JNC 8 - Charleston APRN Conference 2014/2014_Kelly.pdf · JNC-8 Worth the Wait! Kelly W. Jones, Pharm.D., BCPS McLeod Family Medicine Center Director of Pharmacotherapy Education

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Adult Medicine Update

20th Annual APRN Conference

Kelly W. Jones, Pharm.D., BCPS

McLeod Family Medicine Center

Director of Pharmacotherapy Education

JNC-8

Worth the Wait!



Director of Pharmacotherapy Education

JAMA, Published online, December 18, 2013

Disclaimer

I have no conflict of interest relating

in the material covered today.

I do not serve on any speaker bureau.

I do not have any personal grants

concerning the area of discussion today.

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Objectives

1. Discuss the history of the Joint National Committee report for treating hypertension.

2. List the 9 recommendations made by the panel for practice change.

3. Discuss the major change in the blood pressure goal in the elderly and list the controversial issues regarding the change.

4. List the limitations associated with the guideline and how that relates to pay for practitioner performance by insurance companies.

5. Discuss the Institute of Medicine’s report on practice guidelines.

Early Approach to Therapy

Early treatment pioneers – 1940’s

Walter Kempner (Duke University)

Developed the Kempner diet – rice, fruits, low in sodium, fat, protein and calories

Reginald Smithwick (Boston University)

Developed a surgical approach - lumbodorsal sympathectomy and splanchnictomy, etc

Robert Wilkins (Boston University)

Medication approach – he studied many of Smithwick’s patients

He helped NIH and Squibb Institute to develop medications

NEJM 2009;361(9):878-87

Early Approach to

Therapy

Wilkins was joined later by

Edward Freis, his research

fellow

Freis was later recruited to

Georgetown VA hospital

where he conducted the

famous two VA Cooperative

Trials

NEJM 2009;361(9):878-87

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Early Approach to Therapy

Pentaquine

First drug Freis tested

Came out of the anti-malarial program

of WWII

Veratrum viride

Herb

Had side effects – nausea and vomiting that limited it’s use

He ultimately worked with…………..

..…Thiazides

Thiazides hit the market in 1957/58

First outcome trial was published in JAMA in 1967 and

1970

VA Cooperative Study Group

Reserpine +hydralazine + thiazide on CV outcomes

Gutsy research in a time when treatment of BP was

considered of no value and worse yet potentially harmful.

It’s essential you know…..

JAMA 1967;202:1028-34

JAMA 1970;213:1143-52

Birth of a new drug!

In fact a new drug was developed for this trial!!

Ser-Ap-Es®

Was discontinued from the market in year 2000

It was a sad day for Dr. NB!

Then along came others Ser-A-Gen®, Seralazide®,

Serpazide®

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VA Trial II – trial was longer and involved lower diastolic BP for entry

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Mary

Lasker Freis later won the Lasker

Award for clinical research in

1971

Mary Lasker was so

impressed with the research

that she pushed the Secretary

of Health, Education, and

Welfare to establish a national

program for hypertension

education. In 1972, the

National High Blood Pressure

Education Program was

developed by the NIH, which

ultimately led to JNC reports.

The first publication was in

1976.

JNC Publication History

JNC 8: published 2014








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JNC Report Summary

JNC 1, 1976

Use DBP only with treatment at >105, and treatment could be consider for DBP 90 to 104

Thiazides were drug of choice

JNC 2, 1980

Introduced the mild, moderate, severe idea

Still only used DBP

DBP 90 to 104 was considered mild

Introduced the step-care approach to treatment

JNC 3, 1984

Addressed SBP as isolated SBP at >160, mild isolated BP 140-159

Also suggested that those at 140 might be “high normal” and at risk

BB were added as an initial treatment option

JNC Report Summary

JNC 4, 1988

Was mostly about drug therapy, adding ACEI and CCB to the

step-care list even when there were no RCT’s with these

agents.

JNC 5, 1992

Isolated systolic HTN was recognized and recommended for

treatment

Diuretics and BB were preferred using evidence, acknowledging

the inconsistency with BB.

Dropped the mild, moderate, high classification and moved

towards 4 stage system

JNC Report Summary

JNC 6, 1997

Established the concept of a goal BP

General < 140/90

Diabetes or CKD <130/85

Changed 4 stages to 3 stages

Introduced the concept of compelling indications: could begin any medication with emphasis on comorbidities

Stresses lifestyle modification and this could be used in mild to moderate HTN and drugs delayed 6-12 mths

JNC-7, 2003

Reduces staging to 2

Reduced goals in diabetes and CKD to < 130/80

Calls attention to prehypertension, those < 140/90

Highlights combination therapy for initial therapy for those 160/100

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The JNC 8, 2014

Guideline Panel

Panel used the IOM report on Clinical Practice Guidelines We Can Trust to develop the guidelines.

17 voting members were all experts in HTN, picked from 400 nominees

Primary care 6 14 MD’s

Geriatrics 2 1 Pharm.D.

Cardiology 2 1 RN (PhD)

Nephrology 2 1 PhD *

Nursing 1

Pharmacology 2

NHLBI, NIDDK organizations 2

4 of the 17 report financial disclosures

*1 PhD was our very own Dan Lackland of USC, Epidemiologist

Not JNC-8?

Really not the JNC 8, but let’s preserve the history!

June 2013 – NHLBI announced its decision to discontinue development of clinical guidelines, but to partner with organizations to develop guidelines.

Why? IDSA complicated legal proceedings concerning a Lyme Disease guideline – concerns disclosure issues.

IDSA physicians testifying against physicians who are not complying with these guidelines.

Recent mammography screening issue from USPSTF

The panel chosen by NHLBI chose to publish independently for timely reasons.

In the future, these guidelines will be tied to ACC/AHA – or at least I think so…..

Questions Guiding the Evidence

Used a Delphi method to generate 3 questions

1. In adults with HTN, does initiating antihypertensive

pharmacologic therapy at specific thresholds improve

health outcomes?

2. In adults with HTN, does treatment with

antihypertensive pharmacologic therapy to a specific BP

goal lead to improvements in health outcomes?

3. In adults with HTN, do various antihypertensive drugs

or drug classes differ in comparative benefits and harms

on specific health outcomes?

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Evidence Review Criteria

Excluded studies with follow-up < 1 year and if N < 100

Studies had to report specific health outcomes, e.g.,

mortality, MI, HF, hospitalization, various coronary

interventions, ESRD (see article for exhaustive list)

Limited studies to RCT’s

Studies were graded for quality as high, moderate, low

1966 to 2009 with two reviews from 2009-2013 to cover

for misses

Guideline Procedures

All studies and all recommendations were voted on

75% majority agreement to approve

9 recommendations made

Recommendations 1 to 5 address question 1 and 2

Recommendations 6 to 8 address question 3

Recommendation 9 addresses treatment strategies

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Recommendation 1

In general populations aged 60 years or older

Pharmacotherapy if SBP or DBP > 150/90

Treat to a goal of < 150/90

Grade A, strong recommendation, but not a unanimous

vote

Based on HYVET, Syst-Eur, SHEP, JATOS, VALISH,

CARDIO-SIS

JATOS and VALISH were 2 Japanese trials evaluating intense vs

conservative treatment of BP in elderly.

