New Drugs of 2007 Part 3

1. New Drugs of 2007 Part 3 Presented by: Sarah Rodriguez, PharmD Drugs Covered: azithromycin (Azasite®) doripenem (Doribax™) raltegravir (Isentress™) maraviroc (Selzentry™) temsirolimus (Torisel™)

2. Azithromycin Azasite® Manufactured by: Inspire www.prescribingreference.com

3. Azithromycin (Azasite®) Therapeutic Class • Ophthalmic antimicrobial Indications • Treatment of bacterial conjunctivitis caused by • Haemophiliusinfluenzae • Staphylococcus aureus • Streptococcus mitis • Streptococcus pneumoniae • CDC coryneform group G Azasite® (Azithromycin) package insert. Durham, NC: Inspire. May 2007.

4. Mechanism of action Interferes with bacterial protein synthesis by binding to the 50S ribosomal subunit Pharmacokinetics Systemic absorption is minimal Azithromycin (Azasite®) Azasite® (Azithromycin) package insert. Durham, NC: Inspire. May 2007.

5. Azithromycin (Azasite®) Dosing and Administration • 1 drop in the affected eye(s) twice daily for two days, then 1 drop daily for five days Cost • $66.25/bottle(AWP) Azasite® (Azithromycin) package insert. Durham, NC: Inspire. May 2007.

6. Azithromycin (Azasite®) Contraindications & Precautions • No contraindications • Severe allergic reactions have been seen with systemic use of azithromycin • Long-term use can result in resistant infections developing Drug Interactions • None identified Adverse Effects • Eye irritation most common Azasite® (Azithromycin) package insert. Durham, NC: Inspire. May 2007.

7. Azithromycin (Azasite®) Azasite® (Azithromycin) package insert. Durham, NC: Inspire. May 2007.

8. Azithromycin (Azasite®) Protzko E, Bowman L, Abelson M, Shapiro A. Phase 3 Safety Comparisons for 1.0% Azithromycin Polymeric Mucoadhesive Eye Drops versus 0.3% Tobramycin Eye drops for Bacterial Conjunctivitis. Invest Ophthalmol Vis Sci. @007;48:3425-3429.

9. Azithromycin (Azasite®) Patient Education • Wash hands before using • Avoid touching the tip of the bottle to the eye • Important to complete full course of therapy • Do not wear contact lenses

10. Azithromycin (Azasite®) Place in Therapy • Less frequent dosing than other available treatments for bacterial conjunctivitis Clinical Pearls • Offers no therapeutic advantage over currently available products

11. Question 1 Which of the following is an advantage of azithromycin (Azasite®) over other treatments for bacterial conjunctivitis?

12. 15 Answer now! • It is much more efficacious than other available agents • Systemic absorption allows for eradication of the causative bacteria elsewhere in the body • It requires less frequent dosing than other available agents • It can be used in infants less than one year of age

13. Question 2 A doctor calls the pharmacy wishing to prescribe azithromycin (Azasite) for bacterial conjunctivitis. This agent is currently non-formulary at your institution. Which of the following agents would be a valid therapeutic alternative?

14. 15 Answer now! • Meropenem • Gentamicin • Prednisolone • Ceftazidime

15. Doripenem Doribax™ Manufactured by: Ortho-McNeil www.prescribingreference.com

16. Doripenem (Doribax™) Therapeutic Class • Carbapenem antibiotic Indications • Complicated intra-abdominal infections • Complicated urinary tract infections, including pyelonephritis Doripenem (Doribax®) Package Insert. Raritan, NJ: Ortho-McNeal. October, 2007.

17. Mechanism of action Binds to penicillin binding proteins Inhibits synthesis of bacterial cell wall Bacteriocidal Pharmacokinetics Distribution: 8% protein bound Concentrates in peritoneal fluid, retroperitoneal fluid, gallbladder, bile, and urine Metabolism: Metabolized to an inactive, open ring form by dehydropeptidase-1 Not a substrate for CYP450 Elimination: Renal Half-life is 1 hour Doripenem (Doribax™) Doripenem (Doribax®) Package Insert. Raritan, NJ: Ortho-McNeal. October, 2007.

18. Doripenem (Doribax™) Dosing and Administration • Complicated intra-abdominal infections • 500 mg infused over 1 hour every 8 hours for 5 – 14 days • Complicated urinary tract infections • 500 mg infused over 1 hour every 8 hours for 10 days Cost • $95.83/dose (AWP) Doripenem (Doribax®) Package Insert. Raritan, NJ: Ortho-McNeal. October, 2007.

