Upload
others
View
0
Download
0
Embed Size (px)
Citation preview
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
1
CE Activity Information & Accreditation
ProCE, Inc. (Pharmacist and Tech CE)
1.0 contact hour
Funding: This activity is self‐funded through
2
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.
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 2
Submission of an online self‐assessment and evaluation is the
Online Evaluation, Self-Assessmentand CE Credit
Submission of an online self assessment and evaluation is the only way to obtain CE credit for this webinar
Go to www.ProCE.com/PharMEDiumRx
Print your CE Statement online
Live CE Deadline: May 8, 2015
CPE Monitor
3
– CE information automatically uploaded to NABP/CPE Monitor within 1 to 2 weeks of the completion of the self‐assessment and evaluation
Event Code
Code will be provided at the end of today’s activityEvent Code not needed for On‐Demand
Ask a Question
Submit your questions to your site manager.
Questions will be answered at the end of the presentation.
4
Your question. . . ?
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 3
Resources
Visit www.ProCE.com/PharMEDiumRx to access:
Handouts– Handouts
– Activity information
– Upcoming live webinar dates
– Links to receive CE credit
5
Mary Lynn Moody, BSPharm
Clinical Associate Professor
Department of Pharmacy Practice
University of Illinois at Chicago
6
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 4
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
7
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
8
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 5
New Molecular Entitities (NME)
Refer to handout for the next 3 slides
9
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
10
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 6
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
11
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
12
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 7
Part I: Focus on Anti-infectives
New agents to compete with vancomycin
New dosing strategies
New drug classes
13
14
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 8
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
15
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%)
16
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 9
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
17
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%])
18
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 10
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
19
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
20
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 11
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
21
Dalbavancin (Dalvance)
22
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 12
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
23
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
24
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 13
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)
25
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)
26
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 14
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%)
27
Pharmacist Clinical Points
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
28
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 15
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
29
Oritavancin (Orbactiv)
30
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 16
Oritavancin (Orbactiv)6,7
Lipoglycopeptide agent
Bactericidal
Approved for acute bacterial skin and skin structure infections (ABSSSI)
Gram-positive organisms MRSA VRSAMRSA, VRSA
31
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
32
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 17
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
33
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
34
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 18
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
35
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
36
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 19
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
37
Oritavancin Side Effects6
Headache: 7%
Nausea: 9.9%
Vomiting: 4.6%
Abcess (limb or subcutaneous): 3.8%
Diarrhea: 3.7%
38
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 20
Pharmacist Clinical Points
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
39
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
40
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 21
41
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
42
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 22
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
43
Ceftolozane/Tazobactam11
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
44
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 23
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)
45
Ceftolozane/Tazobactam12
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)
46
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 24
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
47
Ceftolozane/Tazobactam10
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)
48
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 25
Ceftolozane/Tazobactam10
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%
49
Pharmacist Clinical Points
May restrict and reserve for resistant gram negative infectionsgram-negative infections
Additional data needed to demonstrate superiority
Concerns with patients who have renal impairment
50
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 26
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
51
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]
52
New Drugs 2014 – Part 1PharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 27
53
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