Clozapine

326.82

326.82

227-313-7

J60AR2IKIC

757429

DTXSID5022855

C28936

Yellow crystals from acetone-petroleum ether

N05AH02|N - Nervous system

2933990090

30.9

3.23

pale yellow

1.3±0.1 g/cm3

183-184 °C

489.2±55.0 °C at 760 mmHg

9℃

1.681

ethanol: 1 mg/mL

Store at RT

1.12X10-8 mm Hg at 25 deg C (est)

LD50 in mice, rats (mg/kg): 61, 58 i.v.; 199, 260 orally (Lindt)

7.5None

Henry's Law constant = 9.29X10-15 atm-cu m/mol at 25 °C (est)

7.5|pKa = 7.50|pKa1 3.70; pKa2 7.60|pKa1 = 3.92 (imine); pKa2 = 7.75 (amine); pKa3 = 15.90 (secondary amine) (est)

178.8 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]|177.5 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Hydroxyl radical reaction rate constant = 3.76X10-10 cu cm/molecule-sec at 25 °C (est)

III

6.1(b)

UN 2811 6.1/PG 3

3

22-36/37/38-68-63-39/23/24/25-23/24/25-11

26-36/37-45-16-7

HP1750000

Xn,Xi,T,F

Stable under recommended storage conditions.

Missing Phrase - N15.00950417-P280

H301-H341-H361

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.|SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Incompatible materials: Oxidizing agents

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including clozapine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Stephens P; A Review of Clozapine: An Antipsychotic for Treatment Resistant Schizophrenia. Comp Psychiatry 31 (4): 315-26 (1990). This report reviews over 25 years of literature of the development, pharmacology, proposed mechanism of action, efficacy, adverse effects, and recommendations for use of clozapine.|Ereshefsky L et al; Clin Pharm 8 (10): 691-709 (1989). The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosage, and cost of the atypical antipsychotic drug clozapine are reviewed.

|Danger|H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P264, P270, P281, P301+P310, P308+P313, P321, P330, P405, and P501|Aggregated GHS information provided by 118 companies from 15 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H301: Toxic if swallowed [Danger Acute toxicity, oral]

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).|Body Protection: Complete suit protecting against chemicals, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Skin protection: Handle with gloves.|Eye/face protection: Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.|Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

ACCIDENTAL RELEASE MEASURES. Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust.; Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.; Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.|Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.

The liquid chromatography-electrospray ionization-tandem mass spectrometer (LC-MS/MS) method coupled with an automated solid-phase extraction procedure has been developed to identify 22 psychiatric pharmaceuticals, including seven anxiolytic-sedative-hypnotics, six antidepressants, and nine anti-schizophrenia drugs, in wastewater samples from two psychiatric hospital wastewater treatment plants (P-WWTPs) and three municipal wastewater treatment plants (M-WWTPs) in Beijing, China. Analyte recoveries from spiking experiments in the WWTP influent and effluent at three concentrations ranged from 70% to 110%, excluding sulpiride, ziprasidone, and olanzapine. Method detection limits for five, eight, and nine analytes in the WWTP influent and effluent were 20-80, 1-16, and <1 ng/L, respectively. High psychiatric pharmaceutical concentrations (e.g., approx 942 ng/L oxazepam, 5552-12,782 ng/L clozapine, 2762-9832 ng/L sulpiride, and 2030-4967 ng/L quetiapine) were frequently observed in P-WWTP influent compared to M-WWTPs. Although P-WWTPs typically had higher removal rates, significantly higher concentrations of the target compounds were observed in the P-WWTP secondary effluent than in the M-WWTP influent (e.g., approx 752 ng/L oxazepam, approx 8183 ng/L clozapine, approx 10,833 ng/L sulpiride, and approx 1168 ng/L quetiapine). Thus, the discharge control of psychiatric pharmaceuticals from psychiatric hospitals requires improvement.

