Asaleptin - General Information
A tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Asaleptin is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent.
Pharmacology of Asaleptin
Asaleptin is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives and is indicated for the treatment of schizophrenia. Asaleptin 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. Asaleptin 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 Asaleptin. Asaleptin's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Asaleptin's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Asaleptin's antagonism of adrenergic a1 receptors may explain the orthostatic hypotension observed with this drug.
Asaleptin for patients
Patients who are to receive CLOZARIL should be warned about the significant risk of developing agranulocytosis. Patients should be advised to report immediately the appearance of lethargy, weakness, fever, sore throat, malaise, mucous membrane ulceration or other possible signs of infection. Particular attention should be paid to any flu-like complaints or other symptoms that might suggest infection.
Patients should be informed that CLOZARIL tablets will be made available only through a special program designed to ensure the required blood monitoring in order to reduce the risk of developing agranulocytosis. Patients should be informed that their WBC count and ANC will be monitored as follows:
- Weekly blood tests are required for the first 6 months.
- If acceptable WBC counts and ANCs (WBC 3500/mm3 and ANC ≥2000/mm3) have been maintained during the first 6 months of continuous therapy, then WBC counts and ANCs can be monitored every 2 weeks for the next 6 months.
- Thereafter, if acceptable WBC counts and ANCs have been maintained during the second 6 months of continuous therapy, WBC counts and ANCs can be monitored every 4 weeks.
Patients should be informed of the significant risk of seizure during CLOZARIL treatment, and they should be advised to avoid driving and any other potentially hazardous activity while taking CLOZARIL.
Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration.
Patients should be informed that if they miss taking CLOZARIL for more than 2 days, they should not restart their medication at the same dosage, but should contact their physician for dosing instructions.
Patients should notify their physician if they are taking, or plan to take, any prescription or over-the-counter drugs or alcohol.
Patients should notify their physician if they become pregnant or intend to become pregnant during therapy.
Patients should not breast-feed an infant if they are taking CLOZARIL.
The risks of using Clozapine in combination with other drugs have not been systematically evaluated.
Pharmacodynamic-related Interactions: The mechanism of Clozapine induced agranulocytosis is unknown; nonetheless, the possibility that causative factors may interact synergistically to increase the risk and/or severity of bone marrow suppression warrants consideration. Therefore, Clozapine should not be used with other agents having a well-known potential to suppress bone marrow function.
Given the primary CNS effects of Clozapine, caution is advised in using it concomitantly with other CNS-Active drugs or alcohol.
Orthostatic hypotension in patients taking clozapine can, in rare cases (approximately 1 case per 3,000 patients), be accompanied by profound collapse and respiratory and/or cardiac arrest. Some of the cases of collapse/respiratory arrest/cardiac arrest during initial treatment occurred in patients who were being administered benzodiazepines; similar events have been reported in patients taking other psychotropic drugs or even Clozapine by itself. Although it has not been established that there is an interaction between Clozapine and benzodiazepines or other psychotropics, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug.
Clozapine may potentiate the hypotensive effects of antihypertensive drugs and the anticholinergic effects of atropine-type drugs. The administration of epinephrine should be avoided in the treatment of drug induced hypotension because of a possible reverse epinephrine effect.
Pharmacokinetic-related Interactions: Clozapine is a substrate for many CYP 450 isozymes, in particular 1A2, 2D6, and 3A4. The risk of metabolic interactions caused by an effect on an individual isoform is therefore minimized. Nevertheless, caution should be used in patients receiving concomitant treatment with other drugs that are either inhibitors or inducers of these enzymes.
Concomitant administration of drugs known to induce cytochrome P450 enzymes may decrease the plasma levels of clozapine. Phenytoin, nicotine, and rifampin may decrease Clozapine plasma levels, resulting in a decrease in effectiveness of a previously effective Clozapine dose.
Concomitant administration of drugs known to inhibit the activity of cytochrome P450 isozymes may increase the plasma levels of clozapine. Cimetidine, caffeine, and erythromycin may increase plasma levels of Clozapine, potentially resulting in adverse effects. Although concomitant use of Clozapine and carbamazepine is not recommended, it should be noted that discontinuation of concomitant carbamazepine administration may result in an increase in Clozapine plasma levels.
In a study of schizophrenic patients who received clozapine under steady state conditions, fluvoxamine or paroxetine was added in 16 and 14 patients, respectively. After 14 days of co-administration, mean trough concentrations of clozapine and its metabolites, N-desmethylclozapine and clozapine N-oxide, were elevated with fluvoxamine by about three-fold compared to baseline concentrations. Paroxetine produced only minor changes in the levels of clozapine and its metabolites. However, other published reports describe modest elevations (less than two-fold) of clozapine and metabolite concentrations when clozapine was taken with paroxetine, fluoxetine, and sertraline. Therefore, such combined treatment should be approached with caution and patients should be monitored closely when Clozapine is combined with these drugs, particularly with fluvoxamine. A reduced Clozapine dose should be considered.
