Table 2.

List of candidate drug–drug interactions (DDIs) discussed and the final pairs accepted by the expert panel as critical DDIs

#	Candidate drug–drug interaction pair (object–precipitant drug/class)	Status	Considerations suggested by the expert panel	Final DDI pair and suggested membership*
				Object class	Precipitant class
3	Amphetamine and derivatives–MAO inhibitors	Accepted	Consider downgrading membership of selegiline due to its selective MAO-B inhibition; only at higher doses does it lose specificity and inhibit MAO-A	Amphetamine derivatives:  Dexmethylphenidate  Dextroamphetamine  Methylphenidate  Lisdexamefetamine  Methamphetamine  Phendimetrazine  Pseudoephedrine  Amphetamine  Benzphetamine  Diethylpropion  Phentermine  Atomoxetine	MAO inhibitors:  Tranylcypromine  Phenelzine  Isocarboxazid  Procarbazine  Selegiline
4	Atazanavir–gastric pH alkalizing agents (proton pump inhibitors (PPIs) + H2 blockers)	Accepted	Only include PPIs and remove H2 blockers from precipitant class based on literature evidence Add dexlansoprazole to precipitant class	Atazanavir	Proton pump inhibitors (PPIs):  Omeprazole Lansoprazole Pantoprazole Rabeprazole Esmoprazole
6	Febuxostat–azathioprine/mercaptopurine	Accepted	No suggestions made	Febuxostat	Azathioprine and mercaptopurine
8	Fluoxetine–MAO inhibitors	Accepted	Expand object class to include other SSRIs instead of only fluoxetine Expand object class to include serotonergic agents	Selective serotonin reuptake inhibitors (SSRIs):  Fluoxetine  Paroxetine  Citalopram  Escitalopram  Sertraline  Fluvoxamine  Duloxetine  Nefazodone  Desvenlafaxine  Milnacipran  Venlafaxine	Monoamine oxidase (MAO) inhibitors:  Tranylcypromine  Phenelzine  Isocarboxazid  Procarbazine  Selegiline
11	Irinotecan–ketoconazole	Accepted	Modify precipitant class to include strong CYP3A4 inhibitors†	Irinotecan	CYP3A4 inhibitors† Protease inhibitors:  Ritonavir  Nelfinavir  Atazanavir  Indinavir  Saquinavir  Amprenavir  Darunavir  Lopinavir  Tipranavir  Fosamprenavir  Saquinavir Macrolides:  Clarithromycin  Erythromycin  Telithromycin  Amiodarone  Verapamil  Diltiazem Azoles:  Ketoconazole  Itraconazole  Fluconazole  Voriconazole  Nefazodone  Aprepitant  Cimetidine
16	Narcotic analgesics–MAO inhibitors	Accepted	Insufficient evidence to add fentanyl derivatives (sufentanyl, alfentanyl) to the object class.	Narcotic analgesics:  Meperidine  Methadone  Tapentadol  Fentanyl  Tramadol  Dextromethorphan	MAO inhibitors:  Tranylcypromine  Phenelzine  Isocarboxazid  Selegiline  Procarbazine
20	Tricyclic antidepressants (TCAs)–selegiline	Accepted	No evidence of interaction when selegiline is administered transdermally; consider route specificity Expand precipitant class to MAO-inhibitors	Tricyclic antidepressants (TCAs)	MAO inhibitors:  Tranylcypromine  Phenelzine  Isocarboxazid  Selegiline  Procarbazine
21	QT prolonging agents–QT prolonging agents	Accepted	Include all high risk category drugs from http://www.torsades.org ‡ Remove drugs that are off-market or not available in the United States—astemizole, levomethadyl, mesoridazine, probucol, sparfloxacin, and terfenadine as they are off market. Cisapride may be available on an investigational, limited-access basis Add nilotinib which has a black box warning regarding QT-prolongation and sudden death	QT prolonging agents‡	QT prolonging agents‡