Clozapine carries a black-box warning for agranulocytosis.|IDENTIFICATION AND USE: Clozapine has been shown to be an effective, relatively rapid-acting, broad-spectrum antipsychotic agent in both uncontrolled and controlled studies of patients with schizophrenia.Clozapine has been used in a limited number of patients with advanced, idiopathic parkinsonian syndrome for the management of dopaminomimetic psychosis associated with antiparkinsonian drug therapy, but adverse effects such as sedation, confusion, and increased parkinsonian manifestations may limit the benefit of clozapine therapy in these patients. Clozapine is used to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for such behavior, based on history and recent clinical state. Although the safety and efficacy of clozapine in children and adolescents younger than 16 years of age have not been established, the drug has been successfully used for the management of childhood-onset schizophrenia in a limited number of treatment-resistant children and adolescents. Clozapine is used for the symptomatic management of schizophrenia in severely ill patients whose disease fails to respond adequately to other antipsychotic therapy. HUMAN EXPOSURE AND TOXICITY: The most frequent adverse effects of clozapine involve the central and autonomic nervous systems (e.g., drowsiness or sedation, hypersalivation) and the cardiovascular system (e.g., tachycardia, hypotension). While the frequency and severity of some adverse effects (e.g., extrapyramidal reactions, tardive dyskinesia) appear to be less with clozapine than with other antipsychotic agents, other potentially serious adverse effects (e.g., agranulocytosis, seizures) may occur more frequently with clozapine therapy, and the potential risks and benefits should be evaluated carefully whenever therapy with the drug is considered. Although it has been suggested that a local genetic or environmental factor or factors may have been involved in the Finnish cases, the existence of such a factor has not been documented. During a 2 month period in Finland there were 18 reports of severe blood disorders (9 fatal) associated with clozapine. Agranulocytosis accounted for 8 of the deaths and leukemia probably for the ninth. Experience in 22 other countries outside Finland where clozapine had been marketed indicated an incidence of agranulocytosis of 0.3 per 1000 compared with an incidence almost 20 times as high in Finland and with 0.1 to 0.8 per 1000 for other tricyclic neuroleptics. patients who received flexible dosages of clozapine (mean dosage: 274.2 mg daily) for approximately 2 years had a 26% reduction in their risk for suicide attempts or hospitalization to prevent suicide compared with those who received flexible dosages of olanzapine (mean dosage: 16.6 mg daily); the treatment-resistant status of patients was not predictive of response to clozapine or olanzapine. ANIMAL STUDIES: Repeated oral administration to rats (6 months) and to dogs (3 months) decreased wt gain with doses of 20 mg/kg or more in rats and of 10 mg/kg or more in dogs. Hepatic hypertrophy, which was not strictly dose-dependent, was not associated with either histological changes or changes in blood chemistry and was completely reversible after discontinuation of treatment. No toxic signs were observed in rats or in dogs. Clozapine in daily oral doses of 20 or 40 mg/kg to rats and rabbits had no teratogenic effects and no influence on the fertility of male and female rats. At 40 mg/kg, however, clozapine inhibited growth of suckling young of treated mothers. Fertility of F1 treated mothers was normal and development of F2 showed no abnormalities. Clozapine hydrochloride inhibited conditioned avoidance behavior in rats, also inhibited writhing syndrome induced by phenylbenzoquinone in mice, and decreased body temp. Clozapine hydrochloride antagonized tremor and lacrimation induced by oxotremorine in mice, decreased the acute toxicity of physostigmine and 5-hydroxyindol acetate level in brain.

Serum enzyme elevations arise in up to two-thirds of patients on clozapine but are usually modest and resolve spontaneously after 6 to 12 weeks, often not requiring dose modification or discontinuation. Occasionally, serum enzyme elevations are associated with symptoms of nausea, weakness and abdominal discomfort, and therapy should be discontinued or managed with careful dose reduction.

