New Drug Update 2015: A Formulary Approach J. Russell May, Pharm.D., FASHP Clinical Professor University of Georgia College of Pharmacy

New Drug Update 2015: A Formulary Approach

J. Russell May, Pharm.D., FASHP

Clinical Professor

University of Georgia College of Pharmacy

DisclosureDr. May has nothing to disclose concerning possible financial or personal relationships with commercial entities (or their competitors) mentioned in this presentation.

Objectives

After attending the lecture and discussion, the attendee should be able to:

Compare and contrast newly approved drugs with older agents regarding their pharmacology, pharmacokinetics, efficacy, safety, dosage and cost.

Apply the “formulary approach” to evaluating new drugs.Analyze potential utility of drugs in the pipeline for possible release in

the next two years.

Drugs Under Consideration

• Suvorexant (Belsomra®) by Merck• Dapagliflozin (Farxiga®) by Bristol-Myers Squibb

• (note: empagliflozen (Jardiance®) also approved)• Dulaglutide (Trulicity®) by Lilly• Liraglutide (Saxenda®) by Novo Nordisk• Deoxycholic Acid (Kybella®) by Kythera• Dalbavancin (Dalvance®) by Durata• Oritavancin (Orbactiv®) by Medicines Co.• Tedizolid (Sivextro®) by Cubist• Ceftolozane/tazobactam (Zerbaxa®) by Cubist• Ceftazidime/avibactam (Avycaz®) by Actavis• Peramivir (Rapivab®) by Biocryst• Vedolizumab (Entyvio ®) by Millenium• Eluxadoline (Viberzi®) by Patheon • Naloxegol (Movantik®) by Astra Zeneca• Ivabradine (Corlanor®) by Amgen

Formulary Approach

• A finite list of therapeutic agents• Established value in light of current medical opinion

• Sufficiently broad to meet the usual clinical problems

• Avoids duplication of clinical effect• Subject to continuing revision based on new therapeutic knowledge

Formulary Criteria

For a drug to be recommended for addition to our Formulary, it must meet at least one of the following:• New Pharmacological Class• More Efficacious • Safer• Pharmacokinetic Advantage (clinically relevant)• More Cost Effective

Pharmacology

• Orexin receptor antagonist• Orexin neuropeptide signaling system is a promoter of wakefulness• Wake promoting neuropeptides are blocked

• First in class• Indication: Treatment of insomnia

• Sleep onset and/or sleep maintenance• Schedule IV medication

Suvorexant (Belsomra®)


Pharmacokinetics• Peak concentrations in 2 hours

• Range 30 minutes – 6 hours• Food will delay Tmax• Bioavailability ~80 %

• Highly protein bound (>99%)• Metabolized by CYP 3A4• Primarily eliminated in feces (66%)

Efficacy• 2 randomized, placebo-controlled, double-blind studies (N = 1260) • Results using polysomnography

month 1 month 3

• Sleep onset (minutes) - 8 to -10 0 to - 8• Sleep maintenance (minutes) -24 to -26 -17 to -31

note: all values superior to placebo


Prescribing Information, Merck & Co., August 2014

Safety• Safety studies performed (next day)

• Driving (some impairment)• Memory/balance (OK at usual doses)

• No clear evidence of withdrawal effects• Nighttime “sleep driving” and other complex behaviors (increased risk with higher doses)

• Worsening of depression (increased risk with higher doses)

• Drug interactions with 3A4 inhibitors


Dosage and Cost• 10 mg orally: 30 minutes before bed

• At least 7 hours remaining before wake time• Maximum dose 20 mg at bedtime

• Available as 5, 10, 15, and 20 mg tablets

• Cost: $315.72 per 30 tablets (all strengths)


Criteria• New Pharmacological Class• More Efficacious • Safer • Pharmacokinetic Advantage (clinically relevant) • More Cost Effective


Pharmacology• A sodium-glucose co-transporter 2 (SGLT2)

inhibitor • Second in class

• Empagliflozin (Jardiance®) is third in class• By inhibiting SGLT2:

• Decreases glucose reabsorption• Increases glucose excretion• Lowers blood glucose levels

• Indication• Oral treatment of type 2 diabetes• Added bonus: may reduce systolic blood pressure

and weight

Dapagliflozin (Farxiga®)

Dapagliflozin (Farxiga®)Pharmacokinetics

• T max; < 2 Hours• Metabolized by UGT 1A9 • Eliminated in feces (21%) and urine (75%)• Half-life = 12.9 hours

