Recognition of drug-induced pulmonary disease and

CREDIT:
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Continuing Education
EARN CE CREDIT FOR THIS ACTIVITY AT WWW.DRUGTOPICS.COM
AN ONGOING CE PROGRAM OF THE UNIVERSITY OF CONNECTICUT
SCHOOL OF PHARMACY AND DRUG TOPICS
educationaL oBJectiVeS
Goal: To review the common medications
associated with pulmonary toxicity and how
to recognize and treat idiopathic pulmonary
fibrosis
After participating in this activity,
pharmacists will be able to:
●
●
●
Identify the major drugs and drug classes
that can cause pulmonary disease
Identify risk factors and monitoring plans for
the commonly prescribed medications that
can induce pulmonary reactions
Describe the pathophysiology and clinical
presentation of idiopathic pulmonary fibrosis
Discuss new and emerging drug therapies
for idiopathic pulmonary fibrosis
The University of Connecticut School of
Pharmacy is accredited by the Accreditation
Council for Pharmacy Education as a provider
of continuing pharmacy education.
Pharmacists are eligible to participate in the
knowledge-based activity, and will receive up to 0.2
CEUs (2 contact hours) for completing the activity,
passing the quiz with a grade of 70% or better, and
completing an online evaluation. Statements of credit
are available via the CPE Monitor online system and
your participation will be recorded with CPE Monitor
within 72 hours of submission.
ACPE# 0009-9999-15-036-H01-P
Grant Funding: This activity is supported by an independent educational grant from Boehringer Ingelheim
Pharmaceuticals, Inc.
Supported by an educational grant from Genentech
Novartis Pharmaceuticals Corporation
Activity Fee: There is no fee for this activity.
Recognition of drug-induced
pulmonary disease and management
of idiopathic pulmonary fibrosis
Tayla N. Rose, PharmD
ASSISTANT CLINICAL PROFESSOR, DEPARTMENT OF PHARMACY AND HEALTH SYSTEMS SCIENCES, NORTHEASTERN UNIVERSITY, SCHOOL OF PHARMACY, BOSTON, MA, AND AMBULATORY CARE CLINICAL PHARMACY
SPECIALIST, LYNN COMMUNITY HEALTH CENTER, LYNN, MA
Alexa A. Carlson, PharmD, BCPS
ASSISTANT CLINICAL PROFESSOR, DEPARTMENT OF PHARMACY AND HEALTH SYSTEMS SCIENCES, NORTHEASTERN UNIVERSITY, SCHOOL OF PHARMACY, BOSTON, MA
Abstract
Drug-induced pulmonary disease is a potential adverse effect associated with a
number of medications, most notably amiodarone and bleomycin. Management
of this condition generally includes immediate cessation of the offending agent
and treatment with systemic corticosteroids. Idiopathic pulmonary fibrosis (IPF),
a form of interstitial lung disease, has been plagued by a lack of effective pharmacotherapeutic management options. In 2014, pirfenidone and nintedanib were
approved by the FDA, making these agents the first treatments to be approved for
the treatment of mild-to-moderate IPF in the United States. New guidelines for
the management of IPF were released in 2015, with a conditional recommendation for pharmaceutical management of IPF with pirfenidone and nintedanib.
Initial release date: November 10, 2015
Expiration date: November 10, 2018
To obtain CPE credit, visit www.drugtopics.com/cpe
and click on the “Take a Quiz” link. This will direct
you to the UConn/Drug Topics website, where you will
click on the Online CE Center. Use your NABP E-Profile
ID and the session code: 15DT36-KXF58 to access
the online quiz and evaluation. First-time users must
pre-register in the Online CE Center. Test results will
be displayed immediately and your participation will
be recorded with CPE Monitor within 72 hours of completing the requirements.
For questions concerning the online CPE
activities, e-mail: [email protected].
Faculty: tayla n. Rose, Pharmd, and alexa a. carlson, Pharmd, BcPS
Dr. Rose is an assistant clinical professor at the Department of Pharmacy and Health System Sciences,
Northeastern University, School of Pharmacy, Boston, MA, and an ambulatory care clinical pharmacy
specialist at Lynn Community Health Center, Lynn, MA. Dr. Carlson is an assistant clinical professor at
the Department of Pharmacy and Health System Sciences, Northeastern University, School of Pharmacy,
Boston, MA.
Faculty Disclosure: Dr. Rose and Dr. Carlson have no actual or potential conflict of interest associated
with this article.
Disclosure of Discussions of Off-Label and Investigational Uses of Drugs: This activity may contain discussion
of unlabeled/unapproved use of drugs in the United States and will be noted if it occurs. The content and
views presented in this educational program are those of the faculty and do not necessarily represent
those of Drug Topics or University of Connecticut School of Pharmacy. Please refer to the official
information for each product for discussion of approved indications, contraindications, and warnings.
54
Drug topics
Novemb er 2015
DrugTopics .c om
IMAGE: GETTY IMAGES / SEBASTIAN KAULITZKI./ HEMERA / GETTY IMAGES PLUS
●
continuing education
cpE sEriEs: MtM For tHE pAtiENt WitH rEspirAtorY
DisEAsE
Welcome to the CPE series, Medication
Therapy Management for the Patient with
Respiratory Disease, which was designed for
pharmacists who take care of patients with
respiratory disease. Beginning in April 2015
and continuing through December 2015,
pharmacists can earn up to 18 hours of
CPE credit with 9 monthly knowledge-based
activities from the University of Connecticut
School of Pharmacy and Drug Topics.
Background
This series kicked off in April and May
with MTM essentials for asthma management—Part 1 and Part 2. In June and
July, the focus shifts to MTM essentials
for chronic obstructive pulmonary disease (COPD) management. The August
CE activity is a primer on inhalers and
nebulizers. In September, pharmacists
have the opportunity to learn about allergic rhinitis management. In October,
present within the first year of therapy
but may appear as late as two years into
treatment. Amiodarone-induced toxicity
is believed to be caused by dose-related
direct cellular toxicity via oxygen free radicals and an abnormally high concentration
of phospholipids.4 Additionally, some patients may display immune-mediated and
inflammatory reactions. Although toxicity is
believed to be more likely at higher doses
(specifically doses greater than 400 mg
daily), toxicity is possible at any dose.3,4
As such, patients should be prescribed
the lowest effective dose, and monitoring
should be conducted for all patients taking
amiodarone.
