DRBA exposure - box5168.temp.domainsbox5168.temp.domains/~accuscri/wp-content/uploads/2018/07/April... · affective disorder, alcohol/substance abuse, diabetes, HIV/AIDS longer

Page | 1 www.accuscriptspharmacy.com April 2018

We at AccuScripts Pharmacy strive to collect and publish the most meaningful, worthwhile and current information

in our quarterly newsletters to benefit direct and indirect caregivers, and urge that these newsletters be widely

distributed so that all can read and benefit from this publication. We further encourage the distribution of these

newsletters to physicians, specialists, nurse practitioners and nurses, as much of the newsletter contents consists of

clinical updates and other important long-term care related topics.

Richard Isaacson, MD and director of the Alzheimer’s Prevention Clinic at Weill Cornell

Medicine and New York Presbyterian, has announced that Pfizer is abandoning its entire

Alzheimer disease (AD) portfolio. As we all know, Pfizer Laboratories immerses itself into all

kinds of R and D of medications, especially when a widespread medical disorder (e.g.

Alzheimer’s) is so prevalent world-wide. But perhaps, according to Dr Isaacson, a thorough

explanation to the entire international medical community and people in general needs to be

undertaken, as many may feel this very large pharmaceutical researcher and developer of

medicines is now behaving in a very unethical and immoral manner in light of the overwhelming

need to reign in the total morbidity, mortality and heartbreak that Alzheimer’s creates.

Drug development takes years and years and millions (sometimes billions) of dollars to go from

the research bench to bedside. There have been overwhelming numbers of research and

development failures (well over 90%) where companies have attempted to usher in a

breakthrough for treating/curing or mitigating Alzheimer’s over the past couple of decades.

When a drug company says it is no longer going to invest all that time and money because of the

99% likelihood of failure, we would hope those paying attention to this issue would understand

that.

But Dr. Isaacson goes on to say there is a very good chance the worst is behind us. There

are many exciting drugs in the pipeline. There are many clinical trials going on in phase 3 and

even more clinical trials in phase 1 and 2. The mentality of researchers (collectively) is now to

closely examine all micro-processes involved in Alzheimer’s neurodegeneration so that new

drug entities can exert their mechanism of

action at many of the varied anatomical sites

where a breakdown in neurotransmission is

occurring. In addition, much closer

observations are being undertaken to tie

together any (pre-existing or present) co-

morbidity/co-morbidities that may play a role

in predisposing one to Alzheimer’s, or

exacerbating this dementing illness.

Pfizer has decided that a lot of research is

going on right now, and there are a lot of

companies invested with decades of

infrastructure, and the pipeline looks pretty promising. Esai, Janssen and Novartis are a few

examples of such an infrastructure being in place (with the culmination, albeit some years back,

In this issue:

Managing 3 Common Disorders in Elderly 2 Iron Deficiency Anemia 7 New FDA Warning: Clarithromycin & Opiates 7 New FDA Approved Agents 8

GOING TO OHCA?

VISIT US AT BOOTH 307!


in the marketing of Aricept, Razadyne and Exelon). Hence, it may not be the best idea for

Pfizer to invest yet more money into new drugs that may not pan out for the next 10 or 20 years

or longer.

Tardive dyskinesia (TD) is a complex involuntary movement disorder that has a rather

structured set of clinical manifestations. It is thought that dopamine receptor hypersensitivity is

the underlying condition responsible for this disorder of involuntary movements. Providing a

source of dopamine antagonism long-term may result in gradual hypersensitization of dopamine

receptors, which, in turn, may initiate a pathogenic cascade leading to excess dopamine

signaling.

TD remains a significant burden among certain patient populations, especially where

dopamine D2 receptor antagonism is being utilized (i.e., this being the primary mechanism of

antipsychotic [and other] medications). Dopamine Receptor Blocking Agents (DRBAs) are

primarily (but certainly not exclusively) used for treating a range of psychiatric disorders. Due

to the heterogeneity of patients and other clinical challenges, it is important to consider a patient-

centered approach for managing TD.