22	Ramelteon–fluvoxamine	Accepted	Limit precipitant class to strong CYP 1A2 inhibitors: fluvoxamine, amiodarone, ticlopidine, and ciprofloxacin No literature available for other CYP1A2 inhibitors	Ramelteon	Specific CYP1A2 inhibitors:†  Fluvoxamine  Amiodarone  Ticlopidine  Ciprofloxacin
23	Rifampin–ritonavir	Accepted	Expand the object class to include only strong CYP3A4 Inducers† From the above list remove CYP3A4 inducers like glucocorticoids, troglitazone, modafinil, all barbiturates, and pioglitazone since no literature supporting their interaction Include rifapentine and bosentan Expand precipitant class to include all protease inhibitors Remove weak inducers like oxcarbazepine Efavirenz and nevirapine interact with only some protease inhibitors and are indicated for concurrent use in most combinations One KB vendor suggested further limiting the object class to include only rifampin and St John's wort in the object class as other inducers can be safely given by just adjusting dosages	Strong CYP3A4 inducers:†  Bosentan  Rifapentine  Carbamazepine  Rifabutin  Rifampin  St John's wort	Protease inhibitors:  Ritonavir  Amprenavir  Atazanavir  Darunavir  Fosamprenavir  Indinavir  Lopinavir  Nelfinavir  Saquinavir  Tipranavir
25	HMG Co-A reductase inhibitorsProtease inhibitors	Accepted	Expand precipitant class to include CYP3A4 inhibitors Remove cerivastatin due to off-market status from object class Remove atorvastatin from object class since magnitude of interaction is less than for other statins	HMG Co-A reductase inhibitors  Simvastatin Lovastatin	CYP3A4 inhibitors† Protease inhibitors: Indinavir  Saquinavir  Tipranavir  Ritonavir  Nelfinavir  Atazanavir  Amprenavir  Darunavir  Lopinavir Macrolides:  Clarithromycin  Erythromycin  Telithromycin  Amiodarone  Verapamil  Diltiazem Azoles:  Ketoconazole  Itraconazole  Fluconazole  Voreconazole  Nefazodone
27	Telithromycin–ergot alkaloids and derivatives	Accepted	Modify object class to CYP3A4 inhibitors Remove from object class: amiodarone, verapamil, diltiazem, fluconazole, nefazodone, aprepitant, and cimetidine due to lack of evidence Remove ergoloid mesylates from precipitant class due to lack of vasoconstrictive properties	CYP3A4 inhibitors†Protease inhibitors:  Indinavir  Saquinavir  Tipranavir  Ritonavir  Nelfinavir  Atazanavir  Amprenavir  Darunavir  Lopinavir Macrolides:  Clarithromycin  Erythromycin  Telithromycin Azoles:  Ketoconazole  Itraconazole  Voreconazole	Ergot alkaloids and derivatives:  Ergotamine  Methylergonovine  Dihydroergotamine  Ergonovine
28	Tizanidine–ciprofloxacin	Accepted	Modify precipitant class to include CYP 1A2 inhibitors	Tizanidine	CYP 1A2 inhibitors:†  Ciprofloxacin  Fluvoxamine  Mexiletine  Propafenone  Zileuton  Amiodarone  Ticlopidine
30	Tranylcypromine–procarbazine	Accepted		Tranylcypromine	Procarbazine
31	Triptans–MAO inhibitors	Accepted	Keep only three triptans (sumatriptan, zolmitriptan, and rizatriptan) for object class For precipitant class include moclobemide and methylene blue	Triptans:   Sumatriptan   Zolmitriptan   Rizatriptan	Monoamine oxidase (MAO) inhibitors:  Tranylcypromine  Phenelzine  Isocarboxazid  Moclobamide  Methylene blue

^*Membership is suggested but not intended to represent every member in the drug class. Specific exceptions, as suggested by the panel, are described where necessary in the column labeled “Considerations suggested by the expert panel”.

^†CYP-450 inhibitors and inducers obtained from the list provided by the FDA¹⁶ and Flockhart's table from the University of Indiana School of Medicine.¹⁷

^‡http://www.torsades.org (accessed 29 Jul 2011).