Neither trial found a difference in primary outcome trial

Corollary Recommendation 1

In the general population aged 60 years or older, if

pharmacologic treatment for high BP results in lower

achieved SBP (for example, <140) and treatment is not

associated with adverse effects on health or quality of life,

treatment does not need to be adjusted.

Expert Opinion – Grade E

Related to some members wanting to continue JNC-7

recommendations of < 140

Their concern relates to treatment in high-risk patients like

those with CVD, stroke, black race, multiple risk factors

It is a call for more research!

Recommendation 2

In the general population younger than 60 years

Pharmacotherapy if DBP >90 or higher

Treat to a goal DPB of < 90.

Ages 30 to 59, Grade A recommendation

Ages 18 to 29, grade E (just no data in those < 30 years)

Based on HDFP, Hypertension Stroke Cooperative, MRC,

ANBP, VA Cooperative

The panel found evidence that there is no benefit in treating

patients to a DBP goal of 80 or lower or 85 or lower compared

with 90 or lower (HOT trial)

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Recommendation 3

In the general population younger than 60 years

Pharmacotherapy if SBP >140

Treat to a goal SBP of <140

Grade E – expert opinion

Based on discussion

No compelling evidence to change current practice and no

research to test this

Recommendation 4

In the population aged 18 years or older with CKD


Goal = BOTH SBP and DBP < 140/90


No evidence to direct lower numbers vs 140/90

Some evidence show no benefit with lower numbers

AASK Trial, REIN-2 Trial

One trial post-hoc analysis shows lowering BP reduces kidney

outcomes – observational only

No studies in the aged with CKD – individualize therapy,

considering frailty, comorbidities and albuminuria.

Recommendation 5

In the population aged 18 years or older with diabetes


Goal = BOTH SBP and DBP < 140/90


SHEP, Sys-Eur, UKPDS – moderate quality trials show that

treating SBP to < 150 is helpful for macrovascular

outcomes

No evidence of SBP of 140 vs 150

So opinion to treat to < 140

ACCORD-BP

no difference in outcomes for SBP 120 vs 140

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What’s should the DBP be?

DBP

Could the magic number be 90?

Could the magic number be 85?

Some would quote HOT trial but the lower outcome

differences in DBP of 90 vs 80 was based on post-hoc

analyses.

UKPDS compared DBP of 105 and 85 – clear benefit

here but can’t distinguish between 85 and 90.

Recommendation 6

In the general nonblack population, including those with

diabetes, initial treatment should include a thiazide-type

diuretic, CCB, ACEI or ARB.

Moderate Recommendation – Grade B

Based on RCT, comparing drugs head to head.

Placebo-controlled trials not used for drug selection.

Does not apply to normotensive CAD or HF patients.

Dosing is essential – see table 4, slide 32

Thiazide-type = thiazide, chlorthalidone, indapamide

Recommendation 6

All 4 classes yield similar results on health outcomes

except for heart failure.

For heart failure outcomes:

Initial treatment with a thiazide was more effective than ACEI

or CCB

ACEI was more effective than CCB

Panel did not think the evidence was compelling enough to

recommend one over the other. It may be that a drop in BP is

more important than what you use.

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Recommendation 6

Beta-blocker are not recommended for initial treatment.

Meta-analyses showing BB do not reduce outcomes.

No reduction in outcomes compared to ARBs (LIFE Trial). May

see increase in stroke.

Alpha-Blockers are not recommended for initial therapy.

ALLHAT trial – worse CVD, HF, combined CV outcomes vs

diuretic

Other common antihypertensives were not considered

initial therapy due to lack of comparative data.

Clonidine, hydralazine, spironolactone, reserpine, furosemide

Recommendation 7

In the general black population, including those with

diabetes, initial pharmacotherapy should include a

thiazide-type diuretic or CCB.

General black population – Grade B

Blacks with diabetes – Grade C

ALLHAT prefers thiazides over ACEI

CCB were picked over ACEI because of the high rate of

stroke in ACEI treated black patients in ALLHAT.

No good comparative trials in blacks.

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Recommendation 8

In the population aged 18 years or older with CKD and

hypertension, initial (or add-on) pharmacotherapy should

include an ACEI or ARB to improve kidney outcomes.

This applies to all patients with HTN regardless of race

or diabetes status.

Moderate Recommendation - Grade B

Less evidence on CV outcomes in the CKD patient. In

fact there are trials that show no improvement with these

agents vs BB or CCB.

IDNT trial did not show improved HF outcomes in CKD

patients taking an ARB vs CCB.

So…..?

What if the person is black and has CKD?

Previous recommendations call for blacks to get thiazide-type

diuretic or CCB.

Consensus statement – In blacks with CKD and

proteinuria, use an ACEI or ARB as initial therapy due to

high rate of progression to ESRD.

If there is no proteinuria – use Thiazide or CCB, or ACEI

or ARB

ACEI or ARB would be your add on drug.

Be aware of K+ and SCr when using ACEI or ARB’s in

CKD patients.

Recommendation 9

If goal BP is not reached within a month:

Increase dose of initial drug

Or add a second drug

Adjust the two medications and add a third drug if

needed

Do not use ACEI or ARB together

If four medications are needed – then add from the other

antihypertensive group (clonidine, spironolactone,

hydralazine, etc)


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Recommendation 9

Methods of drug delivery

Expert opinion

No comparison between these methods

Surprises

It is evidence-based, using RCT’s!

No huge pronouncement of chlorthalidone.

Atenolol is still in the dose list as daily.

No huge comment on combination therapy.

ACEI/CCB did not beat out ACEI/HCTZ

No strong recommendation for spironolactone as the 4th drug in difficult to treat patients.

No specific review of lifestyle therapies. They do support the 2013 Lifestyle Work Group (Circulation 2013).

No statement on quality core measure junk and the need for insurance companies to apologize to MD’s!

No surprise really!

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Limitations of the JNC 8 Guidelines

Guideline does not address comorbidities.

No observational studies or MA, or systematic reviews

(Yea!)

Excluded trials where the patients were normotensive –

ONTARGET, HOPE Trials

They could not distinguish the difference in SBP vs. DBP

on outcomes.

The review did not account for adverse events and the

effect on outcomes.

Kelso’s Wow Factor!

140/90 is a reasonable goal

150/90 in those > 60 years

The benefit of treating to lower BP levels with

pharmacotherapy is NOT established!

“…these recommendations are not a substitute for clinical

judgment, and decisions about care must be considered and

incorporate the clinical characteristics and circumstances of

each individual patient.”

Page E13, last paragraph

Thoughts

Prior guidelines were based on the totality of evidence - observational trials, RCT’s, meta-analysis, GOBSAT

The term “guideline” was borrowed from a mountain-climbing technique in which experienced guides mark the best and safest paths for hikers to take by placing ropes along the way.

In medicine, guidelines were formed to suggest safe direction when managing difficult clinical situations.

So… should these type guidelines be distilled into performance measures?

…deviations from guidelines have become less tolerated

They need to be cognizant of unintended consequences

Peterson Editorial, JAMA, Published online, December 18, 2013

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Thoughts

We need to harmonize these guidelines with other

cardiovascular risk guidelines and recommendations to

assess a more comprehensive CV risk profile.

