Challenges of Pharmacotherapy in the Treatment of Cystic

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Transcript Challenges of Pharmacotherapy in the Treatment of Cystic

Challenges of
Pharmacotherapy in the
Treatment of Cystic Fibrosis
Hanna Phan, Pharm.D.
Clinical Assistant Professor
Clinical Pharmacy Specialist, Pediatric Pulmonary Medicine
Residency Program Director, Pediatric Pharmacotherapy
Department of Pharmacy Practice and Science
The University of Arizona - College of Pharmacy
• Review common medications used in the
outpatient and inpatient settings in the
treatment of cystic fibrosis (CF)
• Identify challenges of treatment adherence
in CF
• Understand the role of a clinical
pharmacist as part of an interdisciplinary
team in management of CF
**Conflict of Interest: I have no relevant financial relationships to disclose for
this presentation.
Disease Severity, Age, and Therapy
SA, 2 yo ♀
Creon 12,000
AquADEK liquid
EN, 7 yo ♀
Creon 12,000
Source CF
Dornase alfa
Fluticasone NS
CPT = Chest physical therapy
CM, 30 yo ♂
Creon 24,000
Source CF
Dornase alfa
NaCl 7% Solution
Fluticasone NS
JS, 50 yo ♂
Ultrase MT 20
Source CF
Vitamin D
Dornase alfa
Insulin lispro
Insulin lantus
Fluticasone NS
Docusate sodium
CF Drug Therapy Basics
• Therapy selection depends on CF severity
and organ systems affected
– Pulmonary, infectious diseases, etc.
– Gastrointestinal, hepatic, etc.
• Different pharmacokinetics with CF
– Drug selection, dosing, frequency, adverse
• Off-label medication use
• ‘Polypharmacy’ is a common concern
Pharmacokinetic Challenges
in CF
• Absorption
– Differences in gastric pH
– Slower GI motility
• Distribution
– Larger volume of distribution
• Metabolism
– Possible difference in hepatic clearance
• Elimination
– Increased renal clearance
Overall Goals of Therapy
 Prolong survival
 Optimize/improve quality of life
 Slow disease progression
 Achieve normal growth and development
 Decrease hospitalization frequencies and duration
 Minimize adverse drug reactions
Pulmonary Drug Therapy
Bronchodilators – β agonists1
• Nebulized or HFA inhaler
• Commonly used as part of
– Bronchial hyperresponsiveness,
– Prevent bronchospasm during
respiratory therapy and other
inhaled treatments
• Albuterol
– 2.5mg nebulized BID (w/ CPT),
increased during exacerbation an/or
• Levalbuterol
– When to use versus albuterol?
– Why is it not used for everyone?
Images, accessed 11/15/09:
Dornase alfa (Pulmozyme®)1,2
• Recombinant DNA enzyme
• Selectively cleaves
extracellular DNA from
pulmonary secretions,
improve viscoelastic
properties of secretions
– Promotes airway clearance of
mucous  reduce respiratory
infection risk
– ↓ Hospital LOS, duration of IV
• Given as part of CPT
Image, accessed 11/15/09:
Hypertonic Saline1,3,4
• Increases hydration of airway
surface liquid via osmotic flow
– Breaks ionic bonds in mucus
– Stimulates cilial beat via the
release of prostaglandin E2
– Helps improve mucociliary
– Causes sputum production and
cough  improve airway
• Should precede dose with
bronchodilator (i.e., albuterol) to
decrease incidence of
bronchospasm, part of CPT
• 3% (3.5%) and 7% solutions
Image, accessed 11/15/09:
• Inhaled
– Budesonide (Pulmicort®), Fluticasone
(Flovent ®)
– Attenuate reactive airways, reduce
– Concurrent asthma
• Systemic (oral)
– Prednisone
– Reduce inflammation (?)
Image, accessed 11/15/09:
High-dose Ibuprofen1,5
• Inhibits the migration,
adherence, swelling, and
aggregation of neutrophils,
as well as the release of
lysosomal enzymes
– Decreases rate of decline of
FEV1, decreases
– Study population…
• Requires pharmacokinetic
• ADE concerns: GI bleeding
• Currently not used in all
Image, accessed 11/21/09:
• “Anti-inflammatory” agent
– Immunomodulatory properties
– Suppresses inflammation
– Alters biofilm formation
• Not “antibiotic prophylaxis”
• Mon-Wed-Fri regimen
• Considerations
– Check for presence of atypical
– Patient weight
– Presence of mucoid P.
aeruginosa (but new data!)
