Compounding Medicines in an American Hospital SystemKenneth Y. Tsai, MD, PhD Reviewing Byun M et al., ... What if all you can find out for a preparing a formulation is 10 mg / mL?

Dallas, Texas PEOPLE QUALITY EFFICIENCY GROWTH

Compounding Medicines in an

American Hospital System

Association of Portuguese Hospital Pharmacists

Lisa D. Ashworth, BS Pharm, RPh, FACA November 21, 2015

Privileged and Confidential


2

Territory

Dallas, Texas PEOPLE QUALITY EFFICIENCY GROWTH Privileged and Confidential


Children’s Healthcare System of Texas

4 Privileged and Confidential

Dallas 487 beds

(Critical Care, NICU, Hem/Onc, Cardiac)

Level I Trauma Center, ER

Outpatient Clinics

2 Retail Pharmacies

Metroplex 18 Outpatient Provider

Locations

Plano 72 beds

Critical Care, Hem/Onc, Med / Surg, Eating Disorders &

Outpatient Clinics

Southlake Outpatient Clinics &

Surgery Services

Homecare Nursing, PT, OT &

Coming – Pharmacy Services

Our Children’s

House 24 beds

Rehabilitation and

Feeding Services


2014

785,563 Total Patient Encounters

342,708 Ambulatory Visits

7th largest Pediatric health care provider in the US

2.6 million square footage

562 licensed beds

28,355 Surgeries

~ 4 million doses dispensed

$51 million Charity Care


Barcode Driven

Safety

4 hour cartfill and delivery

Omnicell

Draw up Most doses

~60 of doses compounded

Repackaging


7

Hospital Area

•University of Texas

Southwestern Medical

Center and School

•Parkland Hospital System


Age – Pediatrics (age: womb to age 18 yo(+), N of 1, case reports, rare and unusual

diseases

Socioeconomic – Access to prescribed medicines

Ethnicity

Technology Advances – Sonogram allows us to detect congenital cardiac abnormalities

and spina bifida in the womb…and even correct in the womb, or immediately

after birth

Blood Test Advances – Metabolic disorders such as amino acid deficiencies

Cultural

Medical

Religious Beliefs

8

Most Patient’s Are Complex


Early and Specific Diagnosis

• January 2, 2014Childhood Kaposi Sarcoma — A Rare Genetic Predisposition Explained Kenneth Y. Tsai, MD, PhD Reviewing Byun M et al., J Exp Med 2013 Aug 26; 210:1743

• Inherited human OX40 deficiency underlies classic Kaposi sarcoma of childhood

• An ethnogeographic predisposition to classic Kaposi sarcoma (KS) is well established in people of Mediterranean descent. Until now, an autosomal recessive predisposition has also been suspected (but not established) in otherwise-healthy individuals with the exceptionally rare condition of childhood-onset KS unrelated to immunodeficiency. Byun and colleagues have identified an underlying cause of genetic predisposition to KS in an HIV-negative Turkish woman born to consanguineous parents who presented with classic KS at age 14. Unlike patients with childhood KS related to Wiskott-Aldrich syndrome or IFN-γ receptor 1 deficiency, she had no history of primary immunodeficiency. Comparative whole exome sequencing of her, her parents, and an unaffected sibling revealed a R65C mutation in OX40 (TNFRSF4) — a receptor found on activated T cells. The mutant allele is expressed poorly in T cells and causes a complete loss of function in signaling. Though she had normal lymphocyte counts and antibody titers, she had low numbers of memory T and B cells and defective memory T-cell recall responses. Interestingly, KS expresses OX40 ligand strongly, suggesting that interaction with T cells through OX40 may be relevant for immune responses against KS.

• Byun M, Ma CS, Akcay A, Pedergnana V, et al. Inherited human OX40 deficiency underlying classic Karposi sarcoma of childhood. JEM July 29, 2013; 210 (9): 1743-1759.

http://www.jwatch.org/content/2014/NA33115?query=etoc_jwderm











Therapeutic Gaps

Children – Tiny, Small, Medium and Large

Tastes bad

Smells bad

Burns mouth

Too many times a day

Ease of measuring

Ease of administration

Route (oral, rectal, feeding tube, topical, IV)

Makes stomach hurt

Side effects

Not commercially manufactured in a dosage form or strength for children

No treatment or Non-Compliance


Non-compliance

Research shows that only about half of people

take their medications as prescribed.

They may fill a prescription but not take the drugs as instructed

or

they may discontinue a course of treatment before it's completed….

Resulting in increased costs to health care systems.

http://www.latimes.com/health/la-he-healthcare-pharmacist-20110316,0,7587341.story

http://www.nehi.net/news/press_releases/110/nehi_research_shows_patient_medication_nonadherence_costs_health_care_system_290_billion_

annually

Pharmacists are perfectly positioned to help address the drug "adherence" problem.

