NEW DRUGS PART II 7/7/ ANNUAL MEETING ANTIBIOTICS AND ANTIFUNGALS DISCLOSURE BACTERIA OBJECTIVES ANTIBIOTIC RESISTANCE

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1 ANTIBIOTICS AND ANTIFUNGALS NEW DRUGS PART II JACQUELINE KING, PHARM.D. PHARMACY OPERATIONS SUPERVISOR UFHEALTH CANCER CENTER TARA MCNULTY, CPHT, RPHT PROJECT MANAGER WELLCARE HEALTH PLANS, INC DISCLOSURE Jacqueline King, Pharm.D. I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation Tara, McNulty, CPhT, RPhT I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation BACTERIA OBJECTIVES Explore new medications for the treatment of infectious diseases, including HIV and Hepatitis C Analyze the impact of the new agents within clinical practice Utilize drug information to prevent medication misadventures ANTIBIOTIC RESISTANCE Antibiotic resistance occurs when an antibiotic has lost its ability to control or kill bacterial growth Causes of antibiotic resistance: Drugs not appropriately prescribed, not completing courses of antibiotics, human to human contact First superbug in the United States 1

2 GENERATING ANTIBIOTICS INCENTIVES NOW Incentives for creating antibiotics and antifungals Extends the exclusivity for new antibiotics Speeds development and review of new antibiotics Development of updated clinical trial guidance Requires listing of pathogens that pose a threat to public health Products given Qualified Infectious Disease Product (QIDP) designation DALVANCE Generic Name: Dalbavancin Class: Glycopeptide Antibiotic Use: Acute bacterial skin and skin structure infections (ABSSSI) Prevents cross-linking and interferes with cell wall synthesis Dosage Form(s): Intravenous 500 mg vial Dalvance [package insert]. Allergan Pharmaceuticals, Inc. Parsippany, NJ; January LIST OF QUALIFIED PATHOGENS DALVANCE GRAM POSITIVE Clostridium difficile Enterococcus species Staphylococcus aureus Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes GRAM NEGATIVE Acinetobacter species Burkholderia cepacia complex Campylobacter species Enterobacteriaceae Helicobacter pylori Neisseria gonorrhoeae Neisseria meningitidis Pseudomonas species Vibrio cholerae Dose: Single dose regimen 1,500 mg as a single dose Two dose regimen: 1,000 mg as an initial dose, then 500 mg as a single dose 1 week later Adverse Effects: GI side effects, headache Preparation: Reconstitute with 25 ml of SWFI or D5W for each 500 mg vial Swirl gently to mix Total time from reconstitution to administration should be less than 48 hours Dalvance [package insert]. Allergan Pharmaceuticals, Inc. Parsippany, NJ; January LIST OF QUALIFIED PATHOGENS DALVANCE FUNGUS/MOLD/YEAST Aspergillus species Candida species Coccidioides species Cryptococcus species MYCOBACTERIA Mycobacterium tuberculosis complex Non-tuberculous mycobacteria species Pearls One time dose Long half life means medication last in the system for weeks Renal adjustment necessary Spectrum: ABSSSI: Staphylococcus aureus (including methicillin-susceptible and methicillinresistant strains), Streptococcus pyogenes, Streptococcus agalactiae, S. dysgalactiae, Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus), and Enterococcus faecalis (vancomycin-susceptible strains) Dalvance [package insert]. Allergan Pharmaceuticals, Inc. Parsippany, NJ; January