MULTIPLE FACETS OF CLINICAL COMPLEXITY CO-EXIST:

-patient types: broad patient demographics exist; regardless of age, race, gender or other

characteristics, anyone prescribed a DRBA can develop TD. DRBAs are used clinically for an

assortment of medical disorders, most notably:

psychiatric (esp psychotic) disorders

depression (esp major depressive disorder)

gastrointestinal disorders e.g. emesis, g.e.r.d., gastroparesis

There are certain demographic / medical risk factors associated with increased likelihood of TD

onset:

older age (particularly 55 yrs of age and up)

female gender (esp those postmenopausal)

non-caucasian ethnicity

Hx or presence of brain damage, dementia, acute extrapyramidal symptoms, major

affective disorder, alcohol/substance abuse, diabetes, HIV/AIDS

longer / higher doses of DRBAs (often times at or just after 1 month exposure by the

elderly)

at the end of a short period after DRBA withdrawal

Clinical decision-making in managing TD where withdrawal of antipsychotic agents is being

considered must be weighed against the impact this may have on the patient’s psychiatric

stability and overall level of daily functioning.

-presentation of symptoms (location of involuntary movements):

tongue

lips

jaw

trunk

extremities


-severity of symptoms (which may differ):

mild involuntary movements (possibly unnoticed by the patient) to a disabling condition

TD usually evolves into a full syndrome over days or weeks, then stabilizes but may have an

ongoing presence of chronic waxing and waning with fluctuating symptoms

symptoms can increase with emotional arousal, activation, distraction and diminish with

relaxation, sleep or volitional effort

-impact on ADL’s (multidimensional) and personal wellness:

possible jeopardy of psychiatric stability

diminishing every day functionality

impairment of physical health

decline of emotional status

lowering of quality of life

decreasing ability to engage in dialog

decreasing swallowing capability

increase in discomfort and possible emergence of pain

dental issues

impairment of ambulation / gait

breathing complications

-diagnostic criteria and the ability to differentiate between classes or types of TD:

ruling out any possible atypical factors / precipitating causes needs to be undertaken before

narrowing TD down to the two most prevalent types (tardive dyskinesia vs parkinsonism).

DRBA exposure – ascertain if patient is being treated by or has recently been managed on a

DRBA; also the clinician must consider that TD may be masked by ongoing antipsychotic

treatment and the TD symptoms only become apparent when the antipsychotic agent is

reduced (in dosage), switched or discontinued.

presence of mild/moderate/severe abnormal involuntary movements may be graded on any

one of a few assessment scales e.g. the AIMS, DISCUS, BARS, SAS.

differentiating between TD (inclusive of stereotypy) and drug-induced involuntary

movements / parkinsonism is a significant part of the diagnostic work-up….

TD (stereotypy) nonrhythmic, repetitive, purposeless hyperkinetic symptoms, usually of orofacial

and lingual musculature: chewing, bruxism, protrusion, curling or twisting of the

tongue, lip smacking, puckering, sucking and pursing; retraction, grimacing or

bridling of the mouth, bulging of the cheeks; eye blinking and blepharospasm

choreoathetoid movements of the fingers, hands or upper or lower extremities

seemingly purposeful, repetitive and coordinated movements in the limbs or trunk

may be seen as well as axial symptoms affecting the neck, shoulders, spine or pelvis

respiratory muscles of the upper airways, chest and diaphragm can be involved,

causing gasping, stridor, interrupted flow of speech, paradoxical breathing, dyspnea

on exertion, and other respiratory symptoms; audible respiratory noises, continuous

humming or moaning may be exhibited.


Parkinsonism rest tremor, bradykinesia, rigidity

drug-induced parkinsonism: if resolves within weeks of DRBA discontinuation

tardive parkinsonism: if persists for months/years after DRBA discontinuation and

normal DAT SPECT (dopamine transporter imaging with single-photon emission

computed tomography). (abnormal DAT SPECT is indicative of underlying

Parkinson’s disease).