JNC 8 recommendation is based on a single risk factor - BP

Guidelines never integrate care for many of the actual

patients we see.

Treatment guidelines are:

..like maps!

clinical evidence is the preferred route

IOM - A Good Guideline….?

Be based on a systematic review of the existing evidence

Be developed by a knowledgeable, multidisciplinary panel of experts and representatives from key affected groups

Consider important patient subgroups and patient preferences, as appropriate

Be based on an explicit and transparent process that minimizes distortions, biases, and conflicts of interest

Provide a clear explanation of the logical relationships between alternative care options and health outcomes, and provide ratings of both the quality of evidence and the strength of recommendations

Be reconsidered and revised as appropriate when important new evidence warrants modifications of recommendations.

http://www.iom.edu/Reports/2011/Clinical-Practice-Guidelines-We-Can-Trust.aspx

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IOM Report on Guidelines we can trust

To find the report, just google!

Standards

1. Establish transparency

2. Manage conflicts of interest

3. Guideline development group composition

4. Clinical practice guideline–systematic review intersection

5. Establishing evidence foundations for and rating strength of

recommendations

6. Articulation of recommendations

7. External review

8. Updating

http://www.iom.edu/Reports/2011/Clinical-Practice-Guidelines-We-Can-Trust.aspx

Does the IOM report have

something missing?

The Users’ Guide to the Literature, EBM Working Group

both recommend asking the right questions.

Maybe the IOM systematic review process addresses this?

Are the recommendations valid?

Were all important options and outcomes considered?

Did the developers consider all reasonable options?

Does the guidelines ignore outcomes your patient cares about? What about

harm?

Does the recommendations consider cost? and to whom?

Users’ Guide to the Medical Literature

JAMA 1995;274:570-4 (August 16)

JNC-8 comments on the importance but does not specifically address it!

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Guideline Analysis

Yes to all questions = good guideline

Were all important options and outcomes considered?

Major issue – no comments on harm or cost

They do mention their importance

Was an explicit and sensible process used to identify, select,

and combine evidence?

Multidisciplinary participation?

Graded recommendations?

Are the recommendations applicable to your patient?

Discussion?

Primary Care Medication Update

2014


Associate Professor of Family Medicine


Florence, South Carolina

[email protected]

www.PharmReach.org

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Objectives

1) Identify new therapeutic agents recently introduced to the market and explain their appropriate uses.

2) Describe the indications and the most important adverse events and precautions of each new therapeutic agent.

3) Compare and contrast new medications to others within similar therapeutic categories.

4) Describe any important drug interactions and pharmacokinetic parameters that are clinically relevant.

5) Discuss any evidence-based clinical trials that may be published about the medications to aid in therapeutic selection.

Self-Assessment

Questions

1. Vortioxetine is indicated for the treatment of?

a. Hot flashes

b. Weight loss

c. Depression

d. Pain

2. Ospemifene is a new SERM that is indicated for the treatment of?

a. Osteoporosis

b. Prevention of recurrent breast cancer

c. Hot flashes

d. Dyspareunia

Self-Assessment

Questions

3. Which medication increases bladder capacity and has the lowest rate of dry mouth?

a. Tolteridine

b. Solifenacin

c. Mirabegron

d. Oxybutynin

4. Phentermine/topiramate ER is a REMS medication because?

a. The medication causes seizures

b. The medication causes headache

c. The medication causes seizures

d. The medication causes teratogenicity

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Self-Assessment

Questions

5. True/False Questions

___Aclidinium is a novel new inhaler used to treat acute abdominal pain from IBS.

___Canaglifloxin has side effects we need to monitor. The main issue is monitoring liver function tests twice a year.

___Suboxone® tabs was recently taken from the market for it’s high rate of addiction.

___Solumetrix fine particle technology is a dry milling technology that makes particles 50 to 200 times smaller and prevents agglomeration.

___Fidaxomicin is a new tetracycline-like antibiotic, used for the

treatment of MRSA wound infections.

___Levomilnacipran is an enantiomer of milnacipran. Both drugs are

indicated for the treatment of fibromyalgia.

New Drug Report for 2012

45 New Molecular Entities/Biologicals

12 cancer medications

8 misc injections

4 radiological agents

4 vaccines

3 HIV

2 ophthalmological

2 mab’s

35 new formulations

2 discontinued meds

Budeprion XL 300 mg (bupropion) – not bioequivalent

Suboxone tabs – high rate of accidental ingestion by children vs film formulation

New Drug Report for 2013

28 New Molecular Entities 10 primary care agents

Several dyes and MRI contrast

3 kinase inhibitors for cancer

Thalidomaide analogue for multiple myeloma

Another oral multiple sclerosis agent (dimethyl fumerate)

9 New Biological Botulism antitoxin

Influenza vaccine – not grow in egg, cell culture version

Ado-Trastuzumab – HER2 targeted antibody

Prothrombin complex concentrate (Kcentra®) For warfarin reversal in acute major bleeding

Coagulation Factor 9 – for hemophilia B

Golimumab – Simponi Aria® - TNF blocker

41 New Dosage Forms

As of Sept 2013

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Flu Vaccine Explosion!

Quadrivalent – 4 instead of 3 strains

Increases cost by $6

Contains two B strains, which is more prevalent in kids

FluMist

Only quadrivalent, for healthy, nonpregnant, age 2 to 49

Fluarix, FluLaval, Fluzone

Will have both Tri and Quad versions

Only 20% of supply will be Quad – giving either is OK

Flucelvax

A cell culture vaccine, has trace egg

Flublok

Recombinant vaccine, completely egg-free

Generics Report 2012 Eprosartan (Teveten®)

Tizantidine (Zanaflex®)

Escitalopram (Lexapro®)

Ziprasidone (Geodon ®)

Quetiapine (Seroquel®)

Modofinil (Provigil®)

Irbesartan Avapro and Avalide

Levadopa/Carbidopa/entacapone (Stalevo® 100, 150)

Tindazole (Tindamax®)

Tolterodine (Detrol®)

Desloratadine (Clarinex®)

Montelukast (Singulair® Tablet 10 mg)

Pioglitazone (Actos®)

Sildenafil (Revatio® 20 mg)

Fenofibrate (Tricor 48 mg)

Rizatriptan (Maxalt)

Expected Generics 2013 Mupirocin (Bactroban® topical)

Zoledronic Acid (Reclast® injection)

Zolmitriptan (Zomig®)

Candasartan (Atacand®)

Donepezil (Aricept® 23 mg)

Prandin 0.5 MG Tag

Rabeprazole (Aciphex®)

Duloxetine (Cymbalta®)

Hydromorphone (Exalgo®)

Hydrocortisone butyrate (Lociod Lipocream®)

Estradiol patch (Vivelle-Dot®)

Esomeprazole strontium – new branded generic expected 2014

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Top 10 Therapeutic Class for 2013

1. Antidiabetic

Insulins, GLP-1 agents

2. Analgesic-Antiinflammatory

Humira®, Enbrel®, Celebrex®, Simponi®

3. Antiviral

Atripla®, Truvada®, Incivek®, Reyataz®

4. Psychotherapeutic and Neurological

Copaxone®, Gilenya®, Rebif®, Xyrem®, Avonex®

5. ADHD/Anorexic/Obesity

Adderall®, Vyvanse®, Methylphenidate

Source: I’ll never tell!

