ASH Clinical News ACN_4.13_full issue_Web | Page 56

Physician Burnout
Practices Subgroup of the Collaborative for Healing and
Renewal in Medicine (CHARM) project, an initiative of
the Alliance for Academic Internal Medicine. “Without
these improvements, individual efforts, no matter how
intensive, will be futile.” 8
Earlier this year, the CHARM Project published its
“Charter on Physician Well-being,” outlining appropriate
individual, organizational, and system-level interventions
to address physician burnout ( TABLE, page 51).
This is encouraging and, he predicts, is going to make
all the difference. “This is an exciting time because there
stress management, resilience, and self-care skills. 7 That
approach has the unintended consequence of placing the
onus of solving burnout on the people experiencing it.
Dr. Shanafelt emphasized that, while building in-
dividual resilience should be encouraged, “we are now
thinking about this from a systems mindset and at the
national organization level. Those organizations that don’t
follow suit are going to get left behind quickly.”
“Significant system-level changes that address the
root causes of burnout must be implemented at each level
of the profession,” according to findings from the Best
is a higher degree of commitment … to driving change
that can be seen across the country,” he explained.
Like the CHARM project, NAM’s Action
Collaborative brings together several members of the
health-care system (regulators, electronic health record
(EHR) vendors, and leaders from professional societies
and academic centers) to discuss what can be done to
combat burnout. 9 “[The group is] having conversations
about changes that no individual physician, practice
group, or medical center can effect. Those types of
changes have never been on the table before because
the powerful groups that control
those levers have never been engaged
in the conversation,” Dr. Shanafelt
said. “They are now.”
TAVALISSE™ (fostamatinib disodium hexahydrate) tablets
BRIEF SUMMARY OF PRESCRIBING INFORMATION — CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
TAVALISSE is indicated for the treatment of thrombocytopenia in adult patients with chronic immune
thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.
3 DOSAGE FORMS AND STRENGTHS
TAVALISSE is available as: 100 mg tablet: orange, film-coated, round, biconvex tablets debossed with
“100” on one side and “R” on the reverse side; 150 mg tablet: orange, film-coated, oval, biconvex tablets
debossed with “150” on one side and “R” on the reverse side.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Hypertension Hypertension can occur with TAVALISSE treatment; hypertensive crisis occurred in 1%
of patients. Patients with pre-existing hypertension may be more susceptible to the hypertensive effects
of TAVALISSE. Monitor blood pressure every 2 weeks until stable, then monthly and adjust or initiate
antihypertensive therapy to ensure maintenance of blood pressure control during TAVALISSE therapy.
If increased blood pressure persists despite appropriate therapy, TAVALISSE interruption, reduction
or discontinuation may be necessary [see Dosage and Administration (2.3)].
5.2 Hepatotoxicity Elevated liver function tests (LFTs), mainly ALT and AST, can occur with TAVALISSE.
In the placebo-controlled studies, laboratory testing showed maximum ALT/AST levels more than
3 x the upper limit of normal (ULN) in 9% of patients receiving TAVALISSE [see Adverse Reactions (6.1)].
For most patients, transaminases recovered to baseline levels within 2 to 6 weeks of dose-modification.
Monitor liver function tests monthly during treatment. If ALT or AST increase more than 3 x ULN,
manage hepatotoxicity using TAVALISSE interruption, reduction, or discontinuation [see Dosage and
Administration (2.3)].
5.3 Diarrhea Diarrhea occurred in 31% of patients treated with TAVALISSE. Severe diarrhea occurred in
1% of patients treated with TAVALISSE. Monitor patients for the development of diarrhea. Manage diarrhea
using supportive care measures, including dietary changes, hydration and/or antidiarrheal medication,
early after the onset of symptoms. Interrupt, dose reduce, or discontinue TAVALISSE if diarrhea becomes
severe (Grade 3 or above) [see Dosage and Administration (2.3)].
5.4 Neutropenia Neutropenia occurred in 6% of patients treated with TAVALISSE; febrile neutropenia
occurred in 1% of patients. Monitor the ANC monthly, and for infection during treatment. Manage toxicity
with TAVALISSE interruption, reduction or discontinuation [see Dosage and Administration (2.3)].
5.5 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, TAVALISSE
can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk
to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for
at least 1 month after the last dose. [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)].
6 ADVERSE REACTIONS
6.1 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. TAVALISSE was studied in
two randomized, double-blind, placebo-controlled trials that were identical in design. The data described
below reflect exposure to TAVALISSE in 102 patients with chronic ITP who had received one or more prior
ITP treatment(s). Groups were stratified with respect to splenectomy and severity of thrombocytopenia.
