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Disclosures

• Nothing to disclose

Clinical Pearls: Significant Drug Interactions

Teresa Kam, PharmD, CPP University of North Carolina Medical Center

Learning Objectives Patient Case

• Describe the classifications of drug interactions JW is a 43 yo male admitted for newly diagnosed Ph+ B- • Explain clinical outcomes resulting from drug interactions cell ALL • Identify examples and management strategies of drug • Past Medical History • Labs interactions in the oncology population – Hyperlipidemia 138 102 18 106 – Depression 4.1 24 0.96 • Allergies Ca: 8.4 Phos: 4.3 – Penicillin Mg: 2.3 Uric acid: 6.9 LDH: 764

7.1 15.3 16 20.2 ANC: 0.3

Patient Case, cont. Prevalence Induction Chemotherapy Other Medications • At least one potential drug-drug interaction found in 27-58% • Dasatinib • Allopurinol of ambulatory cancer patients • Cyclophosphamide + Mesna • Levofloxacin (prophylaxis) • At least one potential severe drug interaction involving • Vincristine • Pantoprazole chemotherapy found in 14% of patients ≥70 years old • Doxorubicin • Posaconazole (prophylaxis) • At least one potential drug-drug interaction in 46% of patients • Dexamethasone • Sertraline receiving oral anticancer drugs • IT Cytarabine + • Simvastatin • Drug-drug interactions estimated to be cause of approximately 4% of deaths Hydrocortisone • Valacyclovir (prophylaxis) • IT Methotrexate + • Ondansetron premed + prn Hydrocortisone • Prochlorperazine prn

Popa MA, et al. J Geriatr Oncol 2014; http://dx.doi.org/10.1016/j.jgo.2014.04.002. Van Leeuwen RW, et al. Br J Cancer 2013; 108: 1071-1078.

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Current Trends Cost of Drug Interactions

• FDA estimates that >25% of antineoplastic agents in • Morbidity and mortality due to drugs costs $136 billion per year pipeline now are planned as oral drugs • Drug interactions represents 3-5% of in-hospital medication errors • Chronic daily dosing of oral chemotherapies • Drug interactions may contribute to 20-30% of adverse drug • Chronic disease state = Long-term cancer treatment reactions • Longer survival time = Increased medications for • Drug-drug interactions associated with longer length and increased treatment of comorbidities cost of hospitalization (OR 4.38 and 1.79, respectively)

Preventable Adverse Drug Reactions: A Focus on Drug Interactions. Available at: www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm110632.htm Weingart SN, et al. J Natl Compr Canc Netw 2008;6(supp3):S1-S14. Kohler GI, et al. Int J Clin Pharmacol Ther 2000;38:504-513. Riechelmann RP, et al. J Natl Cancer Inst 2007; 99: 592-600. Moura C, et al. J Pharm Pharmaceut Sci 2009;12:266-272.

Medications Involved Risk Factors for Drug Interactions

• Chemotherapy (13-29%) • – Traditional Number of drugs – Oral chemotherapy – Each additional medication (OR 1.4; P<0.0001) – Hormonal agents – Use of ≥8 drugs associated with potential drug • Supportive care medications interaction (P=0.0004) – Anti-emetics • – Pain medications Use of over the counter drugs (OR 0.56; P=0.045) – Anti-infectives • Type of medication (vs. supportive care meds only) • Non cancer-related medications – Drugs for comorbid conditions only (OR 8.6; • Complementary alternative P<0.0001) medications • Cancer type – Brain (OR 6.7; P=0.0025)

Riechelmann RP, et al. Cancer Chemother Pharmacol 2005;56:286–290. Popa MA, et al. J Geriatr Oncol 2014; http://dx.doi.org/10.1016/j.jgo.2014.04.002 Riechelmann RP, et al. J Natl Cancer Inst 2007; 99: 592-600. Riechelmann RP, et al. J Natl Cancer Inst 2007; 99: 592-600. Van Leeuwen RW, et al. Ann Oncol 2011; 22:2334-2341.