Top 10 Therapeutic Class for 2013

The other 5 classes

1. Antihyperlipidemic

2. Dermatologicals

3. PPI’s

4. Inhalers

5. Antihypertensives

Specialty Pharmacy

• While affecting less than 2% of the general population,

specialty conditions in 2012 accounted for 24.5% of the

country’s total drug spend within the pharmacy benefit,

the highest percentage on record.

• ~30% of total drug spent for the typical commercial plan

sponsor in 2012

• In 2012, the Food and Drug Administration approved 22

new specialty drugs, many of which will cost more than

$10,000 per month of treatment.

– Express Scripts 2012 Drug Trend Report 3-5-2013

– Specialty drugs are expected to account for 50% of all

drug costs by 2018, according to two new studies.

News Flash from last year – I told you so

Specialty slides per Dr. Wayne Weart

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http://www.artemetrx.com/docs/ARTEMETRX_Specialty_Trend_Rpt.pdf

Future Drug Development

and Therapeutics

• "This is an evolving area where manufacturers are looking to make up for the revenue they’ve been losing to generics as brands go off patent protection.”

• Pharmaceutical companies have an important incentive to develop genetically targeted therapies.

• While standard drug development typically requires 10 to 12 years of clinical testing before marketing approval, targeted agents can enter the market in two to five years because they can be tested in smaller populations and often approved on the basis of a single Phase II trial.

– Zellmer WA, ed. Pharmacy forecast 2013-2017

• www.ashpfoundationorg/pharmacyforecast

Cancer Drug Pricing?

• “This Perspective reflects the views of a large group of

CML experts, who believe the current prices of CML

drugs are too high, unsustainable, may compromise access

of needy patients to highly effective therapy, and are

harmful to the sustainability of our national healthcare

systems. These reflect the spiraling prices of cancer drugs

in general. Of the 12 drugs approved by the FDA for

various cancer indications in 2012, 11 were priced above

$100,000 per year. Cancer drug prices have almost

doubled from a decade ago, from an average of $5,000

per month to more than $10,000 per month.”

– Blood 2013; 121: 4439-4442

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Cancer Drug Pricing?

• If drug price reflects value, then it should be proportional to the benefit to patients in objective measures, such as survival prolongation, degree of tumor shrinkage, or improved quality of life. For many tumors, drug prices do not reflect these endpoints, since most anti-cancer drugs provide minor survival benefits, if at all.

– For example, in pancreatic cancer, where the median survival is 6 months, a new drug that may prolong survival by 2 months, and is priced at $100,000 per year, will cost $67,000 over 8 months survived, or $33,500 per additional month lived, equivalent to $400,000 per additional year lived. Similar calculations can be made for other cancers depending on the expected median survival, additional time lived, and therefore the price of an additional year lived. By these measures, the price of cetuximab was valued at about $800,000 per year of increased survival. In many countries, an additional year lived is judged to be “worth” about $50-100,000. In England, the National Institute for Health and Clinical Excellence (NICE) values a year lived at about 30,000 British pounds, or about $50,000.

• Blood 2013; 121: 4439-4442

Top 3 most expensive drugs in the drug

market

1. $600,000 per year

– Soliris (Eculizumab) approved for the treatment of paroxysmal

nocturnal hemoglobinuria (PNH), and atypical hemolytic-

uremic syndrome.

2. $375,000 per year

Idursulfase (Elaprase®) - appoved to treat Hunter Syndrome,

which is a lysosomal storage disease caused by a deficiency or

absent of this enzyme and has X-linked recessive inheritance

3. $365,000 per year per person

Arylsulfatase B (Nagalzyme®) is an enzyme replacement

therapy for the treatment of mucopolysaccharidoses VI

Number 9 of the most expensive

drugs on the market

9. Avastin - $100,000 per year per person (first approved in 2004)

• Avastin (Bevacizumab) is an angiogenesis inhibitor that slows the growth of new blood vessels and is licensed to treat a variety of cancers including colorectal, breast, lung, glioblastoma, kidney and ovarian. There is varying approval in certain indications worldwide, for example the FDA revoked Genentech’s (the manufacturer) approval in breast cancer on 18th November 2011 because it described no evidence of extended life or improved quality of life as well as causing numerous adverse effects. Furthermore new data presented at the American Society of Clinical Oncology (ASCO) this June (2013) has also failed to show that Avastin prolong survival when added to chemo-radiation therapy for glioblastoma – a type of brain tumour. These are notable setbacks for Roche when it seeks to reach annual sales of $7 billion for the drug, however at ASCO Avastin was shown to prolong the lives of patients with aggressive cervical cancer. – Market Access USA 2013

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Get the App!!

STEPS

Safety

Tolerability

Efficacy

Price

Simplicity

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Mirabegron (Myrbetriq®)

First new mechanism for overactive bladder treatment in

30 years.

A beta-3 adrenergic agonist

Relaxes the detrusor muscle during storage phase of the fill-void

cycle. This increases bladder capacity.

Safety

Can increase BP

Contraindicated in those with severe uncontrolled hypertension

CYP2D6 inhibitor – watch metoprolol, desipramine, flecainide

Can increase levels of digoxin

Watch warfarin – AUC is increased by 4-10%, no real change in

INR, but experience with multidosing is limited. Monitor INR.


Tolerability

Most common side effects

Pooled from 3 studies

Hypertension rate in those hypertensive

Placebo 7.6%, Mirabegron 11.3%

Will typically raise systolic BP 2-6 mmHg

UTI NNH 42

nasopharyngitis NNH 100,

Headache NNH 112

Addition to the Group?

LOW LOW DRY MOUTH

Not anti-muscarinic

Mirabegron 3%

Oxybutynin (Ditropan®) 50-60%

Tolteridine (Detro®l) 40%

Fesoterodine (Toxiaz®) 20-34%

Trospium (Sanctura®) 20%

Solifenacin (Vesicare®) 10-20%

Darifenacin (Enablex®) 10-20%

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Efficacy

Clinical Trial Observations

From three 12-week trials

OAB = urge incontinence, urgency, urinary frequency

60 yrs old, mostly female, white

They had at least 8 micturitions a day with 3 urgent episodes over 3 days

Can take up to 8-weeks to see efficacy

Mean number of incontinent episodes in 24 hrs

incontinence episodes go down from ~2.6 to 1.4 in a day

Number of micturitions in 24 hour day

Number of urinations go down by 1.75 per day

Patient baseline was 11 micturitions, the drug decreases this to 9

Volume voided increases by ~15 ml


Price and Simplicity

Price?

25 mg, 50 mg extended-release tablets

Do not chew, crush, divide

Dose - 25 mg daily

Allow 8 weeks to access efficacy

can increase to 50 mg if tolerated and needed

Take with or without food

No dosing recommendations in pediatrics

What’s New in Women’s Health?

2/5/2014

28

New OTC – Wow!

Qxytrol for women only!

