M
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Volume 1 August

ED

2015

-The Informed Prescriber

N2

HECK

o

Dabigatran (Pradaxa/Prazaxa)
Limited PROBE method undermined the results

Lubiprostone (Amitiza)
Too harmful and expensive for general use as a laxative

CONTENTS （August 2015,Vol. 1, No. 2）
Editorial:
We want good medicines!

16

New Products
Dabigatran: potentially harmful

17

The safe use is compromised without monitoring and an antagonist

Optimal dose may be lower: Subgroup analysis indicates
Information for the patient

21

Lubiprostone:
Too harmful and expensive for general use as a laxative
Plain language summary

24

Adverse Reactions
Propofol-induced death in children: at a Univ. Hospital
Plain language summary
Plain Language Summary
Dabigatran (information for the patient)
Lubiprostone
Propofol

23

27

29
31

23
27
31

MED CHECK - TIP AUGUST 2015 / Vol.1 No.2 ・ Page 15

M
C

ED

-The Informed Prescriber

HECK

Editorial

We want good medicines!
Translated from the editorial in Med Check-TIP (in Japanese) 2015; 15 (May:#59); 50.

Med Check TIP is a bulletin to evaluate(3) Dabigatran was promoted on the basis of

medicinal products: good or bad. We all hope formisleading information suggesting it is superior

really helpful medicines that could save lives or

to warfarin, the standard treatment. (4) It may

alleviate symptoms of disease, while causing little

be hard to expect that medical professionals areharm. As a bulletin, we really hope to present

always be alert for unknown harms.

articles on medicines that work safely with clear-

Considering these situations the “Guideline forcut benefit. However all articles in this issue on

the Safe use of Drugs and Therapeutics in the“new products” are associated with problems. It

Elderly 2015 (draft)” which the Japan Geriatrics

is not our intention to criticise new medicines.

Society announced in April 2015 is valuable,

Unfortunately negative assessments reflect therecommending against the use of many ineffective

reality of pharmaceutical innovation with little

and harmful drugs in the elderly. However, thetherapeutic value since nineties[1].

Guideline did not critically evaluate the safety of

Dr SUNAHARA, Shigeichi is a pioneer ofsome classes of drugs used by many people suchrandomized controlled trials in Japan. He said:

as antihypertensives, statins and proton pump

"Drugs, being foreign to the human body, only byinhibitors, as we commented in this issue (notchance evolve therapeutic value and it is more or

published in the English edition).

less inevitable that they harbor some undesirable

Recently, the Essential Medicine List (EML)

effects. To prevent drug-induced suffering, theof the World Health Organization (WHO) was

following 4 caveats are essential: (1) develop arevised. The revised EML included some new

drug with the least possible hazards; (2) collectbut very expensive products for the treatment of

as detailed information as possible about adverse

intractable disease. A typical one is sofosbuvir forreactions to the drug even after careful screening;

hepatitis C, which was also approved in Japan in(3) find the safest way of drug administration

March 2015. During the development process of

based on the above-mentioned information andsofosbuvir, a homologue showed mitochondrial(4) always be alert for unknown risks [2].

toxicity and further development was stopped.

The “therapeutic values” expected in suchproducts as dabigatran, lubiprostone and propofol

Would the problem be overcome with sofosbuvir?
Further in-depth analysis is essential.

all discussed in this issue, have been found “onlyWe will examine this new product closely in theby chance”. However, dabigatran, for example, has

next issue of Med Check TIP (No 3). We will also

been marketed without taking account of caveats

deal with the products in the EML, because we(1) and (2). To be specific, the use of dabigatran isconsider many of them to be essential to medical

associated with several problems; (1) The limitedcare in Japan also, even though they were

PROBE method was used in the design of theintroduced into medicine many years ago.

pivotal clinical trials of dabigatran for approval,(2) Clinical trials for approval were performed

References

without tests to predict hemorrhage). Dabigatran

1) ISDB Declaration on therapeutic advance in the use of medicines2001:

was approved and marketed without information

http://www.isdbweb.org/documents/uploads/Declaration/ISDB-decl-english.pdf

to prevent hemorrhage. The result was deaths

2) Sunahara, S. Key note reports In Soda ed. Proceedings of the Kyoto International

due to bleeding that have occurred frequently.

Conference Against Drug-Induced Sufferings 1979, Excerpta Medica, 1980

Page 16 ・ MED CHECK - TIP AUGUST 2015 / Vol.1 No.2

New
New Products
Products
Dabigatran: potentially harmful
The safe use is compromised without monitoring and an antagonist
Optimal dose may be lower: Subgroup analysis indicatesTranslated and revised based on Med Check TIP (in Japanese) 2015; 15 (May:#59); 51-54.