Efficacy• Versus placebo (n = 558, 26 weeks)

• HbA1c (%) Change: -0.8 to - 0.9 vs – 0.2• Add on to metformin (n = 546, 26 weeks)

• HbA1c (%) Change: -0.7 to – 0.8 vs -0.3• Add on to metformin vs metformin + glipizide

• N = 816, 52 weeks• HbA1c (%) Change: -0.5 vs -0.5

• Positive results when added to pioglitazone, sitagliptin, or insulin


Prescribing Information, AstraZeneca., March 2015

Safety• Genital mycotic infections

• Men 2.8% • Women 7 – 8.4%

• Urinary tract infections 5%• Diuretic effect: volume depletion• Increased serum creatinine• Slight increase in fractures and LDL• Bladder cancer warning• Less hypoglycemia


Dosage and Cost• 5 mg orally once daily• May increase to 10 mg if needed and tolerated• Do not give to patients with GFR < 60

• Discontinue if GFR falls below 60• Note: cut off for canagliflozin is 45• Note: cut off for empagliflozin is 45

• Cost: $347 for one month supply• Compare three agents in class

• Other 2 are $360 - $370




Pharmacology• Glucagon-like peptide (GLP-1) receptor agonist:

Increases cAMP in beta cells leading to glucose-dependent insulin release. Also decreases glucagon secretion and slows gastric emptying time

• Similar to: exenatide (2005 & 2010), liraglutide (2010), and albiglutide (2014)

• Indication:• Adjunct to diet and exercise to improve glycemic

control in adults with type 2 diabetes mellitus

Dulaglutide (Trulicity®)


Pharmacokinetics• Bioavailability after SC injection = 47 – 65%• Metabolized by protein catabolism pathways• Half-life ~ 5 days• No dosage adjustment

• Age, weight, or renal or hepatic impairment

Efficacy• Monotherapy versus metformin: 52 week, double-blind study (n =

807)• HbA1C change from baseline: -0.7 vs -0.6 (n.s.)• FSG change from baseline: -26 vs -24 (n.s.)

• Add-on to metformin versus sitagliptin: 52 week, double-blind study (n = 972)• HbA1C change from baseline: -0.9 vs -0.4 (p<0.001)• FSG change from baseline: -30 vs -14 (n.s.)

• Add-on to metformin and TZD versus exenatide BID: 26 week, double-blind study (n = 976)• HbA1C change from baseline: -1.3 vs -1.0 (p<0.001)• FSG change from baseline: -34 vs -24 (n.s.)


Prescribing Information, Eli Lilly and Co., March 2015

Safety• Black box warning: Risk of thyroid C-cell tumors• Pancreatitis• Hypoglycemia

• Symptomatic: 0.75 mg = 2.6% 1.5 mg = 5.6%

• Others: (note: % for 0.75 mg doses)• Nausea 12.4% Vomiting 6.0%• Diarrhea 8.9% Abdominal pain 6.5%• Decreased appetite 4.9% Dyspepsia 4.1%• Fatigue 4.2%


Dosage and Cost• Once weekly (anytime of day)• SC in abdomen, thigh, or upper arm• Start with 0.75 mg, may be increased to 1.5 mg if needed• If dose is missed, administer within 3 days

• Cost:• Trulicity® 0.75 mg or 1.5 mg $146.50*• Tanzeum® 30 mg or 50 mg $106.59*• Victoza ® 18 mg/3 ml $256.39**

*1 week of therapy**~2 weeks of therapy


Criteria• New Pharmacological Class• More Efficacious • Safer • Pharmacokinetic Advantage (clinically relevant)

• More Cost Effective


Pharmacology• Glucagon-like peptide (GLP-1) receptor agonist:

Increases cAMP in beta cells leading to glucose-dependent insulin release. Also decreases glucagon secretion, slows gastric emptying time , decreased food intake

• Similar to: exenatide (2005 & 10), dulaglutide (2014), and albiglutide (2014)

• Indication:• An adjunct to a reduced calorie diet and increased physical

activity in adults with a BMI:• 30 or greater• 27 or greater in the presence of at least 1 weight-related co-morbidity

Liraglutide (Saxenda®)

Liraglutide (Saxenda®)Pharmacokinetics

• Bioavailability after SC injection = 55%• Highly protein bound ~ 98%• Endogenously metabolized without a specific organ as a route of elimination