3 SIVEXTRO Generic Name: Tedizolid Class: Oxazolidinone Antibiotic Use: Acute bacterial skin and skin structure infections Inhibits protein synthesis by binding to the 50S bacterial ribosomal subunit which prevents the formation of the 70S initiation complex that is essential for the bacterial translation process ORBACTIV Dosage Form(s): Intravenous 400 mg vial Dose: 1,200 mg as a single dose Adverse Effects: GI side effects, Headache Preparation: Reconstitute each 400 mg vial with 40 ml SWFI and swirl Withdraw 120 ml from the 1000 ml D5W bag Add 120 ml from three reconstituted vials Sivextro [package insert]. Merck Pharmaceuticals, Inc. Whitehouse Station, NJ; July Orbactiv [package insert]. The Medicines Company. Parsippany, NJ; January SIVEXTRO Dosage Form(s): Intravenous 200 mg vial and 200 mg tablet Dose: IV, Oral 200 mg once daily Adverse Effects: GI Effects, headache Preparation: Reconstitute with 4 ml SWFI. Swirl gently to mix then further dilute in 250 ml of normal saline. ORBACTIV Pearls One time dose Long half life makes medication last in the system for weeks No renal adjustments (not studied) Spectrum: ABSSSI: Staphylococcus aureus (including methicillin-susceptible and methicillinresistant isolates); Streptococcus pyogenes; Streptococcus agalactiae; Streptococcus dysgalactiae, Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus); and Enterococcus faecalis (vancomycin-susceptible isolates only) Sivextro [package insert]. Merck Pharmaceuticals, Inc. Whitehouse Station, NJ; July Orbactiv [package insert]. The Medicines Company. Parsippany, NJ; January ORBACTIV Generic Name: Oritavancin Class: Glycopeptide antibiotic Use: Acute bacterial skin and skin structure infection Inhibits cell wall synthesis in several ways Inhibits the polymerization step by binding to peptidoglycan precursors Inhbits crosslinking by binding to bridging segments Disrupts bacterial membrane integrity ZERBAXA Generic Name: Ceftolozane and Tazobactam Class: Cephalosporin Antibiotic Use: Complicated Intra-abdominal Infection (ciai) and Complicated Urinary Tract Infection (cuti) Ceftolozane: Inhibits bacterial cell wall synthesis by inhibiting the final step of peptidoglycan synthesis Tazobactam: Irreversibly inhibits certain beta-lactamases Orbactiv [package insert]. The Medicines Company. Parsippany, NJ; January Zerbaxa [package insert]. Merck Pharmaceuticals, Inc. Whitehouse Station, NJ; July

4 ZERBAXA Dosage Form(s): Intravenous 1.5 g vial Dose: ciai: 1.5 g every 8 hours with metronidazole cuti: 1.5 g every 8 hours Adverse Effects: CNS Effects, GI Effects Preparation: Add 10 ml of manufacturer recommended diluent to the vial which results in a concentration of ceftolozane 88 mg/ml and tazobactam 44 mg/ml approximately AVYCAZ Dosage Form(s): Intravenous 2.5 g vial Adult Dose: ciai: 2.5 g every 8 hours with metronidazole cuti: 2.5 g every 8 hours Adverse Effects: Anxiety (10%), Gastrointestinal, Preparation: Add 10 ml of manufacturer recommended diluent to the vial which results in a concentration of ceftazidime 167 mg/ml and avibactam 42 mg/ml Zerbaxa [package insert]. Merck Pharmaceuticals, Inc. Whitehouse Station, NJ; July Avycaz [package insert]. GlaxoSmithKline Manufacturing, Inc. Cincinnati, OH; September ZERBAXA Pearls Zerbaxa 1.5 g: Ceftolozane 1 g and Tazobactam 0.5 g Requires renal adjustment Protect vials from light Stability of 7 days after mixing when refrigerated Spectrum: ciai: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, K. pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius cuti: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa Zerbaxa [package insert]. Merck Pharmaceuticals, Inc. Whitehouse Station, NJ; July AVYCAZ Pearls: Avycaz 2.5 g is Ceftazidime 2 g and 0.5 g Avibactam Requires renal adjustment Protect vials from light Stability of 24 hours after mixing when refrigerated Spectrum: ciai - Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, K. pneumoniae, Proteus mirabilis, Providencia stuartii, and Pseudomonas aeruginosa cuti - Citrobacter freundii, C. koseri, Enterobacter aerogenes, E. cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus spp, and Pseudomonas aeruginosa Avycaz [package insert]. GlaxoSmithKline Manufacturing, Inc. Cincinnati, OH; September AVYCAZ Generic Name: Ceftazidime/Avibactam Class: Cephalosporin Antibiotic Use: Complicated Intra-abdominal Infection (ciai) and Complicated Urinary Tract Infection (cuti) Ceftazidime: Inhibits bacterial cell wall synthesis by inhibiting the final step of peptidoglycan synthesis Avibactam: Inactivates beta-lactamases and protects ceftazidime from degradation CRESEMBA Generic Name: Isavuconazonium Sulfate Class: Azole Derivative, Antifungal Use: Invasive aspergillosis and Invasive Mucormycosis Prodrug metabolized for isavunconazole in the blood. Isavuconazole inhibits the systhesis of ergosterol, a key component in antifungal cell membrane Avycaz [package insert]. GlaxoSmithKline Manufacturing, Inc. Cincinnati, OH; September Cresemba [package insert]. Astellas Pharmaceuticals, Inc. Northbrook, IL; April