Dopamine agonists are often used to manage tardive parkinsonism but are not

effective in TD.

Over-the-years observations and conclusions:

emergent tardive dyskinesia secondary to inducement by medication(s) tends to persist for

years or decades in a significant number of patients who have had the offending drug/drugs

discontinued.

studies have been presented in which roughly 1/3 to 1/2 of all patients withdrawn from

antipsychotic medications (who had shown some signs of dyskinesias during therapy)

experienced an initial worsening of TD at the time of discontinuation.

TD prevalence is estimated to occur (at some time during or after therapy with an

antipsychotic drug) in 20% – 30% of the treated population with prevalence increasing with

advanced age;

in a recent review of 41 studies (n=almost 11,500 subjects), the reported incidence of TD in

this population (who were all treated intermediate to long-term with an antipsychotic) was

found to be:

20.7% among subjects managed on an atypical antipsychotic

30.0% among subjects managed on a typical (1st generation) antipsychotic; the

use of atypical (second generation) antipsychotics was prioritized in an effort to

substantially reduce, if not eliminate, the development of TD; however, this has

obviously not been the case.

Fortunately, within this last year, two medications have been finally approved to manage

different movement disorders….

1) valbenazine (Ingrezza) was the first drug approved to treat adults with tardive dyskinesia.

This drug was granted fast-track approval and in pre-approval clinical trials revealed

significant improvement vs placebo after six months of pharmacotherapy; side effects

include sleepiness and QT wave prolongation; the medication is contraindicated in

patients with any form of abnormal heartbeats associated with QT prolongation.

2) Deutetrabenazine (Austedo) has also been FDA approved for tardive dyskinesia in adults.

The results of the ARM-TD trial in which all patients were diagnosed with TD, those

who received deutetrabenazine (vs placebo) had significant improvement on the AIMS

assessment in contrast to the control (placebo) group, and these same beneficiaries also

had better quality-of-life scores on the modified Craniocervical Dystonia Questionnaire

than did the placebo group.


Heart Failure, amended guidelines due to two recently approved medications:

The two newest heart failure medications that now comprise part of the NYHA algorithm are

sacubitril/valsartan (Entresto) and ivabradine (Corlanor).

To review, the New York Heart Association (NYHA) classifications of heart failure are:

-class I – heart failure (HF) – mildest class – no limitation of physical activity as ordinary

physical activity does not cause symptoms of HF

-class II – HF – slight limitation of physical activity; patient is comfortable at rest, but ordinary

physical activity causes patient to have symptoms of HF

-class III – HF – marked limitation of physical activity; comfortable at rest but less than ordinary

activity causes symptoms of HF

-class IV – HF – unable to carry on any physical activity without symptoms of HF and may have

symptoms of HF at rest.

Just over a year ago, the NYHA algorithmic guidelines were updated to include both

sacubitril/valsartan and corlanor. This update was promulgated by the American College of

Cardiology, the American Heart Association and the Heart Failure Society of America. Because

these two new agents have evidence only for stage C HFrEF (stage C heart failure with reduced

ejection fraction [meaning the presence of structural heart disease w/prior or current symptoms

of HF]), this was the only section of the entire guidelines to be updated.

The NYHA class II to IV algorithm may include one or both of these agents. For a class

II or III HF classification, the clinician may choose (as a 1st step in pharmacotherapy) the

utilization of an ACEi or AIIRB or angiotensin receptor-neprilysin inhibitor (ARNI) + a BB

(beta blocker). Sacubritril is pharmacologically categorized as a neprilysin inhibitor. Neprilysin

inhibitors work to decrease the degradation of natriuretic peptides (natriuretic peptides function

to promote excretion of salt and water, increases capillary function, decreases arterial pressure as

well as renin, angiotensin, aldosterone and anti-diuretic hormone).

Prior to FDA approval, in research trials sacubitril/valsartan reduced the composite

endpoint of cardiovascular death when compared to using enalapril alone by 20%, reduced

hospitalization due to HF by 20% plus symptoms and physical limitations of HF were reduced as

well.