• Half-life ~ 13 hours• Use with caution in renal impairment

Efficacy

• Three 56-week studies vs placebo, double-blindedA = obese or overweight with co-morbidity (n = 3731)B = obese or overweight with diabetes (n = 635)C = obese or overweight with co-morbidity + 5% weigh loss with diet (n = 422)

• % change from baseline (Kg)• A = -7.4 vs -3.0 B = -5.4 vs -1.7 C = -4.9 vs +0.3

• % losing > 5% body weight (%)• A = 62.3 vs 34.4 B = 49.0 vs 16.4 C = 44.2 vs 21.7

• % losing > 10 body weight (%)• A = 33.9 vs 15.4 B = 22.4 vs 5.5 C = 25.4 vs 6.9


Prescribing Information, Novo Nordisk, January 2015

Safety• Black box warning: Risk of thyroid C-cell tumors• Pancreatitis 0.3%• Hypoglycemia 23% (12.7% with placebo)• Others:

• Nausea 39.3% Vomiting 15.7%• Diarrhea 20.9% Abdominal pain 5.4%• Decreased appetite 10.0% Dyspepsia 9.6%• Fatigue 7.5% Constipation 19.4%


Dosage and Cost

• Initiate at 0.6 mg daily for 1 week• SC in abdomen, thigh, or upper arm• At weekly intervals increase dose until at 3 mg per day

Cost: 6 mg/ml multi-dose 3 ml pen $256.39




http://blogs.wsj.com/corporate-intelligence/2013/09/17/eradicating-double-chins-the-next-half-billion-dollar-business/

Pharmacology• Cytolytic agent

• When injected into the skin, it physically destroys the cell membrane lining causing lysis

• Natural bile component• Indication:

• For improvement in the appearance of “moderate to severe convexity or fullness associated with submental fat in adults”

• Not recommended for treatment of subcutaneous fat outside the submental region. (No efficacy or safety information)

Deoxycholic Acid (Kybella®)

Deoxycholic Acid (Kybella®)Pharmacokinetics

• Rapidly absorbed after SC administration• Plasma levels return to endogenous range within 24 hours

• Endogenous deoxycholic acid is a product of cholesterol metabolism and is excreted in the feces• Injected drug “joins the endogenous pool” and is excreted in the feces

Efficacy• Two randomized, double-blind, placebo-controlled trials (n = 514)• Primarily female (85%) and Caucasian (87%)• Efficacy assessments: “1-grade or 2-grade improvements” by MDs and patients• 2-grade 13.4% vs <0.1%• 1-grade 70% vs 18.6%


travisshawmd.comwww.skincarephysicians.net

Prescribing Information, Kythera, April 2015

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http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0CAYQjB0&url=http://www.skincarephysicians.net/cosmetic-surgery/kiss-goodbye-to-double-chin-with-breakthrough-treatment/&ei=klZvVdu1E5a1yATK_oLQBw&bvm=bv.94911696,d.cWc&psig=AFQjCNEStYwK9tAjI0lElrs2EQdW7Ddzkw&ust=1433446381538641

Safety

• Adverse reactions pooled from both trials

Kybella® placebo• Injection site reactions 96% 81%

• Edema/swelling 87% 43%• Pain 70% 32%• Numbness 66% 6%• Induration 23% 3%• Paresthesia 14% 4%

• Headache 8% 4%• Dysphagia 2% <1%


Dosage and Cost• 0.2 ml injections spaced 1 cm apart until all sites in planned treatment area have been injected• Up to 50 injections (or 10 ml) in a single treatment

• Up to 6 single treatments no less than 1 month apart

• 10 mg/ml, 2 ml vial “Available in June”



• More Cost Effective?


Pharmacology• Finally! After years on the pipeline slides• Semi-synthetic lipoglycopeptide

• Interferes with cell wall synthesis• Spectrum = Gram + bacteria• Similar to vancomycin• Indication: treatment of acute bacterial skin and skin structure infections caused by susceptible Gram + organisms

Dalbavancin (Dalvance®)

Dalbavancin (Dalvance®)Pharmacokinetics

• Protein binding = 93%• Not metabolized via CYP 450 enzymes• Excretion:

• 20% in feces• 33% unchanged in urine• 12% metabolite in urine

• Half – life = 346 hours

Efficacy• Two randomized, double-blind trials (n = 1312)

• Dalbavancin versus vancomycin/linezolid• Clinical success rates:

• Dalbavancin 83.1 – 88.1%• Vancomycin/linezolid 84.5 – 88.1%

• Dalbavancin vs linezolid (IV/PO) n = 854• Clinical success rates : 88.9% vs 91.2%*


*Jauregui LE et al. Clin Infect Dis 2005;41:1407-15.

