Chest Physician - March 2013 - (Page 4)
MARCH 2013 • CHEST PHYSICIAN
Why should doctors die differently?
B Y M I C H A E L J.
P I S T O R I A , D. O.
y attention was drawn to a
newspaper article pointing out
that doctors die differently
from their patients. As it turns out, we
often do not request complicated
treatment and life-sustaining therapies. The article referred to a 2012
piece in the Wall Street Journal by Dr.
Ken Murray, who discussed evidence
SPIRIVA® HandiHaler® (tiotropium bromide inhalation powder)
Capsules for Respiratory Inhalation
BRIEF SUMMARY OF PRESCRIBING INFORMATION
DO NOT Swallow SPIRIVA Capsules
FOR ORAL INHALATION ONLY with the HandiHaler Device
INDICATIONS AND USAGE: SPIRIVA HandiHaler (tiotropium bromide inhalation powder) is indicated for
the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive
pulmonary disease (COPD), including chronic bronchitis and emphysema. SPIRIVA HandiHaler is indicated to reduce exacerbations in COPD patients.
CONTRAINDICATIONS: SPIRIVA HandiHaler is contraindicated in patients with a hypersensitivity to
tiotropium, ipratropium, or any components of SPIRIVA capsules [see WARNINGS AND PRECAUTIONS]. In
clinical trials and postmarketing experience with SPIRIVA HandiHaler, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash have been
WARNINGS AND PRECAUTIONS: Not for Acute Use: SPIRIVA HandiHaler is intended as a once-daily
maintenance treatment for COPD and is not indicated for the initial treatment of acute episodes of
bronchospasm (i.e., rescue therapy). Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue, or throat), rash,
bronchospasm, anaphylaxis, or itching, may occur after administration of SPIRIVA HandiHaler. If such a
reaction occurs, therapy with SPIRIVA HandiHaler should be stopped at once and alternative treatments
should be considered. Given the similar structural formula of atropine to tiotropium, patients with a
history of hypersensitivity reactions to atropine should be closely monitored for similar hypersensitivity reactions to SPIRIVA HandiHaler. In addition, SPIRIVA HandiHaler should be used with caution in
patients with severe hypersensitivity to milk proteins. Paradoxical Bronchospasm: Inhaled medicines,
including SPIRIVA HandiHaler, can produce paradoxical bronchospasm. If this occurs, treatment with
SPIRIVA HandiHaler should be stopped and other treatments considered. Worsening of Narrow-Angle
Glaucoma: SPIRIVA HandiHaler should be used with caution in patients with narrow-angle glaucoma.
Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma
(e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red
eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop. Worsening of Urinary Retention: SPIRIVA
HandiHaler should be used with caution in patients with urinary retention. Prescribers and patients
should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difﬁculty passing urine, painful urination). Instruct patients to consult a physician immediately should any of
these signs or symptoms develop. Renal Impairment: As a predominantly renally excreted drug, patients
with moderate to severe renal impairment (creatinine clearance of )50 mL/min) treated with SPIRIVA
HandiHaler should be monitored closely for anticholinergic side effects.
