New Drug Update 2012

1. New Drug Update 2012 Nancy Letassy, PharmD, CDE Professor University of Oklahoma College of Pharmacy

2. 2012 NewMolecularentities

3. Belviq® (locaserin) • Approved as an adjunct to a reduced caloric diet and increased activity for chronic weight management in adult with a BMI of >30 or >27 in presence of type 2 diabetes, hypertension, or dyslipidemia • Serotonin 2c agonist that activates receptor in the brain to decrease food consumption and promote satiety.

4. Belviq® (locaserin) Adverse reactions: • Headache, dizziness, euphoria, cognitive impairment, hallucinations • Fatigue, dry mouth, diarrhea, constipation • Hypoglycemia in patients on a glucose lowering agent • Bradycardia • Decreased white and red blood cells

5. Qsymia® (phentermine and topiramate) • Indicated for chronic weight management in obese or overweight adults with at least one weight-related comorbidity such as hypertension, type 2 diabetes or dyslipidemia • Combines low doses of phentermine and extended-release topiramate • Weight loss on average 20 pounds in one year • Previously called Qnexa®

6. Qsymia® ADR • cognition, fatigue, dizziness, dysgeusia, insomnia, constipation, dry mouth, tachycardia, depression, anxiety, kidney stones, decreased sweating and increased body temperature, hypokalemia, metabolic acidosis, hypoglycemia, hypotension.

7. Qsymia® • Ensure adequate fluid intake to decrease risk of renal stones • Advise patients to watch for decreased sweating and increased body temperature with increased physical activity in hot weather

8. Qsymia®ADR • Monitor for suicidal thoughts and behavior • Monthly pregnancy tests • Monitor blood pressure • Monitor blood glucose in those on glucose lowering agents • Check potassium, bicarbonate, creatinine, and other electrolytes

9. Elelyso® (taliglucerase alfa) • Hydrolytic, lysosomal, glucocerebroside-specific enzyme indicated for a long-term enzyme replacement therapy (ERT) for adults with a confirmed diagnosis of Type 1 Gaucher disease.

10. Gaucher Disease • Most common form: Type 1 non-neurological • Cause: absence of glucocerebrosidase in lysosomes • Fatty material accumulates in spleen and liver • Symptoms can begin early in life or adulthood • Spleen, liver, lungs, brain and bone marrow affected • Increased bruising, fatigue, increased fractures, lung and kidney impairment, anemia • Autosomal recessive

11. Treatment of Gaucher Disease • Current treatment • Enzyme replacement therapy (ERT) • Cerezyme®: mammalian cell –recombinant • 10-15% antibodies; allergic reactions • VPRIV®: human cell recombinant • Elelyso®: plant cell recombinant

12. Eleyso® • Gene for human enzyme is inserted into carrot cells. • Decreases liver and spleen volume, anemia, increases platelets. • Dose: 60 units/kg IV over 1-2 hours every 2 weeks • Adverse Drug Reactions • Infusion reactions--Usually mild • Reduce risk by slow infusion rate, pretreat with antihistamines or corticosteroids • Common ADRs • URI, throat infections, UTI, extremity pain

13. Chemotherapeutic agents

14. Erivedge® (vismodegib) • First and only oral agent approved for treatment of adults with metastatic basal cell cancer (BCC) or locally advanced BCC recurrent post-surgery or those not candidates for surgery or radiation

15. Erivedge® MOA • Designed to inhibit selectively the Hedgehog pathway • This pathway is active in the proper development of embryos. • In adults it is less active except for tissue repair and maintenance • . When it malfunctions it can result is diseases like BCC.

16. Erivedge® Dosing • Dose: 150 mg capsule every day until disease progression or until unacceptable adverse reaction. • Verify pregnancy 7 days before administration. • Embryo-fetal death or severe birth defects can occur • Continue birth control 7 months past last dose. Males using Erivedge encouraged to use a condom with spermicide even if post-vasectomy while on medication and two months thereafter. • Do not donate blood or blood products while taking this drug and for 7 months after last dose.

17. Erivedge® ADRs • GI: change in how things taste or loss of taste, nausea, diarrhea, decreased appetite, constipation and vomiting • Joint aches, Muscle spasms • Hair loss • Weight loss • Tiredness

18. Inlyta® (axitinib) • Kinase inhibitor for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. • Inhibits vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 • These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression.

