Drug Interactions in Breast Cancer Patients

Noha El Baghdady, M.Sc.

What do you think about these combinations ?

• FAC protocol + Cabamazepine+ Allopurinol • Capecitabine + Warfarin• Tamoxifen + Warfarin• Lapatinib + Voriconazole

Drug Interactions

An adverse drug response produced by the administration of a drug or co-exposure of the drug with another substance, which modifies the patient’s response to the drug.

Introduction

• Drug interactions are an important cause of patient visits to emergency departments (Raschetti R., et al., 1999)

• Approximately 20% to 30% of all adverse events (AEs) are caused by interactions between drugs (Sasu-Tenkoramaa & Fudin, 2013)

Cancer Outpatients

In cancer patients, the exact incidence of DDIs are unknown but it has been estimated that about one-third of cancer outpatients are at risk of developing a DDI (Sasu-Tenkoramaa & Fudin, 2013).

Egypt

• Few published literatures reviewed role of the clinical pharmacist in Egypt, and limited number of hospitals in Egypt involving pharmacist in the therapeutic care of the patients (Sabry, Farid, & Aziz, 2009).

• In the oncology unite in one of the Egyptian Hospitals, a Study was done to review the most frequent DDIs to identify the Impact of the clinical pharmacists’ work on the patient care.

Adverse Drug Events3%

Drug in-teractions

29%

Dose ad-justment

8%

Drug selection33%

Improper Dosage24%

Lab Monitoring2%

Oncology Clinical Pharmacy Recommendations

Adverse Drug Events

Drug interactions

Dose adjustment

Drug selection

Improper Dosage

Lab Monitoring

Egypt

More than 30% of the patients reported that they did not know the

purpose of at least one of their drugs and only read package inserts (Pis)

selectively. Whereas 36% read about drug interactions, more reported

reading about side effects (65%) and contraindications (60%) in PIs. Sixty-

nine per cent of patients reported that they needed more information

about their drugs.

Sources of drug information for patients with chronic conditions in Alexandria, Egypt, Amin ME, Chewning BA, Wahdan AM.(Feb. 2011)

Pharmaceutical interactions

Examples

• Invanze(ertapenem), Phenytoin, Herceptin # Gsw 5%.

• Noradrenaline, Ambizome, Fungizone & Oxaliplatin # Ns 0.9%.

• Tienam # Ringer Lactate.• Dopamine # sodium bicarbonate.• Penicillin + Aminoglycosides … Insol. Precept.• Ciprofloxacin + Furosemide …..

Pharmacokinetic Interactions(PK) • The most common PK interactions

in oncology are those that affect drug metabolizing enzymes:

1- The cytochrome P450 (CYP450) enzymes2- The efflux pump p-glycoprotein (P-gp)3- Protein-binding displacement (generally albumin or α-glycoprotein).

Pharmacodynamic drug interaction

• One drug causes a change in patient response to another drug without altering that drug’s pharmacokinetics

Pharmacogenetic interactions

Chemotherapy

Ketoconazole

CarBAMazepineAzithromycin

Fosphenytoin

FLUoxetine

CycloSPORINE

Doxorubicin

CYP3A4 Inducers (Strong)

P-glycoprotein Inhibitors

CYP2D6 Inhibitors (Strong)

D

DOXOrubicin (Conventional) / CYP2D6 Inhibitors (Strong)FLUoxetine; Terbinafine (Systemic)

Risk Rating D: Consider therapy modification

Summary CYP2D6 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional).

Severity Major Reliability Rating Fair

Patient Management Seek alternatives to strong CYP2D6 inhibitors in patients treated with doxorubicin whenever possible.

CarBAMazepine

Allopurinol

Fosphenytoin

Cyclophosphamide

CYP2B6 & CYP3A4 Inducers (Strong)

D

4-hydroxycyclophosph

amide

CYP 2B6

Cyclophosphamide / CYP2B6 Inducers (Strong)

CarBAMazepine; Fosphenytoin; PHENobarbital; Phenytoin

Risk Rating D: Consider therapy modification

Summary CYP2B6 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Cyclophosphamide. More specifically, strong CYP2B6 inducers may increase the rate of cyclophosphamide conversion to its primary active metabolite, 4 hydroxycyclophosphamide.

Severity Major Reliability Rating Fair

Patient Management Seek alternatives to strong CYP2B6 inducers when possible in patients receiving cyclophosphamide. Monitor patients receiving these combinations closely for evidence of increased cyclophosphamide toxicity.

Discussion Cyclophosphamide is a prodrug that is converted metabolically to its primary active form (4-hydroxycyclophosphamide) by several enzymes, including CYPs 2A6, 2B6, 2C9, 2C18, 2C19, and 3A.