Patients with hypersensitivity pneumonitis will typically present with cough, shortness of breath, and fever within weeks of
amiodarone initiation.3 In a small subset of
patients (5%-7%), this condition may progress to fibrosis.4 Patients presenting with
symptoms of pleuritic chest pain, shortness of breath, cough, and fever that have
instead developed over months to years of
treatment may have pulmonary alveolitis.3,4
Reduced diffusing capacity of the lung
for carbon monoxide (DLCO) is commonly
seen on pulmonary function testing (PFT)
in patients with amiodarone-induced pulmonary toxicity.4 Rarely, amiodarone may
cause bronchiolitis obliterans with organizing pneumonia (BOOP) or alveolar hemorrhage, a rare life-threatening condition preDrugs/Drug classes that
cipitated by direct injury to the basement
can cause DipD
membrane of alveolar capillaries.4,5
Amiodarone
Amiodarone-induced pulmonary toxicity
Amiodarone-induced pulmonary toxicmay occur in up to 17% of patients treat- ity should be treated with immediate withed with this agent.3 Toxicity will typically drawal of amiodarone and initiation of oral
Drug-induced pulmonary disease (DIPD)
has been attributed to a multitude of medications and may present in a variety of
clinical syndromes depending on the pulmonary tissue affected. Chemotherapeutic
agents, cardiovascular medications, antimicrobial agents, and anti-inflammatory
medications are some of the most common causes of DIPD. This article seeks
to familiarize pharmacists with commonly
prescribed medications that are implicated
in DIPD, along with associated risk factors
and monitoring parameters when available.
Idiopathic pulmonary fibrosis (IPF) is an
interstitial pneumonia of unknown origin
that typically occurs in older adults and
manifests with progressive worsening of
lung function and dyspnea. This chronic
fibrosing pneumonia is limited to pulmonary manifestations and is accompanied
by histopathologic or radiologic changes
consistent with interstitial pneumonia.
For IPF to be diagnosed, the exclusion of
other causes of lung disease, including
the medications listed below, and imaging or biopsy results indicative of IPF are
required.1 The median survival for this disease is approximately two to three years,
making effective therapy of great interest.2
This article will review the most recent information on IPF.
DrugTopics .c om
the CE activity covers MTM essentials
for cold, flu, and sinusitis management.
The November CE activity includes druginduced pulmonary disease recognition
and management of idiopathic pulmonary fibrosis. The series concludes in
December with a focus on MTM essentials for cough management.
The series also offers application-based
and practice-based activities in 2016.
Amiodaroneinduced pulmonary
toxicity may occur
in up to 17% of
patients treated with
this agent. Toxicity
will typically
present within the
first year of therapy
but may appear as
late as two years
into treatment.
corticosteroids.3 Because of amiodarone’s
long half-life, resolution of symptoms may
be delayed and treatment may be needed
for up to 12 months.4,5
Angiotensin-converting enzyme inhibitors
Dry cough may occur in up to 19% of patients treated with angiotensin-converting
enzyme inhibitors (ACE-Is).6,7 While more recent evidence suggests the true incidence
may be far less, perhaps as low as 3%,
it is nonetheless an important adverse effect.8 This cough is believed to be related to
bronchoconstriction caused by a substance
known as bradykinin. Normally, bradykinin is
degraded by ACE. With the addition of an
ACE-I, bradykinin accumulates, stimulating
bronchoconstriction and associated cough.
The appearance of this adverse effect may
Novemb er 2015
Drug topics
55
Continuing Education
Recognition oF diPd and ManageMent oF iPF
be immediate, within hours of ACE-I initiation, or delayed, occurring several months
after initiation.8,9 It is not related to dose.
Preexisting asthma and cigarette smoking
do not appear to be risk factors, however
those of the female sex and Chinese heritage are at increased risk.6,8 Antitussives
are ineffective in the treatment of ACE-Iinduced cough.7 The only effective management is to discontinue the ACE-I, after
which cough typically resolves in a matter of
four weeks.8 To replace ACE-I treatment, an
angiotensin receptor blocker (ARB) may be
initiated, as this class of medications does
not affect bradykinin degradation.
Aspirin
Aspirin-induced asthma (AIA), also known
as aspirin-exacerbated respiratory disease
(AERD), is a clinical syndrome composed
of asthma, sinusitis with nasal polyps, and
bronchospasm that is exacerbated after
ingestion of aspirin and nonsteroidal antiinflammatory drugs (NSAIDs).10 This condition is preceded by viral upper respiratory
tract infection and may result in a loss of
smell.11 Between 4% and 10% of adults
with asthma and 20% of adults with both
asthma and nasal polyps are believed to
have AIA.10,12 AIA is most commonly seen
in female patients aged 30 to 50 years.10
Patients with this condition typically experience symptoms of bronchospasm and congestion and/or rhinorrhea approximately two
hours after taking aspirin.12 However, it is
important to note that symptoms continue
after the offending agent is withdrawn, and
AIA is believed to be a lifelong condition.10
AIA is presumed to be caused by an alteration in the metabolism of arachidonic acid.10
Cyclooxygenase (COX), the enzyme inhibited
by aspirin, is a crucial component of arachidonic acid metabolism. By inhibiting COX, aspirin is believed to decrease the production
of protective prostaglandins and increase the
production of bronchoconstrictive and inflammatory leukotrienes via the enzyme 5-lipoxygenase. This mechanism is supported by the
fact that selective COX-2 inhibitors do not
cause bronchospasm in patients with AIA.11
Inhaled corticosteroids, as recommended in the Guidelines for Diagnosis and
Management of Asthma (EPR-3), are the cornerstone of AIA treatment.10,13 Leukotriene
modifiers have an adjunctive role in therapy
and have been shown to decrease exacer-
56
Drug topics
bations, and salmeterol appears to have
a protective effect beyond its bronchodilatory activity.10 Patients with AIA should be
counseled to avoid aspirin and all forms of
NSAIDs. Alternatively, some patients may
undergo aspirin desensitization.