Abstract:
Dabigatran is a direct thrombin inhibitor. There is an extremely high correlation between aPTT and dabigatranconcentrations. However, the manufacturer maintained that any coagulation test as an indicator for assessing
the risk of hemorrhage had not been established, and coagulation tests were not performed in the RE-LY study,a pivotal clinical trial for approval. They were not required for the drug approval. The clinical trials conductedwithout these tests are potentially dangerous and should be reexamined in ethical terms. The RE-LY study was
conducted by using the PROBE method which could potentially induce biased management of patients favoring
the experimental product. Data from subgroup analysis indicates that an optimal concentration of dabigatran
may be lower than the recommended dose to obtain minimal total events (thromboembolic and hemorrhagic).
Another issue is that in the event of hemorrhage, no antagonists to dabigatran are available. The testing methods
to prevent bleeding should be established by reanalysis of the study data. Developing an antagonist of the drug isalso essential. Until these serious limitations have been addressed, it should not be used.

Introduction
Dabigatran (brand name: Prazaxa) is an oral anticoagulantthat acts as a direct thrombin antagonist [1]. It was
launched in Japan in March, 2011. Recommended usual
dase is 150mg b.i.d. It is indicated "to reduce the risk ofischemic stroke and systemic embolism in patients with nonvalvular atrial fibrillation." Standard treatment for patientswith non-valvular atrial fibrillation is to use warfarin to
keep prothrombin time international normalized ratio (PTINR) appropriately (later explained in detail). Warfarin had
long been the only oral anticoagulant until dabigatran was
introduced, followed by other oral anticoagulants withsimilar mechanisms (note 1). These new oral anticoagulants
prolong coagulation time concentration-dependently as
tested by activated partial thromboplastin time (aPTT), ecarinclotting time (ECT), and thrombin time (TT) mentioned laterin detail [1]. However, monitoring by these tests was not
required in clinical use of the new oral anticoagulants fortheir approval [1]. In August 2011, five months after the
release of dabigatran, five deaths due to serious bleeding
after dabigatran use were reported, and the warning wasissued in the form of a blue letter[2]; (note 2).
Immediately after the warning was issued, the Japanese

Circulation Society announced an urgent statement. While
advocating proper use of the drug, the society has continued
to recommend the use of dabigatran [3b]. In the Guidelines
for Pharmacotherapy of Atrial Fibrillation revised in June2013 [4] (note 3), the use of dabigatran in high-risk patientswith a CHADS2 score of two or higher is recommended with
Level of Evidence B. Dabigatran is listed before any otherdrugs with Level of Evidence A, including warfarin. Warfarin
was listed as the last option despite its high level of evidence.
Moreover, an additional note said "new oral anticoagulants
are preferable to warfarin if they have an equivalent level ofevidence". It seems the revised guideline recommends level-B
dabigatran over level-A drugs, including warfarin [4]; (Suppl.
1).
The revised guideline recommends the new drugs, for which
a method of monitoring is not established and no neutralizer
has been developed, over warfarin, which can be wellmonitored and has neutralizers. We will examine whether
this recommendation is rational, and discuss the mostappropriate treatment for the prevention of ischemic strokeand systemic embolism in patients with non-valvular atrial
fibrillation.

MED CHECK - TIP AUGUST 2015 / Vol.1 No.2 ・ Page 17

New Products
Note 1: Edoxaban (a brand name：Lixiana, launched in July, 2011),
ribaroxaban (brand name xarelto, launched in April, 2012) and apixaban(brand name Eliquis, launched on February, 2013) are on the market
now. Of these, only edoxaban is approved for the indication “to treat
and reduce risk of recurrence of venous thromboembolism (deep veinthrombosis and pulmonary thromboembolism) and to reduce risk ofthromboembolism in patients who received lower limbs orthopedic
surgery including the total knee replacement, total hip replacement andhip fracture".

Note 2: According to the package insert revised in July, 2014, "As any
monitoring method to assess the anticoagulant activity to prevent
bleeding is not established, during administration of the drug, be carefulwith not only the testing results for blood clotting but also any signsof bleeding or anemia. When these signs were noticed, appropriate
measures including immediate stopping the drug and treatment forhemostasis are necessary.

of fibrinogen into fibrin and blood clotting (Figure 1). The
bioavailability of dabigatran is as low as 5-6% [1].
The correlations between plasma concentration (nM) of
dabigatran and results of each clotting test are extremely
high (R2=0.99 for aPTT, R2=1.00 for ECT and R2=1.00 for
thrombin time (TT) (Figure 2, Suppl. 3a and 3b, respectively).
The timing of examination and the optimum (safe andeffective) test value are still unknown (see section (5) in thefollowing page). However, if an aPTT is prolonged, bleedingtime would surely be prolonged (Figure 3, see p19) [1a].
I n a d di t i on , r eg a rd i ng w a r fa r in , c on s id e rat ion is
unnecessary for the timing of INR measurement because its
elimination half-life is 50-100 hours at the stationary state.
Figure 2: Correlation between concentration of dabigatranand coagulation test results: activatedPartial Thromboplastin Time (aPTT）

Note 3: "Atrial Fibrillation Treatment Guidelines" were revised in 2013[4]. It was four years after the 2008 edition (published in November,2009). Recommendation level A shows superior than B.

