New Drugs of 2016: Part 1 PharMEDium Lunch and Learn...

New Drugs of 2016: Part 1PharMEDium Lunch and Learn Series

ProCE, Inc.www.ProCE.com 1

New Drugs of 2016: Part 1

April 7, 2017

Featured Speaker: Mary Lynn Moody, BSPharmDirector, Business DevelopmentDrug Information and Prior Authorization GroupUniversity of Illinois at Chicago

LUNCH AND LEARN

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ProCE, Inc. (Pharmacist and Tech CE)

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Funding: This activity is self‐funded through PharMEDium.

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-Pharmacists

Describe the new drugs approved by the Food and Drug Administration in 2016

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- Technicians

Describe the new drugs approved by the Food and Drug Administration in 2016

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 entities (NME)

Refer to handout for the next three slides

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2016 –Not a Blockbuster Year 1

22 new molecular entities (NME)

Much lower than last year (45)

Below average of 29/year

5 approved in 2015 ahead of schedule

75% qualified for at least 1 expedited designation

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Breakthrough Status2

This designation authorized by Congress in 2012

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

FDA will expedite the development and review of these agents

This year, 32% (7/22) drugs were awarded that breakthrough status

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Orphan drugs2

41% (9/22) approved for orphan diseases

Orphan diseases occur in < 200,000 patients in US

25 million total patients in this category

Financial incentives, tax credits, fee waivers

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13

Lixisenatide (Adlyxin)3

Approved July 27, 2016

5th glucagon-like peptide-1 (GLP-1) receptor agonist

Approved to treat type 2 diabetes mellitus

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Lixisenatide Pharmacokinetics4

Administer within one hour prior to the first meal of the day

Administer subcutaneously in the abdomen, arm or thigh

No difference in rate of absorption

Excreted through glomerular filtration

Elimination half life: 3 hours

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Lixisenatide dosing4,5

Available as 50 mcg/mL, 100 mcg/mL prefilled syringes

Dose is 10 mcg once a day subcutaneously for 14 days

Increase to 20 mcg if needed

Administer within 1 hour prior to the first meal of the day

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Lixisenatide Efficacy6

Head to head comparison to exenatide

Non-inferior to twice daily exenatide

50% of patients in each group achieved HbA1c < 7%

Both drugs exhibited some weight loss

Lixisenatide had less hypoglycemia and GI effects

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Lixisenatide ELIXA trial7

6,068 diabetic patients with MI or unstable angina (6 mos)

Median follow up was 25 months

Designed to assess risk for MI, stroke, hospitalization

Not associated with difference in cardiovascular outcome compared to placebo

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Lixisenatide4,5

Contraindications/Warnings Hypersensitivity/antibody development Pancreatitis risk Renal damage

Adverse effects Hypoglycemia in combination with insulin or

sulfonylureas Nausea (25%) Vomiting (10%) Headache (9%) Diarrhea (8%) Dizziness (7%)

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Lixisenatide Place in therapy

Crowded market

Victoza®-market leader for years

No cardiovascular benefit like Victoza®

Some benefit in patients with GI or hypoglycemia with other GLP-1 agents

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Pharmacist Clinical Points

Be sure patient can demonstrate proper use

Need a new needle each day

Explain what to do if dose is missed, give within hour of next meal

Be sure to educate patient about hypoglycemia and how to manage

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Technician Points

Check to see if the patient needs to have the pharmacist review pen activation process

Be sure patient has needles and supplies when they pick up medication

Notify the pharmacist if the patient does not fill prescription regularly

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Hepatitis C8

Paradigm shift since 2011

Direct acting antiviral (DAA) agents Changed approach to care

Increased effectiveness

In 2014, combination products are an option for an all-oral therapy approach with exceptional efficacy rates (>90%)

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Hepatitis C9

www.Hcvguidelines.org

Response is measured by sustained virologic response (SVR) No detectable HCV RNA ≥ 12 weeks after tx

New combinations have SVR rates near 100%

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Elbasvir and grazoprevir (Zepatier)10

Approved January 28, 2016

Combines 2 DAAs

Approved for the treatment of chronic HCV genotype 1 or 4 infection in adults.

