New Drugs of 2007 Part 1

1. New Drugs of 2007Part 1 Presented by: Sara Tebbe, PharmD Drugs Covered: aliskiren (Tekturna®) ambrisentan (LetairisTM) amlodipine/olmesartan (Azor®) eculizumab (Soliris®) lidocaine (ZingoTM)

2. Aliskiren Tekturna® Manufactured by: Novartis www.prescribingreference.com

3. Aliskiren (Tekturna®) Therapeutic Class • Antihypertensive: Renin Inhibitor Indications • Hypertension alone or in combination with other antihypertensive agents Tekturna® (Aliskiren) Package Insert. East Hanover, NJ: Novartis. September 2007.

4. Mechanism of action Decreases the plasma renin activity (PRA); which is responsible for converting angiotensinogen to angiotensin I Pharmacokinetics Absorption: Bioavailability of ~ 2.5%. With a high fat meal, mean AUC & Cmax are decreased by 71% and 85% Distribution: Steady state reached at 7-8 days Metabolism: CYP3A4 enzyme Elimination: Approximately ¼ appears in the urine as parent drug; unknown how much of the absorbed dose is metabolized Aliskiren (Tekturna®) Tekturna® (Aliskiren) Package Insert. East Hanover, NJ: Novartis. September 2007.

5. Aliskiren (Tekturna®) www.uspharmacist.com

6. Aliskiren (Tekturna®) Dosing and Administration • Starting dose of aliskiren is 150 mg PO daily • Dose may be increased to a max of 300 mg PO daily Cost • ~ $1.89 for 150 mg tab and $2.38 for 300 mg tab Patient Education • Potential to cause hypotension • Medication should be taken at the same time daily • If patient forgets to take medication, take it as soon as remembered; do not double dose • Medication should NOT be administered with a high fat meal Tekturna® (Aliskiren) Package Insert. East Hanover, NJ: Novartis. September 2007.

7. Aliskiren (Tekturna®) Contraindications & Precautions • Pregnancy category: C - first trimester; D - second and third trimesters • Caution in patients with severe renal dysfunction • Concurrent use of ACE-Inhibitor or ARB and the risk of hyperkalemia Drug Interactions • Co-administration of irbesartan reduced the Cmax of aliskiren by ~ 50% • Co-administration of atorvastatin results in a 50% increase in the Cmax and AUC of aliskiren after multiple dosing • Co-administration of ketoconazole results in an 80% increase in plasma levels of aliskiren • Co-administration of furosemide results in a 30% reduction of AUC and 50% reduction of Cmax of aliskiren Adverse Effects • Angioedema, other edema (face, hands, whole body), diarrhea, abdominal pain, dyspepsia, hyperkalemia and cough Tekturna® (Aliskiren) Package Insert. East Hanover, NJ: Novartis. September 2007.

8. Aliskiren (Tekturna®) Pool JL, et al. Am J Hypertens. 2007;20:11-20.

9. Aliskiren (Tekturna®) Strasser RH, et al. J Hum Hyperten. 2007;21:780-87.

10. Aliskiren (Tekturna®) Place in Therapy • May be used as monotherapy for the treatment of hypertension • May be used as add-on anti-hypertensive medication to agents such as ACE-I, ARBs, and diuretics Clinical Pearls • If used with an ACE-I, ARB or aldosterone antagonist; potassium levels should be monitored frequently ACE-I: Angiotensin Converting Enzyme Inhibitor ARB: Angiotensin Receptor Blocker

11. Ambrisentan Letairis™ Manufactured by: Gilead www.prescribingreference.com

12. Ambrisentan (Letairis™) Therapeutic Class • Endothelin Receptor Antagonist (ERA) Indications • Pulmonary arterial hypertension (PAH) WHO Group I • PAH patients with symptoms, to improve exercise capacity and delay clinical worsening Letairis™ (ambrisentan) Package Insert. Foster City, CA: Gilead. June 2007.

