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New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series

ProCE, Inc.www.ProCE.com 1

New Drugs 2014 – Part 1April 10, 2015

LUNCH AND LEARN

Featured Speaker: Mary Lynn Moody, RPh

Director, Business Development Drug Information GroupClinical Associate ProfessorUniversity of Illinois at Chicago College of Pharmacy

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CE Activity Information & Accreditation

ProCE, Inc. (Pharmacist and Tech CE)

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Funding: This activity is self‐funded through

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g y gPharMEDium.

It is the policy of ProCE, Inc. to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. Ms. Moody has no relevant commercial and/or financial relationships to disclose.



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Mary Lynn Moody, BSPharm

Clinical Associate Professor

Department of Pharmacy Practice

University of Illinois at Chicago

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Learning Objectives for Pharmacists

Describe the new drugs approved by the F d d D Ad i i t ti i 2014Food and Drug Administration in 2014

Discuss the role of these agents in therapy

Summarize the adverse effects and potential drug interactions of these new agents

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Learning Objectives for Technicians

Describe the new drugs approved by the Food and Drug Administration in 2014Food and Drug Administration in 2014

Discuss any unique preparation and/or dispensing requirements for these agents

Summarize the adverse effects and potential drug interactions of these new agents that may require pharmacist intervention

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New Molecular Entitities (NME)

Refer to handout for the next 3 slides

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2014: A Banner Year1

41 new molecular entities (NMEs)

Highest number since 1996

17 were designated first in class

12 new infectious disease agents

8 new oncology drugs

16 biologics (35%) approved this year 16 biologics (35%) approved this year

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Breakthrough Status

This designation authorized by Congress in 2012in 2012

Reserved for agents that treat serious or life-threatening diseases or conditions, or those that provide substantial improvement over existing therapy

FDA will expedite the development and FDA will expedite the development and review of these agents

This year, 8 drugs were awarded breakthrough status

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Orphan Drugs

Affect less than 200,000 patients

17 NMEs were designated as orphan drugs, the highest number since the Orphan Drug Act passed in 1983

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Part I: Focus on Anti-infectives

New agents to compete with vancomycin

New dosing strategies

New drug classes

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Tedizolid Phosphate (Sivextro)2

An oxazolidinone, similar to linezolid Bacteriostatic agent Bacteriostatic agent Interacts with 50S subunit of bacteria Approved for acute bacterial skin and skin

structure infections (ABSSSI) Gram-positive organisms including MRSA,

VRSAVRSA Staphylococci Streptococcus Enterococcus

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Tedizolid Phosphate2

Excellent oral absorption (IV to PO is 1:1)

Prodrug is converted to active tedizolid by phosphatases

Not metabolized

Protein binding is 70-90%

Excreted primarily in feces (82%) Excreted primarily in feces (82%), urine (18%)

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Tedizolid Phosphate Dosing2

Available as 200-mg vial, 200-mg tablet

Oral dose can be taken without regard to meals

Dose is 200 mg daily (IV or PO) for 6 days

Infuse intravenously over 1 hour

Incompatible with divalent cations Incompatible with divalent cations

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Tedizolid Phosphate: ESTABLISH-1 Trial3

Primary efficacy end point: Response rate 48 to 72 hr 79.5% (95% CI, 74.8% to 83.7%) (T group) 79.4% (95% CI, 74.7% to 83.6%) (L group) Treatment difference of 0.1% [95% CI, -6.1% to 6.2%])

Secondary end point: Clinical treatment response rates at end of treatment

69.3% (95% CI, 64.0% to 74.2%) (T group) 71.9% (95% CI, 66.8% to 76.7%) (L group) 71.9% (95% CI, 66.8% to 76.7%) (L group) Treatment difference of -2.6% [95% CI, -9.6% to 4.2%])

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Tedizolid Phosphate2

WarningsA id i t i ( 1000 ll / 3) Avoid in neutropenia (<1000 cells/mm3)

Adverse effects Nausea (8%)

Vomiting (4%)

Diarrhea (3%)

Headache (6%)

Dizziness (2%)

