Appendix 1: Grapefruit Interacting Drugs and Associated Oral Bioavailability, Adverse Event(s), Risk Ranking and Potential Alternative

Medications Interacting Drugs Anti-Cancer Agents crizotinib cyclophosphamide dasatinib erlotinib everolimus imatinib lapatinib nilotinib pazopanib sorafenib sunitinib vandetanib venurafenib Anti-Diabetic Agents repaglinide saxagliptin Anti-Infective Agents albendazole artemether erythromycin etravirine halofantrine maraviroc praziquantel primaquine quinine Innate Oral Bioavailability* intermediate high not known intermediate low high incomplete intermediate incomplete intermediate not known not known not known intermediate intermediate Dose-Related Drug Adverse Event(s) torsade de pointes, myelotoxicity loss of efficacy torsade de pointes, myelotoxicity myelotoxicity myelotoxicity, nephrotoxicity myelotoxicity torsade de pointes, myelotoxicity torsade de pointes, myelotoxicity torsade de pointes, myelotoxicity myelotoxicity torsade de pointes, myelotoxicity torsade de pointes, myelotoxicity torsade de pointes, myelotoxicity hypoglycemia hypoglycemia Predicted Interaction Risk Rank ** high intermediate high high high intermediate high high high intermediate high high high intermediate intermediate Potential Alternative Medication(s)***

imatinib

imatinib sorafenib sorafenib

glyburide, metformin, sitagliptin glyburide, metformin, sitagliptin

low low intermediate not known low low low intermediate intermediate

dizziness, headache, nausea enhanced anti-malarial efficacy torsade de pointes skin rash torsade de pointes postural hypotension, syncope dizziness, headache, somnolence myelotoxicity torsade de pointes

intermediate low high low very high very high intermediate high high

clarithromycin doxycycline enfuvirtide doxycycline doxycycline

Appendix to: Bailey DG, Dresser G, Arnold JMA. Grapefruit and medication interactions: forbidden fruit or avoidable consequences? CMAJ 2012; DOI:10.1503/cmaj.120951. Copyright 2012 Canadian Medical Association or its licensors

rilpivirine saquinivir Anti-Inflammatory Agents budesonide oral colchicine methylprednisolone -oral Anti-Lipemic Agents atorvastatin lovastatin simvastatin Cardiovascular Agents amiodarone amlodipine apixaban cilostazol clopidogrel dronedarone eplerenone ergotamine felodipine losartan manidipine nicardipine nifedipine nimodipine nisoldipine nitrendipine propafenone quinidine

not known very low

torsade de pointes enhanced HIV efficacy

high low

nevirapine amprenavir, indinivir

intermediate not known intermediate low very low very low

hyperglycemia, Cushingoid features neutropenia, neuropathy hyperglycemia, Cushingoid features rhabdomyolysis rhabdomyolysis rhabdomyolysis

intermediate intermediate intermediate high very high very high

prednisone, ibuprofen prednisone pravastatin, rosuvastatin, fluvastatin pravastatin, rosuvastatin, fluvastatin pravastatin, rosuvastatin, fluvastatin sotalol warfarin acetylsalicylic acid acetylsalicylic acid sotalol spironolactone a triptan class drug amlodipine amlodipine amlodipine amlodipine amlodipine amlodipine

intermediate high intermediate not known very low low intermediate very low low intermediate low low intermediate very low very low low low high

torsade de pointes hypotension, peripheral edema GI bleeding GI bleeding loss of efficacy torsade de pointes hyperkalemia, serious arrhythmias gangrene, stroke hypotension, peripheral edema loss of efficacy hypotension, peripheral edema hypotension, peripheral edema hypotension, peripheral edema hypotension, peripheral edema hypotension, peripheral edema hypotension, peripheral edema bradycardia, conduction disorders torsade de pointes

high low high high high very high high very high intermediate intermediate intermediate intermediate intermediate intermediate intermediate intermediate intermediate intermediate