Patients randomized to the TAVALISSE arm received 100 mg orally twice daily. Based upon platelet count
and tolerability, if a patient’s platelet count did not increase to at least 50 x 10 9 /L, the TAVALISSE dose could
be increased to 150 mg twice daily after one month. In the placebo controlled studies, the median duration
of TAVALISSE exposure in these studies was 86 days (range 8 to 183) [see Clinical Studies (14) for additional
details for patients on TAVALISSE]. In the ITP double-blind studies, serious adverse drug reactions were
febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis, which each occurred in 1% of patients
receiving TAVALISSE. In addition, severe adverse reactions observed in patients receiving TAVALISSE
included dyspnea and hypertension (both 2%); and neutropenia, arthralgia, chest pain, diarrhea, dizziness,
nephrolithiasis, pain in extremity, toothache, syncope and hypoxia (all 1%) [see Warnings and Precautions
(5.1)]. Table 3 presents the common adverse reactions from these studies.
Table 3: Incidence of Common (≥ 5%) Adverse Reactions from Double-Blind Clinical Studies
(FIT 1 and FIT 2)
Adverse
Reaction
TAVALISSE (N=102)
Mild
%
Moderate Severe
%
%
Placebo (N=48)
TOTAL
%
Mild
%
Moderate Severe
%
%
TOTAL
%
Diarrhea¹ 21 10 1 31 13 2 0 15
Hypertension² 17 9 2 28 10 0 2 13
Nausea 16 3 0 19 8 0 0 8
Dizziness 8 2 1 11 6 2 0 8
ALT increased 5 6 0 11 0 0 0 0
AST increased 5 4 0 9 0 0 0 0
Respiratory infection³ 7 4 0 11 6 0 0 6
Rash⁴ 8 1 0 9 2 0 0 2
Abdominal pain⁵ 5 1 0 6 2 0 0 2
Fatigue 4 2 0 6 0 2 0 2
Chest pain 2 3 1 6 2 0 0 2
Neutropenia 6 3 2 1 6 0 0 0 0
ALT=alanine aminotransferase; AST=aspartate aminotransferase. Note: Common adverse reactions defined as all adverse
reactions occurring at a rate of ≥ 5% of patients in the TAVALISSE group and greater than placebo rate. 1 Includes diarrhea
and frequent bowel movement. ² Includes hypertension, blood pressure (BP) increased, BP diastolic abnormal, and BP
diastolic increased. ³ Includes upper respiratory tract infection, respiratory tract infection, lower respiratory tract infection,
and viral upper respiratory tract infection. 4 Includes rash, rash erythematous and rash macular. 5 Includes abdominal pain,
and abdominal pain upper. 6 Includes neutropenia and neutrophil count decreased.
Table 4: Elevations in Hepatic Transaminases During Placebo-Controlled Clinical Studies
Enzyme
Maximum Level
of Elevation
Alanine aminotransferase
(ALT) and/or Aspartate
aminotransferase (AST)
Number of Patients (%)
TAVALISSE
(N=102) Placebo
(N=48)
>3 and ≤5 x ULN 3 (3) 0
>5 and ≤10 x ULN 5 (5) 0
≥10 x ULN 1 (1) 0
7 DRUG INTERACTIONS
7.1 Effect of Other Drugs on TAVALISSE
Strong CYP3A4 Inhibitors Concomitant use with strong CYP3A4 inhibitors increases exposure to R406
(the major active metabolite), which may increase the risk of adverse reactions. Monitor for toxicities
of TAVALISSE that may require dose reduction (see Table 1) when given concurrently with a strong CYP3A4
inhibitor [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
Strong CYP3A4 Inducers Concomitant use with a strong CYP3A4 inducer reduces exposure to R406.
Concomitant use of TAVALISSE with strong CYP3A4 inducers is not recommended [see Clinical
Pharmacology (12.3)].
7.2 Effect of TAVALISSE on Other Drugs
CYP3A4 Substrates Concomitant use of TAVALISSE may increase concentrations of some CYP3A4 substrate
drugs. Monitor for toxicities of CYP3A4 substrate drug that may require dosage reduction when given
concurrently with TAVALISSE [see Clinical Pharmacology (12.3)].
BCRP Substrates Concomitant use of TAVALISSE may increase concentrations of BCRP substrate drugs (e.g.,
rosuvastatin). Monitor for toxicities of BCRP substrate drug that may require dosage reduction when given
concurrently with TAVALISSE [see Clinical Pharmacology (12.3)].
P-Glycoprotein (P-gp) Substrates Concomitant use of TAVALISSE may increase concentrations of P-gp
substrates (e.g., digoxin). Monitor for toxicities of the P-gp substrate drug that may require dosage reduction
when given concurrently with TAVALISSE [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary Based on findings from animal studies and the mechanism of action, TAVALISSE can cause
fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available
data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration
of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes
that were directly attributed to exposure in utero to the major fostamatinib metabolite (R406) at maternal
exposures (AUC) as low as 0.3 and 10 times the exposure in patients at the maximum recommended human
dose (MRHD), respectively (see Data). Advise pregnant women of the potential risk to a fetus. All pregnancies
have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the
estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4%
and 15-20%, respectively. An estimated background risk of major birth defects and miscarriage for the chronic
ITP population is 8% and 4-11%, respectively.
