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New Drugs 2014 – Part 2PharMEDium Lunch and Learn Series

ProCE, Inc.www.ProCE.com 1

New Drugs 2014 – Part 2May 8, 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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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 Practiceepa t e t o a acy act ce

University of Illinois at Chicago

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Learning Objectives for Pharmacists

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

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New Molecular Entities

Refer to handout for the next 3 slides

1. Food and Drug Adminsitration. Novel new drugs-2014. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM430299.pdf. Accessed March 28, 2015. 9

Hepatitis C

Viral infection

I fl ti f th li Inflammation of the liver

Complications Bleeding

Cirrhosis

Liver cancer

2. American Association for the Study of Liver Diseases and Infectious Disease Society of America. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/full-report-view. Accessed March 28, 2015. 10



Hepatitis C

3.2 million individuals

30% ill d l i h i 30% will develop cirrhosis

At risk Baby Boomers (born 1945-1965)

Veterans

Males

African American and Latinos

Low-income individuals

Prisoners


Hepatitis C: Most Common Risk Factors

Blood transfusion before 1992

Sh i dl / i f i j ti d Sharing needles/syringes for injecting drugs

Needlestick injuries in healthcare workers

Tattoo equipment

Unprotected or high-risk sex

Children born to mothers with Hep C p




Direct-Acting Antiviral Agents

Sofosbuvir (Sovaldi) approved in 2013

2 t d i 2014 2 new agents approved in 2014 Ledipasvir and sofosbuvir (Harvoni)

Ombitavir, paritaprevir, ritonavir, dasabuvir (Viekira Pak)

1. Food and Drug Adminsitration. Novel new drugs-2014. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM430299.pdf. Accessed March 28, 2015. 13

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Ledipasvir/Sofosbuvir (Harvoni)

Approved October 10, 2014

7th d ith b kth h t t 7th drug with breakthrough status

Approved for Hepatitis C genotype 1 infection

First agent not requiring interferon or ribavirin

Direct-acting antiviral agent

90 mg ledipasvir and 400 mg of sofosbuvirg p g

3.Harvoni. [package insert]. Foster City, CA: Gilead Sciences, Inc; October 2014. http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf. Accessed March 20, 2015. 15

Ledipasvir/Dofosbuvir (Harvoni)

Inhibits HCV-NS5B RNA-dependent RNA polymerasepolymerase

Sofosbuvir is prodrug

Active form is GS-331007

Well absorbed, may take with food

Primarily excreted in urine (78%)

T1/2 is 27 hours





Ledipasvir inhibits HCV NS5A

R i d f i l li ti Required for viral replication

Well absorbed

Highly plasma protein bound

98% excreted unchanged in feces


Dosing

One tablet once a day without regard to meals

Previous treatment status Duration of therapy

Tx naïve, with or without cirrhosis 12 weeks

Previous tx, without cirrhosis 12 weeks

Previous tx with cirrhosis 24 weeks

3.Harvoni. [package insert]. Foster City, CA: Gilead Sciences, Inc; October 2014. http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf. Accessed March 20, 2015.

Previous tx, with cirrhosis 24 weeks

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Efficacy

ION 1, 2, 3

1 518 ti t 1,518 patients

Treatment experienced and naïve

94% to 99% efficacy (SVR)

Recommended as initial treatment for genotype 1



No contraindications

D t ith i d (b d di d Do not use with amiodarone (bradycardia and fatal cardiac arrest)

Adverse effects Fatigue (13%)

Headache (14%)

Nausea (7%)

Diarrhea (3%)

Insomnia (5%)




Drug Interactions

Acid-reducing agents ↓ ledipasvir

A ti l t ↓ ff t f H i Anticonvulsants ↓ effects of Harvoni

Rosuvastatin ↑ risk of myopathy

Tenofovir combos ↑ adverse effects of tenofovir


Pharmacist Clinical Points

Review potential drug interactions

Di th i t f li Discuss the importance of compliance

Verify patient understands how and when to get refills

Consider automatic refills and delivery

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Technician Tips

Double check using interaction programs when fillingfilling

Alert pharmacist if purchased with antacids or PPIs

Work with pharmacist to develop call out to ensure refills of this medication

Al t h i t if t fill d ti Alert pharmacist if not refilled on time

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Viekira Pak

Approved December 19, 2014

B kth h th Breakthrough therapy

All-oral combination therapy Two tablets containing ombitasvir (12.5 mg),

paritaprevir (75 mg), and ritonavir (50 mg)