Ivabradine was the first new medication approved by the FDA in almost a decade to

manage systolic heart failure. This agent serves as an add-on medication in NYHA class II – IV

HF conditions in which the left ventricular ejection fraction is <35% and heart rate is >70 bpm at

rest, and patient is on a maximally tolerated dose of a beta blocker or has a contraindication to B-

blocker use. Ivabradine has been shown to reduce hospitalization for HF in patients with

symptomatic stable, chronic HF with reduced ejection fraction (left ventricular ejection fraction)

of 35% or less.

COPD Exacerbations, a comparison of antibiotic efficacies plus consideration for other

pharmacological interventions:

During an acute exacerbation of chronic obstructive pulmonary disease (AECOPD), the

attending clinician has various options to consider in order to reduce the severity and duration of

symptoms.


An exacerbation of COPD is defined as an event in the natural course of the disease

characterized by a change in the patient's baseline dyspnea, cough, and/or sputum and beyond

normal day-to-day variations that is acute in onset and may warrant a change in regular

medication in a patient with underlying COPD.

Exacerbations of COPD are estimated to result in approximately 110,000 deaths and

more than 500,000 hospitalizations per year, with over $18 billion spent in direct costs annually.

In addition to the financial burden required to care for these patients, other “costs,” such as days

missed from work and severe limitations in quality of life are important features of this

condition.

Although respiratory infections are assumed to be the main risk factors for exacerbation

of COPD, other conditions, including industrial pollutants, allergens, sedatives, congestive heart

failure, and pulmonary embolism, have been identified. The cause of an exacerbation of COPD

may be multifactorial, so that viral infection or levels of air pollution may exacerbate the existing

inflammation in the airways, which, in turn, may predispose to secondary bacterial infections.

The main therapeutic strategy is generally to reduce the severity of an exacerbation, with

O2 therapy and bronchial dilation being the initial treatments. Glucocorticoids and antibiotics

can shorten recovery time, improve lung function and hypoxia, and reduce early recurrence and

treatment failure.

Regarding antibiotic pharmacotherapy, this may be considered to be a part of the

complete treatment regimen if it is highly suspected that a primary or secondary bacterial

infection has come about within the bronchial airways (or that a secondary bacterial infection is

suspected to be a significant risk factor in the presence of a viral infection). Multiple recent and

past trials have included a large array of antimicrobial agents to ascertain what may be most

beneficial in eradicating the most commonly found pathogen(s) that inhabit the lower respiratory

tract. To date, only a small handful of agents are considered to be good candidates for managing

the most common bacterial pathogens.

Up until fairly recently, a macrolide antibiotic, dirithromycin (Dynabec – Lilly) had a

high clinical cure rate with a low rate of adverse effects in treating AECOPD. Unfortunately,

this antibiotic is no longer available in the U.S. Ofloxacin, ciprofloxacin and trimethoprim-

sulfamethoxazole also have relatively high clinical cure rates but also have a greater rate of

presenting with adverse effects. Another alternative may be doxycycline which has shown to

produce a greater antimicrobial response rate than placebo, but in clinical trials there were no

significant differences in recurrence or mortality due to AECOPD. Previous studies have

suggested that azithromycin given prophylactically to high risk patients of COPD exacerbations

may lower the risk of recurrent exacerbations, however, this regimen, for a small percentage of

patients, was problematic regarding the onset of adverse effects e.g. hearing loss, liver, kidney

and nervous system problems


Aside from antibiotic therapy, other treatments have an important role in AECOPD

management. Glucocorticoids can accelerate patient recovery, improve lung function and

hypoxia, and reduce treatment failure rates. Beta2 receptor agonists are the first choice for

bronchial dilation and can improve clinical symptoms and lung function; long-term usage may

also reduce the frequency of acute exacerbations and overall mortality. Beta2 receptor agonists

+ an inhaled corticosteroid (combined) may produce even a better treatment effect. N-

acetylcysteine (a mucolytic agent) can be used for the treatment/prophylaxis of COPD or chronic

bronchitis to prevent exacerbations, and tiotropium (Spiriva), an anticholinergic bronchodilator,

has been shown to lessen the frequency of exacerbations.