Pharmacological action of warfarin
Warfarin is an antagonist of vitamin K. Coagulation Factors
II (prothrombin), VII, IX and X, and proteins C and S aresynthetized mainly in the liver. These biologically inactive
coagulation factors become active form by carboxylationof glutamic acid (Glu) residues of coagulation factors into
γ -carboxyglutamic acid (Gla) residues when reduced
vitamin K becomes oxidized vitamin K (vitamin K epoxide) by
γ -glutamyl carboxylase [5]. (Suppl. 2).
After activating coagulation factors, Vitamin K epoxide
is reduced by vitamin K reductase. By inhibiting vitamin
reductase, warfarin inhibits vitamin K cycle and activationof vitamin K-dependent coagulation factors II, VII, IX, and X,
and works as an anticoagulant [5].
Pharmacological action of dabigatran
The full generic name of dabigatran is “dabigatran etexilate
methanesulfonate”. It is a prodrug and is rapidly metabolized
in the liver. It becomes an active form of dabigatran,
which directly inhibits thrombin to inhibit the conversion

Figure 1：Action of oral anticoagulants on coagulation
factors↑
Major bleeding may increase at more than 38 nM (50 ng/mL) [ref 6]
Pharmacokinetics
The inter-individual difference of the total blood level ofdabigatran is extremely large. Among approximately 30
persons receiving the same dose, the maximum plasma
concentration (Cmax) and the area under the curve (AUC)of the highest persons were 30 times (Cmax) and 40 times(AUC) higher respectively than those of the lowest persons[1a]. Figure 4 (see p19 )shows an example. It has also beenreported that the maximum difference exceeded 400 times
in a clinical trial but the pharmaceutical company failed toreport the data [6].
Fasting and postcibal concentrations differ in a single
individual, and after repeated use the difference between
Cmax and nadir (Cmin) is approximately 3-3.5 times.
Because dabigatran is excreted by the kidney, in people withdecreased renal function, it easily accumulates, and AUC
increases. Interactions also occur frequently.
Result from the RE-LY study
The RE-LY study [7] is a single pivotal randomized
controlled study, which provides the evidence base forapproval of dabigatran in most countries, including Japan.
A total of 18,113 patients with atrial fibrillation wererandomly assigned in a non-inferiority trial, using the PROBE(prospective randomized open blinded end-point) method, inwhich only outcome assessment was blinded, and patientsand investigators knew which agents were used during thestudy period. Dabigatran was used at fixed doses (110 mg or
150 mg, twice a day), but the dose of warfarin was adjusted

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Figure 3 ： aPTT and bleeding time after dabigatran administration

Figure 4 ： Inter-individual difference of plasma concentration (Cmax)
of dabigatranInter individual difference of plasma concentration (Cmax) for older products(product 1 and 2） and newer products (product 3 and 4). According to theapproximate measurement from the graph, ratio of concentration of maximum
to that of minimum may be 30. Ratio up to 400 is reported [ref. 6].

Rats were administered (i.v.) with dabigatran (D). At the time justafter injection when plasma concentration may be maximum (15 min.),aPTT and the bleeding time was the most prolonged.
In the 0.3mg/kg or more group, aPTT prolonged more than 30 sec.
and bleeding time prolonged compared with control, 0.1mg/kg groupand baseline data. 1mg/kg group showed more than 70 sec. of aPTT and
more than 4000sec of bleeding time at 15 min. and showed prolonged
bleeding time at 60 min. even when aPTT decreased (significantly morethan the baseline data).
This may mean that bleeding time is closely related to aPTT and riskof bleeding is well predicted by aPTT.

