Concerns

Table 1. Important drug interactions netween P450 isoenzyme
pathways and targeted therapies
P450 isoenzyme
Inducer or Substrate
Reproduced with permission from ONCOLOGY Nurse Edition, 2/09, Anne Landry, Editor- full citation to come Inhibitors of CYP3A4 These drugs may
increase serum levels of bexarotene-
ketoconazole, itraconazole, erythromycin,
gemfibrozil, grapefruit, grapefruit juice; also
(strong) atazanavir, indinavir, nefazodone,
nelfinavir, ritonavir, saquiavir, telithromycin,
voriconazole; (moderate) amprenavir,
aprepitant, diltiazem, fluconazole, verapamil;
and (weak) cimitidine. DO NOT give together
with gemfibrozil; avoid co-administration with
other drug(s) if possible or monitor closely for
drug side effects.
Inducers of CYP3A4 May decrease
serum bexarotene concentrations: rifampin,
phenytoin, Phenobarbital; also
(carbamazepine, dexamethasone, efavirenz,
griseofulvin, modafinil, nafcillin, nevirapine,
primidone, rifabutin, St. John's Wort. Avoid co-
administration if possible. If co-administered,
assess need for increased bexarotene dose.
Do NOT give together with St. John's Wort
Other Bexarotene decreases tamoxifen
plasma concentration by 35%; may also
decrease serum levels of systemic hormonal
contraceptives; Avoid co-administration if
possible, and use 2 types of contraception,
including one type of barrier contraceptive
CYP3A4, 2C19, 1A2; CYP3A4 Inhibitors May increase serum
minor 2D6 and 2C9
levels of bortezomib: ketoconazole, also (strong) atazanavir, clarithramycin, indinavir, itraconazole, grapefruit, grapefruit juice, nefazodone, nelfinavir, ritonavir, saquiavir, telithromycin, voriconazole; (moderate) amprenavir, aprepitant, diltiazem, fluconazole, verapamil; and (weak) cimitidine.
Melphalan-prednisone co-administration increased bortezomib serum levels, but this is not thought to be clinically relevant.
CYP3A4 inducers can theoretically lower
bortezomib levels: rifampin, carbamazepine,
phenytoin, St. John's Wort. Assess for
efficacy of bortezomib and need for increased
drug dose. Do NOT give together with St.
John's Wort
CYP2C9 inhibitor omeprazole co-
administration did not affect bortezomib
serum levels.
CYP3A4 inhibitors These drugs may
decrease metabolism of dasatinib resulting in
increased serum concentrations of dasatinib:
(strong) atazanavir, clarithramycin, grapefruit
juice, grapefruit, indinavir, itraconazole,
ketoconazole, nefazodone, nelfinavir,
ritonavir, saquiavir, telithromycin,
voriconazole; (moderate) amprenavir,
aprepitant, diltiazem, fluconazole, verapamil;
and (weak) cimitidine. Avoid co-
administration; if must give together, monitor
closely for drug toxicity and consider reducing
dasatinib dose.
CYP3A4 Inducers may decrease dasatinib
serum levels (eg, rifampin decreased dasatinib levels by 82%); others: carbamazepine, phenytoin, St. John's Wort. If must co-administer, assess efficacy of dasatinib and need for increased drug dose. Do NOT give together with St. John's Wort Antacids May decrease dasatinib levels;
avoid co-administration or administer at least
2 hours before or after the dasatinib dose
H2-Antagonists/Proton Pump
Inhibitors May decrease desatinib serum
levels; use antacids instead
CYP3A4 substrates drug is a time-
dependent inhibitor of CYP3A4 and may
decrease metabolism of drugs primarily
metabolized by CYP3A4, such as alfentanil,
stemizole, terfenadine, cisapride,
cyclosporine, fentanyl, pimozide, quinidine,
sirolimus, tacrolimus, or ergot alkaloids so
avoid co-administration or monitor drug
closely for side effects; single dose of
dasatinib with simvastatin increases
simavastatin (AUC) serum level by 37%
CYP3A4 Inhibitors decreased metabolism
of erlotinib and increase its plasma
concentration when co-administered with
strong inhibitors: atazanavir, clarithramycin,
indinavir, itraconazole, ketoconazole,
nefazodone, nelfinavir, ritonavir, saquiavir,
telithromycin, voriconazole, grapefruit,
grapefruit juice; co-administration with
ketoconazole ↑ erlotinib AUC by 66%; co-
administation with ciprofloxacin ↑ erlotinib
AUC by 39%.