Beta-blockers
Stimulation of beta-1 receptors in the heart
increases cardiac output, while stimulation
of beta-2 receptors in the lungs dilates the
bronchi. Consequently, while beta-blockade
is of benefit for several cardiovascular indications, it may induce bronchospasm in
patients with asthma and chronic obstructive pulmonary disease (COPD). However,
avoidance of beta-blockers may not be an
appropriate solution for patients with concomitant cardiovascular disease such as
acute myocardial infarction or congestive
heart failure. In patients with bronchospastic disease who are eligible for beta-blocker
treatment, metoprolol and atenolol may be
preferred, depending on indication, because
of their beta-1 selectivity, generic availability, and inexpensive cost.14 At higher doses,
these agents may lose beta-1 selectivity,
and thus the total daily dose should not
exceed 200 mg for metoprolol and 100
mg for atenolol. All noncardioselective betablockers should be avoided, including ophthalmic formulations of timolol, which may
have sufficient systemic absorption to cause
bronchospasm. Patients with bronchospastic
disease who are treated with beta-blockers
should be prescribed a short-acting inhaled
agent for the treatment of beta-blocker-induced bronchospasm. While patients taking
cardioselective beta-blockers may respond
to short-acting inhaled beta-agonists, ipratropium bromide is the preferred treatment.
free radicals, as well as stimulation of the
release of cytokines, particularly tumor necrosis factor-α (TNF-α), from macrophages.
This leads to an inflammatory process in the
interstitium with increased fibroblast activity
that may potentially progress to fibrosis.
The most common pulmonary toxicity
associated with bleomycin is interstitial
pneumonitis; however, bleomycin may also
cause eosinophilic hypersensitivity and
BOOP.15 Pneumonitis is a serious and doselimiting concern, with an incidence as high
as 46% and death occurring in up to 3% of
patients. This condition typically manifests
during the course of bleomycin treatment
but may occur up to six months after treatment cessation. Patients typically present
with reduced exercise tolerance, dry cough,
and, less commonly, fever.
Treatment of bleomycin-induced pulmonary toxicity includes immediate withholding of
further bleomycin doses and, in some cases,
treatment with high-dose systemic corticosteroids. Unfortunately, neither the optimal dose
and duration of corticosteroid treatment nor
the efficacy of these agents in the treatment
of bleomycin-induced pneumonitis has been
fully determined.16 Improvement may be seen
after several weeks of treatment, but full resolution can take over a year.
Cyclophosphamide
Cyclophosphamide-induced pulmonary toxicity is rare, occurring in less than 1% of
patients.17 Pulmonary reactions occurring
within the first few months of cyclophosphamide therapy are attributed to interstitial inflammation and can generally be
treated with corticosteroids. Conversely,
pulmonary fibrosis occurring several years
after therapy, defined as a late-onset reaction, is irreversible and has poor outcomes,
Bleomycin
with a mortality rate as high as 60%. PFT
Bleomycin’s cytotoxic effect is attributed in patients with late-onset reaction shows a
to the generation of free radicals resulting decreased DLCO and vital capacity.
from oxidation of bleomycin-iron complexes.15 These reactive species bind to and Methotrexate
subsequently break DNA strands in can- Methotrexate-induced interstitial lung discerous cells, eventually culminating in cell ease, particularly interstitial pneumonitis,
death. Bleomycin is predominately excreted may occur in up to 11.6% of patients with
unchanged through the kidneys; however, it rheumatoid arthritis (RA) who are treated
is also metabolized by bleomycin hydrolase. with this agent.18,19 Potential risk factors
This enzyme is absent from the lungs and include advanced age, Japanese ethnicskin. Consequently, these tissues are at the ity, past medical history of pulmonary
highest risk for bleomycin toxicity. Endothelial disease, prior use of disease-modifying
cell damage results from the aforementioned antirheumatic drugs, and presence of the
Novemb er 2015
DrugTopics .c om
continuing education
TABLE 1
druGs/druG Classes assoCiated With pulmonarY toXiCitY
Drug/Drug Class
Most Commonly Occurring
Type(s) of Pulmonary Toxicity
Clinical Presentation
Amiodarone
Hypersensitivity pneumonitis
Cough, shortness of breath, fever; occurs within weeks of starting amiodarone treatment
Pulmonary alveolitis
Pleuritic chest pain, shortness of breath, cough, fever; develops slowly months to years after starting
amiodarone treatment
ACE-I
Bronchoconstriction
Dry cough; may occur months after starting ACE-I treatment
Aspirin
Aspirin-induced asthma
Bronchospasm, congestion/rhinorrhea; occurs 2 hours after taking aspirin/nonsteroidal antiinflammatory drugs
Beta-blockers
Bronchospasm in patients
with asthma/COPD
Cough, wheezing, shortness of breath shortly after administration of beta-blocker
Bleomycin
Interstitial pneumonitis
Reduced exercise tolerance, dry cough, sometimes fever; may occur during treatment or up to 6
months after stopping bleomycin treatment
Cyclophosphamide Pulmonary fibrosis
Shortness of breath, cough; progresses over several years after completion of cyclophosphamide
treatment
Methotrexate
Interstitial pneumonitis
Nonproductive cough, shortness of breath; occurs within months to years after starting methotrexate
treatment
Nitrofurantoin
Acute hypersensitivity
Cough, shortness of breath, fever; occurs within a month of starting nitrofurantoin treatment
Chronic toxicity
Cough, shortness of breath; worsens over several months to years after nitrofurantoin treatment
Eosinophilic hypersensitivity
Shortness of breath, fever, cough; occurs within first 6 months after starting sulfasalazine treatment
Sulfasalazine
Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; COPD, chronic obstructive pulmonary disease.