70% of HCV cases are genotype 1 in the US

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Elbasvir and grazoprevir11

Two different mechanisms of action Work at different steps in the virus lifecycle Extensively bound to plasma proteins

(>98.8%) T ½ of elbasvir is 24 hours and 31 hours

for grazoprevir Partially eliminated by oxidative

metabolism, primarily by CYP3A Primary route of elimination: feces (90%)

with less than 1% excreted in urine

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Patients should be tested for hepatitis B infection (HBV) and NS5A resistance if genotype 1a

The recommended dose-one tablet once a day for 12 weeks

No dosage adjustment for renal impairment

Elbasvir and grazoprevirdosing 5, 11

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Dosing duration 11

Patient Type Recommended treatment duration

Genotype 1a or 1b:Treatment naïve or previous treatment with peginterferon and ribavirin

12 weeks

Genotype 4:Treatment naïve 12 weeks

Gentotype 1a and high level NS5A polymorphism

16 weeks in combination with ribavirin

Genotype 1a or 1b previously treated with peginterferon, ribavirin and protease inhibitor


Genotype 4 previously treated with peginterferon and ribavirin


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Elbasvir and grazoprevir- Efficacy12-14

5 clinical trials that included both treatment –naïve as well as treatment –experienced patients

C-EDGE - 306 patients with genotype 1 or 4 were treated for 12 weeks

SVR12 rates were 95% for the genotype1 patients and 100% for the genotype 4 patients

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Elbasvir and grazoprevir –Efficacy14

Stage 4 and 5 kidney disease (C-SURFER)

122 patients enrolled in the trial

SVR12 rate was 94%

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Contraindications Moderate to severe liver disease

Black Box HBV reactivation risk

Screen all patients for HBsAg and anti-HBcbefore starting treatment

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Elbasvir and grazoprevir 11

Warnings Elevated liver enzyme called alanine

aminotransferase (ALT) ○ 1% of patients

○ Women, Asians, elderly

Avoid in severe liver damage

No information in pregnancy or lactation

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Elbasvir and grazoprevir 5,11

Drug Interactions- Contraindicated Anticonvulsants

Rifampin

St John’s Wort

Efavirenz

HIV medications

Cyclosporine

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Drug interactions- Warnings Nafcillin, ketoconazole

Rosuvastatin, atorvastatin

Etravine

Tacrolimus

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Elbasvir and grazoprevir 5,11

Adverse effects Common: nausea, fatigue and headache

Rare: Increased ALT levels (1%)

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Initial detailed counseling session

Importance of adherence and the risks of developing resistance

Probe for any potential barriers to adherence and address them

HBV reactivation: Verify screening was done; Discuss risks of reactivation

Review significant drug interactions

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Technician Tips

Make a reminder in the computer to alert pharmacist if the patient does not return for refill

Alert pharmacist if the patient is purchasing an OTC product to prevent interactions

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Epclusa 15

Approved June 28, 2016

1st fixed dose combination for all HCV genotypes

First single tablet regimen for genotype 2 and 3 that does not require ribavirin

Potential to eliminate need for genotype testing

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Epclusa Pharmacology 5,16

Sofosbuvir inhibits the HCV NS5B RNA-dependent RNA polymerase

Velpatasvir inhibits HCV NS5A protein which is necessary for viral replication

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Epclusa 16

Approved for the treatment of HCV genotypes 1,2,3,4,5,and 6 infections

Decompensated cirrhosis: Epclusa and ribavirin

All patients should be tested for current or prior HBV infection before starting Epclusa

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Epclusa dosing 5,16

One tablet once a day for 12 weeks

Can be taken with or without food

In decompensated cirrhosis, combine Epclusa with ribavirin for 12 weeks

No dose recommendation for severe renal impairment

Can use standard dose in patients with hepatic impairment

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Epclusa Efficacy 17-19

Trial Genotype Results

ASTRAL-1 1,2,3,4,5,6 99% vs. placebo

ASTRAL-2 2 99% vs 94% (sofosbuvir and ribavirin)

ASTRAL-3 3 95% vs 80% (sofosbuvir and ribavirin)

ASTRAL-4 (decompensated)

1,2,3,4,5,6 83-94%

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Epclusa Warnings 16

HBV reactivation

Serious bradycardia

Caution when used with ribavirin

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Epclusa adverse effects 16

Common adverse effects: headache, fatigue, nausea, asthenia and insomnia

Less common: rash (2-5%) and depression (1%)