Oxybutynin 3.9 mg/day

Patch

Ospemifine (Osphena®)

Indication

treatment of moderate to severe dyspareunia associated with

menopause

SERM

selective estrogen receptor modulator (agonist/antagonist)

Agonist on estrogen receptors in the vagina

Antagonist on breast tissue

Some effect on uterine tissue

non-estrogenic

tissue selective effects


Safety Box warning for endometrial hyperplasia and CV events Trials did show a small increase in CV events

DVT incidence – 1.45/1000 ospemifine vs 1.04/1000 for placebo Therefore stop 4-6 weeks prior to a surgery with VTE risk

Hemorrhagic stroke – 1.45/1000 ospemifine vs 0 for placebo Cerebral thromboembolic events were higher in placebo

Endometrial hyperplasia of 5mm was seen in 5% of patients (ARI 3.4%, NNH 30). Monitor for uterine bleeding. Add a progestin?

Metabolized primarily by CYP3A4 and CYP2C9 but CYP2C19 and other pathways also contribute to the metabolism of ospemifene Concomitant administration of fluconazole not recommended

Tolerability Hot flush (NNH 20), vaginal discharge, muscle spasms, hyperhidrosis

UTI’s

2/5/2014

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Efficacy

Approval based on data from three clinical trials

two 12-week efficacy trials

one 52-week long-term safety trial

N = 1889 postmenopausal women.

In both 12-week efficacy trials, statistically significant improvement was demonstrated compared with placebo for vaginal pain with sexual activity, NNT 10

Ospemifene (Osphenia®)

Price

Cost $175/#30 film-coated tablets

Simplicity

Dose: 60 mg once daily with food

Recommended to be taken with food; however AUC

increased if taken with high fat/high calorie meals

Should not be used in women with severe hepatic impairment (has not been studied).

No dose adjustment of OSPHENA is required in women with renal impairment.

Conjugated estrogens/Bazedoxifene

Duavee®

Estrogen + SERM

Can use for hot flashes – has endometrial safety with no increase in breast density or tenderness (SMART-5 trial*)

Indication:

moderate to severe hot flashes of menopause

prevention of postmenopausal osteoporosis

Safety

Same box warning as estrogens

As safe as raloxifene on endometrium**

No need for progestin to prevent endometrial hyperplasia

Endometrial risk is limited by duration of treatment

Risk increases with 5 to 10 years of use of any estrogen therapy

* Obstet Gynecol 2013;121:959-68 **Obstet Gynecol 2005;106:1110-1

2/5/2014

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Duavee®

Safety

Mammography and endometrial biopsy for rule-out is advised

Tolerability

Most common side effects (>5%): muscle spasm (NNH 33), nausea (NNH 33), diarrhea (NNH 33), abdominal pain (NNH 50), dizziness (NNH 50), dyspepsia (NNH 100), neck pain (NNH 100)

No drug interaction data

Efficacy – Clinical Trial Observations

Women with an average of 10 hot flashes a day can expect the frequency to be reduced to 4 per day by week 4.

Osteoporosis trials are DOE – BMD studies. The drug increases density at the lumbar spine and hip. No fracture data


Duavee®

Price

?

Conjugated estrogen is of the equine variety

Tablets: 0.45 conjugated estrogen + 20 mg bazedoxifene

Simplicity

Dose is once daily

Do not use in women > 75 years

Another New Drug for Hot Flashes?

Paroxetine (Brisdelle®) – low dose

Comes in mesylate form – the others are HCl (Paxil®)

First nonhormonal regimen approved by the FDA for hot

flashes.

7.5 mg capsule given at bedtime

Cost : $135/mth

Trials show a difference of 1.2 hot flashes on the average per

day with paroxetine vs placebo

Those with an average of 10 hot flashes per day dropped to 6 using

the medication for 4 weeks

Main side effects: nausea (NNH 50); fatigue (NNH 50);

dizziness (NNH 100)

PL document 291109

2/5/2014

31

Newest Dosage Forms

Minastrin 24 Fe® - first capsule OCP

Lo Minastrin Fe® - new low dose EE – 10 mcg

Quartette® - 84-day pill with escalating estrogen dose

Quadraphasic form of Seasonique®

Chewable Birth Control Pills Femcon Fe is the chewable version of Ovcon-35

Spearmint flavor

Generess Fe, 24 day pill

Wow! Bendectin is back as Diclegis® (B6 + delay-rel doxylamine)

Pregnancy Category A

Dosing: Take two tablets daily at bedtime, increase to a maximum dose of four tablets daily (one in the morning, one mid-afternoon and two at bedtime) if needed

Most common adverse effects: somnolence (19%)

$150 for #30 tabs

Salmon Calcitonin (Miacalcin®) and Cancer

Risk

A joint FDA advisory committee voted 9-12 in March 2013

against the continued marketing of calcitonin salmon products

for preventing osteoporotic fractures, citing limited efficacy

and a slight risk of cancer.

increased risk of cancer was detected in trials for a new oral

formulation.

FDA reviewed more than 20 clinical trials involving oral and nasal-use

products and found a slight, but consistent risk of cancer -- including

melanoma -- in the calcitonin salmon study groups.

FDA is not bound to follow the opinion of its advisory

committees but usually does.

Phentermine/Topiramate ER

Qsymia®

CIV

Indicated as adjunct to diet and exercise

Indication for weight loss in obese (BMI > 30) and

overweight patients (BMI > 27) + one risk factor –

diabetes, HTN, dyslipidemia

Limitations: no data on CV outcomes and outcomes associated

with use of other medications (Rx, OTC, herbals)

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Safety

no data on CV safety

REMS medication

Not recommended in:

pregnancy (birth defects) – pregnancy test in childbearing women before treatment and monthly thereafter and use of effective contraception

those with a suicidal ideations due to the topiramate

Acute angle closure glaucoma

Metabolic acidosis – measure baseline electrolytes

Can increase SCr – do baseline SCr and repeat – watch in renal patients

Assess potential of hypoglycemia in T2DM patients due to weight loss – especially in those on SU and insulin

Weight loss can reduce BP in those taking medications for high BP

Watch with alcohol and other CND depressants

Seizure risk with abrupt withdrawal

Phentermine abuse


Tolerability

Side effect placebo Qsymia 15/92 mg NNH

Paraesthesia 1.9% 19.9% 6

Dizziness 3.4% 10.6% 14

Dysgeusia 1.1% 9.4% 12

Insomnia 4.7% 9.4% 21

Depression 2.2% 4.3% 50

Anxiety 1.9% 4.1% 45

Constipation 6.1% 16.1% 10

Dry mouth 2.8% 19.1% 6

Irritability 0.7% 3.7% 33

Palpitations 0.8%` 1.8% 100

Alopecia 0.7% 3.7% 33


Efficacy

Equip Trial

~n = 1250, 1 yr, BMI > 35

average weight 256 lbs, mean BMI 42

11% weight loss overall on 15/92 mg dose

Weight loss higher with higher doses

67% had 5% loss in body weight after a year

7% weight loss by 8 weeks

Most demonstrate weight loss after beginning therapy

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Conquer Trial

~n = 2500, average weight 227 lbs, BMI 37

More complicated patients – HTN, DM, hyperlipidemia

10% weight loss overall on 15/92 mg dose

Patients got 5% weight loss by 8 weeks

70% got 5% weight loss at one year

84% were considered responders (3%) at 12 weeks

BP, cholesterol, TG went down – but very small reductions


Capsules – take every morning without regard to food 3.75 mg/23 mg – starting dose – free with card