Historically, oral ferrous iron salts are the most economical and effective medication for

the treatment of iron deficiency anemia. Formerly the “traditional” dose of ferrous sulfate (for

adults) has been 325mg (65mg of elemental iron) being given t.i.d. Some very recent research

has essentially upended the rationale for administering ferrous sulfate at this high a dose (and the

Beers criteria which lists potentially inappropriate medications for the elderly also does not

consider this to be a safe or beneficial dose for the aged). (Before going on, a further reminder

on maximizing the absorption of iron may be obtained via avoiding tea and coffee while taking

this supplement, and taking vitamin C 500mg q.d. may enhance iron absorption).

A recent study by Moretti and others suggests that the standard dosing of iron

supplements may be counterproductive. Their research has focused on the role of hepcidin,

which regulates ferroportin and further regulates systemic iron balance, partly in response to

plasma iron levels. The researchers found that when a large oral dose of iron is taken in the

morning, the resultant increase in the plasma iron level stimulates the biosynthesis and release

from the liver of hepcidin. This will, in turn, interfere with the absorption of an iron dose taken

later in the day, and even possibly into the next day (and possibly up to 48 hours after dosing).

By attempting the customization of dosing oral iron at different intervals, Moretti and

colleagues concluded that providing lower dosages and avoiding twice or three times daily

dosing will maximize fractional iron absorption. Results of lowering the intake of (elemental)

iron to 40-80mg every other day will constitute adequate supplementation to bring about a

therapeutic response in treating iron deficiency anemia which would not be achieved any sooner

via higher and/or more frequent dosing. Moretti concludes that a possible additional benefit to

adhering to this q.o.d. regimen may be that improving absorption will reduce gastrointestinal

exposure to unabsorbed iron, thereby reducing adverse g.i. symptoms that frequently are

associated with higher / more frequent dosing.

Back in 2005, the FDA issued (and this author printed) a published warning pertaining to

the use of clarithromycin (Biaxin) in adults with heart disease, specifically, coronary artery

disease (CAD). The published warning indicated a statistically higher risk existed for cardiac

patients to develop heart problems and even experience death who were prescribed

clarithromycin vs patients prescribed this drug with no known cardiac issues.


Very recently, a completed 10 year study (the CLARICOR study) followed up and

observed cardiac patients (and patients without cardiac issues) who had prescribed for them one

or more courses of clarithromycin therapy, each for a 14 day duration. After the 1st year of

follow-up, and for the years beyond, it became unexpectedly clear that there were significantly

more adverse outcomes (related to heart problems and mortality) within the group of

clarithromycin recipients having known cardiac issues than the control group having no such

problems. It is currently unclear as to why there exists an apparent cause-and-effect negative

outcome-relationship affecting heart disease patients prescribed clarithromycin when no such

relationship exists with clarithromycin-receiving patients having no heart issues. Nevertheless,

the newest warning just put forth by the FDA strongly urges practitioners not to prescribe

clarithromycin for any infection (or duration) to a patient with any current or past history of heart

disease, especially coronary heart disease. Another suitable antimicrobial agent indeed needs to

be considered (and prescribed) for the individual afflicted with coronary heart disease and in

need of antibiotic pharmacotherapy.

Also, very recently, the FDA has published new guidelines and required labeling changes

for all cough and cold medicines containing codeine or hydrocodone. “Any medication

containing either of these two opiates are not to be administered to anyone under the age of 18”

states the FDA. In adolescents and children under the age of 18 the risks of giving these

medicines far outweigh their benefits. These risks include (but are not limited to) slowed

breathing, dyspnea, misuse, abuse, addiction, overdose and death.