HLA-A*31:01 allele.20 However, it is difficult to ascertain the true potential for
methotrexate to cause pulmonary toxicity,
as RA itself may manifest in pulmonary
disease in 40% to 70% of patients, and
the cause of pulmonary disease is difficult
to determine based on clinical presentation.19,20 Methotrexate-induced interstitial
pneumonitis is not believed to be dose
related and has been seen in patients using daily low-dose methotrexate.18 The proposed etiology for this condition suggests
the involvement of reactive oxygen species
and cytokines, including nitrous oxide (NO),
interleukin-1 beta (IL-1β), TNF-α, and tumor
growth factor-beta (TGF-β).21
Symptoms of methotrexate-induced toxicity may present within months to years of
treatment initiation.18 The clinical presentation consists of nonproductive cough and
shortness of breath, and PFT shows a reduced DLCO. Additionally, case reports have
suggested that methotrexate may increase
the risk of opportunistic pulmonary infections, such as Pneumocystis carinii pneumo-
Source: Ref 3-9,12,14,15,18,25-27
nia, because of its immunosuppressive effects.22 However, a recent meta-analysis did
not find an increased risk of infections or
noninfectious pulmonary adverse events in
patients with inflammatory bowel disease,
psoriatic arthritis, or psoriasis treated with
methotrexate.19 Further research is needed
to determine the true risk of opportunistic
pulmonary infections occurring in patients
treated with this agent.
and/or the release of reactive oxygen species.5,21,25 Some studies have demonstrated that the incidence of DIPD may be decreased by antioxidants such as vitamin C.25
Acute pulmonary reactions (those occurring with one month of initiation) are often
attributed to hypersensitivity; these patients
may present with cough, shortness of breath,
and fever.24 Patients with chronic reactions
present with increasing shortness of breath
and cough over several months or years, and
these conditions are believed to have a toxic
etiology. The presentation of chronic nitrofurantoin toxicity may resemble that of IPF.
Treatment of nitrofurantoin-induced toxicity includes immediate discontinuation of
nitrofurantoin. In acute cases, clinical improvement is generally seen within one day,
and the risk of mortality is minimal at 0.5%.24
Steroids may be used for patients whose
condition does not improve as expected.
Nitrofurantoin
Nitrofurantoin has been reported to cause
acute pulmonary toxicity in one of 5000
first-time users and fibrosis leading to hospitalization in one of 750 patients who use
this agent over the long term.23 The risk of
nitrofurantion-induced pulmonary toxicity is
highest in elderly female patients with recurrent urinary tract infections.24
DIPD related to nitrofurantoin may manifest in several forms, including inflammation of the alveoli or pulmonary vasculature, Sulfasalazine
hemorrhage, fibrosis, or BOOP.25 Toxicity may The most common manifestations of sulbe mediated by an immunologic response fasalazine-induced pulmonary toxicity are
pneumonitis and eosinophilic pneumonia
secondary to hypersensitivity to the sulfa
pause&ponder
moiety.5,26 Patients with this condition may
How would you counsel a patient who is beginning
present with shortness of breath, fever,
treatment with one of the above medications to
cough, and eosinophilia.26 Decreased DLCO is
monitor for symptoms of diPd?
the most frequently seen abnormality on PFT.
This reaction tends to occur within the first
DrugTopics .c om
Novemb er 2015
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57
Continuing Education
Recognition oF diPd and ManageMent oF iPF
six months of sulfasalazine use. Treatment
consists of withdrawal of sulfasalazine. The
role of corticosteroids in treating these conditions is controversial; the use of these agents
should generally not be recommended.
Less commonly, patients treated with
sulfasalazine may develop fibrosing alveolitis, a chronic interstitial pneumonitis with
fibrosis, which has poorer outcomes and can
be life threatening.26,27 If fibrosing alveolitis is
suspected, systemic corticosteroids should
be recommended.
Table 1 summarizes the common
clinical presentations of the various
DIPDs.3-9,12,14,15,18,25-27
risk factors and
monitoring plans for
medications that can
cause DipD
Unfortunately, out of the aforementioned
medications, only amiodarone and bleomycin
have well-described risk factors and monitoring parameters with respect to DIPD.
Amiodarone
PFT may not be a reliable monitoring parameter because patients taking amiodarone
are almost certain to display some type of
abnormality even in the absence of toxicity.3
However, PFT (specifically DLCO) should be
performed and a chest x-ray should be obtained at baseline.3,4 Chest x-rays should be
repeated yearly while the patient is taking
amiodarone. If pulmonary toxicity is suspected, PFT should be performed and a chest xray should be obtained as soon as possible.
Bleomycin
Bleomycin toxicity appears to be related to
dose and duration of therapy. As such, patients should not receive a total cumulative
dose greater than 400 units.15 However, toxicity is possible at any dose. Pneumonitis fatalities have been reported in patients receiving
a cumulative dose of less than 100 units.
Because bleomycin is primarily renally
excreted, individuals with impaired renal
function, defined as creatinine clearance
lower than 80 mL/min, may be at increased
risk for toxicity.28 Cigarette smoking also increases the risk, as does increased age,
with the risk potentially increased in patients
aged as young as 30 to 40 years.15,28 The
use of supplemental oxygen, including that
used while scuba diving, may increase the
58
Drug topics
risk of death in patients who have received
bleomycin.28 Patients should avoid scuba
diving for at least one year after completion
of treatment. Patients who have received
radiation to the chest may have increased
free radicals, and those who have received
granulocyte colony-stimulating factor (G-CSF)
may have increased cytokines, both of which
may increase the risk of toxicity.15,28
Appropriate monitoring for bleomycin toxicity should consist of baseline PFT followed
by PFT every three weeks during bleomycin
treatment.28 Specifically, decreasing DLCO
appears to be predictive of toxicity; bleomycin should be withheld if a 40% to 60%
decrease in DLCO from baseline is observed.
pathophysiology of ipF
Although by definition the etiology of IPF is
unknown, the current school of thought suggests that the fibrotic process originates in
an inappropriate immune system response
to alveolar epithelial cell (AEC) injury.29 Potential sources of AEC injury include gastroesophageal reflux disease (GERD), viral
respiratory tract infection, and exposure to
inhaled irritants, including cigarette smoke.
Rather than a normal cellular repair response to this injury, excessive amounts
of matrix and collagen are produced, leading to thickening and stiffening of the interstitium and alveoli. Surviving AECs appear
to be permanently altered such that they
are at increased risk for future damage.
Patients who develop IPF are thought to be
susceptible because of a number of genetic
factors, including malformations of surfactant proteins A2 and C and mutations in
telomerase genes. These malformed proteins may increase the vulnerability of AECs
to damage from the aforementioned sources, whereas malfunctioning telomerase
may accelerate cellular death. Mediators
that have been implicated in this fibrotic
process include but are not limited to fibroblast growth factor (FGF), insulin-like growth
factor-binding protein-5, platelet-derived
growth factor (PDGF), TGF-β, TNF-α, and
vascular endothelial growth factor (VEGF).
