Pimozide Clarithromycin

Pimozide Drugs that prolong the QT interval - CYP3A inhibitors (eg, clarithromycin, dirithromycin, erythromycin, itraconazole, ketoconazole, nefazodone, protease inhibitors, sertraline, telithromycin, troleandomycin, voriconazole)... 

Drugs that may be affected by indinavir include antiarrhythmics, clarithromycin, dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressant agents, phosphodiesterase type 5 inhibitors, pimozide, saquinavir, trazodone, cisapride, amiodarone, benzodiazepines, ergot alkaloids, fentanyl, rifamycins, ritonavir. 

Drugs that might be affected by amprenavir include antiarrhythmics, anticonvulsants, azole antifungals, benzodiazepines, calcium channel blockers, cisapride, clarithromycin, cyclosporine, ergot alkaloids, fentanyl, HMG-CoA reductase inhibitors, indinavir, methadone, nelfinavir, oral contraceptives, pimozide, rifabutin, ritonavir, saquinavir, sildenafil, tacrolimus, trazodone, tricyclic antidepressants, warfarin, and zidovudine. 

Drugs that might be affected by lopinavir/ritonavir include ergot derivatives, oral contraceptives, antiarrhythmics, HMG-CoA reductase inhibitors, HIV protease inhibitors, atovaquone, calcium channel blockers, ketoconazole, itraconazole, pimozide, cisapride, clarithromycin, disulfiram, metronidazole, immunosuppressants, midazolam, triazolam, narcotic analgesics, rifabutin and rifabutin metabolite, sildenafil, warfarin, bupropion, clozapine, desipramine, piroxicam, quinidine, theophylline, and zolpidem. 

Aprepitant (Emend) [Centrally Acting Antiemetic] Uses Pre-vents N/V assoc w/ emetogenic CA chemo (eg, cisplatin) (use in combo w/ other antiemetics) Action Substance P/neurokinin l(NKi) receptor antagonist Dose 125 mg PO day 1, 1 h before chemo, then 80 mg PO qAM days 2 3 Caution [B, /-] Contra Use w/ pimozide, Disp Caps SE Fatigue, asthenia, hiccups Interactions T Effects W/ clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin T effects OF alprazolam, astem-izole, cisapride, dexamethasone, methylprednisolone, midazolam, pimozide, terfe-nadine, triazolam, chemo agents, eg, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, vinblastine, vincristine, vinorelbine i effects W/ paroxetine,... 

A child with Tourette s disorder is treated with a daily dose of 2 mg of pimozide for tics. A family doctor treats a streptococcal pharyngitis with clarithromycin, and 24 hours later the child develops palpitations. An electrocardiogram (ECG) reveals a QTc prolongation to 0.465 milliseconds. 

In this example, clarithromycin, a potent CYP3A inhibitor blocks the principal pathway of pimozide metabolism (CYP3A), and plasma concentrations of pimozide increase. A higher pimozide concentration (a pharmacokinetic effect) is associated with prolongation of QT c in EKG readings and potentially fatal torsades de pointes (via potassium channel blockade, a pharmacodynamic effect see Flockhart et al., 2000, May-hew et ah, 2000). As exemplified by this vignette, the... 

Flockhart, D.A., Drici, M.D., Kerbusch, T., Soukhova, N., Richard, E., Pearle, P.L., Mahal, S.K., and Babb, V.J. (2000) Studies on the mechanism of a fatal clarithromycin—pimozide interaction in a patient with Tourette syndrome./Clin Psychopharmacol20-317— 324. 

Desta, Z., Kerbusch, T, and Flockhart, D.A. (1999) Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6). Clin Pharmacol Ther 65 10-20. 

Nevertheless, there is concern about pimozide because it may cause concentration-dependent prolongation of the QT interval. In addition, three patients died suddenly while taking pimozide (199, 200). In the first report, the dose of pimozide had been rapidly adjusted to 70 to 80 mg per day over a 2-week interval. In the second report, clarithromycin was added to a stable dose of pimozide, leading to a substantial reduction in pimozide clearance and increase in its levels. Thus, pimozide should not be administered with CYP 3A inhibitors (see Chapter 3) without careful TDM-driven dose adjustment. 

Flockhart DA, Richard E, Woosley RL, et al. A metabolic interaction between clarithromycin and pimozide may result in cardiac toxicity. Clin Pharmacol Ther 1996 59 189-189. 

Concomitant administration of clarithromycin with cisapride, pimozide, astemizole, or terfenadine is contraindicated. There have been postmarketing reports of drug interactions when clarithromycin and/ or erythromycin are coadministered with cisapride, pimozide, astemizole, or terfenadine resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes). 