5 CRESEMBA Dosage Form(s): 186 mg oral capsule or 372 mg intravenous vial Dose: Initial: 372 mg every 8 hours for 6 doses Maintenance: 372 mg once daily Adverse Effects: Peripheral edema, headache, hypokalemia, GI side effects Preparation: Dissolve with 5 ml of SWFI and add to a 250 ml bag of normal saline or dextrose 5% in water HEPATITIS C Hepatitis is inflammation of the liver Estimated million people living with chronic hepatitis C Of every 100 people infected with hepatitis C will go on to develop chronic liver disease 5-20 will develop cirrhosis over the next years 1-5 will die from the consequences of the disease Cresemba [package insert]. Astellas Pharmaceuticals, Inc. Northbrook, IL; April CRESEMBA Pearls 372 mg isavuconavonium sulfate dose is equivalent to 200 mg isavulconazole Requires no renal adjustment Stability of 24 hours after mixing when refrigerated IV Mixture will precipitate Must administer IV formula with an in-line filter of micron size Capsules must be swallowed whole HEPATITIS C Cresemba [package insert]. Astellas Pharmaceuticals, Inc. Northbrook, IL; April Accessed May 31, HEPATITIS C ZEPATIER Generic Name: Elbasvir and Grazoprevir Class: Antihepaciviral NS5A Inhibitor and Protease Inhibitor Use: Chronic hepatitis C infection, with or without cirrhosis, genotype 1 and 4 Elbasvir is an inhibitor of HCV NS5A which is essential for viral replication and virion assembly Grazoprevir is an inhibitor of HCV NS3/4A protease, necessary for cleavage of protein essential for viral replication Zepatier [package insert]. Merck Pharmaceuticals, Inc. Whitehouse Station, NJ; January Accessed May 31,

6 ZEPATIER TECHNIVIE Dosage Form(s): Oral tablet Fixed combination: 50 mg elbasvir and 100 mg grazoprevir Dose: One tablet daily for weeks (with or without concomitant ribavirin) Adverse Effects: Fatigue, headache, nausea Pearls Can be used in HIV-1 co-infection AWP: $10,920/14 tablets= $65,520-87,360 per treatment course In clinical trials over 90% of patients reached sustained virological response Zepatier [package insert]. Merck Pharmaceuticals, Inc. Whitehouse Station, NJ; January atier/zepatier_pi.pdf. Generic Name: Ombitasvir, Paritaprevir, and Ritonavir Class: Antihepaciviral NS5A inhibit, Protease inhibitor and cytochrome P450 inhibitor Use: Chronic hepatitis C genotype 4 Ombitasvir inhibits HCV NS5A and interferes with viral RNA replication and virion assembly Paritaprevir inhibits HCV NS3/4A protease and interferes with HCV coded poly protein cleavage necessary for replication Ritonavir is a CYP3A inhibitor that increases peak and trough plasma drug concentrations and overall drug exposure Technivie [package insert]. AbbVie Inc. North Chicago, IL; January DAKLINZA Generic Name: Declatasvir Class: Antihepaciviral NS5A Inhibitor Use: Chronic hepatitis C infection genotype 1 and 3 Binds to the N-terminus within Domain 1 of HCV nonstructural protein 5A and inhibits viral RNA replication and virion assembly TECHNIVIE Dosage Form(s): Oral Tablet Fixed Dose: Ombitasvir 12.5 mg, paritaprevir 75 mg, and ritonavir 50 mg Dose: 2 tablets once daily in the morning with/without ribavirin for 12 weeks Adverse Effects: Fatigue, nausea, weakness Pearls: AWP: $1,095.04/2 tablets=$91, Sustained virological response: greater than 90% Daklinza [package insert]. Bristol-Myers Squibb Company. Princeton, NJ; April Technivie [package insert]. AbbVie Inc. North Chicago, IL; January DAKLINZA HUMAN IMMUNODEFICIENCY VIRUS Dosage Form(s): Oral tablet (30, 60, and 90 mg) Dose: 60 mg daily with concomitant sofosbuvir for weeks Adverse Effects: Fatigue, headache, nausea, anemia Pearls Dose adjustments based on drug interactions AWP: $25,200/28 tablets=$75, ,200 per treatment course Sustained virologic response in % of patients Daklinza [package insert]. Bristol-Myers Squibb Company. Princeton, NJ; April