Image, accessed 11/21/09:
Antimicrobial Therapy7,8
• Intravenous (IV), oral (PO), or nebulized
(NMT) route
– Treatment (mean duration ~ 14-21 days)
– Prophylaxis (outpatient, on/off months)
• Factors affecting antibiotic selection:
Cultures and susceptibilities (past and
Often more than one pathogen…
Child vs. adolescent vs. adult
Organ function (i.e., renal, hepatic)
History of allergies and adverse drug events
P. aeruginosa
S. aureus
Fibrosis Foundation Patient Registry.
2001 Annual Data Report to the Center Directors.
Bethesda, MD: Cystic Fibrosis Foundation; 2002.
RL, Burns JL, Ramsey BW. Pathophysiology and management
of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med.
2003 Oct 15;168(8):918-51.
Antibiotics for CF Exacerbation7,8
• Multi-drug resistant (MDR) pathogens are
• 2+ drug therapy approach
– From different drug classes
– Outpatient
• Oral agent(s) + nebulized agent + increased CPT
• IV agent(s) ± oral agent(s) ± nebulized agent +
increased CPT
– Inpatient
• IV agent(s) ± oral agent(s) ± nebulized agent +
increased CPT
Commonly Used Antibiotics in CF:
Oral Agents7,8
• S. aureus
– Methicillin-susceptible (MSSA)
• Cephalexin, amoxicillin/clavulanate
– Methicillin-resistant (MRSA)
• Sulfamethoxazole/trimethoprim, clindamycin,
• P. aeruginosa
– Ciprofloxacin
• H. influenzae
– Amoxicillin/clavulanate, cefuroxime
Commonly Used Antibiotics in CF:
Nebulized Agents 7,8
• P. aeruginosa
– Tobramycin solution (TOBI®)
– Colistimethate (colistin)
Commonly Used Antibiotics in CF:
IV Agents7,8
S. aureus
Nafcillin (MSSA only)
Clindamycin (watch for inducible resistance)
P. aeruginosa
Piperacillin / tazobactam
An aminoglycoside - tobramycin or amikacin
Commonly Used Antibiotics in CF:
IV Agents7,8
S. maltophilia
Sulfamethoxazole / trimethoprim
Piperacillin / tazobactam
Levofloxacin or moxifloxacin
Ticarcillin / Clavulanate + aztreonam
H. influenzae
All drugs listed for P. aeruginosa provide coverage
(rec. 3rd gen cephalosporin), may not need for
double coverage combination
Commonly Used Antibiotics in CF:
IV Agents7,8
B. cepacia
Sulfamethoxazole / trimethoprim, meropenem, or
ciprofloxacin, may need multiple drug combination;
known to be resistant to AGs
Sulfamethoxazole / trimethoprim, minocycline, or
linezolid, multiple drug combinations usually not
Antifungal Agents7,8
Candida spp. (most)
Aspergillus spp.