ADVERSE REACTIONS: The following adverse reactions are described, or described in greater detail,
in other sections: Immediate hypersensitivity reactions [see Warnings and Precautions]; Paradoxical
bronchospasm [see Warnings and Precautions]; Worsening of narrow-angle glaucoma [see Warnings
and Precautions]; Worsening of urinary retention [see Warnings and Precautions]. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reﬂect the rates observed in practice. 6-Month to 1-Year Trials: The data
described below reﬂect exposure to SPIRIVA HandiHaler in 2663 patients. SPIRIVA HandiHaler was
studied in two 1-year placebo-controlled trials, two 1-year active-controlled trials, and two 6-month
placebo-controlled trials in patients with COPD. In these trials, 1308 patients were treated with SPIRIVA
HandiHaler at the recommended dose of 18 mcg once a day. The population had an age ranging from
39 to 87 years with 65% to 85% males, 95% Caucasian, and had COPD with a mean pre-bronchodilator
forced expiratory volume in one second (FEV1) percent predicted of 39% to 43%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded
from these trials. An additional 6-month trial conducted in a Veteran’s Affairs setting is not included in
this safety database because only serious adverse events were collected. The most commonly reported
adverse drug reaction was dry mouth. Dry mouth was usually mild and often resolved during continued
treatment. Other reactions reported in individual patients and consistent with possible anticholinergic
effects included constipation, tachycardia, blurred vision, glaucoma (new onset or worsening), dysuria,
and urinary retention. Four multicenter, 1-year, placebo-controlled and active-controlled trials evaluated
SPIRIVA HandiHaler in patients with COPD. Table 1 shows all adverse reactions that occurred with a frequency of *3% in the SPIRIVA HandiHaler group in the 1-year placebo-controlled trials where the rates
in the SPIRIVA HandiHaler group exceeded placebo by *1%. The frequency of corresponding reactions in
the ipratropium-controlled trials is included for comparison.
Adverse Reactions (% Patients) in One-Year COPD Clinical Trials
Body System (Event)
Placebo-Controlled Trials IpratropiumControlled Trials
(n = 356) (n = 179)
(n = 550) (n = 371)
Body as a Whole
Chest Pain (non-speciﬁc)
Gastrointestinal System Disorders
Resistance Mechanism Disorders
Respiratory System (Upper)
Upper Respiratory Tract Infection
Skin and Appendage Disorders
Urinary Tract Infection
supporting the different decisions
physicians reach about end-of-life care.
He had quoted a 2003 article by Dr.
Joseph J. Gallo and his associates, who
surveyed participants in the Johns
Hopkins Precursors Study, which cov-
Arthritis, coughing, and inﬂuenza-like symptoms occurred at a rate of *3% in the SPIRIVA HandiHaler
treatment group, but were <1% in excess of the placebo group. Other reactions that occurred in the
SPIRIVA HandiHaler group at a frequency of 1% to 3% in the placebo-controlled trials where the rates
exceeded that in the placebo group include: Body as a Whole: allergic reaction, leg pain; Central and
Peripheral Nervous System: dysphonia, paresthesia; Gastrointestinal System Disorders: gastrointestinal
disorder not otherwise speciﬁed (NOS), gastroesophageal reﬂux, stomatitis (including ulcerative stomatitis); Metabolic and Nutritional Disorders: hypercholesterolemia, hyperglycemia; Musculoskeletal
System Disorders: skeletal pain; Cardiac Events: angina pectoris (including aggravated angina pectoris); Psychiatric Disorder: depression; Infections: herpes zoster; Respiratory System Disorder (Upper):
laryngitis; Vision Disorder: cataract. In addition, among the adverse reactions observed in the clinical
trials with an incidence of <1% were atrial ﬁbrillation, supraventricular tachycardia, angioedema, and
urinary retention. In the 1-year trials, the incidence of dry mouth, constipation, and urinary tract infection increased with age [see Use in Speciﬁc Populations]. Two multicenter, 6-month, controlled studies
evaluated SPIRIVA HandiHaler in patients with COPD. The adverse reactions and the incidence rates
were similar to those seen in the 1-year controlled trials. 4-Year Trial: The data described below reﬂect
exposure to SPIRIVA HandiHaler in 5992 COPD patients in a 4-year placebo-controlled trial. In this trial,
2986 patients were treated with SPIRIVA HandiHaler at the recommended dose of 18 mcg once a day.
The population had an age range from 40 to 88 years, was 75% male, 90% Caucasian, and had COPD
with a mean pre-bronchodilator FEV1 percent predicted of 40%. Patients with narrow-angle glaucoma,
or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials.