In 2009, research showed that patients who do not take their medications

as prescribed by their doctors cost the U.S. health care system an estimated

$290 billion in avoidable medical spending every year.










http://www.nehi.net/news/press_releases/110/nehi_research_shows_patient_medication_nonadherence_costs_health_care_system_290_billion_annually






Limited Dosage Forms and Strengths

Why can’t I just rub it on where it hurts?

Can it go down a tube? Is it a “spoon full of sugar?” No more Carbs, Gluten or Lactose!

Can you limit preservatives?

One size does not fit all!

Closing the Gap with

Pharmacy Compounding

12


Nonsterile Preparations

Deficiencies = Thiamine, Zinc, NaCl, Na Phosphate, KCl, K

Phosphate, Selenium, Pyridoxine, Folic Acid, Arginine,

Magnesium, Other Amino Acids

Ophthalmic = EDTA, Vancomycin, Tobramycin

Seizures = Ketogenic Diet (Carbohydrate counting, High Fat),

Zonisamide, Topiramate

Cardiac & Hypertension = Amiodarone, Carvedilol, Tadalafil,

Verapamil, Amlodipine, Sotalol, Mexiletine, Metoprolol,

Metolazone, Labetalol, Hydralazine, HCTZ & Spironolactone,

Spironolactone, Dipyridamole, Clopidogrel, Chlorothiazide,

Captopril

Cancer and Blood Disorders = Thioguanine, Cyclophosphamide,

Leucovorin, Irinotecan, Temozolomide, Methotrexate,

Topotecan, Hydroxyurea, Sunitinib, Etoposide, Dantrolene,

Azathioprine, Allopurinol, IV Chemotherapy


Nonsterile Preparations

Transplant = Tacrolimus, Naltrexone, Beclomethasone, Budesonide

Ear, Nose and Throat = Lidocaine intranasal with Oxymetazoline,

Mastoid Capsules, Magic Mouthwash, Cidofovir

Gastrointestinal & Urinary Tracts = Milk and Molasses Enema,

Neomycin, Ursodiol, Sulfasalazine, Phenazopyridine,

Omeprazole, Lansoprazole, Bethanechol, Acetazolamide, Baclofen,

Glycopyrrolate

Infectious Disease = Vancomycin, Valacyclovir, Sulfadiazine,

Rifabutin, Rifampin, INH, Oseltamivir, Metronidazole,

Hydroxychloroquine, Ganciclovir

Skin = Sirolimus cream, LET gel, ICU Bottom Paste,

Spironolactone, Retinoic Acid, Resorcinol

Cystic Fibrosis = Tobramycin, Gentamicin, Amikacin, Cephalosporins,

Vancomycin all IV or inhaled


Oral Preparation Vehicles

Simple Syrup

Cherry Syrup

Syrpalta Without Dye

Syrpalta

Glycerin

Sorbitol

Water

Methylcellulose

Raspberry Syrup

Combination Vehicles that Suspend, F l a v o r & Preserve


Oral Preparation Vehicles

•Sugar Free versus Sugar – aversion or diet

•Preservatives – affect on children

•Sorbitol – side effects

•Clogging feeding tubes – Just water please!

•Tastes too good – poisonings

•Concentration – stability ease to dose


Flavorings

Strawberry Peppermint

Bubble Gum Tutti-Fruiti

Root Beer Lemon-Lime

Marshmallow Orange

Banana Peach

Chocolate Grape

Cherry…………..


Sterile Preparations

IV Fluids – 0.675% NaCl + Sodium Bicarbonate, Plasma-Lyte + Dextrose 70% + Potassium Phosphate + KCl, Insulin Drip

NICU IV Fluids – Hydrocortisone, Dexamethasone, Chlorothiazide, Heparin Arterial Line

Antibiotics – Piperacillin / Tazobactam, Ampicillin, Meropenem, Ceftriaxone, Ceftriaxone with Lidocaine, Sulfamethathoxazole / Trimethoprim

Gastrointestinal – Esomeprazole, Ranitidine

Cardiac – Amiodarone, Enalapril, Dobutamine, Dopamine, Cath Lab Heparin

Pain – Morphine PCA, Morphine in small concentration 1 mg / mL, Ketamine

Surgery – Cardioplegia, Kidney and Liver Organ Transplant Fluids and Soaks / Baths

Dialysis – Heparin low concentrations, additives to Dialysis fluids

Chemotherapy – Methotrexate, Cytarabine, Vincristine, Vinblastine, Carboplatin, Cisplatin, Etoposide

Investigational –


Neonatal Graves’

• Propylthiouracil (PTU) has been the treatment for Neonatal Grave’s for years (approved in 1947).

The United States Food and Drug Administration issued an alert of serious liver failure and death in

patients treated with PTU in June 2009.

• FDA states “Propylthiouracil should not be used in pediatric patients unless the patient is allergic to

or intolerant of methimazole, and there are no other treatment options available.”

• The patient will need this medication until either their TSH level becomes normal (~8-12 weeks) or ~

11 months when the thyroid can be ablated.

Rivkees SA. The treatment of Graves’ disease in children. J Pediatr Endocrinol Metab 2006 Sep;19(9):1095-111.