Data regarding safety is for acute (6 days) only

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Pharmacist Clinical Points

Verify patient is not neutropenic

Not compatible with any solution containing divalent cations (calcium, magnesium)

Use only in situations where susceptibility is documented or highly suspected to reduce resistance

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Technician Tips2

Do not shake when reconstituting to minimize foamingminimize foaming

Further dilute in 250 mL Sodium Chloride 0.9%; invert the bag gently to mix

Stable for 24 hours at RT or refrigerated; administer within 24 hours of mixing

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Dalbavancin (Dalvance)

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Dalbavancin (Dalvance)4

Lipoglycopeptide

Bactericidal

Destabilizes cell wall and results in bacterial cell death

Approved for use in acute bacterial skin and skin structure infections (ABSSSI)skin structure infections (ABSSSI)

Gram-positive coverage including MRSA

Efficacy in VRSA is poor

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Dalbavancin4

Intravenous administration only

Half life: 147 to 248 hours

Highly protein bound (93%)

Minimal metabolism, excreted as active drug

33% excreted in urine 20% in feces 33% excreted in urine, 20% in feces

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Dalbavancin Clinical Data5

Two phase III trials; 1,312 patients Dalbavancin vs vancomycin/linezolid Dalbavancin vs. vancomycin/linezolid Non-inferior to vancomycin/linezolid Primary endpoint: clinical response rate

(48-72 hours) 79.7% (D) vs. 79.8% (V+L)

S d d i t 20% d ti i Secondary endpoint: ≥ 20% reduction in lesion area 88.6% (D) vs. 88.1% (V+L)

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Dalbavancin Dosing4

Initial dose is 1000 mg followed by 500 mg 1 week later1 week later

CrCl <30 mL/min: 750 mg followed by 375 mg 1 week later

No dose adjustment in hemodialysis

Infuse over 30 minutes to avoid flushing Infuse over 30 minutes to avoid flushing

Caution in moderate/severe hepatic impairment (Child-Pugh Class B or C)

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Dalbavancin Adverse Effects4

Avoid in known hypersensitivity to glycopeptide antibacterial agentsglycopeptide antibacterial agents

Alanine aminotransferase (ALT) elevations reported (3X-10X normal)

Rapid infusion: flushing, urticaria, pruritis, and rash

Nausea (5 5%) Nausea (5.5%) Headache (4.7%) Diarrhea (4.4%)

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Ensure proper follow up for 2nd dose if patient dischargedpatient discharged

Infuse over 30 minutes to prevent reaction (Red Man)

May not be on microbiology panels

May be cross-sensitive with vancomycin; May be cross sensitive with vancomycin; avoid if vancomycin-allergic

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Technician Tips4

Mix only in Dextrose 5% in water

Precipitation in 0.9% Sodium Chloride

Total time from reconstitution to dilution to administration should not exceed 48 hours

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Oritavancin (Orbactiv)

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Oritavancin (Orbactiv)6,7

Lipoglycopeptide agent

Bactericidal

Approved for acute bacterial skin and skin structure infections (ABSSSI)

Gram-positive organisms MRSA VRSAMRSA, VRSA

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Oritavancin6

Half-life of 245 hours

85% protein bound

Not metabolized

5% excreted in urine, 1% in feces

No dosing adjustment required in renal/liver impairmentimpairment

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Oritavancin Dosing6

Infuse 1200 mg intravenously over 3 hours as a single doseas a single dose

Dilute in 1000 mL Dextrose 5% in water ONLY

Use this solution within 6 hours if stored at room temperature or 12 hours refrigerated

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Oritavancin8

2 global clinical trials (SOLO I and SOLO II): non inferiority trial with vancomycinnon-inferiority trial with vancomycin

1,987 patients with ABSSSI

Primary endpoint: clinical response at 48 to 72 hours

Secondary endpoint: 20% reduction of Secondary endpoint: 20% reduction of lesion

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Oritavancin: Clinical Response at 48-72 hours8

Study Oritavancin Vancomycin Difference

SOLO I 82.3% 78.9% 3.4 (-1.6,8.4)

