-medical devices), biologics, and... Suicide (from Latin sui caedere, to kill oneself) is the act of intentionally ending ones own life. ...

History and main uses

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 (weekly) 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. Sandoz is the generics subsidiary of Novartis, one of the Big Pharma pharmaceutical companies. ... 1961 (MCMLXI) was a common year starting on Sunday (the link is to a full 1961 calendar). ... World map showing Europe A satellite composite image of Europe Europe is one of the seven traditional continents of the Earth. ... 1975 (MCMLXXV) was a common year starting on Wednesday. ... The term antipsychotic is applied to a group of drugs used to treat psychosis. ... The United States Food and Drug Administration is the government agency responsible for regulating food, dietary supplements, drugs, cosmetics, medical devices, biologics and blood products in the United States. ... Red blood cells (erythrocytes) are present in the blood and help carry oxygen to the rest of the cells in the body Blood is a circulating tissue composed of fluid plasma and cells (red blood cells, white blood cells, platelets). ... This page is a candidate to be moved to Wiktionary. ... Schizoaffective disorder is a psychiatric diagnosis describing a situation where both the symptoms of mood disorder and psychosis are present. ...

Commonly approved indications

• 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.

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 otherwise resistant acute episodes of mania
• Treatment of psychotic symptoms occurring in patients with dementia of the Lewy-body-type
• Treatment of severe cases of obsessive compulsive disorder
• Treatment of intractable chronic insomnia, if all other measures have failed
• Treatment of schizoid personality disorder
• Treatment of tardive dyskinesia

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. Mania is a medical condition characterized by severely elevated mood. ... Dementia (from Latin de- apart, away + mens (genitive mentis) mind) is the progressive decline in cognitive function due to damage or disease in the brain beyond what might be expected from normal aging. ... For other uses, see Insomnia (disambiguation). ... Schizoid personality disorder (SPD) is a cluster A personality disorder characterized by a lack of interest in social relationships, a tendency towards a solitary lifestyle, and emotional coldness. ... Tardive dyskinesia is a serious neurological disorder caused by the long-term and/or high-dose use of dopamine antagonists, usually antipsychotics and among them especially the typical antipsychotics. ...

Chemistry

It is insoluble in water, soluble in acetone, very well soluble in chloroform. In chemistry, acetone (also known as propanone, dimethyl ketone, 2-propanone, propan-2-one and β-ketopropane) is the simplest representative of the ketones. ... Chloroform, also known as trichloromethane and methyl trichloride, is a chemical compound with formula CHCl3. ...

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

Pharmacology

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 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 also is a strong antagonist at different subtypes of adrenergic, cholinergic, histaminergic and serotonergic receptors.

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 effect 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 hepatically metabolized involving many CYP-450 isoenzymes and eliminated in the urine and faeces.

Metabolism

Clozapine is metabolized via the cytochrome P450 system in humans to polar metabolism 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. Cytochrome P450 Oxidase (CYP2E1) Cytochrome P450 oxidase (commonly abbreviated CYP) is a generic term for a large number of related, but distinct, oxidative enzymes (EC 1. ...

Contraindications

Clozapine is contraindicated in individuals with uncontrolled epilepsy, myeloproliferative disease, or agranulocytosis with prior clozapine treatment. Contraindicated is a medical term to indicate a situation in which a medication or treatment should not be administered. ...

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

Side effects

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 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. In the United States, a black box warning is a type of warning that appears on prescription drugs that may cause serious side effects. ... This article is about the medical condition. ... In medicine (cardiology), myocarditis is inflammation of the myocardium, the muscular part of the heart. ... The circulatory system or cardiovascular system is the organ system which circulates blood around the body of most animals. ... Respiration is the process by which an organism obtains energy by reacting oxygen with glucose to give water, carbon dioxide and ATP (energy). ... Orthostasis - Literally standing upright - commonly used as another term for orthostatic hypotension. ...

Common side effects with clozapine treatment include: constipation, drooling, muscle-stiffness, sedation, tremors, orthostasis, hyperglycemia, and weight-gain. The risks of extrapyramidal symptoms and tardive dyskinesias are much less with clozapine when compared to the typical antipsychotics (also known as conventional antipsychotics or conventional neuroleptics). Constipation or irregularity, is a condition of the digestive system where a person (or animal) experiences hard feces that are difficult to eliminate; it may be extremely painful, and in severe cases (fecal impaction) lead to symptoms of bowel obstruction. ... Drooling (or ptyalism) is caused by saliva flowing outside the mouth. ... It has been suggested that this article or section be merged into Muscular system. ... Sedation is a medical procedure involving administration of sedative drugs, generally to facilitate a medical procedure, such as endoscopy, vasectomy, or minor surgery with local anaesthesia. ... For the film see Tremors (film). ... Orthostasis - Literally standing upright - commonly used as another term for orthostatic hypotension. ... Hyperglycemia or High Blood Sugar is a condition in which an excessive amount of glucose circulates in the blood plasma. ... In the physical sciences, weight is a measurement of the gravitational force acting on an object. ... In human anatomy, the extrapyramidal system is a neural network located in the brain that is part of the motor system involved in the coordination of movement. ... Tardive dyskinesia is a serious neurological disorder caused by the long-term use of traditional antipsychotic drugs. ... Typical antipsychotics (sometimes referred to as conventional antipsychotics or conventional neuroleptics) are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis (in particular, schizophrenia), and are generally being replaced by atypical antipsychotic drugs. ...

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.

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. This article is about the disease that features high blood sugar. ... Ketoacidosis is a type of metabolic acidosis which is caused by high concentrations of keto acids, formed by the deamination of amino acids. ...

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. Se redirects here. ...

Undocumented side effects

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^{[citation needed]}. The shield and spear of the Roman God Mars are often used to represent the male sex In heterogamous species, male is the sex of an organism, or of a part of an organism, which typically produces smaller, mobile gametes (spermatozoa) that are able to fertilise female gametes (ova). ... This article does not cite its references or sources. ... Orgasm is the conclusion of the plateau phase of the sexual response cycle, shared by both men and women. ...

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. A blood cell count is a measurement of the levels of a persons haemoglobin, white cell count and platelets. ...

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. Hematology is the branch of medicine that is concerned with blood and its disorders. ... Also see Pharyngitis Sore Throat is a legendary British noisecore band, credited among others with inventing the genre Sore Throat formed in 1987 as a Crust Punk/ hardcore punk and grindcore act. ... An analogue medical thermometer showing the temperature of 38. ...

More recently, a regular echocardiogram is also recommended to detect myocarditis. The echocardiogram is an ultrasound of the heart. ... In medicine (cardiology), myocarditis is inflammation of the myocardium, the muscular part of the heart. ...

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. A full blood count (FBC) or complete blood count (CBC) is a test requested by a doctor or other medical professional that gives information about the cells in a patients blood. ... Leukopenia or leukocytopenia refers to a decrease in the number of circulating white blood cells (leukocytes) in the blood. ...

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.

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

External links

• Clozaril - Novartis
• Clozapine
• US Clozaril Package Insert (PDF)
• Clozaril Registry Website
• Links to external chemical sources

Novartis Suffern Yes plant is the Swiss companys sole pharmaceutical production facility in the U.S. Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland that manufactures mainstream products such as Benefiber (a fiber supplement) and Lamisil (a foot fungus medicine). ...