7 HUMAN IMMUNODEFICIENCY VIRUS ODEFSEY In 2011, roughly 1.2 million people living with HIV 86% of patients are diagnosed Only 4 in 10 people with HIV are adequately treated Only 3 in 10 people reach viral suppression Life expectancy of a 20 year old taking anti-retroviral therapy: 71 Life expectancy of a 20 year old not taking anti-retroviral therapy: 32 Dosage Form(s): Oral Tablet (Emtricitabine 200 mg, Rilpivirine 25 mg, and Tenofovir Alafenamide 25 mg) Dose: One tablet daily Adverse Effects: Emtricitabine/Tenofovir: CNS Effects, GI Side Effects, Respiratory Effects Rilpivirine: CNS Effects, Hepatic Effects Pearls AWP Cost: $ /30 tablets Tenofovir Alafenadmide requires a lower dose to achieve the same clinical outcomes, with reduced side effects because of lower overall drug exposure Odefsey [package insert]. Gilead Sciences, Inc. Foster City, CA; March a=en. HUMAN IMMUNODEFICIENCY VIRUS EVOTAZ Generic Name: Atazanavir and Cobicistat Class: Antiretroviral Use: HIV-1 Infection (Treatment naïve or treatment experienced) Atazanavir binds to the site of HIV-1 protease activity and prevents protein cleavage Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A Evotaz [package insert]. Bristol-Myers Squibb Company. Princeton, NJ; January ODEFSEY Generic Name: Emtricitabine, Rilpivirine, and Tenofovir Alafenamide Class: Antiretroviral Use: HIV-1 Infection Rilpivirine: Binds to reverse transcriptase Emtricitabine: A cytosine analogue which interferes with HIV viral RNA dependent DNA polymerase activity result inhibition of viral replication Tenofovir Alafenamide Fumurate: An adenosine 5 -monophosphate which interferes with HIV viral RNA dependent DNA polymerase activity result inhibition of viral replication Odefsey [package insert]. Gilead Sciences, Inc. Foster City, CA; March f?la=en. EVOTAZ Dosage Form(s): Oral tablet (Atazanavir 300 mg and Cobicistat 150 mg) Dose: One tablet daily Adverse Effects: Hepatic effects, Ophthalmic effects Pearls: AWP: $1,817.51/30 tablets Evotaz [package insert]. Bristol-Myers Squibb Company. Princeton, NJ; January

8 GENVOYA PREZCOBIX Generic Name: Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Class: Antiretroviral Use: HIV-1 Infection Emtricitabine: A cytosine analogue which interferes with HIV viral RNA dependent DNA polymerase activity result inhibition of viral replication Tenofovir Alafenamide Fumurate: An adenosine 5 -monophosphate which interferes with HIV viral RNA dependent DNA polymerase activity result inhibition of viral replication Genvoya [package insert]. Gilead Elvitegravir: Inhibits catalytic activity of integrase, preventing integration of Sciences, Inc. Foster City, CA; proviral gene in human DNA March pdfs/medicines/hiv/genvoya/genvoy Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A a_pi.pdf. Dosage Form(s): Oral tablet (Darunavir 800 mg and Cobicistat 150 mg) Dose: One tablet Adverse Effects: Dermatologic effects, gastrointestinal effects Pearls AWP Cost: $1, / 30 tablets Can cause fat accumulation in specific areas ( buffalo hump ) Prezcobix [package insert]. Janssen Therapeutics. Titusville, NJ; March GENVOYA USING DRUG INFORMATION TO PREVENT MISADVENTURES Dosage Form(s): Oral tablet (Elvitegravir 150 mg, Cobicistat 150 mg, Emtricitabine 200 mg, and Tenofovir Alafenamide 10 mg) Dose: One tablet daily Adverse Effects: CNS Effects, GI Side Effects Pearls AWP Cost: $3, / 30 tablets Genvoya [package insert]. Gilead Sciences, Inc. Foster City, CA; March dicines/hiv/genvoya/genvoya_pi.pdf. PREZCOBIX Generic Name: Darunavir and Cobicistat Class: Antiretroviral Use: HIV-1 Infection Darunavir binds to the site of HIV-1 protease activity and prevents protein cleavage Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A NEW DRUGS AND ERRORS A Medication Error is "any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer," according to the National Coordinating Council for Medication Error Reporting and Prevention. The FDA reviews about 1400 reports of medication errors per month and analyzes them to determine the cause and type of error. Medication errors cause one death everyday and injure approximately 1.3 million people every year in the United States Prezcobix [package insert]. Janssen Therapeutics. Titusville, NJ; March