Effects from Drug Interactions Audience Response Question #1

• Efficacy Severity • Which one of these factors increases JW’s risk for drug – Increase or decrease in interactions? anti-neoplastic or other A. Age drug effect 14% 9% B. Number of medications • Safety Major C. Type of cancer diagnosis – QT-interval prolongation Moderate – Central nervous system Minor D. Sex depression 77% – Increased bleeding risk

Riechelmann RP, et al. J Natl Cancer Inst 2007; 99: 592-600. B. Number of medications

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Classification of Drug Interactions Pharmaceutical Interactions

• Pharmaceutical • Two or more drugs are altered due to physical or chemical • Pharmacokinetic incompatibility when combined • Mitomycin mixed in Dextrose 5% (D5W) versus NaCl 0.9% (NS) • Pharmacodynamic – At 12 hours: concentrations decreased 10% in NS vs. 33% in D5W – At 24 hours: concentrations decreased 23% in NS vs. 42% in D5W

Lam MS, et al. J Oncol Pharm Practice 2003; 9: 45-85. Quebbeman EJ, et al. Am J Hosp Pharm 1985;42:1750-1754.

Pharmacokinetic Interactions Effects of Gastric pH Modifier DASATINIB (and other TKIs) • One drug alters • pH-dependent solubility absorption, • Randomized, 3-treatment, crossover study in healthy patients distribution, • Compared to dasatinib alone metabolism, or – No difference in exposure when antacid given 2 hours before dasatinib excretion of – Dasatinib exposure reduced by ~60% when famotidine given 10 hours another drug before dasatinib • Recommendations – H2 receptor antagonists and proton pump inhibitors (PPIs) should not be given with dasatinib – Antacids may be given if doses are separated from dasatinib by 2 hours

Lam MS, et al. J Oncol Pharm Practice 2003;9:45-85. Scripture et al. Nature Reviews Cancer 2006;6:546–558. Eley T, et al. J Clin Pharmacol 2009;49:700-709.

Methotrexate + PPIs: Methotrexate + PPIs: Significant Interaction? Significant Interaction? SIGNIFICANT • Theoretical mechanisms • Survey of FDA Adverse Event Reporting System (AERS) – PPI inhibition of renal H+/K+ -ATPase decreases found evidence of PPI interference of methotrexate active tubular secretion of methotrexate elimination – Inhibition of breast cancer resistance protein • Retrospective analysis identified risk factors for delayed (BCRP) involved in methotrexate transport methotrexate clearance – Abnormally high serum creatinine and AST • Adverse effects • Co-administration of PPIs – Increased mucositis • Within group of patients with delayed elimination of – Enhanced myelosuppression methotrexate: significantly more PPI given vs. no PPI given – Nephrotoxicity (41.9% vs. 20%, P<0.05)

Bezabeh S, et al. Oncologist 2012;17:550-554. Reeves DJ, et al. Br J Clin Pharmacol 2014; doi: 10.1111/bcp.12384 Suzuki K, et al. Br J Clin Pharmacol 2008;67:44-49.

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Methotrexate + PPIs: Methotrexate + PPIs: Significant Interaction? Significant Interaction? INSIGNIFICANT INSIGNIFICANT • Retrospective analysis of methotrexate elimination in • After controlling for confounders and possible clustering, PPI patients receiving high dose methotrexate (N=56 patients; not significant predictor of methotrexate level, delayed 201 cycles) elimination, or time to level <0.1 micromole/L • Conclusions PPI No PPI P value – Lack of association between use of PPI and methotrexate elimination Methotrexate level (micromole/L) At 24 hr 8.0 3.9 0.013 – Clinical significance of potential interaction is likely At 48 hr 0.280 0.215 NS At 72 hr 0.075 0.05 0.037 small Delayed elimination (%) – Future prospective trial would allow for control of At 24 hr 19.2 20.2 NS multiple cycles At 48 hr 20.0 11.3 NS At 72 hr 36.2 33.7 NS