7.5 mg/46 mg – on for at least 30 days and up to 12 weeks

11.25 mg/69 mg – use for 2 weeks to titrate to max dose

15 mg/92 mg

Recommended dose: Qsymia 3.75 mg/23 mg daily for 14 days; then increase to 7.5 mg/46 mg daily

Discontinue or escalate dose if 3% weight loss is not achieved after 12 weeks on 7.5 mg/46 mg dose

Discontinue Qsymia if 5% weight loss is not achieved after 12 weeks on maximum daily dose of 15 mg/92 mg

Discontinue 15 mg/92 mg dose gradually to prevent possible seizure

Do not exceed 7.5 mg/46 mg dose for patients with moderate or severe renal impairment or patients with moderate hepatic impairment


Price ~$200/mth

Simplicity

Monitoring

Weight

Contraception

HR

Depression/suicide

Assess side effects

findQsymia,com for a pharmacy certified to dispense

Patients can enroll in the “Q and me” program for lifestyle

change help

2/5/2014

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Luliconazole (Luzu®)

1% in cream base, 30 g; 60 g

Inhibits the enzyme lanosterol demethylase which inhibits

ergosterol synthesis in the fungal cell membranes

Indication: tinea pedis, cruris, corporis

Safety: no issues

Tolerability

local dermatitis

No issues with menstrual bleeds in females documented

Luliconazole (Luzu®)

Efficacy

2 trials - N = 423 patients, 41 yrs, 82% male, tinea pedis

Complete clearance = clinical and mycological cure

Study 1 - 26% with luliconazole, 2% placebo

Mycological cure was better than clinical cure (62% vs 29%)

Study 2 – 14% with luliconazole, 3% placebo

Mycological cure was better than clinical cure (56% vs 15%)

Effective treatment (- KOH, mild erythema, no pruritis)



Simplicity

Dosed once a day for 2 weeks for pedis

Can use for 1 week for other indications

Cutis 2013;91:203-10

Levomilnacipran (Fetzima®) Indication: SNRI for depression

L-enantomer of milnacipran (Savella®) for fibromyalgia The levo form is not indicated for fibromyalgia

Favors NE reuptake inhibition

Safety No unusual safety issues known

Might have fatal reaction when given with MAOI’s

Suicide or behavior change

Hyponatremia? Might see with any SNRI

Might see in patients on a diuretic

No reports with levo form so far

Serotonin syndrome risk

Drug interactions are unlikely Mainly excreted unchanged in the urine

2/5/2014

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Levomilnacipran (Fetzima®)

Tolerability Nausea (NNH10)

Usually self-limiting and will go away over 2 weeks

Discontinuance rate was 1.5%

Constipation (NNH 17)

Hyperhidrosis (NNH 14)

Tachycardia (NNH 25); increase HR (NNH 20)

Palpitations (NNH 25)

Erectile dysfunction (NNH 20) Very low sexual dysfunction rate in females

Vomiting (NNH 25)

Hypertension (NNH 50)-may increase SBP and or DBP 3 mmHg

Monitor BP and heart rate

Weight neutral


Efficacy Three 8-week trials getting approval Used Montgomery-Asberg Depression Rating Scale Study 1

All doses 40mg, 80 mg, 120 mg Baseline MADRS was 36 - lowered points ~4 from placebo

MADRS was reduced -15 points, placebo -11 points

Study 2 All doses 40mg, 80 mg Baseline MADRS was 31 - lowered points ~3 from placebo


Study 3* Dose flexibility study 40mg - 120 mg Baseline MADRS was 35 - lowered points ~3 from placebo


Separation from placebo was around 4 weeks

*J Clin Psychopharm 2014;34(1):1-10


48-week open label extension study Patients in 3 different studies were eligible

Mainly a safety study

53% of patients were in remission at week 48 (MADRS <10)

47% completion rate (53% premature discontinuation)

Discontinuation was withdrawal of consent (14%) and adverse events (13%), 10% lost, poor therapeutic response (6%) Headache 22%

Nausea 16% Adverse events caused 2% withdrawal

Other 4%

No clinical meaningful changes in: LFT’s, metabolic parameters, urinalysis

Mean pulse increase was 9 beats; BP increased ~4 for SBP and DBP

No QT changes

Clin Drug Investig 2013 DOI 10.1007/s40261-013-0126-5

2/5/2014

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Price

20, 40, 80, 120 mg extended-release capsules

Will come in a titration pack (2 - 20 mg caps and 26 - 40 mg caps)

Simplicity

Dose is 40 to 120 mg once daily

Begin 20 mg, increase to 40 mg after 2 days

Max dose is 120 mg

Do not open, crush (extended release)

Renal impairment – max dose is 80 mg; 40 mg for those with severe impairment

Take without regard to meals

If discontinue, taper therapy

Vortioxetine (Brintellix®) LuAA21004

Indication: major depressive disorder

Mechanism of action: mainly an SSRI

Inhibits 5HT3 receptors (reduces nausea?) and stimulates 5HT1A

No NE or dopamine activity

Safety

No QT elongation

No effect on driving performance

Drug interaction: highly metabolized by 2D6, 3A4, 2C19 and others

Do not use with other SSRI’s

Watch 2D6 inhibitors – bupropion, fluoxetine, paroxetine, quinidine

Increase dose of vortioxetine with CYP-inducers – rifampin, carbamazepine, phenytoin

No issue with warfarin, aspirin, alcohol, lithium

Vortioxetine (Brintellix®)

Tolerability

Nausea NNH 4

More common in females, most common in first week, may last 2 weeks

Constipation NNH 33

Vomiting NNH 20

Dizziness NNH 33

Sexual dysfunction more common in males (4%)

ASEX score (sex drive, arousal, etc) NNH 7 for males

No effect on weight in trials

Discontinuation syndrome

In first week after discontinuation

HA, muscle tension, mood swings, anger, dizziness

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Efficacy

Five 6-8 weeks multi-dose studies

Outcomes

HAMD-24 – 2 studies

24 items from anxiety to worthlessness, higher score worse

Difference of 3 to 5 points

Montgomery-Ashbery Depression Scale (MADRS) – 3 studies

Adjunct to HAMD to assess the change by antidepressants

Test for mood and sadness, tension, sleep, appetite, energy, concentration, suicidal ideation and restlessness

Scores 0 to 6, 6 being worse for each 10 questions

Worse possible score is 60, with 44 being someone very severe and 7 as recovered

Difference of 3 to 6 points among 3 trials

Intern Clin Psychopharm 2012;27:215-23; Curr Med Res Op 2012;28:1717-24


Efficacy observations

Response by 2 weeks

Full antidepressant effect by 4-weeks

Maintenance Study

Those achieving remission to a MADRS total score <10

N = 396 of 639 total

61% remained in remission for 4 more weeks

At 24 weeks, 13% had recurrence of depression on vortioxetine and 26% on placebo

Anxiety Studies

No indication

Two 8-week trial

no efficacy for symptoms of GAD in one and efficacy in the other

J Psychopharm 2012;26(11):1408-16 Eur Neuropsych 2012;22:858-66


Price

5, 10, 15, 20 mg tablets

$235/mth

Simplicity

Start 10 mg once daily, increase to 20 mg as tolerated

5 mg and 15 mg is to aid toleration

Half-life – 66 hrs

Steady state achieved in 2 weeks

No effect of food

No dosage adjustments needed in renal impairment, hepatic

impairment, aged

Not scored

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Fluticasone-vilanterol (Breo Ellipta®)