CYP3A4 Inducers rifampicin, rifapentine,
rifabutin, carbamazepine, phenytoin,
phenobarbital, St. John's Wort;
coadministration with rifampicin ↓ erlotinib
AUC by 66%. DO NOT take with St. John's
Wort
CYP3A4 Substrates warfarin- increased
INR and bleeding possible, monitor INR and
decrease warfarin dose as needed
CYP1A2 inducers cigarette smoking:
decreases erlotinib serum levels; encourage
patients not to smoke but if unable to smoke,
consider cautious erlotinib dose increase and
closely monitor for side effects
Ph Altering Drugs erlotinib GI absorption
is dependent on a low gastric pH; omeprazole
↓ erlotinib AUC by 46%; avoid co-
administration with proton-pump inhibitors, or
H2-inhibitors; use antacids if needed, and
administer 2 hours before or after erlotinib
Food ↑ erlotinib absorption to 100%
(compared to dosed absorption of 60%); take
drug 1 hour before or 2 hours after food intake
CYP3A4 Inhibitors decreased metabolism
of erlotinib and increase its plasma
concentration when co-administered with
strong inhibitors: atazanavir, clarithramycin,
indinavir, itraconazole, ketoconazole,
nefazodone, nelfinavir, ritonavir, saquiavir,
telithromycin, voriconazole, grapefruit,
grapefruit juice; co-administration with
itraconazole ↑ gefitinib AUC by 88%; Avoid co-
administration if possible; if not, monitor
closely for gefitinib side effects
CYP3A4 Inducers rifampicin, rifapentine,
rifabutin, carbamazepine, phenytoin,
phenobarbital, St. John's Wort;
coadministration with rifampicin ↓ gefitinib
AUC by 85%. DO NOT take with St. John's
Wort. If must co-administer with pheneytoin or
rifampicin, consider gefitinib dose increase to
500 mg PO daily if no adverse side effects,
and monitor closely
CYP3A4 Substrates warfarin- increased
INR and bleeding possible, monitor INR and
decrease warfarin dose as needed
Ph Altering Drugs erlotinib GI absorption
is dependent on a low gastric pH; ranitidine
and bicarbonate ↓ gefitinib AUC by 44%;
avoid co-administration with proton-pump
inhibitors, or H2-inhibitors; use antacids if
needed, and administer 2 hours before or
after gefitinib
CYP3A4 Inhibitors May increase serum
levels of imatinib mesylate: (strong) atazanavir, clarithramycin, indinavir, itraconazole, grapefruit, grapefruit juice, ketoconazole, nefazodone, nelfinavir, ritonavir, saquiavir, telithromycin, voriconazole; AVOID co-administration; use cautiously if at all together with (moderate) amprenavir, aprepitant, diltiazem, fluconazole, verapamil; and (weak) cimitidine CYP3A4 inhibitors. If must be co-administered, assess closely for increased imatinib toxicity.