Reeves DJ, et al. Br J Clin Pharmacol 2014; doi: 10.1111/bcp.12384 Reeves DJ, et al. Br J Clin Pharmacol 2014; doi: 10.1111/bcp.12384

Cytochrome P450 (CYP) Vincristine + Azole Antifungals

• CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 • Vincristine metabolism mediated by CYP3A subfamily responsible for estimated >90% of drug oxidation and substrate of P-glycoprotein (P-gp) • CYP3A4 • Triazole antifungals inhibit CYP3A4 – Metabolizes ~50% of drugs • Itraconazole and posaconazole also inhibit P-gp – Primarily in liver, but presence in small intestines • Increased adverse effects plays important role in first-pass metabolism – Severe neurotoxicity (peripheral neuropathy) • Genetic polymorphisms identified for CYP2A6, CYP2D6, CYP2C9, – Severe GI symptoms: constipation, ileus, abdominal and CYP2C19 pain/distension • Induction typically seen several days to weeks after drug – Electrolyte abnormalities (hyponatremia and SIADH) administration – Seizures • Inhibition seen immediately after drug administration

Blower P, et al. Crit Rev Oncol Hematol 2005; 55: 117-142. Moriyama B, et al. Mycoses 2012;55:290-297.

Vincristine + Azole Antifungals Audience Response Question #2

• Literature review and analysis of vincristine and azole • How would you manage JW’s vincristine-posaconazole antifungal case reports interaction? • No case reports found for fluconazole A. Continue with concomitant use of both • Median time to adverse drug interaction with vincristine B. Hold vincristine – Itraconazole: 9.5 days C. Empirically dose reduce vincristine – Posaconazole 13.5 days D. Switch posaconazole to alternate anti-fungal – Voriconazole: 30 days • Recommendations – Use alternative non-azole antifungal agent (i.e. echinocandins or liposomal amphotericin B) – Discontinue azole antifungal prior to vincristine administration

D. Switch posaconazole to alternate anti-fungal Moriyama B, et al. Mycoses 2012;55:290-297.

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Pharmacodynamic Interactions QT Prolongation • Torsade de pointes (TdP) more likely to occur with: • Mechanism of action of multiple drugs influence the same – QTc > 500 msec physiological process – Long intervals of prolongation • Can be additive, synergistic, or antagonistic • Incidence of TdP: range from <1 in 10,000 to 1 in 100,000 cases • Considerations in oncology patients Pharmacodynamic Interaction Incidence (%) – Prolonged QTc interval at baseline – General risk factors: older age, underlying coronary CNS Interactions 73% disease, previous myocardial infarction GI Interactions 8% – Cancer-related risk factors: altered drug clearance, QT Prolongation 4% low electrolyte levels, multiple offending medications Other 15%

Van Leeuwen RW, et al. Br J Cancer 2013;108:1071-1078. Blower P, et al. Crit Rev Oncol Hematol 2005;55:117-142. Brell JM, et al. Prog Cardiovasc Dis 2010;53:164-172.

Common QT Prolonging Agents Recommendations

Class Examples • Check EKG 24-48 hours prior to and 1 week after Tyrosine kinase inhibitors (TKIs) Crizotinib, lapatinib, nilotinib, concomitant therapies of multiple QT prolonging pazopanib, sorafenib, sunitinib, medications vandetanib, vemurafenib • Azole antifungal agents Fluconazole, voriconazole, Clinical concern when QTc prolongation of ~>500 msec or posaconazole change from baseline of >60 msec 5HT antagonist antiemetic Ondansetron, granisetron, • Baseline EKG and thorough cardiac and medication history palonosetron, dolasetron should be obtained Arsenic trioxide • Monitor and aggressively replace electrolytes (i.e. K+, Mg2+, Fluoroquinolones Levofloxacin, moxifloxacin, and Ca2+) ciprofloxacin • Preclinical identification of QT effects should have expanded Macrolide antibiotics Clarithromycin, azithromycin, QT assessment in subsequent trials erythromycin