19. Doripenem (Doribax™) Contraindications & Precautions • Severe hypersensitivity reactions have occurred • Clostridium difficile associated diarrhea • Overuse can result in development of drug-resistant bacteria • Cases of pneumonitis reported with inhalational use Drug Interactions • Valproic acid • Probenecid Doripenem (Doribax®) Package Insert. Raritan, NJ: Ortho-McNeal. October, 2007.

20. Doripenem (Doribax™) Adverse Reactions • Headache • Nausea • Diarrhea • Rash • Phlebitis • Seizure Doripenem (Doribax®) Package Insert. Raritan, NJ: Ortho-McNeal. October, 2007.

21. Doripenem (Doribax™) Doripenem (Doribax®) Package Insert. Raritan, NJ: Ortho-McNeal. October, 2007.

22. Doripenem (Doribax™) Doripenem (Doribax®) Package Insert. Raritan, NJ: Ortho-McNeal. October, 2007.

23. Doripenem (Doribax™) Patient Education • Possibility of severe allergic reactions • Only used for the treatment of bacterial infections • Full course of therapy should be completed

24. Doripenem (Doribax™) Place in Therapy: • Broad spectrum antibiotic • Reserve for patients at high risk for serious, multi-drug resistant infections • Effective against Pseudomonas aeruginosa and may be more potent in its activity than other carbapenems • No indication for Pseudomonal infections at this time Clinical Pearls: • Superiority over other carbapenems not established • Pneumonia indication currently under review • Will require 4 hour infusion Zhanel GG, Wiebe R, Dilay L, et al. Comparative Review of the Carbapenems. Drugs 2007;67(7):1027 – 1052. Sakyo S, Tomita H, Tanimoto K, Fujimoto S, Ike Y. Potency of Carbapenems for the Prevention of Carbapenem- Resistant Mutants of Pseudomonas aeruginosa. J Antibiot 2006;59(4): 220-228.

25. Question 3 Which of the following drugs has the same mechanism of action as doripenem?

26. 15 Answer now! • Gentamicin • Colistin • Ceftriaxone • Tigecycline

27. Question 4 Which of the following nosocomial pathogens does doripenem have activity against?

28. 15 Answer now! • Pseudomonas aeruginosa • Methicillin resistant Staphylococcus aureus • Vancomycin Resistant Enterococcus faecalis • Clostridium difficile

29. Life Cycle of HIV: Therapeutic Targets http://img.thebody.com/

30. Raltegravir Isentress™ Manufactured by: Merck www.prescribingreference.com

31. Raltegravir (Isentress™) Therapeutic Class • HIV integrase inhibitor Indications • Treatment of HIV-1 infection • Only used in combination with other agents • Patients with evidence of multi-drug resistance Isentress (Raltegravir®) Package insert. Merck and Company, Whitehouse Station, NJ. October, 2007.

32. Mechanism of action Inhibits HIV-1 integrase Pharmacokinetics Absorption: Bioavailability not known AUC is increased by 19% with a high-fat meal Distribution: 83% protein bound Metabolism: Glucuronidated by UGT1A1 Elimination: 51% of the dose is excreted in the feces 32% in the urine Half-life 9 hours Raltegravir (Isentress™) Isentress (Raltegravir®) Package insert. Merck and Company, Whitehouse Station, NJ. October, 2007.

33. Raltegravir (Isentress™) Dosing and Administration • 400 mg twice daily with or without food Cost • $1,012.50/month(AWP) Contraindications & Precautions • No contraindications • Immune reconstitution syndrome to residual opportunistic infections • Pregnancy category C Isentress (Raltegravir®) Package insert. Merck and Company, Whitehouse Station, NJ. October, 2007.

34. Raltegravir (Isentress™) Drug Interactions • Use caution in giving raltegravir with strong inducers of UGT1A1 • Rifampin can decrease plasma concentrations of raltegravir through UGT1A1 induction • Tipranavir, ritonavir, and atazanavir also affect UGT1A1, but dose adjustment does not appear to be needed • Increased risk of rhabdomyolysis with concurrent use of statins and fibrates Isentress (Raltegravir®) Package insert. Merck and Company, Whitehouse Station, NJ. October, 2007.

35. Raltegravir (Isentress™) Adverse Effects • Most Common • Diarrhea • Nausea • Headache • Fever • Myopathy • Elevated liver enzymes • Especially in those co-infected with Hepatitis B or C Isentress (Raltegravir®) Package insert. Merck and Company, Whitehouse Station, NJ. October, 2007.

36. Raltegravir (Isentress™) Jones, J, Taylor B, Wilkin TJ, Hammer SM. Advances in Antiretroviral Therapy. Top HIV Med 2007;15(2)48:82.