8.2 Lactation
Risk Summary There are no data on the presence of fostamatinib and/or its metabolites in human milk, the
effects on the breastfed child, or on milk production. In rodents, R406 (the major active metabolite) was
detected in maternal milk in concentrations 5- to 10-fold higher than in maternal plasma. Because of the
potential for serious adverse reactions in a breastfed child from TAVALISSE, advise a lactating woman not
to breastfeed during treatment with TAVALISSE and for at least 1 month after the last dose.
8.3 Females and Males of Reproductive Potential
Pregnancy Testing Based on animal studies, TAVALISSE can cause fetal harm when administered to a pregnant
woman [see Use in Specific Populations (8.1)]. For females of reproductive potential, verify pregnancy status
prior to initiating TAVALISSE.
Contraception
Females Based on animal studies, TAVALISSE can cause fetal harm when administered to a pregnant woman
[see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception
during treatment with TAVALISSE and for at least 1 month after the last dose.
Infertility There are no data on the effect of TAVALISSE on human fertility. Based on the finding of reduced
pregnancy rates in animal studies, TAVALISSE may affect female fertility [see Use in Specific Populations (8.1)].
8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. TAVALISSE
is not recommended for use in patients less than 18 years of age because adverse effects on actively
growing bones were observed in nonclinical studies. In subchronic, chronic, and carcinogenicity studies
of TAVALISSE, chondrodystrophy of the femoral head was seen in rodents. In a study in juvenile rabbits,
growth plate dysplasia was observed in the proximal femur and femoro-tibial joint, and bone marrow
cellularity was reduced in the femur and sternum.
8.5 Geriatric Use Of the 102 patients with ITP who received TAVALISSE, 28 (27%) were 65 years of age
and older, while 11 (11%) were 75 years of age and older. In patients 65 years of age and older, 6 (21%)
patients experienced serious adverse events and 5 (18%) experienced adverse events leading to treatment
withdrawal while in patients under 65 years of age, 7 (9%) and 5 (7%) experienced serious adverse events
and adverse events leading to treatment withdrawal, respectively. In patients 65 years of age and older
who received TAVALISSE, 11 (39%) patients experienced hypertension versus 2 (18%) placebo compared
to 17 (23%) in patients under 65 of age versus 4 (11%) placebo. No overall differences in effectiveness were
observed in these patients compared to younger patients.
10 OVERDOSAGE
There is no specific antidote for overdose with TAVALISSE, and the amount of R406 (the pharmacologically
active metabolite of fostamatinib) cleared by dialysis is negligible. In the event of an overdose, monitor
patient closely for signs and symptoms of adverse reactions, and treat the reactions with supportive care
[see Warnings and Precautions (5)].
© 2018 Rigel Pharmaceuticals, Inc. All rights reserved. | TAVA_ITP-18060 0418 | 0418
TAVALISSE is a trademark of Rigel Pharmaceuticals, Inc.
The EHR Elephant in
the Room
Ask a random sample of practicing
clinicians about the causes of burn-
out, and, more than likely, they will
lay blame on EHRs.
“EHRs have been around for a
long time,” Dr. Singavi said. “They
were meant to provide better com-
munication between providers,
more accessible health records for
patients, and better, safer care.” Over
the past 15 years or so, though, that
noble goal has transformed, with
“a billion codes, the pressures of
meaningful-use measures, and an
endless number of clicks.”
Maintaining EHRs has morphed
into almost a full-time job: A 2017
study showed that, for every average
11.4-hour workday, clinicians in
southern Wisconsin spent nearly
six hours in their hospital’s EHR
system. 10 That means doctors were
spending less of their day building
relationships and treating patients,
and more time entering data – often
after they’d left the office.
Increased administrative work,
like entering patient information into
an EHR, forces doctors to limit time
spent with patients, increasing the
risk that they will feel disconnected
from their work. This limited patient
interaction directly hurts physician
wellness, according to Beth Lown,
MD, chief medical officer of the
Schwartz Center for Compassionate
Healthcare in Boston. “We need to
grow the sense of engagement, hap-
piness, and enjoyment in our work,”
she said.
One suggestion for alleviating the
administrative burden on physicians is
outsourcing these duties. For example,
in the emergency department setting,
medical scribes increased efficiency;
they had a neutral effect on patient sat-
isfaction, but, importantly, they were
heavily favored by providers. 11
Breaking the Stigma Cycle
While she believes that delegating
administrative labor to scribes can
help, Dr. Lown emphasized that
November 2018