When the adverse reactions were analyzed with a frequency of *3% in the SPIRIVA HandiHaler group
where the rates in the SPIRIVA HandiHaler group exceeded placebo by *1%, adverse reactions included
(SPIRIVA HandiHaler, placebo): pharyngitis (12.5%, 10.8%), sinusitis (6.5%, 5.3%), headache (5.7%,
4.5%), constipation (5.1%, 3.7%), dry mouth (5.1%, 2.7%), depression (4.4%, 3.3%), insomnia (4.4%,
3.0%), and arthralgia (4.2%, 3.1%). Additional Adverse Reactions: Other adverse reactions not previously
listed that were reported more frequently in COPD patients treated with SPIRIVA HandiHaler than placebo
include: dehydration, skin ulcer, stomatitis, gingivitis, oropharyngeal candidiasis, dry skin, skin infection,
and joint swelling. Postmarketing Experience: Adverse reactions have been identiﬁed during worldwide post-approval use of SPIRIVA HandiHaler. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure. These adverse reactions are: application site irritation (glossitis,
mouth ulceration, and pharyngolaryngeal pain), dizziness, dysphagia, hoarseness, intestinal obstruction
including ileus paralytic, intraocular pressure increased, oral candidiasis, palpitations, pruritus, tachycardia, throat irritation, and urticaria.
DRUG INTERACTIONS: Sympathomimetics, Methylxanthines, Steroids: SPIRIVA HandiHaler has been
used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, and oral and inhaled steroids without increases in adverse drug reactions. Anticholinergics: There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of SPIRIVA HandiHaler with other anticholinergic-containing
drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions
and Adverse Reactions]. Cimetidine, Ranitidine: No clinically signiﬁcant interaction occurred between
tiotropium and cimetidine or ranitidine.
USE IN SPECIFIC POPULATIONS: Pregnancy: Teratogenic Effects, Pregnancy Category C: There are no
adequate and well-controlled studies in pregnant women. SPIRIVA HandiHaler should be used during
pregnancy only if the potential beneﬁt justiﬁes the potential risk to the fetus. No evidence of structural
alterations was observed in rats and rabbits at inhalation tiotropium doses of up to approximately 660
and 6 times the recommended human daily inhalation dose (RHDID) on a mg/m2 basis, respectively.
However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number of live pups at
birth and the mean pup weights, and a delay in pup sexual maturation at inhalation tiotropium doses
of approximately 35 times the RHDID on a mg/m2 basis. In rabbits, tiotropium caused an increase in
post-implantation loss at an inhalation dose of approximately 360 times the RHDID on a mg/m2 basis.
Such effects were not observed at inhalation doses of approximately 4 and 80 times the RHDID on a
mg/m2 basis in rats and rabbits, respectively. These dose multiples may be over-estimated due to difﬁculties in measuring deposited doses in animal inhalation studies. Labor and Delivery: The safety and
effectiveness of SPIRIVA HandiHaler has not been studied during labor and delivery. Nursing Mothers:
Clinical data from nursing women exposed to tiotropium are not available. Based on lactating rodent
studies, tiotropium is excreted into breast milk. It is not known whether tiotropium is excreted in human
milk, but because many drugs are excreted in human milk and given these ﬁndings in rats, caution
should be exercised if SPIRIVA HandiHaler is administered to a nursing woman. Pediatric Use: SPIRIVA
HandiHaler is approved for use in the maintenance treatment of bronchospasm associated with COPD
and for the reduction of COPD exacerbations. COPD does not normally occur in children. The safety and
effectiveness of SPIRIVA HandiHaler in pediatric patients have not been established. Geriatric Use: Of
the total number of patients who received SPIRIVA HandiHaler in the 1-year clinical trials, 426 were <65
years, 375 were 65 to 74 years, and 105 were *75 years of age. Within each age subgroup, there were
no differences between the proportion of patients with adverse events in the SPIRIVA HandiHaler and the
comparator groups for most events. Dry mouth increased with age in the SPIRIVA HandiHaler group (differences from placebo were 9.0%, 17.1%, and 16.2% in the aforementioned age subgroups). A higher
frequency of constipation and urinary tract infections with increasing age was observed in the SPIRIVA
HandiHaler group in the placebo-controlled studies. The differences from placebo for constipation were
0%, 1.8%, and 7.8% for each of the age groups. The differences from placebo for urinary tract infections were –0.6%, 4.6%, and 4.5%. No overall differences in effectiveness were observed among these
groups. Based on available data, no adjustment of SPIRIVA HandiHaler dosage in geriatric patients is
warranted. Renal Impairment: Patients with moderate to severe renal impairment (creatinine clearance
of )50 mL/min) treated with SPIRIVA HandiHaler should be monitored closely for anticholinergic side
effects [see Warnings and Precautions]. Hepatic Impairment: The effects of hepatic impairment on the
pharmacokinetics of tiotropium were not studied.