9 NEW DRUG ERROR PREVENTION To assist with medication error prevention, the FDA has implemented the following: Drug Name Review Drug Labeling and Packaging Bar Code Label Rule Error Analysis Guidance for Industry Education DRUG INFORMATION RESOURCES New drug availability information can be found in the following resources: FDA website Drugs.com Online Drug Information Websites ( Facts and Comparisons, Lexi-Comp, Medi-span) PHARMACY TECHNICIANS AND NEW DRUG ERROR PREVENTION Pharmacy technicians play an important role in avoiding medication misadventures. Technicians can assist with this added layer of safety through the following key safety checks: Key Safety Checks: Prescription Drop-off Obtaining critical patient information Establishing patient need of medication through patient profile overview Order Entry Knowledge of pharmacy terminology and drug names Knowledge of new drug availability Adherence to standard operating procedures (no workarounds) DRUG INFORMATION RESOURCES Referring to the drug s package insert is an excellent resource to familiarize yourself with the following: Indications of use Dosage and Administration Warnings and Precautions Adverse Reactions Drug Interactions Storage and Preparation PHARMACY TECHNICIANS AND NEW DRUG ERROR PREVENTION Key Safety Checks QUESTIONS? Filling and Dispensing Correctly reading a label Avoid short cuts Separating locations for look-a-like medications or similarly packaged drugs Point of Sale Review Verification of patient demographics 9

10 REFERENCES Avycaz [package insert]. GlaxoSmithKline Manufacturing, Inc. Cincinnati, OH; September Cresemba [package insert]. Astellas Pharmaceuticals, Inc. Northbrook, IL; April Dalvance [package insert]. Allergan Pharmaceuticals, Inc. Parsippany, NJ; January Daklinza [package insert]. Bristol-Myers Squibb Company. Princeton, NJ; April Evotaz [package insert]. Bristol-Myers Squibb Company. Princeton, NJ; January Genvoya [package insert]. Gilead Sciences, Inc. Foster City, CA; March Accessed May 31, 2016 REFERENCES Odefsey [package insert]. Gilead Sciences, Inc. Foster City, CA; March Accessed May 31, 2016 Orbactiv [package insert]. The Medicines Company. Parsippany, NJ; January Prezcobix [package insert]. Janssen Therapeutics. Titusville, NJ; March Sivextro [package insert]. Merck Pharmaceuticals, Inc. Whitehouse Station, NJ; July Technivie [package insert]. AbbVie Inc. North Chicago, IL; January Zepatier [package insert]. Merck Pharmaceuticals, Inc. Whitehouse Station, NJ; January Zerbaxa [package insert]. Merck Pharmaceuticals, Inc. Whitehouse Station, NJ; July A4 REFERENCES "U.S. Food and Drug Administration." Novel Drug Approvals for U.S Food and Drug Administration, n.d. Web. 05 June < htm>. "U.S. Food and Drug Administration." New Drug Development and Review Process. U.S Food and Drug Administration, 11 Feb Web. 05 June < nce/ucm htm>. "U.S. Food and Drug Administration." Avoiding Medication Mistakes. U.S Food and Drug Administration, n.d. Web. 05 June < 10

11 Slide 57 A4 Please include citatio for each package insert and study referenced in the presentation. Although in-slide citation was noted, a full reference should be listed at the end Author, 6/7/2016