SOLO II 80.1% 82.9% -2.7 (-7.5, 2.0)

Oritavancin was non-inferior to vancomycin in ABSSSI infections

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Oritavancin Contraindications6

Intravenous unfractionated heparinD t d i i t h i f 48 h AFTER Do not administer heparin for 48 hours AFTER oritavancin

PTT will remain falsely elevated for 48 hours; INR elevated for 24 hours

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Oritavancin Warnings6

Avoid use with warfarin; increases risk of bleeding due to higher exposure of warfarinbleeding due to higher exposure of warfarin

Infusion-related reactions

May be cross-reactive with vancomycin

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Oritavancin Side Effects6

Headache: 7%

Nausea: 9.9%

Vomiting: 4.6%

Abcess (limb or subcutaneous): 3.8%

Diarrhea: 3.7%

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Verify that patient is not receiving heparin or warfarinwarfarin

Infusion reactions: may need to reduce rate of infusion

Osteomyelitis: reported in clinical trials; change antibiotics if this occurs

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Technician Tips6

To prepare dose, dilute three 400-mg vials

Avoid foaming; swirl vials gently, do not shake

Withdraw 120 mL from 1000-mL bag of D5W and discard

Final concentration is 1.2 mg/mL Final concentration is 1.2 mg/mL

Use within 6 hours of preparation if stored at room temperature, 12 hours if refrigerated

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Ceftolozane/Tazobactam (Zerbaxa)9

4th new antibiotic approved this year

Antipseudomonal cephalosporin

QIDP drug; priority review

Approved for cUTI (pyelonephritis)

Approved in combination with metronidazole for cIAIfor cIAI

HAP/VAP under study in phase III trials

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Ceftolozane/Tazobactam10

Inhibits cell wall synthesis

Bactericidal

Tazobactam is beta lactamase inhibitor Protects against hydrolysis

ESBL-producing Enterobacteriaceae

92% excreted renally 92% excreted renally

Half-life of 2.3 hours

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ASPECT cUTI Trial:

Two Phase III trials

1,068 patients

Compared with levofloxacin for 7-day trial

82% of patients had pyelonephritis

Primary efficacy endpoint: complete Primary efficacy endpoint: complete resolution or marked improvement of clinical symptoms and microbiologic eradication

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ASPECT Results11

EndpointCeftolozane/Tazobactam Levofloxacin Difference

Composite microbiologic and clinical cure

83.3% 75.4% 8.0 (2.0 to 14.0)

Microbiologic cure 84.7 % 75.1% 9.7 (1.8 to 17.4)

Clinical cure 95.9% 93.2 % 2.7 (-0.8 to 6.2)

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cIAI trial

979 patients

Ceftolozane/tazobactam and metronidazole vs. meropenem

mITT: 83% (CT) vs. 87.3% (M) 95%CI -4.3 (-9.2, 0.7)( 9.2, 0.7)

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Ceftolozane/Tazobactam Dosing Recommendations10

CrCl >50 mL/min: Infuse 1 5 grams (1 g/0 5 g) every 8 hours over 1 hourInfuse 1.5 grams (1 g/0.5 g) every 8 hours over 1 hour

CrCl 30 – 50 mL/min: 750 mg (500 mg/250 mg) intravenously every 8 hours over 1 hour

CrCl 15 – 29 mL/min: 375 mg 250 mg/125 mg) intravenously every 8 hours over 1 hour

ESRD on HD: Si l l di d f 750 (500 /250 ) f ll d b Single loading dose of 750 mg (500 mg/250 mg) followed by 150 mg (100 mg/50 mg) every 8 hours

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Warnings

Reduced efficacy in renal impairment

cIAI: ↓ cure rates in CrCl 30 – 50 mL/min 85.2% vs. 47.8% (Z+M)

87.9% vs 69.2% (M)

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Adverse effects occurred in 10% – 12% of patientspatients

Adverse effectcIAIvs. Meropenem

cUTIvs. Levofloxacin

Nausea 7.9% 5.8% 2.8% 1.7%

Headache 2.5% 1.8% 5.8% 4.9%

Diarrhea 6.2% 5% 1.9% 4.3%

Fever 5.6% 4% 1.7% 0.9%

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May restrict and reserve for resistant gram negative infectionsgram-negative infections

Additional data needed to demonstrate superiority

Concerns with patients who have renal impairment

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Technician Tips10

Reconstitute with 10 mL SWI or NS to final volume of 11 4 mLvolume of 11.4 mL

Stable 24 hours at room temperature, 7 days refrigerated.