Inhaled corticosteroid – long-acting beta-agonist (LABA) ICS-LABA

Indicated for long-term, once-daily, maintenance treatment of COPD, obstruction symptoms and exacerbation of disease

Not indicated for asthma

Safety Typical LABA box warning for asthma

It is not a rescue dose system

Increases risk of pneumonia like other ICS combo’s Overall incidence 6% in combo vs 3% in vilanterol alone grp

Fatal pneumonia (one case), mainly associated with higher doses

4-trials, no treatment effect on HR, QT interval, BP, no HPA axis suppression


Tolerability

Rinse and spit after use to prevent thrush and dysphonia

Most common side effect

Upper respiratory infection (incidence 7%, NNH 25)

Oral candidiasis (incidence 5%, NNH 33)

Headache (incidence 7%, NNH 50)

Nasopharyngitis (incidence 9%, NNH 100)

Efficacy

7 trials

Dosing studies

Mostly DOE information on FEV1

FEV1 increases by ~200 ml

FEV1 improvement is sustained at 6 months, ~120 ml

Fluticasone-vilanterol (Breo Ellipta®) Efficacy

2 Exacerbation trials, 52 weeks

Exacerbation defined as worsening symptoms – dyspnea, sputum volume, sputum purulence or one of the following: nasal discharge, nasal congestion, fever, cough, wheezing

Severe exacerbation is addition of antibiotics, steroids, or hospitalization

Combination was better than either alone at reducing exacerbation

1.14 exacerbations/yr on vilanterol alone vs 0.9 exacerbations/yr on combination, p < 0.5

Exacerbations defined as those needing steroid, and or antibiotics and or hospitalization

0.86 exacerbations/yr on vilanterol alone vs 0.66 exacerbations/yr on combination, p < 0.5

Exacerbations defined as those requiring systemic steroids

No data splitting the exacerbations into mild vs severe

No data on outcomes

Studies on file with GSK

2/5/2014

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Price ?

Double-foil blisters strips

Simplicity

100 mcg/25 mcg (fluticasone:vilanterol)

#30/inhaler and #14/inhaler institutional pack

I inhalation daily

No dosage adjustment for

geriatrics, hepatic impairment

or renal patients

When dose counter reached “9”,

it turns red

Has lactose taste

Launch date Oct 2013


Umeclidinium/vilanterol (Anoro® Ellipta)

Long-acting Anticholinergic/LABA

Indicated for COPD

Maintenance therapy, not for acute deterioration

NO indication for asthma

Safety

Same old LABA box warning – asthma-related death

Tolerability

No real issues

12-month trial - HA, back pain, sinusitis, cough

2/5/2014

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Umeclidinium/vilanterol (Anoro® Ellipta)

Efficacy

Time to onset – 27 min

Improvements in FEV1

Price

Have a 7-day strip device for institutions

Simplicity

Once daily dosing

No dosage adjustment required

Unique Dosage Forms

Acyclovir buccal tabs (Sitavig®) – for herpes labialis or cold sores – apply to upper gum (canine fossa)– 50 mg. Single dose therapy, give within 1 hour of prodrome. Study shows the episode will last half day shorter than placebo.

Enalapril (Epaned®) – powder for oral solution

Desoximetasone (Topicort® spray 0.25%) – indicated for plaque psoriasis

Diclofenac (Zorvolex®) – 18 mg, 35 mg caps Solumetrix fine particle technology

A dry milling technology that makes particles 50 to 200 times smaller and prevents agglomeration.

Indicated for mild to moderate acute pain

Makes the diclofenac function as a diclofenac potassium – comparable time to peak plasma concentrations, therefore more power with a lower dose

Given three times a day

$85 for either dose for #30 (10 days of therapy)

Unique Dosage Forms

Hydrocodone extended-release

Indication: management of pain that requires daily, around-the-

clock, long-term opioid treatment

It is NOT a “prn” medication

Zohydro ER®

First non-acetaminophen hydrocodone product

Capsules

10, 15, 20, 30, 40, 50 mg

Dosed every 12 hours

Do not crush, chew, dissolve

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Unique Dosage Forms

Methotrexate Injection (Otrexup®)

Weekly subq injection that can be administered at home

Autoinjector with 4 strengths – 10, 15, 20, 25 mg

Buprenorphine/Naloxone (Zubsolv®)

Maintenance treatment of opioid dependence

SL tablet – 1.4 mg; 5.4 mg

More bioavailability that the generic SL versions

Patent Extenders

Desvenlafaxine extended-release (Khedelza®)

SNRI, 50 mg 100 mg tablets

Par Pharmaceuticals version of Pfizer’s Pristiq®

They are bioequivalent. This is not considered a generic.

Khedelza® - $145; Pristiq® - $210

Esomeprazole Strontium

Released by a Korean company called Hanmi

Been in court with AZ over patent violation

Delay-release capsules

24.65 mg of strontium ($150) = 20 mg of esomeprazole Mg ($250)

49.3 mg of strontium ($72) = 40 mg esomeprazole Mg ($250)

Esomeprazole Strontium is a brand name but there are already generics of this one??? How does that happen?

Prices are from GoodRx in my area

Sodium-glucose co-transporter 2 (SGLT2)

inhibitors

Blocks reabsorption of glucose in the kidney, increasing glucose excretion and lowering blood glucose levels

Can be use monotherapy or with metformin, SU, pioglitazone, sitagliptin, insulin

Do not use in type 1 DM

Canagliflozin (Invokana® - in-vo-KAHN-uh) 10 to 5 vote at FDA for approval

Dapagliflozin (Farxiga®) Voted 9 to 6 NOT to release it on the market in July 2011, this

delayed approval till 2012

FDA denied approval in 2012

Related to excess cases of breast and bladder cancers

Also issues of liver injury

Requested data from current studies and extension studies to address the issues.

2/5/2014

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Sodium-glucose co-transporter 2

(SGLT2) inhibitors

Mechanism of Action

Sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen.

Renal threshold for glucose excretion = 180 mg/dl in nondiabetic (at this level or above, we excrete glucose)

Diabetic renal threshold is ~220 mg/dl

Taking the SGLT-2 lowers this threshold to ~80 mg/dl. This will allow the excretion of glucose when serum sugar levels are normal or in the desired range.