Safety• Most common

• Nausea 5.5%• Headache 4.7%• Diarrhea 4.4%

• Red Man Syndrome• Infuse over 30 minutes

• Hypersensitivity reaction• No information on cross-reactivity with vancomycin


Dosage and Cost• 1000 mg IV followed 1 week later with 500 mg• If CrCl < 30 (and not on regular dialysis):

• 750 mg IV then 350 mg 1 week later• Infuse over 30 minutes

• Do not infuse with other medications or electrolytes (D5W only!)

• Cost: $1788 / 500 mg vial (3 vials = $5364)• Considerations…





Pharmacology• Finally! After years on the pipeline slides• Semi-synthetic lipoglycopeptide

• Interferes with cell wall synthesis• Spectrum = Gram + bacteria• Similar to vancomycin• Indication: treatment of acute bacterial skin and skin structure infections caused by susceptible Gram + organisms

Oritavancin (Orbactiv®)

Oritavancin (Orbactiv®)Pharmacokinetics

• Protein binding = 85%• Not metabolized• Excreted unchanged in feces and urine• Half – life = 245 hours

Efficacy• Two randomized, double-blind, controlled, non-inferiority studies (n = 1987)• 1200 mg single dose vs vancomycin 1 gm or 15 mg/kg q12hr for 7 to 10 days

• Clinical success rate for both ~80%


Prescribing Information, Medicines Company, September 2014

Safety• Common adverse effects similar to dalbavancin• Potential interaction with warfarin (Warning)

• May prolong PT and INR for up to 24 hours• Use of IV heparin is contraindicated for 48 hours after

oritavancin administration• Slow infusion over 3 hours required

• Infusion - related reactions: pruritis, urticaria, flushing• Hypersensitivity reaction

• No information on cross-reactivity with vancomycin• Warning section states:

• “if osteomyelitis is suspected or diagnosed, institute appropriate alternative therapy”


Dosage and Cost• 1200 mg infused over 3 hours once• Do not infuse with other medications or electrolytes (D5W only!)

• No dosage adjustment of mild to moderate renal impairment • Not studied in severe renal impairment

• Cost: 400 mg vial = $1600 (3 vials = $4800)





Pharmacology• Oxazolidinone class (e.g., linezolid)• Binds to 50S subunit of the bacterial ribosome…inhibits protein synthesis

• Available IV and PO• Indication: treatment of acute bacterial skin and skin structure infections caused by susceptible Gram + organisms

Tedizolid (Sivextro®)

Tedizolid (Sivextro®)Pharmacokinetics

• Bioavailability of oral = 91%• No dose difference between IV and PO

• Protein binding 70 – 90%• Not metabolized• Elimination: 82% feces and 18% urine• Half-life = 12 hours

Efficacy• Two randomized, double-blind, non-inferiority studies (n = 1315)*• 200 mg once daily for 6 days vs linezolid 600 mg q12hr for 10 days

• Clinical success rates in both groups ~80%• No difference


* One of these published: Prokocimer P et al. JAMA 2013;309(6):559-69.

Safety• Most common:

• Nausea 8% Headache 6%• Diarrhea 4% Vomiting 3%

• Warnings section states: consider alternate therapy in neutropenic patients

• Other effects projected to be similar to linezolid


Dosage and Cost• 200 mg IV or PO once daily for 6 days• IV should be infused over 1 hour• No dosage adjustment for renal impairment

Cost: Oral tedizolid $354 per day for 6 daysOral linezolid $325 per day for 10 days

IV tedizolid $ 282 per day for 6 daysIV linezolid $ 167 per day for 10 days



• More Cost Effective ?