Novemb er 2015
clinical presentation and
progression of ipF
IPF is a form of interstitial lung disease, and
the most common of the idiopathic interstitial pneumonias.30 This disease affects
approximately 150,000 to 200,000 people
in the United States alone.31 Patients with
IPF manifest with nonspecific pulmonary
symptomatology including a nonproductive
cough, shortness of breath on exertion, bibasilar crackles, and clubbing of the fingers.1
IPF is most commonly seen in patients aged
60 to 80 years who have a history of smoking. Once diagnosed with IPF, the majority of
patients have a median survival time of 3.8
years from time of diagnosis,31 with a 20%
survival rate at 5 years.30,32
pharmacologic treatment
options for ipF
Understanding about the presumed pathophysiology of IPF has changed over the
years, with theories shifting from chronic inflammation to abnormal repair mechanisms
of the lungs leading to fibrosis.30 This alteration in the understanding of the pathophysiology of IPF has led to new agents being
studied for the management of the disease.
At present, there is no cure for IPF; treatment options demonstrating benefit have
been studied to hinder disease progression
only. As there are a number of new potential
targets of therapy and a multitude of studies
have recently been published or are ongoing, the focus of this section will be on the
updates addressed in the most recent treatment guidelines. A more complete review of
new agents can be found elsewhere.29
In 2011, the American Thoracic Society
(ATS), European Respiratory Society (ERS),
Japanese Respiratory Society (JRS), and
Latin American Thoracic Society (ALAT)1 produced guidelines for the management of IPF,
the first update since the original consensus statement was released in 2000.33 In
this joint 2011 guideline, no pharmacologic
agents were specifically recommended for
the management of IPF because of a lack
of proven benefit. As such, management
pause&ponder
Based on the growth factors associated with the
pathophysiology of iPF, which medications do you
think would be helpful in its management?
DrugTopics .c om
continuing education
options were to be selected from those given
a conditional recommendation against use.
This weak recommendation against use reflected the need for higher-quality data before
more routine use of the medication could be
recommended for IPF.1 An update to this
guideline was released in July 2015 because
of the availability of new trial data and FDA
approval of two medications for IPF with an
estimated cost of over $100,000/year for
their use in the United States (Table 2).1,2,32
On October 15, 2014, the FDA approved
pirfenidone and nintedanib for the management of mild-to-moderate IPF. These two
agents come with a conditional, or weak,
recommendation for use in the management
of IPF in the most recent guideline update
(Table 2).1,2
The mechanism of pirfenidone in the
treatment of IPF has not been established,
but this agent has been shown to inhibit the
actions of factors associated with the pathophysiologic changes of IPF, such as TGF-β.34
Pirfenidone requires a dosage titration on
initiation of treatment, and retitration should
occur in patients who have missed 14 or
more days of the medication (Table 3).35 A
temporary reduction or cessation in medication therapy may be appropriate for patients
experiencing severe side effects of the medication, most notably photosensitivity and diarrhea. Photosensitivity occurs most commonly
within the first six months of therapy, and
patients should be counseled on proper sun
protection. Nausea, vomiting, diarrhea, and
dyspepsia are the most common adverse effects occurring within the first three months
of therapy; these side effects decrease over
time. Elevated liver function tests (LFTs) were
seen in clinical studies of pirfenidone, leading
to requirements for regular LFT monitoring.
LFTs should be assessed before therapy
initiation, then monthly for six months, and
then every three months. Pirfenidone is a
substrate of the cytochrome P (CYP) 450
system, primarily by CYP1A2, and therefore
a dose adjustment is required when this
agent is used concomitantly with strong and
moderate CYP1A2 inhibitors: one pirfenidone
capsule three times daily with strong CYP1A2
inhibitors and two capsules three times daily
with moderate CYP1A2 inhibitors.35
Phase 2 trials suggested a benefit with
pirfenidone,34,36 and multiple phase 3 trials
then confirmed this benefit. Two studies
(CAPACITY 004 and 006) assessed the efDrugTopics .c om
table 2
Comparison of the 2011 and 2015 Guideline
Recommendations for the Management of IPF
Medication
2011 Recommendation
2015 Recommendation
Acetylcysteine
Conditional against use
Conditional against use
Ambrisentan
Not addressed
Strongly against use
Anticoagulation
Conditional against use
Strongly against use
Azathioprine/prednisone/
acetylcysteine
Conditional against use
Strongly against use
Bosentan
Strongly against use
Conditional against use
Colchicine
Strongly against use
Not addressed
Combination corticosteroid plus Strongly against use
immunomodulator therapy
Not addressed
Corticosteroid monotherapy
Not addressed
Strongly against use
Cyclosporine A
Strongly against use
Not addressed
Etanercept
Strongly against use
Not addressed
Imatinib
Not addressed
Strongly against use
Interferon 1b
Strongly against use
Not addressed
Macitentan
Not addressed
Conditional against use
Nintedanib
Not addressed
Conditional for use
Pirfenidone
Conditional against use
Conditional for use
Sildenafil
Not addressed
Conditional against use
Note: Terminology changed between the 2011 and 2015 guidelines, so the 2011 guideline “weak” recommendation is akin to the 2015 “conditional”
recommendation.