Two 250-mg dasabuvir tablets

Approved for genotype 1 (with or without ribavirin)

5. Viekira Pak. [package insert]. Foster City, CA: Gilead Sciences, Inc; January 2015. http://www.rxabbvie.com/pdf/viekirapak_pi.pdf. Accessed March 28, 2015.6. A 4 drug combination (Viekira Pak) for hepatitis C. Med Letter Drugs Ther. 2015;57(1461):15-17. 25

Viekira Pak

Contains 3 direct-acting antiviral agentsO bit i NS5A i hibit Ombitasvir: NS5A inhibitor

Paritaprevir: NS3/4A protease inhibitor

Dasabuvir: Non-nucleoside NS5B polymerase inhibitor

Ritonavir allows for higher levels of paritaprevir(blocks CYP3A)(blocks CYP3A)

5. Viekira Pak. [package insert]. Foster City, CA: Gilead Sciences, Inc; January 2015. http://www.rxabbvie.com/pdf/viekirapak_pi.pdf. Accessed March 28, 2015.26



Viekira Pak

Ombitasvir undergoes amide hydrolysis

Oth t t b li d i CYP 450 Other agents metabolized via CYP 450

Excreted primarily in feces

Avoid in moderate hepatic impairment


Dosing

Genotype Treatment Duration

1 Vi ki P k d ib i i12 or 24 weeks; longer if

1a Viekira Pak and ribavirino ee s; o ge

patient has cirrhosis

1b Viekira Pak12 or 24 weeks; longer if

patient has cirrhosis

Unknown or mixed Genotype 1a guidelines 12 or 24 weeks

Liver transplant Viekira Pak and ribavirin 24 weeksLiver transplant Viekira Pak and ribavirin 24 weeks

5. Viekira Pak. [package insert]. Foster City, CA: Gilead Sciences, Inc; January 2015. http://www.rxabbvie.com/pdf/viekirapak_pi.pdf. Accessed March 28, 2015.6. A 4 drug combination (Viekira Pak) for hepatitis C. Med Letter Drugs Ther. 2015;57(1461):15-17. 28



Dosing

Two ombitasvir/paritaprevir/ritonavir tablets once a day in the morningonce a day in the morning

One dasabuvir tablet twice a day (morning and evening) with a meal

Ribavirin must be given in genotype 1a, 1b with cirrhosis

Rib i i d i 1000 1200 d d di Ribavirin dose is 1000-1200 mg day depending on weight (75 kg)


Efficacy

PEARL and SAPPHIRE

97% t 100% ffi 97% to 100% efficacy

Nausea (5.5%)

Headache (4.7%)

Diarrhea (4.4%)( )

6. A 4 drug combination (Viekira Pak) for hepatitis C. Med Letter Drugs Ther. 2015;57(1461):15-17.30



Contraindications/Warnings

Severe liver disease (Child Pugh C)

All t it i Allergy to ritonavir

Warning:

Moderate liver disease

Strong CYP3A or CYP2C8 inducers (reduce g (effects of Viekira Pak)

Strong inhibitors of CYP2C8 (increased risk of QT prolongation)


Drug Interactions

Several!

St ti i d i k f th Statins: increased risk of myopathy

Benzodiazepines: prolonged respiratory depression

Gemfibrozil: Increased risk of QT prolongation

Large increase in dasabuvir plasma concentration





Review potential drug interactions

Di i k Discuss pregnancy risk

Teach about compliance; verify understanding of how and when to refill

Explain how long patient will be taking the medication

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Technician Tips

Talk to patient about potential benefits of automatic refillautomatic refill

Alert pharmacist if this medication is not picked up before re-stocking

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Suvorexant (Belsomra)

Approved August 13, 2014

S h d l IV t ll d b t Schedule IV controlled substance

Medication guide required

Orexin receptor antagonist

7. Belsomra [package insert]. Whitehouse Station NJ: Merck and Co Inc; 2014. http://www.merck.com/product/usa/pi_circulars/b/belsomra/belsomra_pi.pdf. Accessed March 31, 2015. 36



Orexin Receptor Antagonist

Orexin receptors promote wakefulness

S i bl k th k d i Suppression blocks the wake drive

In narcolepsy, no or few orexin receptors

Highly plasma protein bound (99%)