Pharmacology• Ceftolozane - inhibition of cell wall synthesis, binds to penicillin binding proteins• PBPs of P. aeruginosa and E.coli

• Tazobactam – irreversible inhibitor of some beta-lactamases and can bind covalently to some chromosomal and plasmid-mediated beta-lactamases

• Indications:• Complicated intra-abdominal infections in combination with metronidazole

• Complicated UTIs including pyelonephritis

Ceftolozane/Tazobactam (Zerbaxa®)

Ceftolozane/Tazobactam (Zerbaxa®)Pharmacokinetics

ceftolozane tazobactam• Cmax ~ 70 mcg/ml ~18 mcg/ml• tmax 1 hour 1 hour• t1/2 ~ 3 hours ~ 1 hour• Metabolism – tazobactam: metabolized to inactive

form• Excretion – ceftolozane and tazobactam metabolite

excreted by kidneys• Dosage adjustment in renal impairment

Efficacy• Complicated intra-abdominal infections

• Double-blind study versus meropenem (n = 979)• 75% Eastern Europe 6.5% U.S.• Cure rates: 94.2% vs 94.7%

• Complicated UTIs (including pyelonephritis)• Double-blind study versus levofloxacin (n = 1068)• “Multi-national” • Cure rates similar: 83.3% vs 75.4%

• Statistically significant difference but included organisms not susceptible to levofloxacin at baseline


Prescribing Information, Cubist, May 2015Wagenlehner F, et al. Lancet 2015;385:1949-56.


• Nausea 7.9%• Diarrhea 6.2%• Pyrexia 5.6%

• Treatment discontinuation due to ADRs ~ 2%• Pregnancy category B• Must adjust dose in renal impairment


Dosage and Cost• Ceftolozane 1 gm/tazobactam 0.5 gm (1.5 gm)

• Infused over one hour• Every 8 hours if CrCl > 50

• Ceftolozane 500 mg/tazobactam 250 mg (750 mg)• Every 8 hours if CrCl = 30 – 50

• Ceftolozane 250 mg/tazobactam 125 mg (375 mg)• Every 8 hours if CrCl = 15 – 29

• Cost: $99.60 for 1.5 gm vial




Pharmacology• Ceftazidime - inhibition of cell wall synthesis, binds to penicillin binding proteins• PBPs of P. aeruginosa and E.coli

• Avibactam - irreversible inhibitor of some beta-lactamases and can bind covalently to some chromosomal and plasmid-mediated beta-lactamases

• Indications:• Complicated intra-abdominal infections in combination with metronidazole

• Complicated UTIs including pyelonephritis

Ceftazidime/Avibactam (Avycaz®)

Ceftazidime/Avibactam (Avycaz®)Pharmacokinetics

ceftazidime tazobactam• Cmax ~ 90 mcg/ml ~15 mcg/ml• t1/2 ~ 3 hours ~ 2.5 hours• Metabolism – both components eliminated primarily unchanged in the kidneys

• Excretion – both excreted by kidneys• Dosage adjustment in renal impairment

Efficacy• “Efficacy of Avycaz® was supported in part by the previous findings of efficacy and safety of ceftazidime for the treatment of cIAI and cUTI”.

• “Contribution of avibactam to Avycaz® was primarily established in vitro and in animal models of infection”.


Prescribing Information, Actavis, February 2015

Safety• Information from Phase 2 studies (n = 101 and 68)• Most common

• Vomiting 14% (meropenem 5%) 0% in cUTI study• Nausea 10% (meropenem 6%) 2% in cUTI study• Constipation 4% (meropenem 1%) 10% in cUTI study• Anxiety 5% (meropenem 1%) 10% in cUTI study

• Pregnancy category B• Must adjust dose in renal impairment


Dosage and Cost

• Ceftazidime 2 gm/avibactam 0.5 gm (2.5 gm)• Infused over 2 hours• Every 8 hours if CrCl > 50

• Ceftazidime 1 gm/avibactam 250 mg (1.25 gm)• Every 8 hours if CrCl = 31 – 50

• Ceftazidime 750 mg/avibactam 190 mg (0.94 gm)• Every 12 hours if CrCl = 16 – 30

• Ceftazidime 750 mg/avibactam 190 mg (0.94 gm)• Every 24 hours if CrCl = 6 – 15

• Ceftazidime 750 mg/avibactam 190 mg (0.94 gm)• Every 48 hours if CrCl = < 5

• Cost: $342 for 2.5 gm vial




Pharmacology• Antiviral drug with activity against influenza virus• Inhibits influenza viral neuraminidase• Efficacy based on trials with primarily influenza A

• Indication:• Treatment of acute uncomplicated influenza in patients 18 and older who have been symptomatic for no more than 2 days

Peramivir (Rapivab®)

