Erythromycin clozapine

The conclusion is that the cytochrome P450 isoenzyme CYP3A4 is of only minor importance in clozapine metabolism, and that because no interaction takes place between clozapine and itraconazole or ketoconazole, both it and other inhibitors of CYP3A4 can be used with clozapine. However, note that raised clozapine levels have been attributed to treatment with the CYP3A4 inhibitor, erythromycin, see Clozapine + Erythromycin , p.747. 

Clozapine is metabolized by hepatic CYP 1A2 and, to a lesser degree, CYP 3A3/4 therefore, the drug is subject to changes in serum concentration when combined with medications that inhibit or induce these enzymes. Serum clozapine levels increase with coadministration of fluvoxamine or erythromycin and decrease with coadministration of phenobarbital or phenytoin and with cigarette smoking (Byerly and DeVane 1996). These pharmacokinetic interactions are particularly important because of the dose-dependent risk of seizures. 

Erythromycin may increase clozapine levels, predisposing to seizures (527). 

Funderburg LG, Vertrees JE, True JE, et al. Seizure following addition of erythromycin to clozapine treatment. Am J Psychiatry 1994 151 1840-1841. 

Cyt 3A3/4 metabolizes clozapine, sertindole, quetiapine common substrates -tricyclic antidepressants, nefazodone, sertraline, carbamazepine, ethosuximide, terfenadine, benzodiazepines, diltiazem, nifedipine, verapamil, erythromycin, cyclosporine, lidocaine, quinidine, cisapride, paracetamol. Common inhibitors -nefazodone, fluvoxamine, fluoxetine, ketoconazole. 

Increased clozapine serum concentrations have been reported with erythromycin (252,253) and can cause adverse effects (SEDA-21, 55). However, in 12 healthy men who took a single dose of clozapine 12.5 mg alone or in combination with a daily dose of erythromycin 1.5 g, the metabolism of clozapine was not altered (254). This... 

In a case of neutropenia the authors suggested that an interaction of clozapine with erythromycin had been the... 

Cohen LG, Chesley S, Eugenio L, Flood JG, Fisch J, Goff DC. Erythromycin-induced clozapine toxic reaction. Arch Intern Med 1996 156(6) 675-7. 

Hagg S, Spigset O, Mjorndal T, Granberg K, Persbo-Lundqvist G, Dahlqvist R. Absence of interaction between erythromycin and a single dose of clozapine. Eur J Clin Pharmacol 1999 55(3) 221-6. 

Usiskin SI, Nicolson R, Lenane M, Rapoport JL. Retreatment with clozapine after erythromycin-induced neutropenia. Am J Psychiatry 2000 157(6) 1021. 

CLOZAPINE MACROLIDES- ERYTHROMYCIN t clozapine levels with risk of clozapine toxicity Clozapine is metabolized by CYPIA2, which is moderately inhibited by erythromycin. Erythromycin is a potent inhibitor of CYP3A4, which has a minor role in the metabolism of clozapine. This may lead to 1 clearance and therefore t levels of clozapine Cautious use advised... 

Clinically important, potentially hazardous interactions with acetylcysteine, adenosine, aprepitant, aripiprazole, buprenorphine, caffeine, charcoal, clarithromycin, clobazam, dorazepate, clozapine, darunavir, dasatinib, delavirdine, dexamethasone, diltiazem, doxacurium, erythromycin, felodipine, fesoterodine, fosamprenavir, imatinib, influenza vaccines, lacosamide, lapatinib, levetiracetam, lopinavir, methylprednisolone, midazolam, nelfinavir, nilotinib, piracetam, prednisolone, propoxyphene, ritonavir, rivaroxaban, rufinamide, solifenacin, St John s wort, telithromycin, temsirolimus, terbinafine, tolvaptan, troleandomycin, verapamil, voriconazole... 