based on the test results of PT-INR. The primary outcome
was stroke and/or systemic embolism. Serious bleeding
was the primary outcome for serious adverse events. The
secondary outcomes were stroke, systemic embolism, ordeath. The median duration of the follow-up period was 2.0
years, and complete follow-up was achieved in 99.9 % ofpatients, with 20 patients lost to follow-up. All analyses werebased on the intention-to-treat principle [7].
The efficacy primary outcome (stroke and systemicembolism) was significantly superior in the dabigatran 150
mg b.i.d group (1.11% per year) than the warfarin group (1.69% per year, P <0.001). The rate of major bleeding was not
significantly different in the dabigatran 150 mg b.i.d group(3.11% per year) compared with the warfarin group (3.36%
per year, p=0.31) (Table-(a)). These results provided the basis
for approval in most countries, including Japan.
However, significantly larger number of participants
discontinued the study product in the dabigatran groups
than in the warfarin group. The PROBE method may be

Table : Summary of the RE-LY study*a ： OR: odds ratio*b ： p value **** ： p<0.0001, *** ： p<0.001, ** ： p<0.01, * ： p<0.05, NS ： p>0.05*c: Primary outcome includes ischemic stroke or systemic embolism.
*d: Net outcome (The net clinical benefit outcome) is the composite outcome including primary outcome, pulmonary embolism, myocardial infarction,
death, or major bleeding.

MED CHECK - TIP AUGUST 2015 / Vol.1 No.2 ・ Page 19

New Products
associated with the rate of discontinuation and could haveaffected the results. We describe limitations of the RE-LY
study in the following section.

how the higher discontinuation influenced the results ofoutcomes especially the major hemorrhagic events.

Limitations of the RE-LY study

A plasma level of dabigatran related to bleeding wasreported in the subgroup analysis of the RE-LY study [14],and the bleeding frequency was 2-3 % at the optimum levelof dabigatran of less than 50ng/mL (32 nM), but 9% at 300
ng/mL and 12 % at over 300 ng/mL [6,14] (suppl. 4a). An
aPTT of less than 38 seconds is compatible with the optimal
concentrations (less than 50 ng/mL or 32 nM), if we apply
the correlation between aPTT and dabigatran concentration
as shown in the Figure 2.
Further data from the RE-LY study should be disclosed
for re-analysis to evaluate what the optimal concentrationof dabigatran is to minimize total events of embolism andhemorrhage as shown in the Supplement 4b (analysis of
total event risk by intensity of anticoagulation [13b]).
(see also An additional analysis using data of the RELY from ref [14] entitled “Optimal dose may be lower:
Subgroup analysis shows” )(1)Discontinued are 10 times more frequent than thosehaving primary outcome in the dabigatran 150 mg group
The proportions of patients discontinued within one year
were 15.5 % , 14.5 % and 10.2 % in 150 mg, 110 mg, andwarfarin groups respectively. Odds ratio of discontinuationin the 150 mg group compared with the warfarin group was
1.62 (95% confidence interval (95% CI): 1.45, 1.80, p<0.0001)(Table-(b)). The 2-year discontinuation rate was 21.2 % ,20.7 % , and 16.6 % , respectively. The odds ratio of the 150
mg group compared with the warfarin group was 1.35
(95 % CI: 1.23, 1.48, p<0.0001). The ratio of proportionof patients with discontinuation to the proportion ofparticipants with the primary outcome was 5 times in thewarfarin group, and as high as 10 times in the 150 mggroup.

(2) Possibility of biased management in favor of the dabigatran
Reasons of discontinuation in the dabigatran 150 mggroup and warfarin group include (1) patient’s decision(7.8 % vs 6.2 % ), (2) serious adverse event (2.7 % vs
1.7 % ), (3) gastrointestinal symptoms (2.1 % vs 0.6 % ), (4)gastrointestinal bleeding (1.3 % vs 0.9% ) (Table-(c)). For all
reasons except outcome events, dabigatran 150 mg group issignificantly higher than the warfarin group. In particular theodds of gastrointestinal symptoms in both dabigatran 150
and dabigatran 110 groups were significantly higher than in
the warfarin group (OR: 3.44, 95% CI: 2.39, 4.95, p<0.0001
and 3.59, 95% CI: 2.50, 5.15, p<0.0001).

(3) Double dummy method combined with dummy PT-INR
was not used
A double-blind randomized controlled trial (RE-COVER
study) of dabigatran for thrombophlebitis was performedby the double dummy method [10]. This was made possibleby adopting the following method. In the RE-COVER study,
PT-INR values within the possible range as seen in thewarfarin group were randomly generated and reported to theparticipants in the dabigatran group. It is unclear why thesame method was not used in the RE-LY study.

(4) No information is available for the proportion of time
when warfarin was out of targeted INR range
In four [16, 18,19,20] among five [16-20] randomized
controlled trials of warfarin in atrial fibrillation, theproportions of the time when INR was within the target level,
lower than the lower limit and higher than the upper limit
were reported. However, in the RE-LY study, only information
within the target level (64 % ) was reported, but no otherinformation, especially proportion of the time higher thanthe upper limit was not reported.