13. Mechanism of action Ambrisentan is a selective endothelin-A (ETA) receptor antagonist approved for use in PAH Pharmacokinetics Absorption: Rapidly absorbed; food has no effect on absorption Distribution:Highly bound (99%) to plasma proteins Metabolism: Through CYP3A4, CYP2C19, and uridine 5'-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S and 1A3S Elimination: Non-renal pathways; half-life of 9-15 hours Ambrisentan (Letairis™) www.body.aol.com Letairis™ (ambrisentan) Package Insert. Foster City, CA: Gilead. June 2007.

14. Ambrisentan (Letairis™) Dosing and Administration • Initiate treatment at 5 mg by mouth daily • Increase dose to 10 mg if tolerated (max) Cost • ~ $165 per tablet ( 5 mg or 10 mg) Patient Education • Tablets may be taken with or without food • Tablets may NOT be split, crushed, or chewed Letairis™ (ambrisentan) Package Insert. Foster City, CA: Gilead. June 2007.

15. Ambrisentan (Letairis™) Contraindications & Precautions • Pregnancy category X • Potential liver injury, dose-dependent • Monitor for hematologic changes (hemoglobin and hematocrit) • Co-administration of ambrisentan and cyclosporine Drug Interactions • P-glycoprotein and UGT inducers • Potent inhibitor of P-glycoprotein, OATP, and CYP3A4 • CYP3A4 or 2C19 Inhibitors Adverse Effects • Peripheral edema, nasal congestion, flushing, and headache Letairis™ (ambrisentan) Package Insert. Foster City, CA: Gilead. June 2007. OATP: Organic Anion Transporting Polypeptide

16. Ambrisentan (Letairis™) Galie N, et al. J Am Coll Card. 2004; 43(12):5S-12S. 6-MWD: 6-minute walk distance

17. Ambrisentan (Letairis™) Place in Therapy • Add on agent for the treatment of pulmonary arterial hypertension (following treatment with CCBs and/or sildenafil) • May be used as monotherapy or with other agents to treat PAH Clinical Pearls • Minimal liver abnormalities as compared to bosentan CCB: calcium channel blocker

18. Amlodipine/Olmesartan Azor® Manufactured by: Daiichi-Sankyo www.prescribingreference.com

19. Amlodipine/Olmesartan (Azor®) Therapeutic Class • Anti-hypertensive: Calcium Channel Blocker (CCB) and Angiotensin II Receptor Blocker (ARB) Indications • Hypertension alone or with other antihypertensive agents Azor® (amlodipine/olmesartan) Package Insert. Parsippany, NJ: Daiichi-Sankyo. December 2007.

20. Amlodipine/Olmesartan (Azor®) Mechanism of action • Amlodipine works by inhibiting the transmembrane influx of calcium ions in cardiac and vascular smooth muscle • Olmesartan inhibits the vasoconstrictor effects of angiotensin II Azor® (amlodipine/olmesartan) Package Insert. Parsippany, NJ: Daiichi-Sankyo. December 2007.

21. Pharmacokinetics (amlodipine) Absorption: Bioavailability ~ 64% to 90% Distribution: ~ 93% bound to plasma proteins, reaches steady-state in 7-8 days Metabolism: ~ 90% is converted to inactive metabolites via hepatic metabolism Elimination: 10% (parent compound) and 60% (metabolites) are excreted in the urine; effective half-life of ~ 45 hours Pharmacokinetics (olmesartan) Absorption: Bioavailability ~ 26% Distribution: Highly bound to plasma proteins (99%); reaches steady-state in 3-5 days Metabolism: Olmesartan medoxomil converted to olmesartan during absorption and no further metabolism of olmesartan Elimination: 35%-50% is eliminated in the feces; effective half-life of ~ 7 hours Amlodipine/Olmesartan (Azor®) Azor® (amlodipine/olmesartan) Package Insert. Parsippany, NJ: Daiichi-Sankyo. December 2007.