Clinically important, potentially hazardous interactions with alprazolam, amphetamines, astemizole, clarithromycin, clozapine, desipramine, dexibuprofen, dextroamphetamine, diethylpropion, droperidol, duloxetine, erythromycin, haloperidol, imipramine, isocarboxazid, linezolid, lithium, MAO inhibitors, mazindol, meperidine, methamphetamine, midazolam, moclobemide, nortriptyline, phendimetrazine, phenelzine, phentermine, phenylpropanolamine, phenytoin, pimozide, pseudoephedrine, selegiline, serotonin agonists, sibutramine, St John s wort, sumatriptan, sympathomimetics, tramadol, tranylcypromine, trazodone, tricyclic antidepressants, troleandomycin, tryptophan, zolmitriptan... 

Because of the risk of seizures with higher clozapine tissue concentrations, inhibition interactions with clozapine are potentially significant. In particular, fluvoxamine has been reported to increase clozapine serum concentrations by an average of two- to threefold and up to fivefold. Fluoxetine and erythromycin may increase clozapine serum concentrations in some patients, but to a lesser degree. Mean clozapine serum concentrations are reported to be 32% lower in smokers compared with nonsmokers." Carbamazepine may also induce clozapine metabolism and lead to lower serum concentrations. ... 

Carbamazepine is metabolized to an active 10,11-epoxide metabolite, thus medications that inhibit 3A4 isoenzymes may result in carbamazepine toxicity (e.g., cimetidine, dUtiazem, erythromycin, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefa-zodone, propoxyphene, and verapamil). " When carbamazepine is combined with valproate, the carbamazepine dose should be reduced because valproate displaces carbamazepine from protein binding sites, thus increasing free levels." Combining clozapine and carbamazepine is not recommended because of the possibdity of bone marrow suppression with both agents. ... 

Acetaminophen, aldrin, alfentanil, amiodarone, aminopyrine, amitriptyline, amprenavir, androstenedione,antipyrine, astemizole, benzphetamine, budesonide, carbamazepine, celecoxib, chlorpromazine, chlorzoxazone, cisapride, clarithromycin, clozapine, cocaine, codeine, cortisol, cyclophosphamide,cyclosporin, dapsone, delavirdine, dextromethorphan, digitoxin, diltiazem, diazepam, erythromycin, 17j3-estradiol, ethinylestradiol, etoposide, felbamate, fentanyl, flutamide, hydroxyarginine, ifosphamide, imipramine, indinavir, ketoconazole, lansoprazole, loratidine, losartan, lovastatin, (iS)"mephen3d in, methadone, mianserin, miconazole, mifepristone, nelfinavir, nevirapine, nicardipine, nifedipine, odansetron, omeprazole, orphenadrine, proguanil, propafenone, quinidine, quinine, rapamycin, retinoic acid, ritonavir, saquinavir, selegiline, serindole, sufentanil, sulfinpyrazone, tacrolimus, tamoxifen, tamsulosin, taxol, teniposide, terfenadine, tetrahydrocannabinol, theophylline, toremifene, triazolam, trimethadone, trimethoprim, troleandomycin, verapamil, warfarin, zatosetron, Zolpidem, zonisamide... 

Anecdotal data suggest that erythromycin can increase clozapine serum levels (via CYP1A2 blockade), with toxic effects. 

A study in healthy subjects found no evidence of an interaction between clozapine and erythromycin, but three case reports describe clozapine toxicity (seizures in one patient, drowsiness, incoordination and incontinence in another and neutropenia in the third) when the patients were given erythromycin. 

A randomised, crossover study in 12 healthy subjects found that erythromycin 500 mg three times daily did not affect the pharmacokinetics of a single 12.5-mg dose of clozapine. ... 

Uncertain. One suggestion is that erythromycin might have inhibited the cytochrome P450 isoenzyme CYP3A4, which has a minor role in the metabolism of clozapine, leading to a reduced clearance, which resulted in increased serum clozapine levels and toxicity. - Clozapine is mainly metabolised by CYP1A2, which is not known to be affected by the mac-rolides. 

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