(5) PROBE method-possibly unreliable due to potential bias
Periodical testing of PT-INR was performed in the warfaringroup in the RE-LY study, while no test was performedin the dabigatran groups. In the RE-LY study, the PROBE
method was used due to the claim that double blinding was
impossible. Hence, participants and investigators could know
the identity of the assigned products.
Although the report of RE-LY says that all analyses werebased on the intention-to-treat principle [7], it is not known
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(6) Dabigatran level of 50 ng/mL (38 second for aPTT) is
critical to bleed

Post-marketing surveillance and suit in the United States
Dabigatran was prescribed for 270,000 people in the UnitedStates during three months in 2011. Of these, 932 reported
serious adverse reactions. Among them, 543 were hospitalized,
25 had sequelae, and 120 died [11]. Approximately one in
300 who took dabigatran got serious adverse reactions, andone in 2,300 who took dabigatran died.
After the marketing of dabigatran began in the UnitedStates, many of those who were prescribed dabigatrandied, and their families sued the manufacturer, Boehringer
Ingelheim Co. (BI Co.). BI Co. announced that they would
pay 650 million U. S. dollars (approximately 70 billion yen)
to settle the cases in June 2014 [6]. In the suit, internal
documents of BI Co. were disclosed. They indicated that if
the coagulation tests were used to prevent bleeding, it could
have reduced the large number of bleeding accidents [6]. As
shown in the previous section, it is reasonable to infer thatmeasurement of aPTTs could prevent substantial proportionof the bleeding accidents.
What is the best outcome for efficacy and safety inanticoagulant use?
The primary outcome should be the long term all-cause
mortality, because it is the strongest and the least biased
among all the outcomes [22,23]. However, RCTs for thetreatment of non-valvular atrial fibrillation did not observe
patients for longer than two years. The net clinical benefit
outcome (the net outcome) is one of the options for outcome.
However this is not reported in the five RCTs for warfarin.
It may be reasonable that proportion of events withischemic stroke/systemic embolic events + major hemorrhage(abbreviated as “IS/SEE/MH” may be considered as the third
best “primary outcome” of anticoagulant therapy [12, 13, 15].
Optimal PT-INR should be the value by which thefrequency of “the best primary outcome” becomes the least.
For the anticoagulant therapy with warfarin, optimal PTINR to obtain the least IS/SEE/MH was reported as 1.6-2.6
in Japan [12]. A recently published large-scale investigation,the J-RHYTHM Registry [13] also confirmed that this(1.6-2.6) of PT-INR was optimal to obtain the least IS/SEE/
MH. Yamaguchi et al [24] reported in their randomized
controlled trial that low intensity warfarin treatment group(target INR: 1.9 and the range: 1.5 to 2.1) was safer thanthe conventional-intensity group (target INR:2,5 and therange: 2.2 to 3.5) because of the lower incidence of major
hemorrhage with no difference in the incidence rate ofischemic events. According to our re-analysis using the data
in Yasaka’s paper [12], the least IS/SEE/MH was observed
during PT-INR 1.6 to 2.19 [25]. J-RHYTHM Registry [13]showed the least IS/SEE/MH was obtained during PT-INR 1.6
to 1.99 and the next least during 2.0 to 2.59.
These results are consistent with the results from the
BAATAF study in which target PT-INR were determined as 1.5

to 2.7 and the PT-INR within the target level was achieved
83 % of duration and the least stroke and major hemorrhagic
events were obtained.
In practice: a summary of the treatment of the non-valvularatrial fibrillation
The first-line drug for patients with non-valvular atrial
fibrillation is warfarin. The target PT-INR may be 1.6 to 2.19
(less than 2.6). We do not recommend the use of newer
oral anticoagulants, including dabigatran, until methods ofmonitoring and more effective and safer use are established.
If the plasma concentration of dabigatran increases, aPTT, ECT,and thrombin time may be prolonged, and the risk of bleeding
may increase (see the next section "Optimal dose may be far
lower": an additional analysis using the data from ref [14]).