22. Amlodipine/Olmesartan (Azor®) Dosing and Administration • Initiate at 5/20 mg PO daily and titrate to desired BP goal • Available as 5/20, 5/40, 10/20 or 10/40 mg tablets Cost • Between $1.86 and $2.68 per tablet Patient Education • Potential to cause hypotension • Take this medication at the same time each day • If patient forgets to take medication take it as soon as remembered; do not double dose Azor® (amlodipine/olmesartan) Package Insert. Parsippany, NJ: Daiichi-Sankyo. December 2007.

23. Amlodipine/Olmesartan (Azor®) Contraindications & Precautions • Pregnancy category: C - first trimester; D - second through third trimesters • Caution in severe renal and/or hepatic dysfunction • Concurrent use of ACE-I or ARB and risk of hyperkalemia • Caution in patients with severe obstructive coronary artery disease or congestive heart failure Drug Interactions • No clinically significant drug interactions Adverse Effects • Edema, dizziness, palpitation, and flushing Azor® (amlodipine/olmesartan) Package Insert. Parsippany, NJ: Daiichi-Sankyo. December 2007.

24. Amlodipine/Olmesartan (Azor®) Azor® (amlodipine/olmesartan) Package Insert. Parsippany, NJ: Daiichi-Sankyo. December 2007.

25. Amlodipine/Olmesartan (Azor®) Place in Therapy • This combination product may be appropriate for patients who desire a smaller pill burden • May also be used as an add-on anti-hypertensive medication Clinical Pearls • If compliance is an issue or if this agent is cheaper through insurance, amlodipine/olmesartan may be beneficial to the patient.

26. Eculizumab Soliris® Manufactured by: Alexion Pharmaceuticals www.prescribingreference.com

27. Eculizumab (Soliris®) Therapeutic Class • Monoclonal antibody Indications • Paroxysmal nocturnal hemoglobinuria (PNH) Soliris® (eculizumab) Package Insert. Chesire, CT: Alexion. June 2007.

28. Mechanism of action Monoclonal antibody that specifically binds to and inhibits the terminal complement mediated intravascular hemolysis in PNH patients Pharmacokinetics Distribution: Volume of distribution ~ 7.7 L Elimination: Half life ~ 272 ± 82 hours Eculizumab (Soliris®) www.soliris.net Soliris® (eculizumab) Package Insert. Chesire, CT: Alexion. June 2007.

29. Eculizumab (Soliris®) Dosing and Administration • 600 mg every 7 days for 4 weeks, followed by • 900 mg for the fifth dose 7 days later, then • 900 mg every 14 days thereafter Cost • 300mg vial is ~ $4992 Patient Education • Patients must be vaccinated against meningococcus • Potential for serious hemolysis when eculizumab is discontinued Soliris® (eculizumab) Package Insert. Chesire, CT: Alexion. June 2007.

30. Eculizumab (Soliris®) Contraindications & Precautions • May have an increased susceptibility to infections • May result in infusion reactions • Pregnancy category C Drug Interactions • No drug interactions have been studied or reported Adverse Effects • Meningococcal infections, headache, back pain, nausea, fatigue and cough Soliris® (eculizumab) Package Insert. Chesire, CT: Alexion. June 2007.

31. Eculizumab (Soliris®) Hillmen P, et al. N Engl J Med.2006;355:1233-43.

32. Eculizumab (Soliris®) Hillmen P, et al. Blood. 2007;110 (12):4123-28.

33. Eculizumab (Soliris®) Place in Therapy • Only pharmacologic agent indicated to treat PNH Clinical Pearls • Do not initiate in patients with N. meningitidis infection or who are not vaccinated against N. meningitidis

34. Lidocaine Zingo™ Manufactured by: Anesiva www.prescribingreference.com

35. Lidocaine (Zingo™) Therapeutic Class • Amide local anesthetic Indications • To provide local analgesia prior to venipuncture or peripheral intravenous cannulation in children 3-18 years of age • Zingo (lidocaine) Package Insert. Tempe, AZ: Anesiva. September 2007.