CYP3A4 inducers can lower imatinib
serum levels. If co-administered with:
rifampin, dexamethasone, phenytoin, carbamazepine, phenobarbital, rifabutin; increase imatinib dose by 50%. Do NOT give together with St. John's Wort CYP3A4 Substrates Imatinib interferes
with CYP3A4 metabolism of the following
drugs
● ↑ simvastatin levels: monitor LDL and concentrations; avoid concurrent administration dihydropyridine calcium channel blockers, HMG-CoA reductase inhibits may have ↑ serum levels; use cautiously and monitor patient closely ● eletriptan (Repax) do not administer within 72 hrs of imatinib; monitor VS closely Interference with drugs metabolized
by CYP2D6 if drugs metabolized by
CYP2D6 are co-administered with imatinib,
serum drug levels of these drugs will be
elevated; co-admiinister cautiously and
monitor closely;
Warfarin do not co-administer; use low
molecular weight heparin (LMWH)
Acetaminophen ↑ serum acetaminophen
serum levels
CYP3A4 inhibitors These drugs may
decrease metabolism of lapatinib resulting in
increased serum concentrations of lapatinib:
(strong) atazanavir, clarithramycin, grapefruit
juice, grapefruit, indinavir, itraconazole,
ketoconazole, nefazodone, nelfinavir,
ritonavir, saquiavir, telithromycin,
voriconazole. Avoid co-administration; if must
give together with strong inihibitor, monitor
closely for drug toxicity and consider reducing
lapatinib dose. Use cautiously if at all, and
monitor patient closely if co-administered with
(moderate) amprenavir, aprepitant, diltiazem,
fluconazole, verapamil; and (weak) cimetidine
CYP3A4 inhibitors.
CYP3A4 Inducers may decrease lapatinib
serum levels: carbamazepine, phenytoin,
rifampicin, phenobaribital, dexamethasone,
rifabutin, St. John's Wort. If must co-
administer, assess efficacy of lapatinib and
need for increased drug dose. Do NOT give
together with St. John's Wort
CYP3A4 and CYP2C8 substrates
Lapatinib inhibits both pathways so assess for
toxicity in co-administered drugs which are
metabolized by either pathway;
p-glycoprotein (Pgp) metabolism
(transport system) if lapatinib co-
administered with Pgp substrates (eg,
loperamide, dexamethasone), assess for
toxicity from increased substrate
concentration. Conversely, lapatinib is also a
substrate of Pgp so that if given with an
inhibitor of Pgp (eg, quinidine), lapatinib drug
levels are likely to be elevated; assess for
lapatinib toxicity
CYP3A4 Inhibitors These drugs may
increase serum levels of nilotinib- also
(strong) atazanavir, ketoconazole,
itraconazole, grapefruit, grapefruit juice,
indinavir, nefazodone, nelfinavir, ritonavir,
saquiavir, telithromycin, voriconazole;AVOID
co-administration with strong inhibitors; if
must co-administer, consider dose reduction
of nilotinib and monitor patient closely for
toxicity, including QT intervals on EKG. Co-
administer cautiously if at all drugs which are
moderate [amprenavir, aprepitant, diltiazem,
erythromycin, fluconazole, verapamil]or weak
[cimitidine] inhibtors of CYP3A4 ; monitor
closely for drug side effects.
Inducers of CYP3A4 May decrease
serum nilotinib concentrations: rifampin,
phenytoin, phenobarbital, carbamazepine,
dexamethasone, rifabutin, rifapentin, St.
John's Wort. Avoid co-administration if
possible. If co-administered, assess need for
increased nilotinib dose by 50%. Do NOT
give together with St. John's Wort.
Substrates:
● Nilotinib is an inhibitor of CYP3A4, competitive substrate so INR needs to be monitored closely and dose adjusted frequently [warfarin is metabolized by CYP2C9 and CYP3A4 so warfarin should be avoided if ● Nilotinib is a substrate of the efflux transporter P-gycoprotein (Pgp)- if administered with Pgp inhibitors (eg, quinidine), serum concentration of nilotinib will be increased; avoid co-administration CYP3A4 inhibitors no interaction
CYP3A4 inducers may increase the
metabolism of sorafenib and decrease its
serum level; rifampin, phenytoin,
phenobarbital, carbamazepine,
dexamethasone, rifabutin, rifapentin, St.
John's Wort. Avoid co-administration if
possible. If co-administered, assess need for
increased sorafinib dose. Do NOT give
together with St. John's Wort.