The Food and Drug Administration and American Thyroid Association. Propylthiouracil-Related Liver Toxicity: Public Workshop, April 19,

2009, Washington, D.C.


Phone a friend

Where would you look for a methimazole compounded formulation?

What if all you can find is for animals?

Journals and Books

from many countries

Odd Publications:

Tablets & Capsules or

Drug Development

Discovery

Investigational

Studies


Neonatal Graves’

What concentration would you desire for a dose of 0.25 mg / kg in this 8.8 lb (4 kg) infant?

1 – 5 mg / mL

What if all you can find out for a preparing a formulation is 10 mg / mL?

Dose = 1 mg = 0.1 mL

What pitfalls do you expect when formulating for this medication?

Beyond-use Date (14 days), measuring small doses of concentrated medication

United States Pharmacopeia Study 5 mg / mL = 14 days


Pain Control

Consulted by the Pain Team on a Teenage Male who needs better pain control

Was on Methadone IV but there is a shortage of this manufactured product

Changed to Hydromorphone IV, needing up to 500 mg every 24 hours

Added Lidocaine IV continuous

Lorazepam IV every 3 – 4 hours scheduled and prn

Oral methadone liquid had been tried and did not work due to little or no gut absorption

Can we give methadone buccal?


Pain Control

Leaning towards the nurses crushing tablets at the bedside, mix with honey and apply in each buccal pocket.

Upon further review he has many health issues, but foremost he has had a bone marrow transplant due to Sickle Cell Disease and has developed Graft versus Host Disease of the gut.


Pain Control

Evaluation of drug available and vehicle for a paste to place in each buccal

pocket.

Our pharmacy stocked methadone tablets in 5 and 10 mg only.

Methadone is bitter – need flavor

Methylcellulose would be a good to bind the drug and hold it in the buccal

pocket, it is flavorless

Manufactured product with methylcellulose and orange flavor was chosen

5 mg / 0.5 mL, 15 mg / 1.5 mL every 8 hours increased to 15 mg / 2 mL every 6 hours

Formula: 1. Methadone tablets crushed to fine powder

2. Mix with orange flavor methylcellulose

3. QS with Water to form a paste

4. Package in oral dosing syringes


Active Pharmaceutical Ingredient (API) versus Commercial Manufactured Product as Drug Source

Possible

Pluses:

The API would have allowed for more drug in a smaller volume

More absorption due to finer particles

More accurate potency of finished preparation

Achieved a blood level through buccal absorption using commercial tablets

Minuses:

Keeping track of a narcotic raw material (API)

Commercial tablets = gritty preparation

Equipment and ingredients to prepare a troche dosage form


Children Grow to Become Adults—

but may not be able to tolerate adult dosage forms

Hematology & Oncology

In the United States Acute ALL Survival1

1962 = 4%

Today = 94%

All childhood cancers survival2

1975 – 1977 = 58.1%

1996 – 2003 = 79.6%

Cardiology: Survival for infants with congenital heart defects has increased dramatically with surgeries for Patent ductus arteriosus ligation; Hypoplastic left heart repair, Tetralogy of Fallot repair, Atrial and Ventricular septal defect repair, Truncus arteriosus repair, and others.

26

1. http://fundraising.stjude.org/site/PageServer?pagename=tribute_Facts

2. http://www.cancer.gov/cancertopics/factsheet/Sites-Types/childhood


Healthcare systems will continue to be complex, and maneuvering these systems will continue

to be scary for patients.

Patient’s will continue to be from the womb to death with Socioeconomic, Ethnic, Cultural,

Religious, and Medical challenges.

Technology and Blood Test Advances will continue and allow the diagnosis of diseases

requiring personalized medication(s).

As pharmacists in the health-care system (institutional, ambulatory or hospice). we are in a

unique position to be a great part of the therapy/treatment team to help reform payment

systems, engage and educate providers and patients, and leverage healthcare technologies for

each patient to have the best healthcare possible.

Children Grow to Become Adults—

but may not be able to tolerate adult dosage forms

27

Dallas, Texas PEOPLE QUALITY EFFICIENCY GROWTH 28

“For 42 years, I made small, regular deposits of education,

training and experience…and the experience balance was

sufficient that on January 15th I could make a sudden, large

withdrawal.”

Chesley “Sully”

Sullenberger

Pilot US Airways 1549

January 15, 2009


Square pegs don’t fit into round holes!

29

Questions?

Dallas, Texas PEOPLE QUALITY EFFICIENCY GROWTH Privileged and Confidential 30

Lisa D. Ashworth, BS Pharm, RPh, FACA

Children’s Health System of Texas

Compounding Specialist – All Campuses

Dallas, Texas USA

Direct: 469-955-2451

[email protected]

Thank You

Documents

Compounding Medicines in an American Hospital SystemKenneth Y. Tsai, MD, PhD Reviewing Byun M et al., ... What if all you can find out for a preparing a formulation is 10 mg / mL?