CYP3A metabolism

60% excreted in feces, 23% in urine,

Half-life is 12 hours


Dosing

10 mg given 30 minutes before sleep

7 h b f k i 7 hours before awakening

Maximum dose: 20 mg

Take on empty stomach

5 mg for patients taking moderate CYP3A inhibitors (e.g., diltiazem)

Higher serum levels in obese females

4. Facts and Comparisons. [database online] Indianapolis, IN: Clinical Drug Information. LLC; http://online.factsandcomparisons.com. Accessed March 22, 2015.7. Belsomra [package insert]. Whitehouse Station NJ: Merck and Co Inc; 2014. http://www.merck.com/product/usa/pi_circulars/b/belsomra/belsomra_pi.pdf. Accessed March 31, 2015. 38



Efficacy

3 clinical trials compared with placebo

S i t l b Superior to placebo

FDA rejected 30-mg and 40-mg doses

High incidence of next-day somnolence


Contraindications and Warnings

Narcolepsy

Warnings:

Do not take doses above 20 mg

Avoid driving, operating heavy machinery

Caution in elderly, ↑ balance problems y, ↑ p




Drug Interactions

Additive effect with CNS drugs (narcotics and benzos)benzos)

Reduce dose with moderate CYP3A inhibitors (erythromycin, fluconazole)

Do not use with strong CYP3A inhibitors (ketoconazole, saquinavir, clarithromycin)


Adverse Effects

Somnolence (dose dependent)

P t ti l b l bl i ld l Potential balance problems in elderly

Diarrhea

Dizziness

Abnormal dreams

Use caution dosing for obese womeng




Pharmacist Counseling Tips

Dispense with same precautions as other sleeping agentssleeping agents

Discuss the risks of next-day somnolence

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Technician Tips

Schedule IV substance

Ab t ti l Abuse potential

Be alert for overuse, and notify the pharmacist

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Vorapaxar (Zontivity)

Approved by FDA on May 18, 2014

Fi t i l First in class

Protease activated receptor-1 antagonist (PAR-1)

Irreversible antiplatelet agent

2.08-mg tablet

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Completely different pathway

A i i th b th Aspirin: thromboxane pathway

Clopidrogel: inhibits adenosine diphosphate (ADP) receptor

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100% bioavailable

≥99% l t i b d ≥99% plasma protein bound

Metabolized via CYP3A4 and CYP2J2

Eliminated by feces

Half-life is 8 days

Once stopped, effects continue for 4 weekspp ,

8. Zontivity. [package insert]. Whitehouse Station NJ.: Merck and Co Inc.; May 2014. http://www.merck.com/product/usa/pi_circulars/z/zontivity/zontivity_pi.pdf. Accessed March 30. 2015. 48




Prevention of thrombotic eventsP i MI Previous MI

Peripheral vascular disease

Must be given in combination with aspirin or clopidrogel

Administer 1 tablet once a day

4. Facts and Comparisons. [database online] Indianapolis, IN: Clinical Drug Information. LLC; http://online.factsandcomparisons.com. Accessed March 22, 2015.8. Zontivity. [package insert]. Whitehouse Station NJ.: Merck and Co Inc.; May 2014. http://www.merck.com/product/usa/pi_circulars/z/zontivity/zontivity_pi.pdf. Accessed March 30. 2015. 49

Contraindications

History of stroke, intracranial hemorrhage, or transient ischemic attack (TIA)transient ischemic attack (TIA)

Active bleeding




Warnings

Can cause bleeding, intracranial hemorrhage

A id i hi h i k ti t Avoid in high-risk patients Elderly

Low body weight

Liver or renal dysfunction

Do not combine with NSAIDs, SSRIs, or anticoagulants


Drug Interactions

Avoid use with strong inhibitors/inducers of CYP3ACYP3A Inhibitors: clarithromycin, saquinavir, nefazodone,

nelfinavir

Inducers: rifampin, St. John’s wort, carbamazepine, phenytoin





Ensure patient is taking aspirin or clopidrogel

C id di ti h i ti Consider medication synchronization

Review drug interactions

Discuss bleeding risks

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Technician Tips

Can also verify that patient is taking aspirin or clopidrogelclopidrogel

Alert pharmacist if there is a break in combination therapy

If patient purchases OTC medications, let the pharmacist know to check for interactions