Substrates:
ifosfamide) and CYP2C8 (eg,
rapaglinide, amiodarone, ibuprofen,
loperamide): substrate drug serum
levels increased ; monitor patient
closely for drug toxicity
UGT1A9 (eg, propofol) : sorafinib
inhibits glucuronidation by these
pathways so substrate serum levels
may be increased
CYP2C9 substrate
potential increased INR; monitor and correct warfarin dose frequently Chemotherapy (other) interactions:
● Docetaxel: ↑ 36-80% docetaxel AUC; ↑ Cmax 16-32%; co-administer with caution, if at all ● Doxorubicin: ↑ 21% AUC; use together ● Fluorouracil: ↑ 21-47% as well as ↓ 10% in fluorouracil AUC; use caution when co-administering with 5-FU/leucovorin CYP3A4 Inhibitors These drugs may
increase serum levels of sunitinib: (strong)
atazanavir, clarithromycin, ketoconazole,
itraconazole, grapefruit, grapefruit juice,
indinavir, nefazodone, nelfinavir, ritonavir,
saquinavir, telithromycin, voriconazole;
AVOID co-administration with strong
inhibitors; if must co-administer, consider
dose reduction of sunitinib to 37.5 mg PO
daily and monitor patient closely for toxicity
and effect. Co-administer cautiously if at all
drugs which are moderate [amprenavir,
aprepitant, diltiazem, erythromycin,
fluconazole, verapamil]or weak [cimitidine]
inhibtors of CYP3A4; monitor closely for drug
side effects.
Inducers of CYP3A4 May decrease
serum sunitinib concentrations: rifampin,
phenytoin, phenobarbital, carbamazepine,
dexamethasone, rifabutin, rifapentin, St.
John's Wort. Avoid co-administration if
possible. If co-administered, assess need for
increased sunitinib dose to a maximum of
87.5 mg PO daily. Do NOT give together with
St. John's Wort.
Strong CYP3A4 Inhibitors May increase
serum temsirolimus levels (strong):
Clarithromycin, itraconazole, ketoconazole,
atazanavir, indinavir, nefazodone, nelfinavir,
ritonavir, saquinavir, telithromycin, grapefruit,
grapefruit juice, and voriconazole. Avoid co-
administration; if must be given together,
consider temsirolimus dose decrease to 12.5
mg weekly; when interacting drug
discontinued, allow 1-week wash-out period,
then resume dose taking prior to adding
interactive drug
Strong Inducers May decrease serum
temsirolimus level: dexamethasone,
phenytoin, carbamazepine, rifampin, rifabutin,
rifampacin, pentobarbital. If must give
together, consider temsirolimus dose
increase to 50 mg weekly; when interacting
drug is discontinued, resume dose given prior
to adding interacting drug. Teach patient NOT
to take St. John's Wort.
Strong CYP3A4 Inhibitors May increase
serum tretinoin level (strong): Clarithromycin, itraconazole, ketoconazole, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, grapefruit, grapefruit juice, and voriconazole; also erythromycin, cimetidine, verapamil, diltiazem, and cyclosporine: no data exists to show increased or decreased effect. However, ketoconazole was shown to ↑ tretinoin plasma AUC by 72%. Use together cautiously if at all.
Strong CYP 3A4 Inducers May decrease
serum tretinoin level: dexamethasone,
phenytoin, carbamazepine, rifampin, rifabutin,
rifampacin, pentobarbital. No data exists to
show increased or decreased effect Use together cautiously.
Substrates antifibriloytic agents (eg,
tranexamic acid, aminocaproic acid, aprotinin:
may cause fatal thrombotic complications;
use together cautiously if at all
References
● Beijnen JH, Schellens JH. Drug interactions in oncology. Lancet Oncol 2004;5: 489-496.
● Lynch T, Price A. The effects of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician 2007; 76(3): 391-396 ● Meijerman I, Beijnen JH, Schellens JHM. Herb-drug interactions in oncology: Focus on mechanisms of induction. The Oncologist 2006; 11:742-752 ● Scripture CD, Figg WD. Drug interactions in cancer therapy. Nat Rev Ca 2006; 6(7):546-558 ● Sparreboom A, Cox MC, Acharya MR, Figg WD Herbal remedies in the United States: Potential adverse interactions with anti-cancer agents J Clin Oncol 2004;22(12): 2489-2503 ● Zhou S, Gao Y, Jiang W et al. Interactions of herbs with cytochrome P450. Drug Metab Rev 2003;35: 35-98.

Source: http://static.ons.org/Online-Courses/ChemoRenewal/readings/p450.pdf