LD50 Rat iv 41.6 mg/kg|LD50 Rat sc 240 mg/kg|LD50 Rat im 210 mg/kg|LD50 Rat oral 251 mg/kg

97% (bound to serum proteins)

Clozapine's production and administration as an antipsychotic(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.3X10+4(SRC), determined from a structure estimation method(2), indicates that clozapine is expected to be immobile mobility in soil(SRC). The pKa value of 7.60(3) indicates that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Clozapine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2015).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.3X10+4(SRC), determined from a structure estimation method(2), indicates that clozapine is expected to adsorb to suspended solids and sediment(SRC). The pKa value of 7.60(3) indicates clozapine will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 63(SRC), from an estimated log from its log Kow of 3.23(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2015).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), clozapine, which has an estimated vapor pressure of 1.1X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase clozapine may be removed from the air by wet and dry deposition(SRC). Clozapine absorbs UV light at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Clozapine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Clozapine absorbs UV light at wavelengths of 215, 230. 261 and 297 nm(2) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 63 was calculated in fish for clozapine(SRC), using a log Kow of 3.23(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of cloazpine can be estimated to be 1.3X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that clozapine is expected to be immobile in soil. The pKa value of 7.60(3) indicates that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Clozapine has been shown to absorb to biosolids in wastetreatment sludge; log Koc values of 3.56, 3.54 and 3.41 have been reported in sludges from Denver, CO and Mines Park, AS(5), corresponding to Koc values of 3,630, 3,567 for the Denver sludge samples and 2570 for the Arkansas sludge sample(SRC).

The pKa value of 7.60(1) indicates clozapine will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water and mosit soil surfaces is not expected to be an important fate process. Clozapine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-8 mm Hg(SRC), determined from a fragment constant method(2).

Occupational exposure to clozapine may occur through inhalation and dermal contact with this compound at workplaces where clozapine is produced or used. Exposure to clozapine among the general population may be extended to those administered the drug, an antipsychotic. (SRC)

Clozapine has been measured in sweat at 49-5,609 per patch following an oral does of 200-700 mg/day(1).

For use in patients with treatment-resistant schizophrenia.|FDA Label

Clozapine was the first atypical antipsychotic approved for treatment of schizophrenia. Because it is associated with severe and potentially fatal side effects (agranulocytosis), its use is restricted to refractory schizophrenia, and monitoring during therapy is required. Clozapine therapy is associated with serum aminotransferase elevations and in rare instances has been linked to clinically apparent acute liver injury.

Antipsychotic Agents

Clozapine has known transformation products that include Norclozapine.

Antipsychotic Agents; GABA Antagonists; Serotonin Antagonists|Clozapine tablets are indicated for the management of severely ill schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia. Because of the significant risk of agranulocytosis and seizure associated with its use, clozapine tablets should be used only in patients who have failed to respond adequately to treatment with appropriate courses of standard drug treatments for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs.|Clozapine has been used in a limited number of patients with advanced, idiopathic parkinsonian syndrome for the management of dopaminomimetic psychosis associated with antiparkinsonian drug therapy, but adverse effects such as sedation, confusion, and increased parkinsonian manifestations may limit the benefit of clozapine therapy in these patients. Attempts to relieve antiparkinsonian drug-induced delusions, paranoia, and hallucinations by reduction of antiparkinsonian drug dosage or administration of typical antipsychotic agents often aggravate parkinsonian symptoms. Limited data suggest that administration of clozapine in dosages of 6.25-400 mg daily can improve psychotic symptoms within a few days, reportedly without exacerbating parkinsonian manifestations. However, in a controlled study in a limited number of patients receiving clozapine dosages up to 250 mg daily, exacerbation of parkinsonian manifestations and development of delirium occurred frequently despite prevention of antiparkinsonian drug-induced deterioration of psychosis;88 it has been suggested that rapid clozapine dosage escalation may have contributed to the observed negative effect on parkinsonian manifestations and delirium.|Clozapine is used to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for such behavior, based on history and recent clinical state. Efficacy of clozapine for this indication has been established in a multicenter, randomized, open-label clinical study (the International Suicide Prevention Trial [InterSePT]) of 2 years' duration comparing clozapine and olanzapine in patients with schizophrenia (62%) or schizoaffective disorder (38%) who were judged to be at risk for recurrent suicidal behavior.|For more Therapeutic Uses (Complete) data for CLOZAPINE (8 total), please visit the HSDB record page.