Optimal dose may be far lower: Subgroup analysis shows
An additional analysis using data of the RE-LY from ref [14]Assessment by the preferable primary outcome (IS/SEE/MH)
Summary of subgroup analysis: from ref [14]We consider that “ischemic stroke/systemic embolism” andIn the subgroup analysis of the RE-LY study, plasma“major bleeding events” (IS/SEE/MH) may be one of the mostconcentrations of dabigatran obtained from 9,183 patients
preferable outcomes. This is estimated by adding the risks
were reported in relation to the clinical outcomes ofof “major bleeding” to the risks of “ischemic stroke/systemicischemic stroke/systemic embolism and major bleeding
embolism” as indicated by the red vertical line shown in theusing univariate and multivariate logistic regression and
Figure 5 (original figure without red vertical lines is shown in
Cox regression models. Among 9,183 patients, 112 ischemic
the suppl.5).
strokes/systemic emboli (1.3 % ) and 323 major bleeds(3.8 % ) were recorded. A multiple logistic regression model
showed that the risk of ischemic
events was inversely related to Figure 5: Dabigatran concentration and risk of "ischemic stroke/systemic embolism+ major bleeding events" [red vertical lines are added to the figure in ref 14]
trough dabigatran concentrations(p=0.045), with age and previous
stroke (both p < 0.0001) as
significant covariates. Multiple
logistic regression showed major
bleeding risk increased with
dabigatran exposure (p < 0.0001),
age (p < 0.0001), ASA use (p <0.0003), and diabetes (p = 0.018)
as significant covariates. The
authors concluded that ischemic
stroke and bleeding outcomes werecorrelated with dabigatran plasma
concentrations and individual
benefit–risk might be improvedby tailoring dabigatran dose
after considering selected patientcharacteristics.
Figure 5 is the summary fifure of
the results of subgroup analysis
showing the risk of ischemic
stroke/systemic embolism andTotal risk of “ischemic stroke/systemic embolism + major bleeding events” is estimatedmajor bleeding events for 72-yearby adding the risks of major bleeding on the risks of “ischemic stroke/systemic embolism +old male atrial fibrillation patientmajor bleeding events” as indicated by the red vertical line shown in the above (Figure 5 ) .
with prior stroke and diabetes
As we could consider the optimal concentration of dabigatran may be the concentration
correlated with the dabigatran
at which the total risk of “ischemic stroke/systemic embolism + major bleeding events” isthe least, it may be about 15 ~ 30 ng/mL (11 ~ 23 nM) from the data in ref [14]. Hence notplasma trough concentrations.
only 150mg b.i.d but also 110 mg b.i.d. may be far more compared with optimal dose.

MED CHECK - TIP AUGUST 2015 / Vol.1 No.2 ・ Page 21

The best plasma concentration may be far lower
As we could consider the optimal concentration of
dabigatran may be the concentration at which the total
risk of IS/SEE/MH is the lowest, it could be simply readapproximately 15-30 ng/mL (11-23 nM) for a 72-year old
man with history of previous stroke and diabetes from the
Figure 5 (based on the data from the subgroup analysis [14].
The results of optimal concentration of dabigatran for otherages (65, 75 and 85 years) estimated from the data as shownin the figure 1 of the subgroup analysis [14] may not be sodifferent as the results from the 72-year old man with historyof previous stroke and diabetes. Hence, not only the plasma
concentration obtained by the 150mg b.i.d but also by the
110 mg b.i.d. may be far higher compared with the optimal
concentration.
Ongoing dose (110 or 150 mg b.i.d.) may be higher than the
optimalA dose of 110 mg b.i.d. shows about 65 ng/ml ofgeometric mean of plasma concentration (10 percentile and90 percentile were 28 and 155 ng/mL respectively). This is
3 times higher than 21 ng/mL if this is an optimal plasma
concentration. As for the dose of 150 mg b.i.d, geometricmean of plasma concentration was 91 ng/mL (10 percentile
and 90 percentile were 52 and 275 ng/mL respectively).
This is 4 times higher than a possible optimal plasma
concentration (21 ng/mL). We do not know what the real
optimal dose of dabigatran is, as we could not know what
had happened in the discontinued participants. However,according to these data, optimal dose of dabigatran may be
far lower than not only 150 mg b.i.d but also 110 mg b.i.d.
Best outcome analysis of warfarin group by PT-INR value isessential
Because IS/SEE/MH may be the preferable outcome to
be used to determine the optimal target of PT-INR [12, 13,15] and because re-analysis of dabigatran groups using IS/
SEE/MH as the preferable outcome suggested lower optimal
concentration of dabigatran, re-analysis of warfarin groupusing IS/SEE/MH as the preferable outcome by PT-INR value
is essential.