Therefore lower serum glucose and HbA1c

Also lowers weight


inhibitors

Safety

FDA is requiring post-marketing study for side effect issues:

CV outcomes (stroke concern)

pancreatitis, LFT abnormalities, malignancy. Hypersensitivity rxns,

photosensitivity watch

Bone safety study

Two pediatric trials

Volume depletion reactions in the elderly

hypotension, dizziness, OH, syncope, dehydration

Higher in elderly over 75 years, those on loops, renal impairment

(CrCl 30-60)

Pooled studies of 13 trials with dapagliflozin – very low risk

2/5/2014

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Safety Issues: Canagliflozin (Invokana®)

Issue Comparator Canaglifozin

100 mg

Canaglifozin

300 mg

NNH

Bone Fracture 14% 18% 17% ~25

Hypersensitivity 3% 3.8% 4.2% ~100

Photosensitivity 0.1% 0.2% 0.2% 1000

Pancreatitis 0.9% 2.7% 0.9% ?

Volume depletion

rxns

1.5% 2.3% 3.4% ~50, higher

dose

Hyperkalemia* 16% 12% 27%

8 pooled trials, n = 6177, exposure from 38 to 50 weeks

*watch with moderate renal impairment potassium-sparing diuretics, ACEI/ARB’s

No increase in fracture rate in a pooled analysis with dapagliflozin*

*Post Grad Med 2012;124:62-72

Safety Issues: Dapaglifloxin

Bladder cancer

22 trials

Rate was 0.17% vs 0.03% placebo

After adjustments, there were 4 extra cases of bladder cancer

Data insufficient to determine cause and effect

Increase in HCT

Increase LDL 4% as compared to placebo in 13 pooled

trials

NO increase in QT

No drug interaction issues

No unacceptable increase in CV events

Post Grad Med 2013;125(3):181-9


inhibitors

Tolerability for both agents

Most common side effects

Vulvovaginal candidiasis (NNH 14 for both agents)

Patients with a history of genital mycotic infections and uncircumcised

males were more likely to develop genital mycotic infections. (10-12% in

women and 3-4% in men).

UTI (NNH 50 for both agents)

Has a diuretic effect – caution in elderly – orthostasis

Increased Urination/Polyuria: 4-6% of patients

2/5/2014

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inhibitors

Efficacy – drops HbA1c, no outcome studies

Study

Canagliflozin

Duratio

n

HbA1c

difference vs

comparator

100 mg

300 mg Weight

changes

100 mg

300 mg

vs placebo 26 wks -0.91 -1.18 -2.2kg -3.3kg

vs metformin 26 wks -0.62 -0.77 -2.5 kg -2.9 kg

with added

insulin >30

units per day

18 wks -0.63 -0.72 -1.8 kg -2.3 kg

Dapagliflozin studies have similar effects on HbA1c as above

Dapagliflozin + metformin – average HbA1c reduction of 2, 47% got HbA1c <7

More weight reduction with combination vs metformin alone ~ 4 more lbs


inhibitors

Results from 52-Week Clinical Study Comparing

Canagliflozin to Glimepiride in Combination with Metformin

1450 patients; mean age 56; eGFR 90; 52% men; A1c (%) ~7.8;

weight (Kg) ~87

Results:

A1c (%) -0.82 (100mg); 0.93(300mg); -0.81 (glimepiride)

Weight (Kg) -4.2 (100mg); -4.7 (300mg); +1.0 (glimepiride)

Dapagliflozin + metformin vs glipizide + meformin

Similar reduction in HbA1c (-0.5)

Biggest difference was a drop in weight with SGLT2 group (~6 lbs)

Sodium-glucose co-transporter 2

(SGLT2) inhibitors

Results from 52-Week Clinical Study Comparing

Canagliflozin to Sitagliptin (100mg) in Combination with

Metformin and Sulfonylurea

755 patients; mean age 57; GFR 88; 56% men; A1c~8.1; Weight

(Kg) ~88-90

Results:

A1c (%) -1.03 (300mg) -0.66 (sitagliptin)

Weight (Kg) -2.5 (300mg) +0.3 (sitagliptin)

Similar reductions in HbA1c with dapaglifloin vs sitagliptin

2/5/2014

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Sodium-glucose co-transporter 2(SGLT2)

inhibitors - Price and Simplicity

Canagliflozin (Invokana®)

Dose

100 mg, 300 mg tablets

Start 100 mg before the

first meal of the day

Increase to 300 mg when

tolerated

Stay with 100mg if CrCl is

45 to 60 ml/min

CrCl < 45 – do not use

Cost: ~ $9.00/dose

Dapagliflozin (Farxiga®)

Dose

5 mg, 10 mg tablets

Start 5 mg daily, increase

only as needed

Do not use with CrCl < 60

Adjust other medications

to reduce hypoglycemic

risk, esp insulin, SU

Cost: ?

Sodium-glucose co-transporter 2(SGLT2)

inhibitors

Systematic Review and Meta-Analysis

Screened 585 articles, used data extraction techniques

Ended up with 49 primary studies

There were 9 extension studies

Limitation: not all data was based on intention to treat

This review is important due to the questions that we

have already generated.

Ann Intern Med 2013;159:262-74

Results

Outcomes SGLT2 Inhibitor Comment

HbA1c vs placebo -0.66%

HbA1c vs comparator -0.06%

Weight vs comparator -1.8 kg

Systolic BP -4.5

UTI OR = 1.42 Incidence in DM = 5%

Mycotic infections OR = 5.0 Incidence in DM 7-10%

Hypoglycemia Similar as to other agents

CV events and death inconclusive

Bladder cancer Higher incidence with dapagliflozin

P-value = not estimable

9 to 1 with dapa

5 to 4 with cana

Breast cancer Higher incidence with dapagliflozin

P-value = not estimable

9 to 1 with dapa

12 to 6 with cana

Fractures <1.6% with dapagliflozin Higher fracture rate in

those with renal imp.

2/5/2014

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Self-Assessment

Questions

1. Vortioxetine is indicated for the treatment of?

a. Hot flashes

b. Weight loss

c. Depression

d. Pain

2. Ospemifene is a new SERM that is indicated for the treatment of?

a. Osteoporosis

b. Prevention of recurrent breast cancer

c. Hot flashes

d. Dyspareunia

Self-Assessment

Questions

3. Which medication increases bladder capacity and has the lowest rate of dry mouth?

a. Tolteridine

b. Solifenacin

c. Mirabegron

d. Oxybutynin

4. Phentermine/topiramate ER is a REMS medication because?

a. The medication causes seizures

b. The medication causes headache

c. The medication causes seizures

d. The medication causes teratogenicity

Self-Assessment

Questions

5. True/False Questions

___Aclidinium is a novel new inhaler used to treat acute abdominal pain from IBS.

___Canaglifloxin has side effects we need to monitor. The main issue is monitoring liver function tests twice a year.

___Suboxone® tabs was recently taken from the market for it’s high rate of addiction.

___Solumetrix fine particle technology is a dry milling technology that makes particles 50 to 200 times smaller and prevents agglomeration.

___Fidaxomicin is a new tetracycline-like antibiotic, used for the

treatment of MRSA wound infections.

___Levomilnacipran is an enantiomer of milnacipran. Both drugs are

indicated for the treatment of fibromyalgia.

Documents

JNC 8 - Charleston APRN Conference 2014/2014_Kelly.pdf · JNC-8 Worth the Wait! Kelly W. Jones, Pharm.D., BCPS McLeod Family Medicine Center Director of Pharmacotherapy Education