Ceftolozane/tazobactam dose Volume to withdraw

1.5 gm (1 g/0.5 g) 11.4 mL (entire contents)

750 mg (500 mg/250 mg) 5.7 mL

375 mg (250 mg/125 mg) 2.9 mL

150 mg (100 mg/50 mg) 1.2 mL

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References1. Food and Drug Adminsitration. Novel new drugs-2014.

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM430299.pdf. Accessed March 28, 2015.

2. Sivextro [package insert]. Lexington, MA: Cubist Pharmaceuticals; 2014. http://sivextro.com/pdf/sivextro-prescribing-info.pdf. Accessed March 29, 2015.

3. Prokocimer P, De Anda C, Fang E et al. Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections: the ESTABLISH 1 randomized trial JAMA 2013; 309(6):559 569skin structure infections: the ESTABLISH-1 randomized trial. JAMA 2013; 309(6):559-569.

4. Dalvance [package insert]. Chicago, IL: DurataTherapeutics; 2014. http://www.frx.com/pi/dalvance_pi.pdf. Accessed March 29, 2015.

5. Boucher HW, Wilcox M, Talbot GH et al. Once-weekly dalbavancin versus daily conventiona therapy for skin infection. New Engl J Med . 2014; 370(23):2169-79.

6. Orbactiv [package insert]. Parsippany, NJ: The Medicines Company; 2014. http://orbactiv.com/. Accessed March 29, 2015.

7. Zhanel GG, Calic D, Schweizer F. New lipoglycopeptides: a comparative review of dalbavancin, oritavancin and telavancin. Drugs 2010;70(7):859-886.

8. Corey GR, Kabler H, Mehra P, et al. Single-Dose Oritavancin in the treatment of acute bacterial Skin Infections. N Engl J Med. 2014;370 (23):2180-2190.

9. Food and Drug Administration. FDA approved new antibacterial drug Zerbaxa. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427534.htm. Accessed March 28, 2015.

10 Z b [ k i t] L i t MA C bi t Ph ti l 201410. Zerbaxa [package insert]. Lexington, MA: Cubist Pharmaceuticals; 2014. http://www.zerbaxa.com/pdf/PrescribingInformation.pdf. Accessed March 28, 2015.

11. Wagenlehner F, et al. Efficacy and safety of ceftolozane/tazobactam versus levofloxacin in the treatment of complicated urinary tract infections (cUTI) including pyelonephritis in hospitalized adults: Results from the Phase 3 ASPECT-cUTI trial. In: Proceeding of the 24th European Congress of Clinical Microbiology and Infectious Diseases. May 10-13, 2014. Barcelona, Spain. Abstract #eP449.

12. Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis 2015 Feb 10. pii: civ097. [Epub ahead of print]

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New Drugs Approved in 2014

Generic Name Brand Name Manufacturer Indication

1. Nivolumab Opdivo Bristol Myers Squibb

Unresectable or metastatic melanoma

2. Peramivir Rapivab Biocryst Influenza in adults

3. Ceftolozane/tazobactam Zerbaxa Cubist Complicated intra‐abdominal infections (cIAI) and complicated urinary tract infections (cUTI).