Some codeine-containing cough medicines are available OTC in a few states, and the

FDA is also considering regulatory action for these products. Ironically, in Ohio, it is still legal

for a pharmacist to dispense/sell a limited amount (4 ounces) of an exempt narcotic C-V

preparation once every 48 hours to an individual who must produce a pictured ID and a provide a

signature indicating he has purchased said product. In a state where opiate use has become so

rampant and widespread (especially in the southern Ohio counties), one wonders why the Ohio

Board of Pharmacy has not banned, wholesale, the sales and distribution of all C-V exempt

narcotic products.

With Americans still being in the throes of the 2017-2018 flu season, the US Food and

Drug Administration’s Vaccines and Related Biological Products Advisory Committee has

selected the influenza vaccine strains for the 2018-2019 season (which includes distribution

within the entire northern hemisphere).

Overall vaccine efficacy for this past and present year’s flu season against influenza

A(H3N2) – the predominate strain of influenza this season, has been about 25% according to

FDA Commissioner Scott Gottlieb, MD. Though Dr Gottlieb has stated this season’s vaccine

pick was appropriate, his colleagues and other epidemiologists are working to determine why the

vaccine was less effective than expected.

It seems to this author that agreeing to and formulating an influenza vaccine this far in

advance of the next flu season would increase the risk of a ‘mismatch’ phenomenon upon the

arrival of next year’s season. A process known as ‘antigenic drift’ is an inherent and ongoing

event that all viruses experience as they replicate; each new generation’s genetic code or gene

makeup will differ slightly from the preceding generation’s. The greater the length of time that


passes when the original vaccine is paired with the current (or expected) circulating virus, the

greater the antigenic drift phenomenon comes in to play, and in the worst case scenario we could

ultimately experience a significant mismatch between the (far) future circulating virus and what

the original vaccine composition consisted of.

Ztlido patches (1.8% topical lidocaine patch) by Sorrento Therapeutics received the green

light from the FDA. This topical bandage-like patch has been approved to manage postherpetic

neuralgia (PHN), a common complication of shingles. The manufacturer claims their product

improves upon the Lidoderm patch by offering better adhesion and delivers equivalent doses of

lidocaine in a more effective manner, thus being able to accomplish analgesia with a lower

percentage strength patch (1.8%), which, in theory, should reduce the severity of any possible

adverse effects upon application.

The FDA has cleared tildrakizumab-asmn (llumya, Sun Pharmaceuticals) for adults with

moderate-to-severe plaque psoriasis who are eligible for systemic therapy or phototherapy. This

selective interleukin (IL)-23p19 inhibitor given by subcutaneous injection is administered at a

dose of 100mg q 12 weeks after the completion of the initial series of a subcu dose at week 0 and

week 4. The outcome of the reSURFACE 1 and reSURFACE 2 trials involving over 900 adults

with moderate-to-severe plaque psoriasis revealed a 75% reduction in the Psoriasis Area Severity

Index Score and Physician’s Global Assessment score of “clear” or “minimal” at week 12 after

two doses. Tildrakizumab-asmn may increase the risk of infection and treatment with this agent

should not be initiated in patients with a clinically active infection.

FDA has okayed extended-release amantadine (Osmolex ER) for Parkinson’s….

Osmotica Pharmaceutical has also received an FDA approval for administering this product to

manage drug-induced extrapyramidal symptoms in adults. The once-a-day formulation is

available in three strengths – 129mg, 193mg and 258mg tablets. The initial dose is 129mg q

AM, and the dosing may be increased weekly to a maximum daily dose of 322mg q AM. The

drug should not be administered in frank renal failure (cr cl < 15ml/min/1.73m2).

Feels like the pharmacy “right around the corner.”

Our marketing & sales team who both makes the

promises and produces the service:

Denis Holmes, President

[email protected]

Craig Baughman, VP Operations

[email protected]

Matt Lengauer, Director of Customer Service

[email protected]

Documents

DRBA exposure - box5168.temp.domainsbox5168.temp.domains/~accuscri/wp-content/uploads/2018/07/April... · affective disorder, alcohol/substance abuse, diabetes, HIV/AIDS longer