Van Leeuwen RW, et al. Lancet Oncol 2014;15:e315-326. Brell JM, et al. Prog Cardiovasc Dis 2010;53:164-172. Brell JM, et al. Prog Cardiovasc Dis 2010;53:164-172. Strevel EL, et al. J Clin Oncol 2007;25:3362-3371.

Current Strategies

• Drug interaction alerts at point of Computerized Physician Order Entry (CPOE) • Drug interaction alerts upon pharmacist verification • Admission medication reconciliation • Discharge medication reconciliation • Adverse event reporting (i.e. FDA MedWatch) STRATEGIES TO PREVENT DRUG INTERACTIONS

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Alert Fatigue Therapeutic Drug Monitoring

• Frequent “false” alarms or warnings that may not be clinically • Rationale significant – Marked inter-individual pharmacokinetic variability • Institute for Safe Medication Practices (ISMP) – Relationship identified between plasma recommendations concentrations and pharmacodynamic end points – Reduce sensitivity of alert system • Oral targeted chemotherapy – Significant drug-drug interactions – Identify conditions that lead to the most serious – Chronic usage adverse events – Availability of bio-analytical methods – Report invalid or clinical insignificant warnings – Limited intra-individual PK – Generate report of bypassed alerts – Expensive treatments

ISMP. Heed this warning! Don’t miss important computer alerts. Available at: https://www.ismp.org/newsletters/acutecare/articles/20070208.asp Paci A, et al. Eur J Cancer 2014; http://dx.doi.org/10.1016/j.ejca.2014.04.014

Therapeutic Drug Monitoring Therapeutic Drug Monitoring EXAMPLES • Imatinib • Challenges – Cmin associated with hematological, cytogenetic, and – Time and cost of lab draws, processing, and molecular responses and progression-free survival interpretation – Free AUC relationship with number of toxicities • High dose methotrexate – Shipment to laboratory if not done at location – Monitoring of drug elimination and prevention of – Prospective validation of TDM challenging to toxicity perform – Does not provide guidance for dose adjustment – Relationships between PK and PD are more • Busulfan difficult to ascertain for drug combinations – Target AUC range minimizes non-relapse mortality and toxicities, while maximizing efficacy – Accounting for other specific factors

Widmer N, et al. Eur J Cancer 2014; http://dx.doi.org/10.1016/j.ejca.2014.04.015 Paci A, et al. Eur J Cancer 2014; http://dx.doi.org/10.1016/j.ejca.2014.04.014 Russell JA, et al. Biol Blood Marrow Transplant 2013;19:1381-1386. Paci A, et al. Eur J Cancer 2014; http://dx.doi.org/10.1016/j.ejca.2014.04.014

Role for Pharmacists Audience Response Question #3

• Link between oncologists and general practitioners • Which of the following do you think is the most • Reporting adverse drug events effective way to prevent adverse events caused by drug • Therapeutic drug monitoring interactions? • Complementary alternative medicine and food interactions A. Increase adverse event reporting • Tempering alert fatigue B. Therapeutic drug monitoring C. Refining clinically significant drug interaction alerts D. Increase accuracy of medication reconciliation

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Conclusion

• Drug-drug interactions can be categorized into pharmaceutical, pharmacokinetic, and pharmacokinetic interactions • Despite significant advancements in technologies and clinical knowledge, drug-drug interactions continue to account for costly adverse drug events • The role for pharmacists is expanding and Clinical Pearls: Significant Drug Interactions evolving as new strategies for identifying clinical outcomes of interactions are explored and Teresa Kam, PharmD, CPP developed University of North Carolina Medical Center

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