Peramivir (Rapivab®)Pharmacokinetics

• Cmax reached at the end of a 30 minute IV infusion

• Protein binding < 30%• Not significantly metabolized• Half-life ~ 20 hours• Excreted unchanged in the urine

Efficacy• Acute uncomplicated influenza in adults

• Randomized, blinded, placebo-controlled study • (n = 297, 98 received the 600 mg dose)• Influenza A virus 99%• Alleviation of symptoms: 24 hours quicker• Afebrile : 12 hours sooner

• Serious influenza requiring hospitalization• Efficacy could not be established (n = 398)


Prescribing Information, BioCryst Pharmaceuticals, December 2014

Safety• Most common: diarrhea• Carries warning labeling for:

• Serious skin/hypersensitivity • Stevens-Johnson syndrome• Erythema multiforme

• Neuropsychiatric events• Increased risk of hallucinations, delirium, abnormal behavior


Dosage and Cost• Single 600 mg IV infusion over 15 – 30 minutes if CrCl > 50• For CrCl 30 – 49 give 200 mg• For CrCl 10 – 29 give 100 mg

• Dilute in 0.9% or 0.45% sodium chloride, D5W, or lactated Ringers to maximum volume of 100 ml.

• Cost: 200 mg/20 mL vial: $380 • With normal renal function: $1140 (600 mg)




Pharmacology

• Humanized monoclonal antibody• Binds to 4 7a b integrin and blocks the interaction of 4 7a b with mucosal adressin cell adhesion molecule-1 (MAdCAM-1)

• The interaction between 4 7 a b and MAdCAM-1 contributes to the chronic inflammation: a hallmark of ulcerative colitis and Crohn’s disease

• Indications:• Adult ulcerative colitis (with criteria for use)• Adult Crohn’s disease (with criteria for use)

Vedolizumab (Entyvio ®)


Pharmacokinetics• Complicated• Clearance is via both linear and non-linear pathways

• Half-life ~ 25 days at the 300 mg dose• Volume of distribution = 5 L• Not studied in patients with liver or renal impairment

Efficacy• Ulcerative colitis (UC): randomized, double-blind

placebo controlled 6 week study (n = 374)• Clinical response = 47% vs 26% (placebo)• Clinical remission = 17% vs 5%• Improvement in mucosa = 41% vs 25%• UC 52 week follow-up in responders

• Crohn’s Disease: randomized, double-blind, placebo controlled 6 week study (n = 368)• Clinical remission = 15% vs 7% (placebo)


See August 22, 2013 issue of New England Journal of Medicine


• Nasopharyngitis (13%) Headache (12%)• Arthralgia (12%) Nausea (9%)• Pyrexia (9%) URTI (7%)

• Others: fatigue, cough, bronchitis, influenza, back pain, rash, pruritis, sinusitis, other pain

• Hypersensitivity warning• Infection warning


Dosage and Cost• 300 mg infused IV over 30 minutes

• Week 0, 2, and 6 then every 8 weeks• Discontinue if no improvement by week 14• Patient must be up to date on vaccines before starting therapy

• Cost: $5783 per 300 mg dose


Criteria• New Pharmacological Class• More Efficacious ?• Safer • Pharmacokinetic Advantage (clinically relevant) • More Cost Effective


Pharmacology• A mu-opioid receptor agonist

• In animals, interacts with opioid receptors in the gut

• Indication:• In adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D)

Eluxadoline (Viberzi®)


Pharmacokinetics• Bioavailability: not determined• Tmax 1.5 hours (range 1 to 8 hours) with food

2 hours (0.5 to 6 hours) fasting• High fat meal will decrease Cmax

• Half-life ranges from 3.7 to 6 hours• Metabolism not well defined but:

• OATP1B1 inhibitors (cyclosporine, some anti-retrovirals) and strong CYP inhibitors (ciprofloxacin, fluconazole, clarithromycin) may increase levels and response.

• Primarily excreted via feces

Efficacy• 2 randomized, double-blind, placebo-controlled studies (n = 2486)• Composite response rate (abdominal pain score and reduction of stool consistency score) at 26 weeks for 100 mg dose: • 29% vs 19% (study 1) 33% vs 20% (study 2)• Both statistically significant


Prescribing Information, Patheon, May 2015


• Constipation 8% Nausea 7%• Abdominal pain 5% Vomiting 4%

• Drug interactions:• OATP1B1 inhibitors• Strong CYP inhibitors• Drugs that cause constipation

• Abuse potential??? Schedule: pending


Dosage and Cost• 100 mg twice daily with food• 75 mg twice daily with food if patient...