Lopinavir/Ritonavir (Kaletra) [Anrirelroviral/Protease Inhibitor] Uses HIV Infxn Action Protease inhibitor Dose Adults. Tx naive 2 tab PO daily or 1 tab PO bid Tx experiencedpt 1 tab PO bid (T dose if w/ amprenavir, efavirenz, fosamprenavir, nelfinavir, nevirapine) Peds. 7-15 kg 12/3 mg/kg PO bid 15-40 kg 10/2.5 mg/kg PO bid >40 kg Adult dose w/ food Caution [C, /-] Numerous interactions Contra w/drugs dependent on CYP3A/CYP2D6 (Table VI-8) Disp Tab, soln SE Avoid disulfiram (soln has EtOH), metronidazole GI upset, asthenia, T cholesterol/triglycerides, pancreatitis protease metabolic synd Interactions T Effects Wl clarithromycin, erythromycin T effects OF amiodarone, amprenavir, azole andfungals, bepridil, cisapride, cyclosporine, CCBs, ergot alkaloids, flecainide, flurazepam, HMG-CoA reductase inhibitors, indinavir, lidocaine, meperidine, midazolam, pimozide, propafenone, propoxyphene, quinidine, rifabutin, saquinavir, sildenafil, tacrolimus, terfenadine, triazolam, zolpidem 1 effects Wl barbiturates, carbamazepine, dexamethasone, didanosine, efavirenz, nevirapine, phenytoin, rifabutin, rifampin, St. John s wort 1 effects OF OCPs, warfarin EMS Use andarrhythmics and benzodiazepines... 

T effects OF amiodarone, astemizole, atorvastadn, barbiturates, bepridil, bupropion, cerivastatin, cisapride, clorazepate, clozapine, clarithromycin, desipramine, diazepam, encainide, ergot alkaloids, estazolam, flecainide, flurazepam, indinavir, ketoconazole, lovastatin, meperidine, midazolam, nelfinavir, phenytoin, pimozide, piroxicam, propafenone, propoxyphene, quinidine, rifabutin, saquinavir, sildenafil, simvastatin, SSRIs, TCAs, terfenadine, triazolam, troleandomycin, zolpidem X effects W/ barbiturates, carbamazepine, phenytoin, rifabutin, rifampin, St. John s wort, tobacco X effects OF didanosine, hypnotics, methadone, OCPs, sedatives, theophylline, warfarin EMS T Effects of amiodarone, diazepam, midazolam and BBs, may need X- doses concurrent use of Viagra-type drugs can lead to hypotension X- effects of warfarin concurrent EtOH use can T adverse effects T glucose ODs May cause an extension of adverse SEs symptomatic and supportive Rivasrigmine (Exelon) [Cholinesterase Inhibitor/Anri ... 

In 12 healthy volunteers given oral pimozide 6 mg after 5 days of treatment with clarithromycin (500 mg bd) or placebo, pimozide significantly prolonged the QTC interval in the first 20 hours in both groups (maximum changes in QTC 16 and 13 ms respectively) (3). 

Clarithromycin inhibits the metabolism of pimozide, pimozide plasma concentrations increase, and there is an increased risk of cardiotoxicity through prolongation of the QT interval and fatal ventricular dysrhythmias (3). 

PROPAFENONE I. ANTIARRHYTHMICS - disopyra-mide, procainamide 2. ANTIBIOTICS - macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinolones (especially moxifloxacin), quinupristin/ dalfopristin 3. ANTICANCER AND IMMUNOMODULATING DRUGS -arsenic trioxide 4. ANTIDEPRESSANTS - TCAs, venlafaxine 5. ANTIEMETICS-dolasetron 6. ANTIFUNGALS-fluconazole, posaconazole, voriconazole 7. ANTIHISTAMINES - terfenadine, hydroxyzine, mizolastine 8. ANTI-M ALARIALS - artemether with lumefantrine, chloroquine, hydroxychloroquine, mefloquine, quinine 9. ANTIPROTOZOALS - pentamidine isetionate 10. ANTIPSYCHOTICS-atypicals, phenothiazines, pimozide II. BETA-BLOCKERS - sotalol 12. BRONCHODILATORS -parenteral bronchodilators 13. CNS STIMULANTS - atomoxetine Risk of ventricular arrhythmias, particularly torsades de pointes Additive effect these drugs prolong the Q-T interval. Also, amitriptyline, clomipramine and desipramine levels may be t by propafenone. Amitriptyline and clomipramine may t propafenone levels. Propafenone and these TCAs inhibit CYP2D6-mediated metabolism of each other Avoid co-administration... 

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