Source: Ref 1,2
fect of pirfenidone compared to placebo in
patients with IPF. Study 004 showed that
statistically fewer patients taking pirfenidone
had a change in forced vital capacity (FVC)
of at least 10% versus those taking placebo,
with patients taking pirfenidone demonstrating a reduction in disease progression over
the 72-week period.37 This outcome did not
meet significance in Study 006, but significant improvements in patients with a change
in FVC of at least 10% with pirfenidone were
demonstrated in a pooled analysis.37 Patients treated with pirfenidone in the pooled
analysis also had significant improvements
in six-minute walk distance, and progressionfree survival with numerical improvements in
all-cause mortality, and mortality related to
IPF in the pooled analysis.37 Similar to the
CAPACITY trials, the ASCEND study demonstrated improvements with pirfenidone in the
rate of decline of lung function as assessed
by FVC and in six-minute walk distance. However, no significant improvements in dyspnea
or mortality were observed.38 Based on the
reduction in the rate of pulmonary decline,
pirfenidone was given a conditional recommendation for use in the 2015 guidelines.2
Nintedanib is a tyrosine kinase inhibitor
that antagonizes the receptors of several
inflammatory mediators, including but not
limited to FGF, PDGF, and VEGF. This agent
is approved for the treatment of IPF at a
dose of 150 mg twice daily taken with food
(Table 3).39 The most common adverse effect associated with nintedanib is diarrhea,
which is most likely to occur within the first
three months of treatment. Other notable
adverse effects include nausea, vomiting,
and abdominal pain. For patients experiencing adverse effects, a temporary reduction
in the dose to 100 mg daily or cessation
of the medication may be needed. As elevated LFTs were noted in clinical trials, LFTs
must be assessed before the initiation of
treatment, then monthly for three months,
and then every three months. Nintedanib
should not be used in pregnant women
because of the risk for fetal harm, and
women should be counseled on appropriate use of contraception during nintedanib
treatment. Other precautions for the use
of nintedanib include an increased risk
of bleeding, gastrointestinal perforation,
and arterial thromboembolic events. Nintedanib is a substrate of P-glycoprotein and
CYP3A4, and coadministration of medications affecting these pathways may cause
elevations in nintedanib exposure.39
Novemb er 2015
Drug topics
59
Recognition oF diPd and ManageMent oF iPF
Continuing Education
TABLE 3
pirfenidone and nintedaniB pharmaColoGY
Medication
Dosage
Monitoring
Adverse Reactions
Drug Interactions
Pirfenidone 261-mg
capsules
Initiate at 1 capsule 3 times daily for 7 days, then Liver function tests
2 capsules 3 times daily for 7 days, then continue
the maintenance dose of 3 capsules 3 times
daily with food
Nausea
Abdominal pain
Diarrhea
Vomiting
Rash
CYP1A2
Nintedanib 100- and
150-mg capsules
150 mg twice daily with food
Diarrhea
Nausea
Abdominal pain
Vomiting
Increased liver function
tests
CYP3A4
PGP
Liver function tests
Abbreviations: CYP, cytochrome P; PGP, P-glycoprotein.
Nintedanib has been found to be effective at reducing disease progression and
improving lung function. In TOMORROW, a
phase 2 trial over a 12-month period, patients were randomized to receive placebo
or nintedanib dosed at 50 mg daily, 50 mg
twice daily, 100 mg twice daily, or 150 mg
twice daily.40 Compared to placebo, nintedanib 150 mg twice daily demonstrated
improved outcomes pertaining to lung function. Secondary outcomes such as exacerbations and respiratory quality of life scores
were also significantly improved in the nintedanib groups. However, nintedanib 150
mg twice daily was also associated with
a higher number of patients discontinuing
treatment because of adverse effects, the
most common of which were gastrointestinal in nature. In two phase 3 trials, INPULSIS-1 and INPULSIS-2, nintedanib 150
mg twice daily was compared to placebo
for a 52-week period.41 Treatment with nintedanib was associated with improvements
in the rates of decline of pulmonary function
over time as measured by FVC. As in the
phase 2 trial, nintedanib was associated
with higher rates of gastrointestinal side
effects, leading to more discontinuations
of the study drug. Based on the results of
these trials, the 2015 guideline conditionally recommends the use of nintedanib for
patients with IPF.2
With the most recent guideline update,
four medications were given the designation
of conditional recommendation against use
in IPF, which is similar to the previous guideline designation of weak recommendation
against use (Table 2).1,2 One such agent, Nacetylcysteine, maintained its designation
from the 2011 guidelines. As a free radical
scavenger, N-acetylcysteine may be of benefit for patients with IPF, as an imbalance of
60
Drug topics
Source: Ref 33,37
oxidants and antioxidants may play a role in
disease progression.42 When studied for use
as monotherapy, this agent was associated
with no statistical difference in FVC versus
placebo43,44 and demonstrated no benefit on
mortality or exacerbation outcomes.44
Sildenafil, a phosphodiesterase-5 inhibitor, has also been studied for use in the
IPF population. STEP-IPF, a phase 3 trial
comparing sildenafil to placebo over a 12week treatment period followed by a 12week open-label assessment of sildenafil
in all patients, found no significant difference between sildenafil and placebo in the
primary outcome (improvement of ≥20% in
six-minute walk distance at 12 weeks).45
Statistically significant improvements with
sildenafil were observed for some secondary outcomes, including the University of
California, San Diego Shortness of Breath
Questionnaire; the St George’s Respiratory
Questionnaire; and the carbon monoxide
diffusion capacity. The two groups demonstrated no difference in adverse event
rates. A similar lack of benefit with sildenafil for the six-minute walk distance was observed in another small trial conducted over
a six-month period.46 The 2011 guidelines
did not make recommendations regarding
the use of sildenafil. However, sildenafil
was given the designation of conditional
recommendation against use for IPF in the
2015 guidelines because of the lack of
clinical benefit in pertinent outcomes and
cost of therapy (Table 2).1,2
Bosentan and macitentan, dual endothelin receptor A and B antagonists used
in the treatment of pulmonary hypertension, have also been studied in patients
with IPF.2,47 These agents were thought to
benefit patients with IPF by blocking the
effects of endothelin-1, a growth factor and
Novemb er 2015
vasoconstrictor thought to be involved in
the pathophysiology of both IPF and pulmonary hypertension. Macitentan was not addressed in the 2011 guideline, but bosentan was given a strong recommendation
against use because of the cost of therapy
and quality of evidence. Since the 2011
guidelines were released, newer evidence
regarding both agents has become available.1 The BUILD-1 and BUILD-3 trials assessed bosentan versus placebo in the IPF
population.48,49 BUILD-1 occurred over 12
months and found no difference between
bosentan and placebo in improvement of
the six-minute walk distance. Bosentan
was more effective than placebo in secondary outcomes of the trial including quality of
life scales and time to disease progression
or death, although these differences were
