Common Oral Chemotherapy Interactions

Oral chemotherapy medications are widely used among cancer patients, but they have a narrow therapeutic index, and their pharmacokinetics and pharmacodynamics can easily be altered by various foods and medications. Although these interactions pose a threat to patients, pharmacists can play a large role in minimizing them.

It’s important to read the package insert before taking oral chemotherapy medications. Some of them should be taken with food or on an empty stomach. Many of them can interact with calcium-containing products, grapefruits, or even high-fat meals, resulting in increased systemic exposure and toxicity.

Oral chemotherapy medications commonly interact with anticoagulants, acid suppressors, and antibiotics/antifungals. Most of these interactions occur because they inhibit or induce a variety of enzymes like the CYP450s and pathways like P-glycoprotein.

Anticoagulant Interactions

Oral chemotherapy medications can affect certain anticoagulants’ absorption or prolong a patient’s QTc interval. The anticoagulant most notorious for exhibiting a variety of drug interactions is warfarin. One way to properly manage this interaction is to closely monitor a patient’s PT/INR or ECG and adjust the dose if necessary.

Acid Suppressor Interactions

Proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), and antacids can affect bioavailability or delay elimination of certain chemotherapy medications because some have pH-dependent absorption and require an acidic environment to work. Common PPIs include esomeprazole (Nexium), lansoprazole (Prevacid), omeprazole (Prilosec), and pantoprazole (Protonix), while common H2RAs include cimetidine (Tagamet), famotidine (Pepcid), and ranitidine (Zantac). To avoid potential interactions, a PPI should be switched to a H2RA, or H2RAs/antacids should be taken 2 hours before or after the chemotherapy medication. However, these recommendations are drug-specific.

Antibiotic/Antifungal Interactions

Any medications that are CYP450 inhibitors or inducers will most likely interact with oral chemotherapy medications. Erythromycin, clarithromycin, and the azole antifungals, including fluconazole and ketoconazole, are all potent CYP3A4 inhibitors. To avoid this interaction, avoid concomitant administration or adjust the chemotherapy medication’s dose, which should be increased if given with a CYP450 inducer and decreased if given with a CYP450 inhibitor.

There are many other medications that cause drug interactions, and no chemotherapy medication is the same, so it’s important to clarify concomitant drugs before taking any of these medications.

Here’s a helpful overview of oral chemotherapy medications’ interactions:

Drug

Substrate

Competitive

Inhibitor

Competitive

Inducer

Warfarin effects

QTc prolongation

Effect of Acid Suppression on Absorption

Take with food

Take on empty stomach

Grapefruit Interaction

Abiraterone

(Zytiga)

3A4*

2D6+++, 1A2+++, 2C19++,

2C9++, 3A4 ++, 2C8+++

No

No

None

Yes

Afatinib (Gilotrif)

BCRP, P-gp

BCRP, P-gp

No

No

Not studied

Yes

Altretamine (Hexalen)

No

No

None

Yes

Anastrozole (Arimidex)

1A2+

2C8+, 2C9+, 3A4+

None

Axitinib (Inlyta)

3A4*, 3A5*, 1A2-, 2C19-, UGT1A1

No

Not studied

No

Yes

Bexarotene (Targretin)

3A4-

3A4+

Not studied

Not studied

Not studied

Yes

Moderate

Bicalutamide (Casodex)

3A4++

Yes

No

None

Bosutinib (Bosulif)

3A4*, P-gp

P-gp

No

Yes

Yes

Yes

Busulfan (Myleran)

3A4*

Not studied

Not studied

Not studied

Cabozantinib (Cometriq)

2C9-, 3A4*

P-gp

Not studied

Possible

Not studied

Yes

Yes

Capecitabine (Xeloda)

2C9+++

Yes

Not studied

No

Yes

Chlorambucil (Leukeran)

Not studied

Not studied

Not studied

Yes

Crizotinib (Xalkori)

3A4*, P-gp

3A4++, P-gp, 2B6+++

Not studied

Yes

Possible

Yes

Cyclophosphamide (Cytoxan)

2A6-, 2B6*, 2C19-, 2C9-, 3A4-

3A4+

2B6++, 2C9++

Not studied

Not studied

Not studied

Yes

Dabrafenib (Tafinlar)

3A4, 2C8, P-gp, BCRP

3A4++, 2B6, 2C8, 2C19, UDP

Yes

Not studied

Possible

Yes

Yes

Dasatinib (Sprycel)

3A4*

3A4+

Possible

Yes

yes

Yes

Deferasirox (Exjade)

UGT1A1*

1A2++, 2C8++

3A4++

Yes

No

No

Yes

Eltrombopag (Promacta)

1A2-, 2C8-, UGT1A1-, UGT1A3, BCRP*

2C8++, OATP1B+++, BCRP++, UGT1A1, UGT1A3, UGT1A4, UGT1A6

No

No

No

Yes

Enzalutamide (Xtandi)

2C8*, 3A4*

P-gp

2C19++, 2C9++, 3A4+++

Yes

Possible

No

Erlotinib (Tarceva)

3A4*, 1A2-

Yes

Not studied

Yes

Yes

Moderate

Estramustine (Emcyt)