• does not have gall bladder• is unable to tolerate 100 mg• is receiving concomitant OATP1B1 inhibitors• has mild to moderate hepatic impairment

• If a dose is missed, take at next scheduled time, do not take 2 doses at once

• Cost: anticipated availability: first quarter of 2016




Pharmacology• An opioid antagonist binding at the mu-opioid receptor peripherally in the gastrointestinal tract

• Decreases the constipating effects of opioids• A PEGylated derivative of naloxone

• minimal penetration in the CNS• Indication:

• Treatment of opioid-induced constipation in adults with chronic non-cancer pain

Naloxegol (Movantik®)

Naloxegol (Movantik®)Pharmacokinetics

• Peak concentrations in < 2 hours• Secondary peak 0.5 – 3 hours after the first

• High fat meal increased rate and extent of absorption

• Metabolized via CYP 3A4 system• Majority excreted via feces

Efficacy• 2 randomized, double-blind, placebo-controlled studies (n = 1352)• Primary endpoint: response (> 3 SBMs per week and a change from baseline of >1 SBM per week fro at least 9 of 12 study weeks and 3 out of the last 4. For the 25 mg dose:• 44% versus 29% in study 1 (p = 0.001)• 40% versus 29% in study 2 (p = 0.021)


Prescribing Information, AstraZeneca, January 2015


• Abdominal pain 21% (placebo 7%)• Diarrhea 9% (placebo 5%)• Nausea 8% (placebo 5%)• Flatulence 6% (placebo 3%)

• Opioid withdrawal symptoms can occur• Drug interactions:

• Use with strong 3A4 inhibitors contraindicated• e.g., ketoconazole

• Try to avoid use with moderate 3A4 inhibitors• e.g., diltiazem If unavoidable use 12.5 mg dose


Dosage and Cost• 25 mg once daily by mouth• If not tolerated decrease to 12.5 mg once daily

• Take on an empty stomach 1 hour prior to first meal of the day

• Stop laxatives before starting naloxegol• May resume laxatives after 3 days if constipation remains

• Cost: $299.52 for a 1 month supply




Pharmacology• Blocks the hyperpolarization-activated cyclic nucleotide-gated channel responsible for the cardiac pacemaker If current, which regulates heart rate.

• Causes a dose-dependent reduction in heart rate• Indication:

• To reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤ 35%, who are in sinus rhythm with resting heart rate ≥ 70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.

Ivabradine (Corlanor®)

Ivabradine (Corlanor®)Pharmacokinetics

• Bioavailability: ~ 40% because of first pass elimination in the gut and liver

• Food delays absorption by ~ 1 hour and increases plasma exposure (take with meals)

• Extensively metabolized by CYP 3A4• Drug interactions

• Half life ~ 6 hours• Excretion of metabolites via feces and urine

Efficacy• Randomized, double-blind, placebo-controlled trial in

patients with NYHA class II to IV heart failure, left ventricular ejection fraction <35 and resting heart rate >70 (n = 6558)• Reduced the risk for combined endpoint of hospitalization for

worsening heart failure or cardiovascular death based on a time to event analysis (hazard ratio : 0.82, 95%CL 0.75 – 0.9)• Effect was only on the reduction in risk for hospitalization.

• 2nd study with ejection fraction <40 and heart rate >60, NYHA class II or III heart failure showed no benefit

• 3rd study in class I heart failure showed no benefit


Prescribing Information, Amgen, April 2015


• Bradycardia 10%• Hypertension 8.9%• Atrial fibrillation 8.3%• Luminous phenomena 2.8%

• Note: has to do with the mechanism of action• See PPI for Warnings and Precautions


Dosage and Cost• Start at 5 mg orally twice daily• After 2 weeks adjust dose based on heart rate• Maximum dose is 7.5 mg twice daily• In patients with conduction defects or in whom bradycardia could lead to hemodynamic compromise, start at 2.5 mg twice daily