Serious symptomatic bradycardia when combined with amiodarone

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Epclusa drug interactions 16

Serious symptomatic bradycardia when combined with amiodarone

Reduced effects of Epclusa Acid blocking/neutralizing drugs

Anticonvulsants

Rifampin

Some HIV drugs, St John’s Wort

Increased digoxin levels when combined

Increase levels of statins when combined

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Initial detailed counseling session

Importance of adherence and the risks of developing resistance

Probe for any potential barriers to adherence and address them

HBV reactivation: Verify screening was done; Discuss risks of reactivation

Review significant drug interactions

48



Technician Tips

Make a reminder in the computer to alert pharmacist if the patient does not return for refill

Alert pharmacist if the patient is purchasing an OTC product to prevent interactions

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Eteplirsen 20

Approved September 19, 2016

Accelerated approval pathway as an orphan drug

Seventh rare pediatric disease priority review voucher issued

Confirmed mutation of the dystrophin gene amenable to exon 51 skipping Which affects about 13% of the population

with Duchenne Muscular Dystrophy (DMD)

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Eteplirsen 21

Antisense oligonucleotide Binds to exon 51 in the RNA that codes for

dystrophin Allows “skipping” of exon 51

Formation of a partially functional dystrophin protein

The plasma protein binding of eteplirsen is low (6-17%)

Volume of distribution of the drug is 600 mL/kg

Primarily excreted through the kidneys and the elimination half-life is 3 to 4 hours

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Eteplirsen Dosing 5,21

30 mg/kg of body weight once a week

Infused over 35 to 60 minutes

Dilute in 0.9% sodium chloride to a final volume of 100 to 150 mL

Not studied in patients with liver or kidney disease so dose adjustments are not reported

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Eteplirsen Efficacy 22

FDA Advisory Committee did not support approval Not enough evidence FDA Commissioner interceded and approved the

agent in spite of this Pivotal clinical trial included only 12 boys with DMD Surrogate end-point of dystrophin increase in

skeletal muscle not clinical improvement Substantial flaws in the initial clinical trial submitted FDA required the manufacturer to conduct additional

studies to keep approval

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Eteplirsen Side Effects 21

Common side effects: Balance (38%)

Vomiting (38%)

Skin rash (25%)

Other adverse effects (≥10%) confusion, arthralgia, severe itching, catheter

site pain, and upper respiratory tract infection

Rare: transient erythema, facial flushing, and elevated temperature on the days that eteplirsen was administered

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Limited to Specialty Pharmacies

Counsel the parents/guardian of the child

Administered intravenously once a week Specialty pharmacy or home compounded?

Pharmacists may recommend an anesthetic cream for the infusion

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Technician Tips

Allow vials to warm to room temperature

Do not shake

Administer immediately, no preservative

Dilute in 0.9% sodium chloride only

Final volume of 100 to 150 mL

Can store final product in refrigerator for 24 hours if needed

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58



Bezlotoxumab(Zinplava) 23

October 21, 2016

Fast Track Approval

Reduce the recurrence of Clostridium difficile infection (CDI)

Use with an antibacterial drug

NOT approved to treat CDI

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Bezlotoxumab 24

Human monoclonal antibody

Binds to C. difficile toxin B and neutralizes effect

Eliminated by catabolism so no need to adjust dose in renal or liver impairment

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Bezlotoxumab Dosing 24

Single dose: 10 mg/kg administered as an intravenous infusion

Dilute drug with 0.9% sodium chloride or Dextrose 5% in water

Final concentration ranges from 1 mg/mL to 10 mg/mL

Use a 0.2 to 5 micron in-line filter Administer over 60 minutes. Do not

administer IV push or bolus

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Bezlotoxumab Efficacy 24

MODIFY I and II studies enrolled 2,655 patients

Both hospital and outpatient settings

Primary endpoint –recurrence of CDI within 12 weeks: lower with Zinplava(17.4%, p=0.0003) compared to 27.6% in placebo