Scedosporium apiospermum
Antibiotic Prophylaxis1,11
• Some patients may be given oral antibiotic
therapy for prophylaxis (rare)
• Most common form is nebulized antibiotics
– Tobramycin solution (TOBI®)
– Colistimethate (colistin)
• The above are given twice a day, 28 days
on/off schedule
Gastrointestinal and Nutritional
Drug Therapy
Concurrent GI/Nutrition Issues
Malabsorption (pancreatic insufficency)
Gastroesophageal reflux disease (GERD)
Hepatobiliary disease
Distal intestinal obstruction syndrome
• Poor intake/appetite
• CF related diabetes (CFRD)
Pancreatic Insufficiency12,13
• Pancreatic enzyme replacement therapy
• Several manufacturers
– Creon®, Pancrease®, Pancrearb®, Ultrase®,
Viokase®, ZenPep®, Pangestyme™
• FDA Ruling
– All manufacturers of pancreatic enzyme
products must secure FDA approval of their
products by submitting New Drug Application
by 4/2009 in order to remain available to
Image, accessed 11/29/09: Up-to-date 2009 ©;jsessionid=539B6F5A1A27621314B31A4EB12EB98C.1003?imageKey=PEDS%2
Pancreatic Insufficiency12
• Nutritional supplements
– Fat-soluble vitamins
• Vitamins A, D, E, and K
– ADEK®, AquADEK®, SourceCF®
• Vitamin D
– Ergocalciferol
• Vitamin E
– Over the counter supplement formulations (capsules)
– Iron supplements
• Ferrous sulfate, ferrous gluconate
• Considerations with GERD medications…
Gastroesophageal reflux
disease (GERD)15,16
• > 25-30% incidence
• Histamine-2 receptor antagonists (H2RA)
– Famotadine
– Ranitidine
• Proton pump inhibitors (PPI)
– Pantoprazole,lansoprazole,
omeprazole, esomeprazole
– “Enzyme Boosting”
Images, accessed 11/29/09:
• Often related to CFRD
• Affects the ability of the stomach to empty
its contents
– No blockage (obstruction)
• Drug therapy that helps nausea/vomiting
– Ondansetron (Zofran®)
– Prochlorperazine (Compazine®)
• Drug therapy can help increase motility
– Metoclopramide (Reglan®)
– Erythromycin (E-Mycin®)
Hepatobiliary Disease
• Up to 30% incidence, usually later in life
• Bile duct obstruction from abnormal bile
composition and flow (cholestasis)
• Potential complications:
– Cirrhosis
– Biliary colic secondary to cholelithiasis
– Portal hypertension  liver transplant
• Drug therapy: Ursodiol
– Ursodeoxycholic acid
– 30 mg/kg/day BID (max 300 mg
• Clinical effects
– Slows progression of disease,
improves bile flow
– Displaces toxic bile acids and
reduces liver enzymes
– Stimulates bicarbonate and
chloride secretion
Image, accessed 11/29/09:
Distal intestinal obstruction
syndrome (DIOS)
• Obstruction of the right colon and/or
terminal ileum with viscid fecal matter
• Presentation: colicky periumbilcal and/or
right lower quadrant pain, abdominal
distension, nausea/vomiting, decreased
stool output
• Risk factors:
– PERT non-adherence, dehydration, narcotic
Distal intestinal obstruction
syndrome (DIOS)
• Treatment
– Hydration
– Use of drug therapy
• Polyethylene glycol (Miralax®, GoLytely®)
• Enemas
• N-acetylcysteine
– Surgical resection
Poor Appetite19
• CF anorexia due to:
– Elevated serum cytokines due to chronic
– Smell/taste disturbance due to sinusitis
– Aggressive nutritional interventions
– Behavioral/psychosocial factors
• Not all CF patients will require drug
therapy, but continued nutritional failure
leads to considered added drug therapy
Poor Appetite: Appetite
• Megesterol
– Synthetic progestin with antiestrogenic effects
– Cytokine inhibition
• Cyproheptadine
– Histamine and serotonin antagonist
– Side effect of appetite stimulation
• Dronabinol
– Psychoactive substance, side effect of appetite stimulation
• Mirtazipine
– Antidepressant, side effect of appetite stimulation and weight
CF-Related Diabetes (CFRD)20
• Not really Type I or 2 diabetes mellitus…
• Insulin vs. oral agents
– Standard = Insulin (e.g. insulin glargine (longacting) + lispro (intermittent short-acting)) +
carbohydrate counting
– Oral agents not recommended, but
occasionally used
• Evidence demonstrating efficacy lacking
• Possible affects of drug therapy on serum
glucose levels
Other Concurrent Drug Therapy
• Pediatric
– Psychiatric disorders
• Attention deficit hyperactivity disorder (ADHD)
• Major depressive disorder
– Seizure disorder
• Adult
– Psychiatric disorders
• Bipolar disorder
• Major depressive disorder
– Hypertension
– Hyperlipidemia
“Keep watch also on the fault of
patients which often make them lie
about the taking of things prescribed.”