BOXED WARNING: 1. AGRANULOCYTOSIS: Because of a significant risk of agranulocytosis, a potentially life threatening adverse event, clozapine should be reserved for use in (1) the treatment of severely ill patients with schizophrenia who fail to show an acceptable response to adequate courses of standard antipsychotic drug treatment, or (2) for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at risk of re-experiencing suicidal behavior. Patients being treated with clozapine must have a baseline white blood cell (WBC) count and absolute neutrophil count (ANC) before initiation of treatment as well as regular WBC counts and ANCs during treatment and for at least 4 weeks after discontinuation of treatment. Clozapine is available only through a distribution system that ensures monitoring of WBC count and ANC according to the schedule described below prior to delivery of the next supply of medication.|BOXED WARNING: 2. SEIZURES: Seizures have been associated with the use of clozapine. Dose appears to be an important predictor of seizure, with a greater likelihood at higher clozapine doses. Caution should be used when administering clozapine to patients having a history of seizures or other predisposing factors. Patients should be advised not to engage in any activity where sudden loss of consciousness could cause serious risk to themselves or others.|BOXED WARNING: 3. MYOCARDITIS: Analyses of post-marketing safety databases suggest that clozapine is associated with an increased risk of fatal myocarditis, especially during, but not limited to, the first month of therapy. In patients in whom myocarditis is suspected, clozapine treatment should be promptly discontinued.|BOXED WARNING: 4. OTHER ADVERSE CARDIOVASCULAR AND RESPIRATORY EFFECTS: Orthostatic hypotension, with or without syncope, can occur with clozapine treatment. Rarely, collapse can be profound and be accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension is more likely to occur during initial titration in association with rapid dose escalation. In patients who have had even a brief interval off clozapine, i.e., 2 or more days since the last dose, treatment should be started with 12.5 mg once or twice daily. Since collapse, respiratory arrest and cardiac arrest during initial treatment has occurred in patients who were being administered benzodiazepines or other psychotropic drugs, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug.|For more Drug Warnings (Complete) data for CLOZAPINE (20 total), please visit the HSDB record page.

Clozapine is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives and is indicated for the treatment of schizophrenia. Clozapine is a selective monoaminergic antagonist with high affinity for the serotonin Type 2 (5HT₂), dopamine Type 2 (D2), 1 and 2 adrenergic, and H1 histaminergic receptors. Clozapine acts as an antagonist at other receptors, but with lower potency. Antagonism at receptors other than dopamine and 5HT₂ with similar receptor affinities may explain some of the other therapeutic and side effects of clozapine. Clozapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Clozapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Clozapine's antagonism of adrenergic a1 receptors may explain the orthostatic hypotension observed with this drug. Patients should be counseled regarding the risk of hypersensitivity reactions such as agranulocytosis and myocarditis with clozapine use. Clozapine induced agranulocytosis, which is a reduction in the absolute neutrophil count or white blood cell count, places the patient at an increased risk for infection. Agranulocytosis is most likely to occur in the first 3-6 months of therapy, but it can still occur after years of treatment. The mechanism is thought to be a dose-independent and immune-mediated reaction against neutrophils. Patients are strictly monitored by lab testing (complete blood count with differential) to ensure agranulocytosis is detected and treated if it occurs. Testing is initially completed at one-week intervals but is expanded to two-week intervals at six months, and then four-week intervals at twelve months if lab results have been within an appropriate range. Monitoring parameters may change if there is any break in therapy. In Canada, the patient's lab values are reported to the manufacturer for hematological monitoring, and in the USA, the patient's lab values are reported to the REMS (Risk Evaluation and Mitigation Strategy) program. These programs function to notify the care provider of any significant drop in WBC/neutrophil count, or if there is a drop below a threshold level. Patients who enter the "Red" zone (WBC<2x109/L or ANC<1.5x109/L) should normally not be re-challenged. Clozapine induced myocarditis is a hypersensitivity reaction that usually occurs in the third week of clozapine therapy and about 2% of clozapine patients. Monitor the patient's troponin, CRP, ECG at baseline, and 28 days into treatment. Follow guidelines for appropriate next steps according to the patient's lab results. If myocarditis occurs, the patient should not be re-challenged with clozapine

Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in SCHIZOPHRENIA; senile dementia; transient psychosis following surgery; or MYOCARDIAL INFARCTION; etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus. (See all compounds classified as Antipsychotic Agents.)|Drugs that bind to but do not activate GABA RECEPTORS, thereby blocking the actions of endogenous GAMMA-AMINOBUTYRIC ACID and GABA RECEPTOR AGONISTS. (See all compounds classified as GABA Antagonists.)|Drugs that bind to but do not activate serotonin receptors, thereby blocking the actions of serotonin or SEROTONIN RECEPTOR AGONISTS. (See all compounds classified as Serotonin Antagonists.)

Rapid and almost complete|Approximately 50% of the administered dose is excreted in the urine and 30% in the feces.|Clozapine is almost completely metabolized prior to excretion and only trace amounts of unchanged drug are detected in the urine and feces. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive.|In man, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a clozapine solution. Following a dosage of 100 mg b.i.d., the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady-state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg b.i.d. dosing. Food does not appear to affect the systemic bioavailability of clozapine. Thus, clozapine may be administered with or without food. Clozapine is approximately 97% bound to serum proteins.|Clozapine is rapidly absorbed after both single and repeated oral doses, with steady-state concentrations attained within eight to ten days after beginning therapy.

Hepatic|Manic and schizophrenic patients were given neuroleptic clozapine at 300-500 mg daily and metabolites of clozapine were isolated from urine and analyzed by gas chromatography-mass spectrometry. Clozapine was converted into 2 metabolites by replacement of chlorine atom by a hydroxyl or methylsulfide group. Further metabolites were the N-demethyl deriv of 1st two metabolites. A metabolite with an oxidized piperazine ring was also found, and possibility of a metabolite with an oxidized sulfur is suggested.|/Clozapine/ is metabolized to N-oxideclozapine and N-desmethylclozapine, which have less pharmacological activity than the parent compound and are excreted in the urine and, to a lesser extent, in the feces.|Clozapine has known human metabolites that include Clozapine N-glucuronide, Clozapine-N-oxide, and N-Desmethylclozapine.

8 hours (range 4-12 hours)|The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life, after achieving steady-state with 100 mg b.i.d. dosing, of 12 hours (range: 4 to 66 hours).

Clozapine's antipsychotic action is likely mediated through a combination of antogistic effects at D2 receptors in the mesolimbic pathway and 5-HT2A receptors in the frontal cortex. D2 antagonism relieves positive symptoms while 5-HT2A antagonism alleviates negative symptoms.|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 antipsychotic drug products. In particular, although clozapine does interfere with the binding of dopamine at D1, D2, D3 and D5 receptors, and has a high affinity for the D4 receptor, it does not induce catalepsy nor inhibit apomorphine-induced stereotypy. This evidence, consistent with the view that clozapine is preferentially more active at limbic than at striatal dopamine receptors, may explain the relative freedom of clozapine from extrapyramidal side effects. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and serotonergic receptors.