not significant.48 BUILD-3 similarly found a
nonsignificant improvement in the primary
outcome of time to death or IPF progression in the bosentan group versus placebo,
with no significant improvements in quality of life questionnaires.49 Similarly, the
MUSIC study, a phase 2 trial comparing
macitentan to placebo, did not demonstrate a significant difference with macitentan in the primary outcome of change
in FVC or in the secondary outcome of
mortality at 12 months.50 As such, both
agents were given a conditional recommendation against use in the 2015 guidelines
because of lack of mortality benefit and
high cost of therapy (Table 2).1,2
Unlike other pulmonary hypertension
medications shown to have some benefit
in secondary outcomes such as dyspnea in
the IPF population, ambrisentan has been
found to be potentially detrimental to patients with IPF. Similar to bosentan and
macitentan, ambrisentan works through
DrugTopics .c om
continuing education
antagonism of entothelin-1, but ambrisentan is selective for the endothelin receptor
A subtype.51 The efficacy of ambrisentan
for patients with IPF was studied in the
ARTEMIS-IPF trial.52 This trial was terminated early because ambrisentan was
associated with a significantly higher rate
of respiratory hospitalizations and disease
progression at the time of the interim analysis. As such, the 2015 guidelines strongly
recommend against the use of ambrisentan for the management of IPF and the
management of pulmonary hypertension
in patients with comorbid pulmonary hypertension and IPF.2
The use of imatinib, a tyrosine kinase
inhibitor similar to nintedanib, was not addressed in the 2011 guidelines, but the
2015 update strongly recommends against
the use of this agent in patients with IPF; a
trial failed to demonstrate benefit for imatinib versus placebo in the outcomes of
disease progression or death, and imatinib
was associated with an increased risk of
adverse events over a 96-week period.1,2,53
Before the release of the 2011 guidelines, one study evaluated the use of anticoagulants plus corticosteroids versus corticosteroids alone in patients with IPF and
found a potential benefit on survival with
the addition of anticoagulation; however,
this study had multiple methodological issues.54 The ACE-IPF study assessed the
effect of warfarin versus placebo on mortality, hospitalization, and reduction in FVC
in patients with IPF.55 This trial was stopped
early because of a lack of benefit and an increase in all-cause mortality associated with
anticoagulant use. As such, the 2015 guidelines were adjusted to strongly recommend
against the use of warfarin in IPF outside of
other indications because of the potential
risk of adverse effects.2
The combination of azathioprine, prednisone, and acetylcysteine has also been
assessed for the treatment of patients with
IPF. The INFIGENIA study assessed the effect of acetylcysteine when added to the
combination of prednisone and azathioprine
pause&ponder
What role does
a pharmacist
have in the
management of
therapy for iPF?
DrugTopics .c om
and found that the addition led to preservation of FVC at 12 months.56 Based on the
data available, the 2011 guidelines made
a weak recommendation against the use
of this combination.1 Because of the methodological issues with INFIGENIA, another
study, PANTHER-IPF, was conducted to assess the effect of the three-drug regimen on
patients with IPF. This trial was stopped early
at a planned interim analysis because of an
increased risk of death and hospitalization
in the triple-therapy group.57 Based on these
results, the 2015 guideline recommends
strongly against the use of this combination
therapy because of the potential for harm.2
IPF is associated with a number of comorbid conditions. Two such disease states
are GERD and pulmonary hypertension, both
of which occur in patients with IPF to significant degrees.1,2 GERD has been suggested
as a risk factor for IPF due to microaspiration
leading to AEC injury.1,2,29 In addition, GERD
is common in patients with IPF.1,2 As such,
management of this comorbid condition is a
focus to prevent worsening of disease. Both
the 2011 and 2015 guidelines provided a
conditional recommendation for the use of
acid suppression therapy in patients with
IPF due to the potential for improvements
in survival and lung function.1,2 Similar to
GERD, pulmonary hypertension is a common
comorbid condition found in patients with IPF
that impact the disease prognosis.2 Current
guidelines make no specific recommendations regarding the effective management
of pulmonary hypertension in patients with
IPF; however, consideration should be given
to the worsened outcomes seen in patients
with IPF who were treated with ambrisentan,
as such it should be avoided in IPF with a
strong recommendation against use regardless of pulmonary hypertension diagnosis.2
Other treatment considerations for patients
with IPF should include the use of long-term
oxygen therapy in patients with resting hypoxemia, pulmonary rehabilitation, vaccinations,
lung transplantation, and palliative care as
appropriate.1,2
conclusion
DIPD is a potential adverse effect of many
commonly prescribed medications, including but not limited to amiodarone, ACE-Is,
aspirin, beta-blockers, bleomycin, cyclophosphamide, methotrexate, nitrofurantoin, and
sulfasalazine. Before initiation of treatment
On October
15, 2014, the
FDA approved
pirfenidone and
nintedanib for the
management of
mild-to-moderate
IPF.
with these medications, pharmacists should
counsel patients about potential symptoms
that may indicate pulmonary toxicity. Specifically, patients taking amiodarone should undergo chest x-ray and PFT, including DLCO, at
baseline, with chest x-ray repeated annually.
Patients taking bleomycin should undergo
baseline PFT with PFT repeated every three
weeks until the end of treatment. Although
management of DIPD is specific to the offending medication, in all cases, the primary
intervention is immediate cessation of the
injurious agent.
With new information and updated ATS/
ERS/JRS/ALAT guidelines available for the
management of IPF, change to current practices will need to occur. Agents previously
used, such as N-acetylcysteine and anticoagulation, have not been found to be helpful
and may in some cases be harmful in this
patient population. In patients with IPF, initial
therapy should include either pirfenidone or
nintedanib. The currently available clinical data
and guidelines do not preferentially select one
agent over another. Future research should
evaluate the potential for combination or sequential therapy with these agents to allow
for better care. With improved understanding
of the pathophysiology of IPF, new trials are
ongoing, which could potentially lead to more
effective therapy over the long term.
References are available online at
www.drugtopics.com/cpe.•
For immediate cpE credit,
take the test now online at
www.drugtopics.com/cpe
once there, click on the link below
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Novemb er 2015
Drug topics
61
test questions
1. Which of the following statements about
nintedanib is most correct?
a. Nintedanib has been shown to reduce
mortality in IPF compared to placebo.
b. Nintedanib has been shown to worsen
six-minute walk distance in patients with IPF.
c. Nintedanib has been shown to decrease
exacerbation rates in patients with IPF.
d. Nintedanib has been shown to worsen
pulmonary function in patients with IPF.