Appendix to: Bailey DG, Dresser G, Arnold JMA. Grapefruit and medication interactions: forbidden fruit or avoidable consequences? CMAJ 2012; DOI:10.1503/cmaj.120951. Copyright 2012 Canadian Medical Association or its licensors

rivaroxaban sibutramine sildenafil tadalafil ticagrelor vardenafil verapamil CNS Agents aprepitant alfentanil oral buspirone carbamazepine dextromethorphan diazepam fentanyl oral fluvoxamine ketamine oral lurasidone methadone midazolam oral oxycodone pimozide quazepam quetiapine sertraline triazolam ziprasidone

high not known intermediate intermediate intermediate intermediate intermediate intermediate intermediate very low high very low low intermediate not known low low high intermediate intermediate intermediate intermediate very low intermediate intermediate intermediate

GI bleeding hypertension hypotension hypotension GI or kidney bleeding hypotension complete heart block drowsiness, headache respiratory depression dizziness, sedation ataxia hallucinations, somnolence sedation respiratory depression adverse change in mood respiratory depression torsade de pointes, orthostatic hypotension, syncope respiratory depression sedation respiratory depression torsade de pointes sedation dizziness, somnolence dizziness, somnolence sedation torsade de pointes

intermediate intermediate intermediate intermediate high intermediate high low high high low high intermediate high intermediate very high very high intermediate intermediate high high low high intermediate intermediate high

warfarin

acetylsalicyclic acid diltiazem

hydromorphone, morphine oxazepam, tamazepam phenytoin, clonazepam alprazolam, oxazepam, tamazepam hydromorphone, morphine citralopram, paroxetine, escitalopram hydromorphone, morphine haloperidol, risperidone olanzapine alprazolam, lorazepam hydromorphone, morphine haloperidol, risperidone, olanzapine alprazolam, oxazepam temazepam haloperidol, risperidone, olanzapine citralopram, paroxetine, escitalopram alprazolam, lorazepam haloperidol, risperidone

Appendix to: Bailey DG, Dresser G, Arnold JMA. Grapefruit and medication interactions: forbidden fruit or avoidable consequences? CMAJ 2012; DOI:10.1503/cmaj.120951. Copyright 2012 Canadian Medical Association or its licensors

olanzapine Estrogens estradiol ethinylestradiol Gastrointestinal Agents cisapride domperidone Immunosuppressant Agents cyclosporine everolimus sirolimus tacrolimus Urinary Tract Agents darifenacin fesoterodine solifenacin silodosin tamsulosin low intermediate intermediate low breast cancer risk, thrombosis breast cancer risk, thrombosis torsade de pointes torsade de pointes intermediate intermediate high very high metoclopramide metoclopramide

low low low low low intermediate high intermediate intermediate

nephrotoxicity myelotoxicity, nephrotoxicity myelotoxicity, nephrotoxicity nephrotoxicity urinary retention, constipation urinary retention, constipation torsade de pointes postural hypotension, dizziness postural hypotension, dizziness

high high high high intermediate intermediate intermediate intermediate intermediate

* Innate oral drug bioavailability is the population average: very low (<10%), low (>10-30%), intermediate (>30 70%), high (>70%) ** Predicted Risk Rank is based initially upon the seriousness of the dose-related adverse drug effect and then adjusted dependent upon the innate oral bioavailability of the drug, which is used to determine the potential magnitude of increase in systemic drug concentration (see text). There are four categories of risk ranking: very high, high, intermediate, low. It is recommended for older patients, particularly the elderly, that drugs in the very high or high category that consumption of grapefruit or other interacting citrus fruits should be contraindicated during pharmacotherapy until proven safe or that a suggested alternative non-interacting drug be employed when available. *** Potential alternative medication(s) include established or predicted (italics) commonly prescribed drugs (Top 100 prescribed in 2011 in Canada) with the same therapeutic indication that have no or minor pharmacokinetic interaction with grapefruit or other interacting citrus fruits.

Appendix to: Bailey DG, Dresser G, Arnold JMA. Grapefruit and medication interactions: forbidden fruit or avoidable consequences? CMAJ 2012; DOI:10.1503/cmaj.120951. Copyright 2012 Canadian Medical Association or its licensors