Higher risk of heart failure in at risk patients

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Bezlotoxumab Warnings 24

No contraindications

Heart failure reported in trials History of heart failure: 12.7% in Zinplava

group; 4.8% in placebo group

Reserve use when benefit outweighs risk in patients with history of heart failure

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Bezlotoxumab Adverse Effects 24

Common Infusion related reactions (10%)

Nausea (7%)

Pyrexia (5%)

Headache (4%)

Rare Ventricular tachyarrhythmia

Heart failure

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Confirm patient is receiving antibacterial for CDI

Do not co-administer in the same line with other drugs

May administer via central or peripheral line

Only single dose therapy

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Technician Tips

Must dilute prior to administration

Do not shake vial

Dilute with 0.9% sodium chloride or Detrose 5% in Water to final concentration of 1 mg/mL to 10 mg/mL

May store 16 hours at room temp or 24 hours refrigerated

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Conclusions

Much fewer number of drugs approved in 2016

Majority of those approved were orphan, fast track agents

Not much impact on compounding business

Critical to understand these new agents

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References1. United States Food and Drug Administration. Novel Drug Approvals 2016.

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm483775.htm. Accessed January 8, 2017.2. United States Food and Drug Administration. Novel Drugs Summary 2016.

https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm534863.htm. Accessed March 3, 2017.3. United States Food and Drug Administration. FDA approves Adlyxin to treat type 2 diabetes.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm513602.htm. Accessed March 3, 2017.4. Adlyxin [package insert]. Bridgewater NJ: Sanofi-Aventis LLC. July 2016.5. Facts and Comparisons. [database online] Indianapolis, IN: Clinical Drug Information. LLC;

http://online.factsandcomparisons.com. Accessed January 15, 2017.6. Rosenstock J, Raccah D, Koranyi L et al. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in

type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2013;36(10):2945-2951. 7. Pfeffer MA, Claggett B, Diaz R et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N

Engl J Med. 2015;373(23):2247-2257.8. McCaughan GW. New therapies against HCV: Expected risks and challenges associated with their use in the liver

transplant setting. J Hepatol. 2012;57(6):1361-1667.9. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org.

Accessed March 1, 2017.10. United States Food and Drug Administration. FDA approves Zepatier for treatment of chronic hepatitis C genotypes 1

and 4. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm483828.htm. Accessed March 4, 2017. 11. Zepatier [package insert]. Whitehouse Station NJ: Merck & Co., Inc. February 2017.12. Rockstroh JK, Nelson M, Katlama C et al. Efficacy and safety of gazoprevir (MK-5172) and elbasvir (MK-8742) in

patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial. Lancet HIV. 2015;2(8):e319-e327.

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References13. Buti M, Gordon SC, Zuckerman E et al. Grazoprevir, elbasvir, and ribavirin for chronic hepatitis C virus

genotype 1 infection after failure of pegylated interferon and ribavirin with an earlier-generation protease inhibitor: Final 24-Week results from C-SALVAGE. Clin Infect Dis. 2016;62(1):32-36.

14. Roth D, Nelson DR, Bruchfeld A et al. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet. 2015;386(10003):1537-1545.

15. United States Food and Drug Administration. FDA approves Epclusa for treatment of chronic Hepatitis C virus infection. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm508915.htm. Accessed March 5, 2017.

16. Epclusa [package insert]. Foster City CA: Gilead Sciences, Inc. February 2017.

17. Younossi ZM, Stepanova M, Feld J. et al. Sofosbuvir/velpatasvir improves patient-reported outcomes in HCV patients: results from ASTRAL-1 placebo-controlled trial. J Hepatol. 2016;65(1):33–39.

18. Younossi ZM, Stepanova M, Sulkowski M et al. Ribavirin-free regimen with sofosbuvir and velpatasvir is associated with high efficacy and improvement of patient-reported outcomes in patients with genotypes 2 and 3 chronic hepatitis C: Results from Astral-2 and -3 clinical trials. Clin Infect Dis.2016;63(8):1042-1048.

19. Younoss ZM, Stepanova M, Charlton M et al. Patient-reported outcomes with sofosbuvir and velpatasvir with or without ribavirin for hepatitis C virus-related decompensated cirrhosis: an exploratory analysis from the randomised, open-label ASTRAL-4 phase 3 trial. Lancet Gastroenterol Hepatol. 2016;1(100031):122–132.