5th Century BC
Therapy Adherence
• Adherence to CF treatment continues to
be a challenge
– Drug therapy
• Factors in adherence
– Age-specific
• Child vs. adolescence vs. adult
– Patient-specific
• Patient or caregiver beliefs
• Financial
Age Specific Factors 21
Infants & Young Children
• Caregiver administration
• Caregiver beliefs regarding
medicine, treatment of
• Reasons for nonadherence:
– Forgetting
– Multiple caregivers
– D/C due to resolution of
– Misunderstanding
– Resistance from child
– Concern regarding adverse
effects or lack of efficacy
• Patient administration
• Age of “adherence nadir”
• Growing independence vs.
parental involvement
• Reasons for nonadherence:
– Risk-taking behavior,
invincible perspective
– Peer influence
– Adverse effects
– Forgetting/timing
– Psychosocial/psychiatric
What are CF Patients Adherent
With? 22
Arias Llorente RP. García CB, Díaz Martín JJ. Treatment compliance in children and adults with cystic
fibrosis. J Cystic Fib. 2008; 7:359-367.
Children vs. Adolescent
Group 1:
<12 years
Group 2:
≥ 12 years
Zindani GN, Streetman DD, Streetman DS, Nasr SZ. Adherence to treatment in children and adolescent patients
with cystic fibrosis. J Adolesc Health. 2006 Jan;38(1):13-7.
Approaches to Increase
• Patient and caregiver education
– School system involvement
• Assess regimen at visits – create schedule
to suite patient’s daily routine if possible
• Tools used to measure adherence
– Medication Event Monitoring System ([MEMS]
APREX, a division of AARDEX, Inc., Union
City, California)
– Track empty vials? Refills?
– I-neb™ AAD system
CF Interdisciplinary Team
Clinical Pharmacist
Nurse Clinician
Clinical Dietitian
Respiratory Therapist
Social Worker
Health Care Trainees (e.g. MSW, MD, RT,
Role of the Clinical Pharmacist
Educate other health care professionals
about therapy options based on the most
recent biomedical literature.
Patient/caregiver education regarding
mediation use, safety, and efficacy.
Recommend and monitor CF regimens
(i.e., kinetics, medication review)
Serve as a clinical researcher in
evaluating effective and safe treatment
options for children, adolescents, and
adults with CF.
My Pathway to Pediatric Pulmonary
Undergraduate studies
(The University of Michigan)
Clinical Practice
(Pediatrics, NICU)
3 years
Clinical Assistant Professor
and Clinical Pharmacy
(The University of Arizona,
College of Pharmacy)
Doctor of Pharmacy (PharmD)
(The University of Michigan)
4 years
Postdoctoral Fellowship
(The Ohio State University, The
Research Institute at
Nationwide Children’s
2 years
Continued scholarship,
practice, and teaching in
pediatric pharmacotherapy
with focus in pulmonary
My Role at the UA Pediatric
Pulmonary Center
CF Clinic
• Intake and
assessment of
medication regimens
• Assessment of
• Recommend drug
therapy for
maintenance and
• Education
• Notified of new
admissions to UMC
• Evaluate and assess
patient data (e.g.,
cultures) and
recommend initial
regimen and lab
• Weekly rounding
with team to assess
progress and
recommend any
changes in therapy
Scholarship and
• Participate in
research in the ARC
• Asthma
• CF
• Participate in the
education of health
care professional
• Fellows
• Residents
• Students
• PPC trainees
• CF drug therapy is multi-faceted, often
involving multiple organ systems with use
of various dosage forms.
• Drug dosing in CF may differ from non-CF
due to differences in pharmacokinetics
and pharmacodynamics, although much is
still unknown.
• Interdisciplinary approach to drug therapy
selection and patient education is
essential to optimize outcome
[email protected]
Flume PA, O’Sullivan BP, Robinson KA, et al. Cystic Fibrosis Pulmonary Guidelines: Chronic medications for
maintenance of lung health. Am J Respir Crit Care Med. 2007;176:957-969.
2. Nasr SZ, Kuhns LR, Brown RW, Hurwitz ME, Sanders GM, Strouse PJ. Use of computerized tomography and
chest x-rays in evaluating efficacy of aerosolized recombinant human DNase in cystic fibrosis patients younger
than age 5 years: a preliminary study. Pediatr Pulmonol. 2001 May;31(5):377-82.