Cyclophosphamide / Allopurinol

Risk Rating C: Monitor therapy

Summary Allopurinol may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, bone marrow suppression.

Severity Moderate Reliability Rating Good

Patient Management Monitor for toxic effects (eg, changes in CBC) of cyclophosphamide if allopurinol is initiated or the dose is increased, especially in patients receiving long-term allopurinol therapy (eg, for gout).

Discussion Allopurinol has been reported to increase the bone marrow suppressant

effects of cyclophosphamide as much as threefold. A pharmacokinetic study in 11 individuals demonstrated an average increase in toxic

cyclophosphamide metabolites of 37.5%.

Capecitabine • Antacids that contain aluminium and

magnesium can increase the bioavailability of capecitabine.

• Altered coagulation has been reported in patients who have taken warfarin concurrently with capecitabine.

• Capecitabine and Pantoprazole Impact of Co-administered Drugs on Drug Monitoring of Capecitabine in Patients with Advanced Colorectal Cancer, 3376, 3371–3376.

Vitamin K Antagonists / Capecitabine

Risk Rating D: Consider therapy modificationSummary Capecitabine may increase the serum concentration of Vitamin K Antagonists. (inc. warfarin by 57% & dec. its clearance by 37%)

Severity Moderate Reliability Rating GoodPatient Management Monitor INR and signs/symptoms of bleeding closely when starting or stopping capecitabine in a patient receiving a vitamin K antagonist (e.g., warfarin).

Anticoagulant dose adjustment will likely be necessary, and effects may increase with subsequent cycles of capecitabine.

Targeted Therapy

Tyrosine Kinase Inhibitors

• The tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myelogenous leukemia (CML) are involved in multiple drug interactions.

• Among the epidermal growth factor receptor (EGFR) inhibitors, erlotinib (Tarceva) represent high risk for common CYP450 interactions. Lapatinib (Tykerb) is a TKI that inhibits two EGFR inhibitors: ERB1 and ERB2 (HER2). It is both a substrate and an inhibitor of CYP3A4.

• Lapatinib & Cyp 3A4 inhibitor (Voriconazole – Clarithromycin)

• Patient Management Use of strong CYP3A4 inhibitors should generally be avoided during treatment with lapatinib.

• If an overlap in therapy cannot be avoided, consider reducing lapatinib dose to 500 mg/day during, and within 1 week of completing, treatment with the strong CYP3A4 inhibitor

Hormonal Therapy

Tamoxifen

• Tamoxifen is a selective estrogen receptor modulator used in breast cancer treatment.

• Compared to tamoxifen, endoxifen and 4-hydroxytamoxifen have a 100-fold greater affinity for the estrogen receptor and 30 to 100-fold potency in suppressing any estrogen-dependent cell proliferation.

• Endoxifen and 4-hydroxytamoxifen have a 100-fold greater affinity for the estrogen receptor and 30 to 100-fold potency in suppressing any estrogen-dependent cell proliferation.

Title Tamoxifen / CYP2D6 Inhibitors (Strong)

Risk Rating X: Avoid combination

Summary CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, strong CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites.

Severity Major Reliability Rating Good

Patient Management Avoid concurrent use of strong CYP2D6 inhibitors with tamoxifen when possible as the combination may be associated with a reduced clinical effectiveness of tamoxifen.

CYP2D6 Inhibitors (Strong) Interacting Members BuPROPion; Cinacalcet; Cocaine; Delavirdine; FLUoxetine; Lopinavir; Methotrimeprazine; PARoxetine; QuiNIDine; Ritonavir; Stiripentol; Terbinafine (Systemic); Thioridazine; Tipranavir

Tamoxifen

TamoxifenVitamin K Antagonists:

International labeling: This combination is not specifically contraindicated in some non-U.S. labels.

Risk Rating X: Avoid combinationSummary Tamoxifen may increase the serum concentration of Vitamin K Antagonists. Severity Major Reliability Rating FairPatient Management Combined use of tamoxifen with warfarin is contraindicated in U.S. labeling due to risk of excessive anticoagulant response and resultant increased risk of bleeding. It is expected that tamoxifen would interact with other coumarin derivatives in a similar manner. Of note.

In The Practice

Onset Of the Action

Individual Variations

Many interactions will not be obvious in most

individuals, but when an interaction occurs, it may

lead to considerable morbidity, or mortality.

Clinical Significance

THE Magic KEY

Separation

Monitor Clinical Response

Check

Patient Education

FDA Warning

THANK YOU