Oral Chemotherapy PRESENTED BY: SANDEEPKUMAR B ALABB IGAR I

CYCLE 7 : QUAL ITAS PHARMACY SERV ICES

FEBRUARY 1 ST, 2 0 1 6

Objectives •Review the etiology and epidemiology of cancer

•Overview of underlying principles of chemotherapy

•Understand the pharmacology of the common oral chemotherapy agents dispensed at Qualitas Pharmacy Services

Disease State Overview

Background •Oral chemotherapy agents primarily target specific molecular components, are typically cytostatic, and are involved in long-term therapy

•Many new chemotherapy agents are exclusively available as oral formulations

Epidemiology •In 2015, there were 1.7 million cancer diagnoses and 600,000 patients cancer-related deaths

•Approximately 39.6 percent of men and women will be diagnosed with cancer

•Most common cancers:

PROSTATE

BREAST LUNG

Etiology •The exact cause of cancer is unknown

•Theory: multi-step process of initiation, promotion, and progression that involves an interaction between environmental, genetic, and immunologic factors • Initiation: exposure to a carcinogen that causes genetic damage and

leads to cellular mutations

• Promotion: carcinogens alter the body's internal environment to promote the growth of mutated cells

• Progression: further changes to cellular DNA allows for tumor invasion into normal tissue and eventually metastasizes

Diagnosis •Diagnosis varies by the specific type of cancer that is suspected

•Possible methods to diagnosis cancer includes: • History and Physical Exam

• Imaging

• Biochemical markers

• Tissue biopsy

Signs & Symptoms •Initially, many cancers present asymptomatically or with non-specific symptoms

•As the cancer progresses, symptoms may reflect the specific tissues/organs the cancer is affecting

•Many organs and areas of the body may become affected as the cancer begins to metastasize into surrounding areas

Treatment •Ideal chemotherapeutic agents are tumor-cell specific

•Chemotherapy agents can affect tumor cells through a variety of mechanisms: alter the cell cycle, inhibit enzymes, block growth factors and receptors, and modify biologic responses

•Certain chemotherapy agents are preferred over others due to the presence of resistance or the predominant pathways that are involved in the progression of specific cancers

Oral Agents

Capecitabine (Xeloda®) •Indication: Local or metastatic colon cancer; metastatic breast cancer

•Mechanism of Action: capecitabine is a prodrug of fluorouracil • Acts as a pyrimidine

antimetabolite inhibits thymidylate synthetase interferes with DNA synthesis

Capecitabine (Xeloda®) •Adverse Drug Reactions: overall, oral capecitabine is less toxic than the IV form, 5-FU • Hand-and-foot syndrome

• GI events

• Hepatotoxicity

• Cardiotoxicity

• Box warning: increased risk of bleeding and death when taken with coumarin-derived anticoagulants

Capecitabine (Xeloda®) •Monitoring and ADR Management • Monitor INR closely if receiving concomitant warfarin

• Monitor for dermatologic reactions

• Identify signs of cardiotoxicity

• Interactions • Other immunosuppressants may enhance the

immunosuppressive effect

• Toxic effects of vaccines are enhanced

• Therapeutic effects of vaccines are diminished

• Capecitabine is a strong CYP2C9 inhibitor

Everolimus (Afinitor®) •Indication • Hormone positive, HER2-negative breast cancer in

postmenopausal women in combination with exemestane

• Pancreatic neuroendocrine tumors

• Renal angiomyolipoma and Renal cell carcinoma

• Subependymal giant cell astrocytoma

•Mechanism of Action: mTOR Inhibitor • Inhibits the mammalian Target Of Rapamycin (mTOR) →

prevents protein synthesis and cell proliferation

• Reduces angiogenesis by inhibiting vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF-1) expression

Everolimus (Afinitor®) •Adverse Drug Reactions • Box Warning: Immunosuppression increases

susceptibility to infection and risk of malignancies

• Hyperglycemia, hyperlipidemia, and hypertriglyceridemia

• Nephrotoxicity

•Monitoring and ADR Management • CBC with differential

• Monitor hepatic and renal function

• Fasting serum glucose and lipid profile

• Monitor for signs and symptoms of infection or malignancy

•Interactions

•Other immunosuppressants may enhance the immunosuppressive effect

•Toxic effects of vaccines are enhanced

•Therapeutic effects of vaccines are diminished

•CYP3A4 inhibitors increase the concentration of everolimus

•CYP3A4 inducers decrease the concentration of everolimus

Everolimus (Afinitor®)