2. Which of the following statements about
pirfenidone is most correct?
a. Pirfenidone has been shown to reduce
mortality in IPF compared to placebo.
b. Pirfenidone has been shown to worsen
six-minute walk distance in patients with IPF.
c. Pirfenidone has been shown to improve
six-minute walk distance in patients with IPF.
d. Pirfenidone has been shown to worsen
pulmonary function in patients with IPF.
3. Which of the following statements about
N-acetylcysteine is most correct?
a. N-acetylcysteine is conditionally
recommended for use in IPF.
b. N-acetylcysteine as monotherapy has
been shown to improve mortality outcomes
in IPF.
c. Guidelines have conditionally
recommended against use of
N-acetylcysteine in IPF.
d. N-acetylcysteine as monotherapy has
been shown to worsen mortality outcomes
in IPF.
4. Which of the following statements best
describes the appropriate use of the
combination N-acetylcysteine/azathioprine/
prednisone for the treatment of IPF?
a.This combination should be recommended
in all patients, as it has been shown to
reduce mortality in patients with IPF.
b. This combination should not be
recommended, as it has been shown to
increase hospitalization and mortality in
patients with IPF.
c. This combination should be
recommended in all patients, as it has
been shown to reduce hospitalizations in
patients with IPF.
d. This combination should not be
recommended, as it has not been shown
to preserve FVC in patients with IPF.
5. Which of the following statements best
describes the relationship of GERD to IPF?
a. GERD is independent of IPF.
b. GERD is a potential source of alveolar
epithelial cell injury.
c. Patients with IPF do not require therapy
for GERD.
d. IPF causes GERD.
6. Which of the following statements
best reflects the current guideline
recommendations for the treatment of
pulmonary hypertension in patients with IPF?
a. Ambrisentan is the drug of choice.
b. Pirfenidone is the drug of choice.
c. Sildenafil is the drug of choice.
d. There are no specific recommendations
at this time.
62
Drug topics
7. Which of the following patients is most likely
to have IPF?
a. A 7-year-old boy with exercise-induced
wheezing and nonproductive cough
b. A 27-year-old woman with dyspnea
while running and no significant past
medical history history
c. A 47-year-old man with a productive
cough and a significant smoking history
d. A 77-year-old man with a nonproductive
cough and clubbing of the fingers
8. Which of the following statements best
reflects the current thought process
regarding IPF pathophysiology?
a. A disease of chronic inflammation
leading to scarring of the lungs
b. A disease of allergic inflammation
leading to improper repair of the lungs
c. An inappropriate immune response to
alveolar epithelial cell injury leading to fibrosis
d. Alveolar epithelial cell injury leading to an
appropriate immune response and fibrosis
9. Which of the following LFT monitoring
recommendations matches the medication
listed?
a. Pirfenidone: before initiation and
monthly thereafter
b. Nintedanib: before initiation and every
other month thereafter
c. Pirfenidone: before initiation, then
monthly for three months, and then every
three months thereafter
d. Nintedanib: before initiation, then
monthly for three months, and then every
three months thereafter
10. Which of the following best matches the
mechanism of action to the agent?
a. Sildenafil: unknown
b. Bosentan: phosphodiesterase-5 inhibition
c. Pirfenidone: tyrosine kinase inhibitor
d. Nintedanib: tyrosine kinase inhibitor
11. Which of the following is true regarding
pulmonary function testing in patients taking
bleomycin?
a. Pulmonary function testing should be
conducted at baseline and at the first sign
of toxicity.
b. Pulmonary function testing should be
conducted at baseline and every three
weeks thereafter.
c. Pulmonary function testing should be
conducted at baseline and every three
months thereafter.
d. Pulmonary function testing should be
conducted at baseline and every three
years thereafter.
12. Which of the following statements describes
an appropriate monitoring plan for a patient
taking amiodarone?
a. Chest x-ray and pulmonary function
testing should be conducted at baseline
only.
b. Chest x-ray and pulmonary function
testing should be conducted at baseline
and annually.
c. Chest x-ray and pulmonary function
testing should be conducted at baseline,
and chest x-ray should be repeated
annually.
Novemb er 2015
d. Chest x-ray and pulmonary function
testing should be conducted at baseline,
and pulmonary function testing should be
repeated annually.
13. Which of the following patients is most likely
to present with AIA?
a. A 35-year-old woman with asthma and
nasal polyps
b. A 42-year-old man with asthma
c. A 21-year-old woman with nasal polyps
d. A 28-year-old man with allergic rhinitis
14. Which of the following is true regarding
amiodarone-induced pulmonary toxicity?
a. Pulmonary toxicity only occurs at doses
greater than 400 mg.
b. Hypersensitivity pneumonitis typically
presents months to years after starting
amiodarone.
c. Pulmonary alveolitis typically presents
within weeks of starting amiodarone.
d. Pulmonary toxicity may occur at any dose.
15. Which of the following is the most common type
of pulmonary toxicity associated with bleomycin?
a. Interstitial pneumonitis
b. Bronchiolitis obliterans with organizing
pneumonia
c. Alveolar hemorrhage
d. Eosinophilic hypersensitivity
16. Which of the following best explains why
it is difficult to determine the true risk of
methotrexate-induced pulmonary disease?
a. Methotrexate-induced pulmonary
disease is extremely rare.
b. Methotrexate-induced pulmonary
disease only occurs at high doses.
c. Methotrexate-induced pulmonary disease
is difficult to distinguish from pulmonary
manifestations of rheumatoid arthritis.
d. Methotrexate-induced pulmonary
disease is difficult to distinguish from viral
upper respiratory tract infections.
17. The risk of pulmonary toxicity among firsttime users of nitrofurantoin is approximately:
a. One in five
b. One in 50
c. One in 500 d. One in 5000
18. The most common etiology for pulmonary
toxicity associated with sulfasalazine is:
a. Unknown
b. Hypersensitivity
c. Direct cellular toxicity
d. Reactive oxygen species
19. Which of the following is true of ACE-Iinduced cough?
a. Patients present with a productive cough.
b. Antitussives are an effective treatment
for ACE-I-induced cough.
c. Cough typically resolves within 4 weeks
of ACE-I discontinuation.
d. Cough is caused by increased
breakdown of bradykinin.
20. Which of the following beta-blockers is least
likely to induce bronchospasm in a patient
with preexisting asthma/COPD?
a. Propranolol
b. Metoprolol
c. Timolol
d. Nadolol
DrugTopics .c om
continuing education
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