4. Ombitasvir, paritaprevir and ritonavir tablets co‐packaged with dasabuvir

Viekira Pak AbbieVie Chronic hepatitis C infection

5. Olaparib Lynparza Astra Zeneca Advanced ovarian cancer associated with defective BRCA genes

6. Finafloxacin Xtoro Alcon Acute otitis externa (swimmers ear)

7. Blinatumomab Blincyto Amgen Philadelphia chromosome‐negative precursor B‐cell acute lymphoblastic leukemia (B‐cell ALL)

8. Pirfenidone Esbriet Intermune Idiopathic pulmonary fibrosis

9. Nintedanib Ofev Boehringer Ingelheim

Idiopathic pulmonary fibrosis

10. Netupitant and palonosetron

Akynzeo Eisai Chemotherapy associated nausea and vomiting

11. Ledipasvir and sofosbuvir

Harvoni Gilead Chronic hepatitis C‐ genotype 1

12. Dulaglutide Trulicity Eli Lilly Type II diabetes REMS

13. Naloxegol Movantik Astra Zeneca Opioid induced constipation

14. Pembrolizumab Keytruda Merck Advanced or unresectable melanoma

15. Eliglusta Cerdelga Genzyme Gaucher disease Type 1

16. Peginterferon beta‐1a Plegridy Biogen Multiple sclerosis

17. Suvorexant Belsomra Merck Insomnia

18. Oritavancin Orbactiv Medicines Acute bacterial skin and skin structure infections (ABSSSI)

19. Empagliflozin Jardiance Boehringer Ingelheim

Type II diabetes

20. Olodaterol Striverdi Respimat

Boehringer Ingelheim

Chronic obstructive respiratory disease

Generic Name Brand Name Manufacturer Indication

21. Idelalisib Zydelig Gilead

Chronic lymphocytic leukemia (CLL) has returned (relapsed). Relapsed follicular B‐cell non‐Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL),

22. Tavaborole Kerydin Anacor Onychomycosis of the toenails

23. Belinostat Beleodaq Spectrum Peripheral T‐cell lymphoma Accelerated approval

24. Tedizolid Sivextro Cubist Acute bacterial skin and skin structure infections (ABSSSI)

25. Efinaconazole Jublia Dow Onychomycosis of the toenails

26. Dalbavancin Dalvance Durata Acute bacterial skin and skin structure infections (ABSSSI)

27. Vedolizumab Entyvio Takeda Moderate to severe ulcerative colitis or Crohn‘s disease

28. Vorapaxar Zontivity Merck Reduce the risk of heart attack and stroke in high risk patients

29. Ceritinib Zykadia Novartis Metastatic non‐small cell lung cancer (NSCLC)

30. Siltuximab Sylvant Janssen Multicentric castleman’s disease (MCD)

31. Ramucirumab Cyramza Eli Lilly Metastatic non‐small cell lung cancer (NSCLC);gastroesophageal junction (GEJ) adenocarcinoma

32. Albiglutide Tanzeum Glaxo Smith Kline

Type II diabetes

33. Apremilast Otezla Celgene Moderate to severe plaque psoriasis

34. Miltefosine Impavido Paladin Leishmaniasis

35. Metreleptin Myalept Amylin Generalized lipodystrophy

36. Droxidopa Northera Chelsea Therapeutics

Neurogenic orthostatic hypotension

37. Elosulfase Vimizim Biomarin Pharmaceuticals

Mucopolysaccharidosis Type IVA (Morquio A syndrome).

38. Tasimelteon Hetlioz Vanda Pharmaceuticals

Non‐24‐ hour sleep‐wake disorder

39. Dapaglifozin Farxiga Bristol Myers Squibb

Type II diabetes

40. Recombinant C1 esterase inhibitor

Ruconest Salix Heriditary angioedema

41. Tavaborole Kerydin Anacor Onychomycosis

2014 New Drugs – First in Class

Generic name Brand name

1. Olaparib Lynparza

2. Blinatumomab Blincyto

3. Pirfenidone Esbriet

4. Nintedanib Ofev

5. Neisseria meningitides, Type B Trumenba

6. Pembrolizumab Keytruda

7. Suvorexant Belsomra

8. Idelalisib Zydelig

9. Vorapaxar Zontivity

10. Siltuximab Sylvant

11. Apremilast Otezla

12. Miltefosine Impavido

13. Recombinant C1 esterase inhibitor Ruconest

14. Metreleptin Myalept

15. Droxidopa Northera

16. Elosulfase Vimizim

17. Ledipasvir and sofosbuvir Harvoni

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