Emergency and supportive measures: 1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. 2. Treat coma, seizures, hypotension, and hyperthermia if they occur. 3. Monitor vital signs ECG for at least 6 hours and admit the patient for at least 24 hours if there are signs of significant intoxication. Children with antipsychotic intoxication should be evaluated for possible intentional abuse. /Antipsychotic drugs/|Specific drugs and antidotes. There is no specific antidote.1. Dystonic reactions. Give diphenhydramine ... or benztropine ... . 2. QRS interval prolongation: treat quinidine-like cardiotoxic effects with bicarbonate ... . 3. Hypotension from these drugs probably involves vasodilation caused by alpha-1 receptor blockade. Treat with iv fluids and, if needed a vasoconstrictor such as norepinephrine or phenylephrine. Theoretically, drugs with beta-2 activity (eg, epinephrine, isoproterenol) may worsen hypotension. 4. QT prolongation and torsade may respond to magnesium infusion or overdrive pacing. /Antipsychotic drugs/|Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antipsychotic drugs/|Enhanced elimination. Owing to extensive tissue distribution, these drugs are not effectively removed by dialysis or hemoperfusion. Repeat-dose activated charcoal has not been evaluated. /Antipsychotic drugs/|For more Antidote and Emergency Treatment (Complete) data for CLOZAPINE (7 total), please visit the HSDB record page.

/HUMAN EXPOSURE STUDIES/ Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Clozapine is not approved for the treatment of patients with dementia-related psychosis.|/SIGNS AND SYMPTOMS/ The most frequent adverse effects of clozapine involve the central and autonomic nervous systems (e.g., drowsiness or sedation, hypersalivation) and the cardiovascular system (e.g., tachycardia, hypotension). While the frequency and severity of some adverse effects (e.g., extrapyramidal reactions, tardive dyskinesia) appear to be less with clozapine than with other antipsychotic agents, other potentially serious adverse effects (e.g., agranulocytosis, seizures) may occur more frequently with clozapine therapy, and the potential risks and benefits should be evaluated carefully whenever therapy with the drug is considered. Because of the substantial risk of clozapine-associated agranulocytosis, which may persist over an extended period of time and be life-threatening or fatal if not detected early and therapy interrupted, clozapine is available for use only through patient-management systems that ensure baseline and periodic blood tests prior to delivery of the next supply of medication; dispensing is contingent on the results of the white blood cell (WBC) count and absolute neutrophil count (ANC).|/SIGNS AND SYMPTOMS/ Orthostatic hypotension, with or without syncope, can occur with clozapine treatment. Rarely, collapse can be profound and be accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension is more likely to occur during initial titration in association with rapid dose escalation. In patients who have had even a brief interval off clozapine, i.e., 2 or more days since the last dose, treatment should be started with 12.5 mg once or twice daily. Since collapse, respiratory arrest and cardiac arrest during initial treatment has occurred in patients who were being administered benzodiazepines or other psychotropic drugs, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug.|/CASE REPORTS/ One patient receiving clozapine experienced a generalized tonic-clonic (grand mal) seizure following accidental ingestion of an extra dose (total dose ingested within 24 hours: 1050 mg); the same patient had another seizure several weeks later, 2 hours after a usual 450-mg morning dose. Results of plasma clozapine determinations obtained at the time of the seizures revealed plasma clozapine concentrations of approximately 2000 ng/mL in each case. Another patient who had been taking clozapine for 27 months had a generalized tonic-clonic seizure following an apparent intentional overdosage (total dose ingested within 24 hours: approximately 3 g), after which the patient made an uneventful recovery. One hour after the seizure, the patient's plasma clozapine concentration was 1313 ng/mL.|For more Human Toxicity Excerpts (Complete) data for CLOZAPINE (10 total), please visit the HSDB record page.

Clozapine

Table: Clozapine Preparations [Table#6022]

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Pharmaceuticals|Pharmaceuticals -> Neuroleptics