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Olaparib (Lynparza)

Poly ADP-ribosome polymerase inhibitor (PARP)(PARP)

Approved for advanced ovarian cancer in patients with BRCA-mutated disease

Approved as monotherapy for patients who have failed 3 or more chemotherapy protocols

C ti d FDA l ti t Continued FDA approval contingent on confirmatory trials

9. Lnyparza. [package insert]. Wilmington DE: AstraZeneca Pharmaceuticals; December 2014.56



Olaparib (Lynparza)

Exploits tumor DNA repair pathway deficiency to preferentially kill cancer cellsto preferentially kill cancer cells

Efficacy based on Phase II trial of 137 patients with advanced ovarian cancer

34% overall response rate (95% CI: 26%,42%)

Median duration of response was 7.9 months


Dosing

400 mg orally twice a day Avoid grapefruit juice Seville oranges Avoid grapefruit juice, Seville oranges

Reduce or hold dose for adverse reactions: 200 mg orally twice a day (400 mg total daily

dose) Further reduction to 100 mg orally twice a day

(200 mg total daily dose)

Dose reduction with CYP3A inhibitors 150 mg orally twice a day (strong inhibitor) 200 mg orally twice a day (moderate inhibitor)




Warnings and Precautions

Myelodysplastic syndrome/acute myeloid leukemialeukemia 2% of patients

Pneumonitis <1%, must discontinue

Fetal toxicity

40% of patients required dose interruption


Adverse Effects

Anemia (34%)

Abd i l i iti (43%) Abdominal pain, vomiting (43%)

Fatigue (66%)

Nasopharyngitis (26%)

Arthralgia and myalgia (22%)




Drug Interactions

Prolongs myelosuppression when combined with other oncology drugswith other oncology drugs

Increased olaparib plasma concentrations with CYP3A inhibitors

Decreased olaparib plasma concentrations with CYP3A inducers


Olaparib (Lynparza)

Trials continue to confirm indication

Additi l i di ti t d i th BRAC Additional indications expected in other BRAC tumors

Gastrointestinal effects and fatigue are common

Only 7% dropped out due to adverse effects

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Pharmacist Counseling Points

Review dosing schedule: take twice a day

Swallow capsule whole; do not open or chew Swallow capsule whole; do not open or chew

Do not take capsules that are deformed or show evidence of leakage

Avoid grapefruit juice, Seville oranges

If weight loss, bruising, bleeding, or weakness occurs, patient should contact physician Can be serious hematology problemC gy p

Describe symptoms of pneumonitis: shortness of breath, cough, wheezing

Counsel on pregnancy risks: Category D

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Technician Tips

Dispense in original container to protect from humidity and lighthumidity and light

Alert pharmacist if medication is not refilled before re-stocking

Verify dose with the pharmacist

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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. American Association for the Study of Liver Diseases and Infectious Disease Society of America. Recommendations for testing managing and treating hepatitis C http://www hcvguidelines org/fullRecommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/full-report-view. Accessed March 28, 2015.

3.Harvoni. [package insert]. Foster City, CA: Gilead Sciences, Inc; October 2014. http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf. Accessed March 20, 2015.

4. Facts and Comparisons. [database online] Indianapolis, IN: Clinical Drug Information. LLC; http://online.factsandcomparisons.com. Accessed March 22, 2015.

5. Viekira Pak. [package insert]. Foster City, CA: Gilead Sciences, Inc; January 2015. http://www.rxabbvie.com/pdf/viekirapak_pi.pdf. Accessed March 28, 2015.

6 A 4 drug combination (Viekira Pak) for hepatitis C Med Letter Drugs Ther 2015;57(1461):15-176. A 4 drug combination (Viekira Pak) for hepatitis C. Med Letter Drugs Ther. 2015;57(1461):15 17.

7. Belsomra [package insert]. Whitehouse Station NJ: Merck and Co Inc; 2014. http://www.merck.com/product/usa/pi_circulars/b/belsomra/belsomra_pi.pdf. Accessed March 31, 2015.

8. Zontivity. [package insert]. Whitehouse Station NJ.: Merck and Co Inc.; May 2014. http://www.merck.com/product/usa/pi_circulars/z/zontivity/zontivity_pi.pdf. Accessed March 30. 2015.

9. Lnyparza. [package insert]. Wilmington DE: AstraZeneca Pharmaceuticals; December 2014.

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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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