19. Inlyta® (axitinib) • 5 to 10 mg PO every 12 hours with a full glass of water. • Reduce dose if liver impairment present or is used with a strong CYP 3A4/5 inhibitor • Avoid grapefruit juice • Both partners need to use effective birth control methods. • Use during pregnancy can cause fetal harm. Most common ADRs (>20%) • GI: diarrhea, decrease in appetite or ability to taste things, weight loss, nausea, vomiting, constipation, stomach pain, heart burn • redness, pain, swelling, numbness, tingling, or itching or peeling of the skin on your hands and feet • Hypertension, dysphonia

20. Inlyta®Warning and Precautions • The following adverse events have occurred: • Hypertension and hypertensive crises • Arterial and venous thrombotic events fatal and nonfatal • Cerebral and GI bleeding, fatal and nonfatal • Hypothyroidism, proteinuria, increased liver enzymes • Fetal harm

21. Kyprolis® (carflizomib) • A proteasome inhibitor for advanced multiple myeloma who have not responded to at least two other drugs. • Multiple myeloma is a malignant increase in plasma cells • Multiple myeloma associated with an increase in proteasome levels • Proteasomes present in all cells to degrade unneeded or damaged proteins

22. Kyprolis® Dosing • Administered IV on two consecutive days every week for 3 weeks followed by a 12 day rest. • Dose: 20-27 mg/m2/day • Common side effects (>30%): nausea, diarrhea, pyrexia, anemia, thrombocytopenia, dyspnea and fatigue

23. Kyprolis®Warnings and Precautions • Heart failure and ischemia • Pulmonary complications and hypertension • Liver toxicity and failure • Tumor lysis syndrome • Infusion reactions • Fetal harm

24. Perjeta® (pertuzumab) • Approved for use in combination with Herceptin® and docetaxal for HER2 positive metastatic breast cancer who have not received prior anti-HER2 or chemotherapy for metastatic disease. • HER2 overexpression correlates with aggressive form of breast cancer—25% of all breast tumor • Dysregulation of HER-mediated signaling pathways results in growth and spread of cancer cells • Inappropriate signaling may lead to uncontrolled cell proliferation, decreased cell death, angiogenesis and increased cancer cell motility.

25. Perjeta® (pertuzumab) • Dose: initial 840 mg IV followed by 420 mg IV every 3 weeks. • Clinical effect: increases progression free survival by 6.1 months

27. Perjeta® Serious ADR • Fetal death and Birth Defects: birth control during treatment and for 6 months after a patient's last dose of Perjeta. Heart problems: reduced heart function and CHF • Infusion-related reactions: fatigue, loss of taste, allergic reactions, muscle pain, and vomiting • Severe allergic reactions: may be severe, may happen quickly, and may affect many areas of the body

28. Xtandi ® (enzalutamide) • An androgen receptor inhibitor for treatment of metastatic castration-resistant prostate cancer previously treated with docetaxel • Dose : 160 mg daily

29. Drug Interactions Avoid co-administration with: • strong CYP2C8 inhibitors (gemfibrozil) and moderate to strong CYP 2C8 inducers (rifampin) • 3A4 inducers (carbamazepine, phenytoin, phenobarbital) or inhibitors (itraconazole), and • Xtandi® is a moderate to strong inducer of 3A4 (cyclosporine), 2C9 (warfarin), 2C19 (omeprazole). This interaction can decrease the effectiveness of these agents.

30. Zaltrap® (ziv-aflibercept) • Indicated for use in a multiple drug combination in the treatment of metastatic colorectal cancer resistant to or has progressed following an oxaliplatin-containing regimen

31. Zaltrap®MAO • An angiogenesis inhibitor that results in decreased neovascularization and decreased vascular permeability

32. Zaltrap® Dosing and ADRs • Dose: 4 mg IV over one hour every two weeks. • Administration continues until disease progression or unacceptable toxicity • Serious adverse reactions: • Hemorrhage • GI perforation • Compromised wound healing • Fistula formation • Hypertension • Arterial thromboembolic events • Proteinuria • Neutropenia

33. Stivarga® (regorafenib) • Recently approved for the treatment of metastatic colorectal cancer. • Oral novel multikinase inhibitor that blocks multiple enzymes that promote cancer growth • 29% increase in survival versus placebo • Black box warning—severe and fatal liver toxicity occurred during treatment

34. Bosulif® (bosutinib) • A kinase inhibitor for treatment of chronic myelogenous leukemia (CML) in adults with chronic, accelerated, or blast phase with resistance or intolerance to prior therapy. • CML due to chromosomal abnormality resulting in the formation of Philadelphia chromosome • Abnormal fusion of Brc-Abl tyrosine kinase implicated in pathogenesis of CML • One source of treatment resistance is activation of Src-family kinases.