References
1) Approval information of dabigatran: http://www.info.pmda.go.jp/ a) Summary basis ofapproval (SBA), b) examination report, c) package insert, d) interview form
2) Japanese Boeringer Ingelheim Co, Prazaxa-induced serious bleeding
http://www.mhlw.go.jp/stf/houdou/2r9852000001m1w3-att/2r9852000001m2fu.pdf3a) MHLW. Warning on the serious bleeding in patients during treatment with an
anticoagulant "Prazaxa capsule":
http://www.mhlw.go.jp/stf/houdou/2r9852000001m1w3.html
3b) Study group of the Guideline on anticoagulation therapy in disease of circulation (6th edin 2009). "An emergency statement about antithrombotic therapy in patients with atrial
fibrillation" August 2011: http://www.j-circ.or.jp/guideline/pdf/statement.pdf
4) A Joint Study team for the guidelines on the pharmacological treatment of atrial fibrillation(2013 revised ed.) http://www.j-circ.or.jp/guideline/pdf/JCS2013_inoue_h.pdf
5) Brunton LL et al. Goodman & Gilman's The Pharmacological Basis of Therapeutics 12thed. 2011,．McGrow-Hill
6) Moore TJ, Cohen MR, Mattison DR. Dabigatran, bleeding, and the regulators. BMJ. 2014
Jul 23;349:g4517
7) Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J et al RE-LY Steering Committee andInvestigators.Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med.
2009;361(12): 1139-51.

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8) Nakamura H et al. MEGA Study Group. Primary prevention of cardiovascular disease withpravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet.
2006 ;368(9542): 1155-63.
9) a) Hama R, Sakaguchi K, Pravastatin (Mevalotin) lower over-all survival. The Informed
Prescriber (TIP): 2006: 21(8/9): 84-86．
b) Sakaguchi K, Hama R, Frawd in Mevalotin trial, “Med Check for your life”: 2006: 6 (24):50-55
10) Schulman S, Kearon C, Kakkar AK et al. (RE-COVER Study Group). Dabigatran versus
warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec
10;361(24): 2342-52
11) a) Institute for Safe Medication Practices, Monitoring FDA Med Watch Reports"QuarterWatch": Signals for Dabigatran and Metoclopramide. January 12, 2012 Data
from 2011 Quarter 1, http://www.ismp.org/QuarterWatch/pdfs/2011Q1.pdfb) Hama R. Dabigatran-induced serious bleeding, Med-Con. 2012. issue12, 22-23 (inJapanese)12) Yasaka M, Minematsu K, Yamaguchi T: Optimal intensity of international normalized
ratio in warfarin therapy for secondary prevention of stroke in patients with nonvalvularatrial fibrillation. Intern Med 2001, 40: 1183?1188
13a) Inoue H, Okumura K, Atarashi H, Yamashita T, Origasa H, et al; J-RHYTHM Registry
Investigators. Target international normalized ratio values for preventing thromboembolicand hemorrhagic events in Japanese patients with non-valvular atrial fibrillation: results of
the J-RHYTHMRegistry. Circ J. 2013; 77(9): 2264-7013b) Kodani E Atarashi H, Inoue H, Okumura K, Yamashita T. Incidence of events andoptimum INR in patients with atrial fibrillation during treatment with warfarin in Japan: A
report from J-RHYTHM Registry (in Japanese). J Jp Soc Clin Physiol 2014: 44 (1): 7-1613c) Kodani E, Atarashi H, Inoue H, Okumura K, Yamashita T; J-RHYTHM Registry
Investigators. Target intensity of anticoagulation with warfarin in Japanese patientswith valvular atrial fibrillation – subanalysis of the J-RHYTHM Registry. Circ J.
2015;79(2):325-30.
Additional reference to English version of MED CHECK TIP No214) Reilly PA et al and RE-LY Investigators. The effect of dabigatran plasma concentrations
and patient characteristics on the frequency of ischemic stroke and major bleeding in
atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term
Anticoagulation Therapy). J Am Coll Cardiol. 2014; 63(4): 321-8.
15) Rosendaal FR, Cannegieter SC, vander Meer FJ, Briet E. A method to determinethe
optimal intensity of oral anticoagulanttherapy. Thromb Haemost 1993;69:236-9.
16) Petersen P, Boysen G, Godtfredsen J, Andersen ED,Andersen B. Placebo-controlled,
randomized trial ofwarfarin and aspirin for prevention of thromboemboliccomplications
in chronic atrial fibrillation: the CopenhagenAFASAK study. Lancet 1989;1:175–9.
(AFASAK I)
17) Boston Area Anticoagulation Trial for Atrial FibrillationInvestigators. The effect of lowdose warfarin on the riskof stroke in nonrheumatic atrial fibrillation. New EnglandJournalof Medicine 1990;323:1505–11. (BAATAF)
18) Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA,Joyner C, et al.Canadian
Atrial Fibrillation Anticoagulation(CAFA) Study. Journal of the American College of
Cardiology1991;18:349–55. (CAFA)
19) Stroke Prevention in Atrial Fibrillation Investigators. TheStroke Prevention in Atrial
Fibrillation Study: Final results.Circulation 1991;84:527–39. (SPAF I)
20) Veterans Affairs Stroke Prevention in Nonrheumatic AtrialFibrillation Investigators.
Warfarin in the prevention ofstroke associated with nonrheumatic atrial fibrillation.
NewEngland Journal of Medicine 1992;327:1406–12. (SPINAF)
21) AguilarMI, Hart R.Oral anticoagulants for preventing stroke in patients with non-valvularatrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane
Database of Systematic Reviews 2005, Issue 3. (Cochrane Review)22) International Society of Drug Bulletins and World Health Organization. Starting or
Strengthening a Drug Bulletin: A Practical Manual 2005. Chapter 8. Reviewing a new
drug: is it a therapeutic advance? Accessed on 10/08/2015, available at:
http://www.isdbweb.org/documents/uploads/manual_full_text.pdf
23) US National Cancer Institute: http://www.cancer.gov/cancertopics/pdq/levels-evidenceadult-treatment/24) Yamaguchi T. Japanese Nonvalvular Atrial Fibrillation-Embolism Secondary Prevention
Cooperative Study Group. Optimal intensity of warfarin therapy for secondary preventionof stroke in patients with nonvalvular atrial fibrillation : a multicenter, prospective,
randomized trial. Stroke. 2000 Apr;31(4):817-21.
25) What is the optimal PT-INR value for non-valvular atrial fibrillation? Med Check TIP
2015: 16 (61)(in Japanese) (Englich version of this article will be published in No 3 issueof Med Check TIP in English)