• Cost: 5 mg or 7.5 mg $450/month




• Droxidopa (Northera®) - neurogenic orthostatic hypotension• Riociguat (Adempas®) - pulmonary arterial hypertension• Macitentan (Opsumit®) - pulmonary arterial hypertension• Pirfenidone (Esbriet®) – idiopathic pulmonary fibrosis• Nintedanib (Ofev®) – idiopathic pulmonary fibrosis• Luliconazole (Luzu®) – topical antifungal• Simeprevir (Olysio®) – hepatitis C• Ombitasvir, Paritaprevir, Ritonavir, Dasabuvir (Viekira Pak ®)• Ledipasvir/Sofosbuvir (Harvoni®) – hepatitis C• Brimonidine (Mirvaso®) – persistent facial redness (rosacea)• Albiglutide (Tanzeum®) – GLP-1 receptor agonist (diabetes)• Eslicarbazepine (Aptiom®) – partial-onset seizures• Apremilast (Otezla®) – active psoriatic arthritis

Other New Approvals of Interest…

Pipeline Drugs 2015+• Antimicrobials

• Isavuconazole (Basilia)• Antifungal IV/PO• UPDATE: FDA approved orphan status to treat invasive

aspergillosis • Clostridium difficile monoclonal antibodies (Medarex)

• C difficile associated diarrhea• Ramoplantin (Oscient)

• C difficile associated diarrhea• New drug class!

Pipeline Drugs 2015+

• Other Antimicrobials• Omadacycline (Paratek)

• Skin and skin structure infections, CAP, UTIs• An aminomethylcycline (oral and IV)• A derivative of minocycline


• Antimicrobials in Phase II Studies (New Chemical Classes Only)• GSK 1322322 (GSK)

• Peptide deformylase• Skin and skin structure infections• Abstract of Phase II study versus linezolid: http://

aac.asm.org/content/early/2014/08/12/AAC.03360-14

• Brilacidin (Polymedix)• “Defensin-mimetic” – small molecules that imitate natural human immunity• MRSA• Bacterial cell membrane lysis• Skin and skin structure infections

• NVC-422 (Actelion)• Oxidation• Ophthalmic use: did not meet primary or secondary endpoints in clinical trial

Butler MS, Cooper MA. Journal of Anitbiotics.2011;64:413-25

http://aac.asm.org/content/early/2014/08/12/AAC.03360-14

http://aac.asm.org/content/early/2014/08/12/AAC.03360-14


Psychiatric Medications• Cariprazone (Forest): phase III

• Prevention of relapse of schizophrenia• Eglumegad (Lilly): phase III

• mGlu2/3 agonist (anxiety, drug addiction?)• Bitopertin (Roche): phase III

• Forbes Magazine, “Most Promising” Schizophrenia• Did not reach primary endpoints in 2 studies • 4 other studies ongoing

• Major depressive disorder (Note: 2 other agents in phase III for MDD).

Pipeline Drugs 2015+Diabetes

• Degludec – anticipated late fall 2012 (didn’t make it)• Ultra long-acting insulin (has been called potential “Blockbuster”)• FDA did not approve, asked for more outcomes data 2/13

• DiaPep277 – Phase III• Immune system modulator may preserve beta-cell function in new onset

type 1 diabetes• http://care.diabetesjournals.org/content/37/5/1392• UPDATE: this article has been retracted. The company has uncovered

evidence that certain employees of Andromeda Biotech, Ltd., which Hyperion acquired in June 2014, engaged in serious misconduct, including collusion with a third-party biostatistics firm in Israel to improperly receive un-blinded DIA-AID 1 trial data and to use such data in order to manipulate the analyses to obtain a favorable result.

http://care.diabetesjournals.org/content/37/5/1392

http://care.diabetesjournals.org/content/37/5/1392


Cholesterol management• Darapladib (GlaxoSmith-Kline):

• Failed to reduce the risk of coronary heart disease death, MI, and urgent coronary revascularization compared with placebo in acute coronary syndrome (ACS)

• Anacetrapib (Merck)* (USAToday cover story!)• Safety data being collected through 2017

*Abstract of clinical trial located here:http://www.ncbi.nlm.nih.gov/pubmed/19185645

http://www.ncbi.nlm.nih.gov/pubmed/19185645




• Idarucizumab• Reversal agent for dabigatran• Phase III ongoing• FDA “breakthrough” designation• No coagulant effects• 2 dose regimen (stat and repeat in 10 minutes)• Availability estimate: 2nd half of 2015

Want a copy of these updated

slides? [email protected]

Questions?

Documents

New Drug Update 2015: A Formulary Approach J. Russell May, Pharm.D., FASHP Clinical Professor University of Georgia College of Pharmacy