Not studied

Not studied

No

Yes

Etoposide (VePesid)

P-gp-, 1A2-, 2E1-, 3A4*

3A4+, 2C9+

Not studied

Not studied

Not studied

Moderate

Exemestane (Aromasin)

3A4*

3A4++

Not studied

Not studied

Not studied

Yes

Everolimus (Afinitor)

P-gp-, 3A4*

Not studied

No

Not studied

Yes

Flutamide (Eulexin)

1A2*, 3A4*

1A2+

Yes

Not studied

Not studied

Gefitinib (Iressa)

2D6*, 3A4*

BCRP, 2C19+, 2D6+

Yes

Not studied

Yes

Yes

Hydroxyurea (Hydrea)

Not studied

Not studied

Not studied

Ibrutinib (Imbruivica)

3A4*

P-gp

Not studied

Not studied

Not studied

Yes

Imatinib (Gleevec)

Pg-p-, 3A4*, 1A2-, 2C9-, 2D6- , 2C19-

3A4++, 2C9+, 2D6++, BCRP++, P-gp

Yes

Not studied

Not studied

Yes

Yes

Lapatinib (Tykerb)

P-gp, 3A4*

P-gp, 3A4+ , 2C8++ , BCRP

Yes

Yes

Not studied

Yes

Yes

Lenalidomide (Revlimid)

P-gp

No

No

Not studied

Letrozole (Femara)

3A4-, 2A6-

2A6+++, 2C19+

No

Not studied

No

Lomustine (CeeNU)

2D6-

3A4+, 2D6+

Not studied

Not studied

Not studied

Yes

Melphalan (Alkeran)

Not studied

Not studied

Not studied

Yes

Mercaptopurine (Purinethol)

Not studied

Not studied

Not studied

Yes

Methotrexate (Trexall)

P-gp, SLCO1B1

Not studied

Not studied

Not studied

Mitotane (Lysodren)

Yes

Not studied

Not studied

Nilotinib (Tasigna)

3A4*, P-gp

3A4+, 2C9++ , 2D6++, 2C8++, P- gp, UGT1A1

2B6++, 2C8++, 2C9++

No

Yes

yes

Yes

Yes

Nilutamide (Nilandron)

2C19*

2C19+

No

No

No

Pazopanib (Votrient)

AA4*, 1A2-, 2C8-, P-gp

2C8+, 2D6+, 3A4+, SLCO1B, UGT1A1

No

Yes

No

Yes

Yes

Pomalidomide (Pomalyst)

1A2*, 3A4*, 26-, 2C19-, P-gp

Not studied

Not studied

Not studied

Yes

Ponatinib (Iclusig)

2C8-, 2D6-, 3A4-, P-gp, BCRP

P-gp, BCRP

Not studied

No

Possible

Yes

Procarbazine (Matulane)

MAOI

Not studied

Not studied

no

Regorafenib (Stivarga)

3A4*, UGT1A9

2C8, 2C9, 2B6, 3A4, 2C19, UGT1A9, UGT1A1, BRCP, P-gp

Yes

No

Not studied

Yes

Yes

Ruxolitinib (Jakafi)

3A4*

Not studied

Yes

No

Yes

Sorafenib (Nexavar)

3A4*, UGAT1A9

2B6++, 2C9++, 2C8+++, UGT1A1, UGT1A9

Yes

Yes

No

Yes

Sunitinib (Sutent)

3A4*

BCRP, P-gp

Not studied

Yes

Not studied

Moderate

Tamoxifen (Nolvadex)

2C9*, 2D6*, 3A4*, 2A6-, 2B6-, 2E1-

2B6+, 2C9+, 3A4+, 2C8++, P-gp

Yes

Not studied

Not studied

Temozolomide (Temodar)

Not studied

Not studied

Not studied

Yes

Thalidomide (Thalomid)

Not studied

Not studied

Not studied

Yes

Thioguanine (Tabloid)

Not studied

Not studied

No

Topotecan (Hycamtin)

P-gp, BCRP

Not studied

No

No

Trametinib (Mekinist)

Not studied

Not studied

Not studied

Yes

Not studied

Tretinoin (Vesanoid)

2A6-, 2B6-, 2C9-, 2C8*

2C9+

2E1

Not studied

Not studied

Not studied

Vandetanib (Caprelsa)

3A4*

P-gp, BCRP

Not studied

Yes

No

Vemurafenib (Zelboraf)

3A4-, P-gp

1A2++, 2D6+, P-gp

3A4++

Yes

Yes

Not studied

Vismodegib (Erivedge)

2C9-, 3A4-,

P-gp

2C8+, 2C9+, 2C19+, BCRP+

No

No

Possible

Vorinostat (Zolinza)

Yes

Yes

Not studied

Yes

^{Empty stomach: medication should be taken 1 hour before or 2 hours after last meal; Major substrate: *; Minor substrate: - ; Weak inducer/inhibitor: +; Moderate inducer/inhibitor: ++; Strong inducer/inhibitor:+++}

Reference

Segal EM, et al. Oral chemotherapy food and drug interactions: a comprehensive review of the literature. J Oncol Pract. 2014;10:e255-68.