OVERDOSAGE: High doses of tiotropium may lead to anticholinergic signs and symptoms. However,
there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg
tiotropium in 6 healthy volunteers. In a study of 12 healthy volunteers, bilateral conjunctivitis and dry
mouth were seen following repeated once-daily inhalation of 141 mcg of tiotropium. Accidental Ingestion: Acute intoxication by inadvertent oral ingestion of SPIRIVA capsules is unlikely since it is not
well-absorbed systemically. A case of overdose has been reported from postmarketing experience. A
female patient was reported to have inhaled 30 capsules over a 2.5 day period, and developed altered
mental status, tremors, abdominal pain, and severe constipation. The patient was hospitalized, SPIRIVA
HandiHaler was discontinued, and the constipation was treated with an enema. The patient recovered
and was discharged on the same day. No mortality was observed at inhalation tiotropium doses up to
32.4 mg/kg in mice, 267.7 mg/kg in rats, and 0.6 mg/kg in dogs. These doses correspond to 7300,
120,000, and 850 times the recommended human daily inhalation dose on a mg/m2 basis, respectively.
These dose multiples may be over-estimated due to difﬁculties in measuring deposited doses in animal
Copyright 2012 Boehringer Ingelheim International GmbH
ALL RIGHTS RESERVED
ered physicians graduating from Hopkins between 1948 and 1964. The researchers obtained responses from
nearly 800 physicians about their endof-life decisions. Compared with 20%
of the general public, 64% of physician respondents had created an advanced directive. Nearly 90% of the
not want CPR if
they were in a
with 25% of the
public not desiring “heroic measures.” Clearly,
outlining the care
that they did and
did not want to receive.
Dr. Murray also mentioned a 1996
study that examined how CPR was
portrayed on television and the potential impact it might have on patients’ decision making. In that paper,
CPR was successful in 75% of the TV
cases, with 67% of patients ultimately
being discharged from the hospital
(N. Engl. J. Med. 1996;334:1578-82).
Compare this with what we know:
CPR rarely works. A 2010 study that
evaluated the impact of 95,000 cases
of CPR in Japan demonstrated that
clearly. Only 8% of patients who had
received CPR survived for more than
1 month. Of those who survived, 3%
were able to lead “normal” lives.
We are able to make objective assessments of the likelihood of success of various therapies in our
patients, but patients do not fully understand the risks and benefits of
their therapy. Once the big picture is
made clear to them, they often opt
for more conservative therapy aimed
at improving quality of life.
We have an obligation to our patients to share with them the reality
of the care they receive. We need to
understand what is important to
them. Do they want to exhaust every
medical option? Do they value comfort and quality time above all else?
We need to ask these questions.
Previously, I wrote about my former colleague Darlene. Had I not
known she did not desire continued
therapy, she would have received several days of great care in the ICU –
but would have died nonetheless.
If dying in comfort and advanced
directives are good enough for us,
they should be good enough for our
Dr. Pistoria is affiliated with
Coordinated Health in Bethlehem, Pa.
Table of Contents for the Digital Edition of Chest Physician - March 2013
Chest Physician - March 2013
Why do doctors die differently?
Switching to a new EHR?
Chest Physician - March 2013
If you would like to try to load the digital publication without using Flash Player detection, please click here.