36. Mechanism of action Amide-type local anesthetic agent that blocks sodium ion channels required for the initiation and conduction of neuronal impulses, resulting in local anesthesia Pharmacokinetics Absorption: Single doses do not produce any detectable plasma concentration of lidocaine Distribution: N/A Metabolism: Unknown if lidocaine is metabolized in the skin Elimination: N/A Lidocaine (Zingo™) • Zingo (lidocaine) Package Insert. Tempe, AZ: Anesiva, Inc. September 2007.

37. Lidocaine (Zingo™) Dosing and Administration • Use one application (0.5 mg lidocaine hydrochloride) to the site of venipuncture or intravenous cannulation approximately 1-3 minutes before insertion • Only one more application may be used on a new location if there is a failed attempt for venous access Cost • Unavailable Patient Education • Loud sound released upon administration / activation • Skin reactions may occur with irritation / allergy • Zingo (lidocaine) Package Insert. Tempe, AZ: Anesiva, Inc. September 2007.

38. Lidocaine (Zingo™) Contraindications & Precautions • Pregnancy category B • Safety use in children under the age of 3 has not been evaluated • Patients with a history of known sensitivity to amide local anesthetics Drug Interactions • None Adverse Effects • Erythema, edema, petechiae, bruising, burning and pain • Zingo (lidocaine) Package Insert. Tempe, AZ: Anesiva, Inc. September 2007.

39. Lidocaine (Zingo™) • Zingo (lidocaine) Package Insert. Tempe, AZ: Anesiva, Inc. September 2007.

40. Lidocaine (Zingo™) Place in Therapy • Local analgesia prior to venipuncture or IV cannulation • Main use is found in pediatric patient population; especially children afraid of needle sticks Clinical Pearls • Analgesia seen within 1-3 minutes and will diminish 10 minutes after administration • Do not use multiple applications at the same location • Zingo (lidocaine) Package Insert. Tempe, AZ: Anesiva, Inc. September 2007.

41. Learning Assessment Question Time!

42. Patient SP is being seen today in his PCP office and it was noted that his BP was 164/102. He is currently taking lisinopril 40 mg PO daily and furosemide 20 mg PO BID. Which of the following medications would be an option to control his hypertension? • Ambrisentan (LetairisTM) • Meloxicam (Mobic®) • Aliskiren (Tekturna®) • Lidocaine (ZingoTM)

43. What is the main benefit of (amlodipine/olmesartan) Azor®? • Less expensive • More effective antihypertensive • Reduced pill burden • Less adverse effects

44. What is the most common adverse effect noted with ambrisentan (LetairisTM)? • Hypotension • Peripheral edema • Dry cough • Sedation

45. Prior to use with eculizumab (Soliris®), it is important that all patients be vaccinated against this? • Varicella • Meningococcus • Typhoid fever • Papillomavirus

46. 4 year old ML is in the ER awaiting peripheral IV cannulation to administer IV fluids and is scared of the pain associated with the procedure. Which product could you recommend that might provide local analgesia for BP that is approved for pediatric use? • Benzocaine (Orajel®) • Procaine (Novocain®) • Lidocaine (Zingo®) • Eculizumab (Soliris®)

47. What is the onset of action of lidocaine used to provide topical analgesia to BP in the previous question? • 15 minutes • Instantly • 15-30 minutes • 1-3 minutes

48. What is the recommended dose range for aliskiren (TekturnaTM)? • 15 – 30 mg PO Daily • 100 - 300 mg PO TID • 25 – 50 grams BID • 150 – 300 mg PO Daily

49. Which of the following is NOT a benefit of ambrisentan (LetairisTM) when compared to bosentan (TracleerTM)? • No drug interactions with sildenafil or warfarin • Fewer adverse reactions • Once daily dosing • Less risk of hepatotoxicity

50. Which of the following should not be considered when initiating a patient on (amlodipine/olmesartan) Azor®? • Serum potassium levels • Blood pressure • Patient age • Renal function