Nilotinib (Tasigna®)

Imatinib (Gleevec®) •Mechanism of Action: binds to BCR-ABL tyrosine kinase and blocks its activity inhibits proliferation of leukemic cells

•Indication:

Nilotinib (Tasigna®) Imatinib (Gleevec®)

Philadelphia chromosome positive chronic

myelogenous leukemia (Ph+ CML)

Philadelphia chromosome positive chronic

myelogenous leukemia (Ph+ CML)

Philadelphia chromosome positive acute

lymphoblastic leukemia (Ph+ ALL)

Aggressive systemic mastocytosis

Dermatofibrosarcoma

Gastrointestinal stromal tumors

Chronic eosinophilic leukemia

Nilotinib (Tasigna®)

Imatinib (Gleevec®) •Adverse Drug Reactions • Nilotinib (Tasigna®)

• Contraindicated if patients have a prolonged QT interval or experiencing hypokalemia or hypomagnesia

• Box Warning: QT prolongation

• Peripheral edema

• Rash, pruritis

• Imatinib (Gleevec®)

• Severe heart failure (HF) and left ventricular dysfunction (LVD)

• Severe hemorrhage

• Severe hepatotoxicity

• Skin rash, multiforme erythema, SJS, DRESS

Nilotinib (Tasigna®)

Imatinib (Gleevec®) •Monitoring and ADR Management •Nilotinib (Tasigna®)

• Monitor cardiovasular status

• Monitor fluid retention, electrolyte levels

• Imatinib (Gleevec®) • Take with a meal and water, and divide large doses to

reduce GI side effects

• Monitor for signs or symptoms of CHF and LVD in patients with cardiac disease, risk factors for cardiac failure, or history of renal failure

• Liver function tests

Nilotinib (Tasigna®)

Imatinib (Gleevec®)

•Interactions •Other immunosuppressants may enhance the immunosuppressive effect

•Toxic effects of vaccines are enhanced

•Therapeutic effects of vaccines are diminished

•Both nilotinib and imatinib are CY3A4 substrates; strong CYP3A4 inducers and inhibitors are not recommended to be used concomitantly

•Antiarryhtmics, QT-prolonging drugs, and PPI’s are not recommended to be used concomitantly with nilotinib

Summary •The development of cancer involves a complex interaction between environmental, genetic, and immunologic factors leading to the initiation, promotion, and progression tumor cells.

•Many new and old chemotherapy agents are becoming available as oral formulations.

•Currently approved oral chemotherapy agents can be used to treat a wide range of cancers through a variety of mechanisms. But they also pose many of the same clinical risks as their parenteral counterparts.

References 1. "U.S. Food and Drug Administration." Hematology/Oncology (Cancer) Approvals & Safety Notifications. Web. 19 Jan. 2016.

2. Weingart, S., P. Bach, and S. Johnson. "NCCN Task Force Report: Oral Chemotherapy." Journal of the National Comprehensive Cancer Network 6.3 (2008): Web. 19 Jan. 2016.

3. Colomer, R., E. Alba, and A. Gonzalez-Martin. "Treatment of Cancer with Oral Drugs: A Position Statement by the Spanish Society of Medical Oncology (SEOM)." Annals of Oncology 21.2 (2010): 196-98. Web.

4. "Cancer Statistics." National Cancer Institute. Web. 19 Jan. 2016.

5. "Signs and Symptoms of Cancer." American Cancer Society. N.p., 11 Aug. 2014. Web. 19 Jan. 2016.

6. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Hudson, OH. Available at: http://online.lexi.com. 19 Jan. 2016.

7. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com. 19 Jan. 2016.

8. Pereiras, Maribel. "Pharmacology of Antineoplastic Agents“” Rutgers University. Oct. 2015. Lecture.

9. Pereiras, Maribel. "Principles of Chemotherapy and Carcinogenesis”. Rutgers University. Oct. 2015. Lecture.

10. Peach, D. "Xeloda 4.8.7." Donna Peach. N.p., 05 Aug. 2012. Web. 19 Jan. 2016

Thank You! Questions?

Quiz Time!