A subset (3%-10%) of the population has reduced activity of certain drug metabolizing enzymes such as the cytochrome P450 isozyme P450 2D6. Such individuals are referred to as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, the tricyclic antidepressants, and clozapine. These individuals may develop higher than expected plasma concentrations of clozapine when given usual doses. In addition, certain drugs that are metabolized by this isozyme, including many antidepressants (clozapine, selective serotonin reuptake inhibitors, and others), may inhibit the activity of this isozyme, and thus may make normal metabolizers resemble poor metabolizers with regard to concomitant therapy with other drugs metabolized by this enzyme system, leading to drug interaction.
Concomitant use of clozapine with other drugs metabolized by cytochrome P450 2D6 may require lower doses than usually prescribed for either clozapine or the other drug. Therefore, co-administration of clozapine with other drugs that are metabolized by this isozyme, including antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.
Clozapine is contraindicated in patients with a previous hypersensitivity to clozapine or any other component of this drug, in patients with myeloproliferative disorders, uncontrolled epilepsy, or a history of Clozapine induced agranulocytosis or severe granulocytopenia. As with more typical antipsychotic drugs, Clozapine is contraindicated in severe central nervous system depression or comatose states from any cause. Clozapine should not be used simultaneously with other agents having a well-known potential to cause agranulocytosis or otherwise suppress bone marrow function. The mechanism of Clozapine induced agranulocytosis is unknown; nonetheless, it is possible that causative factors may interact synergistically to increase the risk and/or severity of bone marrow suppression.
Additional information about Asaleptin
Asaleptin Indication: For the management of severely ill schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia
Mechanism Of Action: The mechanism of action of Asaleptin, as with other drugs used to treat schizophrenia, is unknown. However, it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of dopamine Type 2 (D2) and serotonin Type 2 (5HT2) receptor antagonism.
Drug Interactions: Alprazolam Increased risk of toxicity
Caffeine Caffeine increases the effect and toxicity of clozapine
Carbamazepine Carbamazepine decreases the effect of clozapine, hematologic toxicity
Chlordiazepoxide Increased risk of toxicity
Cimetidine Cimetidine increases the effect of clozapine
Ciprofloxacin Ciprofloxacin may increase clozapine serum levels
Citalopram The antidepressant increases the effect of clozapine
Clobazam Increased risk of toxicity
Clonazepam Increased risk of toxicity
Clorazepate Increased risk of toxicity
Diazepam Increased risk of toxicity
Donepezil Possible antagonism of action
Erythromycin Erythromycin increases the effect of clozapine
Estazolam Increased risk of toxicity
Ethotoin Hydantoin decreases the effect of clozapine
Fluoxetine The antidepressant increases the effect of clozapine
Flurazepam Increased risk of toxicity
Fluvoxamine The antidepressant increases the effect of clozapine
Fosphenytoin Hydantoin decreases the effect of clozapine
Galantamine Possible antagonism of action
Halazepam Increased risk of toxicity
Haloperidol Increases the effect and toxicity of haloperidol
Josamycin Erythromycin increases the effect of clozapine
Lamotrigine Lamotrigine increases the effect and toxicity of clozapine
Lisinopril Lisinopril increases the effect and toxicity of clozapine
Lorazepam Increased risk of toxicity
Mephenytoin Hydantoin decreases the effect of clozapine
Midazolam Increased risk of toxicity
Modafinil Modafinil increases the effect and toxicity of clozapine
Oxazepam Increased risk of toxicity
Norfloxacin Ciprofloxacin may increase clozapine serum levels
Phenytoin Hydantoin decreases the effect of clozapine
Temazepam Increased risk of toxicity
Triazolam Increased risk of toxicity
Rifabutin Rifabutin decreases the effect of clozapine
Rifampin Rifampin decreases the effect of clozapine
Ritonavir Ritonavir increases the effect and toxicity of clozapine
Rivastigmine Possible antagonism of action
Sertraline The antidepressant increases the effect of clozapine
Bromazepam Increased risk of toxicity
Cinolazepam Increased risk of toxicity
Flunitrazepam Increased risk of toxicity
Ketazolam Increased risk of toxicity
Nitrazepam Increased risk of toxicity
Prazepam Increased risk of toxicity
Quazepam Increased risk of toxicity
Food Interactions: Take without regard to meals.
Limit caffeine intake (may reduce clozapine matabolism).
Generic Name: Clozapine
Drug Category: Antipsychotics
Drug Type: Small Molecule; Approved
Other Brand Names containing Clozapine: Asaleptin; Clozaril; Fazaclo ODT; Iprox; Leponex; Lepotex;
Absorption: Rapid and almost complete
Toxicity (Overdose): Not Available
Protein Binding: 97% (bound to serum proteins)
Half Life: 8 hours (range 4-12 hours)
Dosage Forms of Asaleptin: Tablet Oral
Chemical IUPAC Name: 3-chloro-6-(4-methylpiperazin-1-yl)-5H-benzo[c][1,5]benzodiazepine
Chemical Formula: C18H19ClN4
Clozapine on Wikipedia: http://en.wikipedia.org/wiki/Clozapine
Organisms Affected: Humans and other mammals