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References20. United States Food and Drug Administration. FDA grants accelerated approval to first drug for Duchenne

muscular dystrophy. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm521263.htm. Accessed March 6, 2017.

21. Exondys 51 [package insert]. Cambridge MA: Sarepta Therapeutics Inc. September 2016.

22. Eteplirsen (Exondys 51) for duchenne muscular dystrophy. Med Lett Drugs Ther. 2016 Nov 7;58(1507):145-146.

23. United States Food and Drug Administration. FDA approves Merck’s ZINPLAVA™ (bezlotoxumab) to reduce recurrence of Clostridium difficile infection (CDI) in adult patients receiving antibacterial drug treatment for CDI who are at high risk of CDI recurrence. http://www.mercknewsroom.com/news-release/corporate-news/fda-approves-mercks-zinplava-bezlotoxumab-reduce-recurrence-clostridium-. Accessed March 29, 2017.

24. Zinplava [package insert]. Whitehouse Station NJ: Merck and Company. October 2016.

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New Drugs of 2016 Table 1- New drugs of 2016, listed in order of approval date1

Generic Name Brand Name Approval Date Indication Elbasvir (ELB as vir) and Grazoprevir (graz OH pre vir)

Zepatier (ZEP-ah-teer)

1-28-2016 Chronic hepatitis C (HCV) genotypes 1 and 4 infection

Brivaracetam (BRIV a RA se tam)

Briviact 2-18-2016 Partial onset seizures

Obiltoxaximab (oh-bil-tox-AX-i-mab)

Anthim 3-18-2016 Inhalational anthrax

Ixekizumab (IX ee KIZ ue mab)

Taltz 3-22-2016 Moderate to severe plaque psoriasis

Reslizumab (res LIZ ue mab)

Cinqair 3-23-2016 Severe asthma

Defibrotide sodium (de FYE broe tide)

Defitelio 3-30-2016 Hepatic veno-occlusive disease following stem cell transplant

Venetoclax (ven ET oh klax)

Venclexta 4-11-2016 Chronic lymphocytic leukemia in patients with a specific chromosomal abnormality

Pimavanserin (PIM a VAN ser in)

Nuplazid 4-29-2016 Treatment of hallucinations and delusions from psychosis in Parkinson’s disease

Atezolizumab (A te zoe LIZ ue mab)

Tecentriq 5-18-2016 Urothelial type bladder cancer

Daclizumab (dah KLIH zyoo mab)

Zinbryta 5-27-2016 Multiple sclerosis

Obeticholic acid (oh BET i KOE lik AS id)

Ocaliva 5-27-2016 Rare chronic liver disease

Fluciclovine F 18 Axumin 5-27-2016 Diagnostic imaging agent for recurrent prostate cancer detection

Gallium Ga 68 dotatate (GAL-ee-um Ga 68 DOE-ta-tate)

NETSPOT 6-1-2016 Diagnostic imaging agent for rare neuroendocrine tumors

Sofosbuvir (soe FOS bue vir) and Velpatasvir (vel PAT as vir)

Epclusa 6-28-2016 Treatment of all 6 major forms of hepatitis C virus

Lifitegrast (LIF e TEG rast)

Xiidra 7-11-2016 Treat signs and symptoms of dry eye

Lixisenatide (LIX i SEN a tide)

Adlyxin 7-27-2016 Diabetes type 2

Eteplirsen (e TEP lir sen)

Exondys 51 9-19-2016 Duchenne muscular dystrophy

Olaratumab (OH lar AT ue mab)

Lartruvo 10-19-2016 Soft tissue sarcoma

Bezlotoxumab (BEZ loe TOX ue mab)

Zinplava 10-21-2016 Reduce the recurrence of Clostridium difficile infection in adults

Crisaborole (KRIS a BOR ole)

Eucrisa 12-14-2016 Atopic dermatitis in patients two years of age or older

Rucaparib (roo KAP a rib)

Rubraca 12-19-2016 Ovarian cancer

Nusinersen (NUE si NER sen)

Spinraza 12-23-2016 Spinal muscular atrophy

References: 1. United States Food and Drug Administration. Novel Drug Approvals 2016.

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm483775.htm. Accessed January 8, 2017.

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