3. Donaldson SH, Bennett WD, Zeman KL et al. Mucous clearance and lung function in cystic fibrosis with hypertonic
saline. NEJM. 2006;354:241-250.
4. Elkins MR, Robinson M, Rose BR, et al. A controlled-trial of long-term inhaled hypertonic saline in patients with
cystic fibrosis. NEJM. 2006;354:229-240.
5. Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of High-Dose Ibuprofen in Patients with Cystic Fibrosis.
NEJM. 1995:332;848-854.
6. Clement A, Tamalet A, Leroux E, Ravilly S, Fauroux B, Jais, J-P. Long term effects of azithromycin in patients with
cystic fibrosis: a double blind, placebo controlled trial. Thorax 2006;61:895–902.
7. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis.
Am J Respir Crit Care Med. 2003 Oct 15;168(8):918-51.
8. Flume PA, Mogayzel PJ, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ, Marshall BC. Clinical Practice
Guidelines for Pulmonary Therapies Committee. Cystic Fibrosis Pulmonary Guidelines: Treatment of Pulmonary
Exacerbations. Am J Respir Crit Care Med . 2009; 180:802–808.
9. Cystic Fibrosis Foundation Patient Registry. 2001 Annual Data Report to the Center Directors. Bethesda, MD:
Cystic Fibrosis Foundation; 2002.
10. Eubanks V, Koppersmith N, Wooldridge N, et al: Effects of megestrol acetate on weight gain, body composition,
and pulmonary function in patients with cystic fibrosis. J Pediatr 2002; 140:439-444.
11. Ramsey BW, Pepe MS, Quan JM, et al: Intermittent administration of inhaled tobramycin in patients with cystic
fibrosis. N Engl J Med 1999; 340:23
12. Stallings VA, Stark LJ, Robinson KA, Feranchak AP, Quinton H. Evidence-based practice recommendations for
nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a
systematic review. J Am Diet Assoc 2008;108:832-9.
Hendeles L, Dorf A, Stecenko A, Weinberger M. Treat-ment failure after substitution of generic pancrelipase
capsules: correlation with in vitro lipase activity. JAMA 1990;263:2459-61.
Up-to-Date 2009©. Accessed 11/29/09. Cystic fibrosis: Assessment and management of pancreatic
insufficiency. PERT Preparations Table.;jsessionid=539B6F5A1A27621314B31A4EB12EB98C.1003?ima
Durie PR, Bell L, Linton W, Corey ML, Forstner GG. Effect of cimetidine and sodium bicarbonate on pancreatic
replacement therapy in cystic fibrosis. Gut 1980;21:778-86.
Francisco MP, Wagner MH, Sherman JM, Theriaque D, Bowser E, Novak DA. Ranitidine and Omeprazole as
Adjuvant Therapy to Pancrelipase to Improve Fat Absorption in Patients With Cystic Fibrosis. J Pediatr
Gastroenter Nutr. 2002;35:79-83.
Tonelli AR, Drane WE, Collins DP, Nichols W, Antony VB, Olson EL. Erythromycin improves gastric emptying
half-time in adult cystic fibrosis patients with gastroparesis. J Cyst Fibros. 2009 May;8(3):193-7.
Gumaste V, Baum J. Treatment of gastroparesis: an update. Digestion. 2008;78(4):173-9.
Chinuck RS, Fortnum H, Baldwin DR. Appetite stimulants in cystic fibrosis: a systematic review. J Hum Nutr
Diet. 2007 Dec;20(6):526-37.
Zirbes J, Milla CE. Cystic fibrosis related diabetes. Paediatr Respir Rev. 2009 Sep;10(3):118-23.
Thatcher Shope J. Medication compliance. Pediatr Clin North Am 1981; 28: 5-21.
Arias Llorente RP. García CB, Díaz Martín JJ. Treatment compliance in children and adults with cystic fibrosis.
J Cystic Fib. 2008; 7:359-367.
Zindani GN, Streetman DD, Streetman DS, Nasr SZ. Adherence to treatment in children and adolescent
patients with cystic fibrosis. J Adolesc Health. 2006 Jan;38(1):13-7.