37. Raltegravir (Isentress™) Patient Education • Not a cure for HIV • Importance of compliance with antiretroviral regimens • Report any unusual muscle pain or weakness

38. Raltegravir (Isentress™) Place in Therapy: • Novel mechanism of action shown to be efficacious even in patients with very resistant HIV infections • Studies ongoing in treatment naïve patients • Low pill burden Clinical Pearls: • May be particularly effective when given in combination with darunavir and enfuvirtide Jones, J, Taylor B, Wilkin TJ, Hammer SM. Advances in Antiretroviral Therapy. Top HIV Med 2007;15(2)48:82. Correll T, Klibanov OM. Integrase Inhibitors: A New Treatment Option for Patients with Human Immunodeficiency Virus Infection. Pharmacotherapy 2008, 28(1):91 – 100.

39. Question 5 Which of the following co-morbidities in an HIV positive patient may increase the likelihood of toxicity when treated with raltegravir?

40. 15 Answer now! • Hepatitis C • Diabetes mellitus • Chronic renal insufficiency • Kaposi’s sarcoma

41. Question 6 A patient in your unit comes in with new onset of shingles. Upon reviewing his history, you find that he is HIV positive and recently underwent a change in his antiretroviral medications. His physician wants to discontinue the new therapy since it is not working. What is your advice?

42. 20 Answer now! • Agree with the MD and discontinue all antiretroviral therapy immediately • Discontinue all of his antiretroviral agents but one to keep his HIV under control until you figure out what his new regimen will be • Advise the MD to continue the patient’s current therapy and add on raltegravir to maintain better control of his HIV • Advise the MD that the patient just had a change in his antiretroviral medications and his symptoms may be due to immune reconstitution syndrome

43. Maraviroc Selzentry™ Manufactured by: Pfizer www.prescribingreference.com

44. Maraviroc (Selzentry™) Therapeutic Class • CCR5 co-receptor antagonist Indications • Treatment of CCR5-tropic HIV-1 infection • Only in combination with other antiretroviral agents • Treatment experienced patients who have evidence of multi-drug resistance Selzentry® (Maraviroc) Package Insert. Pfizer Labs, New York, NY. August, 2007.

45. Mechanism of action Antagonizes the interaction between CCR5 and HIV gp120 Prevents HIV from entering the cell Pharmacokinetics Absorption: Low bioavailability AUC is decreased by high-fat meal Maraviroc is also a substrate for P-glycoprotein Distribution: 76% protein bound Metabolism: CYP450 3A4 substrate Elimination: 76% of the dose is excreted in the feces 20% in the urine Half-life of 18 hours Maraviroc (Selzentry™) Selzentry® (Maraviroc) Package Insert. Pfizer Labs, New York, NY. August, 2007.

46. Maraviroc (Selzentry™) Cost • $1087.50/bottle(AWP) • Does not differ with strength Selzentry® (Maraviroc) Package Insert. Pfizer Labs, New York, NY. August, 2007.

47. Maraviroc (Selzentry™) Contraindications & Precautions • Black box warning for hepatotoxicity • Preceded by allergic symptoms including rash, eosinophilia, and elevated IgE • Discontinue immediately if patient develops symptoms of hepatitis or elevated liver enzymes • Little data in patients with Hepatitis B, Hepatitis C, or other forms of liver impairment • Cardiovascular events including myocardial infarction and ischemia • Immune reconstitution syndrome to residual opportunistic infections • Increased risk of infection • Increased risk of malignancy Selzentry® (Maraviroc) Package Insert. Pfizer Labs, New York, NY. August, 2007.

48. Maraviroc (Selzentry™) Drug Interactions • Caution in patients with a history of postural hypotension or in those receiving anti-hypertensive medications due to increased risk of symptomatic hypotension • CYP3A4 inducers and inhibitors Adverse Effects • Cough • Fever • Upper respiratory tract infections • Rash • Musculoskeletal pain • Abdominal pain • Dizziness • Hepatotoxicity, especially in patients with pre-existing hepatic dysfunction Selzentry® (Maraviroc) Package Insert. Pfizer Labs, New York, NY. August, 2007.

49. Maraviroc (Selzentry™) Jones, J, Taylor B, Wilkin TJ, Hammer SM. Advances in Antiretroviral Therapy. Top HIV Med 2007;15(2)48:82.

50. Maraviroc (Selzentry™) Patient Education • Not a cure for HIV • Importance of compliance with antiretroviral regimens • Notify physician immediately if symptoms of hepatitis develop such as yellowing of the skin or eyes, abdominal pain, dark urine, or vomiting