35. Bosulif® (bosutinib) • Dose: 500 – 600 mg daily • Avoid use with strong CYP3A inducers or inhibitors • Avoid use with proton pump inhibitors – decrease drug levels • Common ADR (>20%) • Diarrhea, nausea, thrombocytopenia, • Serious ADR • GI toxicity, Hepatic toxicity, fetal toxicity • Fluid retention • Myelosuppression

36. FluMist Quadrivalent ® (influenza vaccine live) • Intranasal influenza vaccine containing four strains of the influenza virus. • Indicated for active immunization for the prevention of disease caused by influenza A subtype and B viruses • Approved for use in person 2 through 49 years of age • Administered intranasally—one-half the dose in each nostril

37. FluMist® Quadrivalent • Do not administer to persons who have had a server allergic reaction to any component: egg protein, gentamicin, gelatin and arginine • Do not administer to children and adolescents through 17 who are on aspirin containing therapy because of risk of Reye’s syndrome Package insert 2012

38. Menhibrix® • A vaccine for prevention of Neisseria meningitidis (C and Y) and Haemophilus influenzae type b infections in children. • Four doses IM at 2, 4, 6, and 12-15 months.

39. Kalydeco® (ivacaftor) • Approved for treatment of cystic fibrosis (CF) in patients ≥6 years who have a G551D mutation in the CFTR gene. • Transmembrane conductance regulator (CFTR) potentiator for cystic fibrosis patients with certain gene mutation • Treats the underlying mutation not just the symptoms • CFTR functions as an anion channel. • Found in epithelial cells of the lungs, liver, pancreas, GIT, skin, reproductive tract. • In CF, CFTR defects results in reduced transport of NaCl resulting in build up of sticky mucus

40. Kalydeco® (ivacaftor) • 150 mg tablet every 12 hours with a high fat meal • Promotes weight gain and improved lung function • Costs $294,000/year. Available for only through specialty pharmacies Adverse Drug Effects • Headache, URI, nasal congestion, nasopharyngitis • Nausea, diarrhea • Rash, dizziness, abdominal pain

41. Kalydeco® Drug Interactions • Strong 3A4 inhibitors like ketoconazole increases levels 8.5-fold; fluconazole 3-fold • Other drugs like rifampin and St. John’s Wort should be avoided • Kalydeco® has potential to inhibit 3A4, P-glycoprotein, and 2C9. • Check levels of cyclosporine, tacrolimusand digoxin and monitor INR (warfarin)

42. Myrbetriq® (mirabegron) • Beta-3 adrenergic agonist for overactive bladder • Simulation promotes relaxation of detrusor muscle in the bladder adding in urination

43. Myrbetriq®(mirabegron) • Dosing: 25 to 50 mg QD • Reduce dose in moderate renal impairment • Warnings and Precautions • Hypertension • Bladder outlet obstruction • Concomitant medications metabolized by CYP2D6. Myrbetriq® is an inhibitor of this pathway. (digoxin)

44. Omontys® (peginesatide) • Erythropoiesis-stimulating agent (ESA) for anemia in dialysis patients • Not indicated for patients: • with CKD not on dialysis • as a substitute for transfusions in acute situations, • On chemotherapy and have anemia not due to CKD • Without demonstrated benefit • Initial dosing: 0.04 mg/kg/month (injectable) • Dose conversion from another ESA based on total weekly dose at that time.

45. Omontys® (peginesatide) • Contraindicated in uncontrolled hypertension • Most common ADRs (>10%): dyspnea, diarrhea, cough, nausea, A-V fistula site complications • Warning: Increased risk of MI, stroke and thromboembolism when Hgb increased to >11 gm/dl Package insert

46. Picato® Gel (ingenol mebutate) • Inducer of cell death indicated in the topical treatment of actinic keratosis • Two strengths: 0.015% and 0.05% gel • Lower strength applied to AK on face and scalp daily for 3 consecutive days • Higher strength applied to AK on trunk and extremities daily for 2 consecutive days

47. Picato® Gel (ingenol mebutate) Warnings and ADRs • Eye disorders: severe eye pain, ptosis, and edema. • Local skin reactions • : vesiculation, pustulation, pruritis, erosions, ulcerations, infection • Headache, nasopharyngitis

48. Stendra® (avanafil) • PDE5 inhibitor for erectile dysfunction • Dose 50 to 200 mg 30 minutes prior to sexual activity PRN (no more than one dose in 24 hours) • Do not use with strong CYP3A4 inhibitors • Decrease dose to 50 mg in 24 hours when using a moderate CYP3A4 inhibitor • Lower dose to 50 mg/day in patients on stable alpha-blocker therapy

49. Stendra® (avanafil) Strong CYP 3A4 inhibitors Moderate CYP 3A4 inhibitors Verapamil Diltiazem Erythromycin Fluconazole Grapefruit juice Ciprofloxacin • Protease inhibitors—ritinovir • Macrolide antibiotics—clarithromycin • Nefazodone • Azole antifungals --ketoconazole

50. Alpha blockers • Selective α1-adrenergic blockers include: • alfuzoxin (Uroxatral) • prazosin (Minipres) • doxazosin (Cardura) • tamsulosin (Flomax) • terazosin (Hytrin) • silodosin (Rapaflo)