Information for the Patient

Dabigatran:
Potentially Harmful
Generic name: dabigatran
Brand name: Pradaxa(US, EU etc)
Prazaxa(Japan)

If you have any questions on this leaflet, please ask
your doctor or pharmacist. Please keep medicines outof reach of children.

What is this medicine?
Atrial fibrillation is a common arrhythmia (irregularheart beat). If you have atrial fibrillation, blood easily
clots inside the heart, and a fragment of the blood clot
travels from the heart to brain or other parts of the
body and may plug the blood vessels. Then, you may
have stroke (brain vessel obstruction) or embolism inother parts of the body. In order to prevent clotting,a drug called “anticoagulant (or a blood thinner)” isprescribed.
*For this purpose, “warfarin” is the standard drug.
*Dabigatran is a newly approved drug for the same
purpose. It is advertised as being very convenient
because blood testing is not necessary.
*However, using dabigatran without monitoring isdangerous because excessive action of blood thinners
may induce bleeding and make it hard to stop.
*For prediction of excess action of warfarin, a test formonitoring is available. However, the excess action of
dabigatran cannot be predicted because no such test isavailable for the drug. In fact, five death cases due to
bleeding were reported and warnings on prescription
were issued in August 2011, 5 months after its launch.
Who must avoid dabigatran?
* A person whose kidney function is lowered (including
the patients on dialysis).
* A person with ongoing bleeding or who is prone tobleeding* A person who had gastric ulcer in the past, cerebral
hemorrhage within the past six months, or who has
other diseases which are likely to cause bleeding*A person who has epidural (surface of spinal nerve)
catheter or whose epidural catheter was extracted
within the past 1 hour.
*A person who is using itraconazole, which enhances
the effects of dabigatran and is likely to induce bleeding.
*Elderly people. Their renal function is usually

decreased, in spite of the apparent normal value ofroutine kidney function test.
How to use properly?
*We do not explain it in detail, because we do notrecommend dabigatran.
*We recommend warfarin instead of dabigatran if you
need a drug to prevent blood clotting.
*The reasons are: (1) excess action of warfarin can bedetected by a test, but that of dabigatran cannot be, (2)antagonists (drugs to weaken an action of a particulardrug) in the case of bleeding is available for warfarin but
not available for dabigatran.
Precautions while using dabigatran*Do not stop dabigatran suddenly, if you are already on
the drug without any sign of adverse effects below. An
alternative drug is necessary to prevent blood clotting.
Discuss with your doctor.
*If you see doctors other than your doctor such as
surgeon or dentist etc, while taking this drug, makesure to inform them that you are taking dabigatran.
Otherwise, it will very hard to stop bleeding after
surgery or tooth extraction. It’s very dangerous.
*Your kidney function must be regularly checked
because it may be affected by the medication and byother reasons...
*Bleeding may become severe even in the case ofslight injury while taking dabigatran. Avoid any intense
exercises and dangerous works.
Adverse effects (Side effects)※ Stop taking dabigatran and see your doctor or callan ambulance (in the case of serious symptoms), if you
have:[Bleeding] Bleeding is the most serious reaction.
Definite or possible sign of bleeding are as follows;
Definite: bleeding from nose, skin (under skin), gums,
hemosputa, coal tar-like stool, coffee-residue-like vomit,
bloody stool and hematuria (red urine).
Sign of cerebral hemorrhage: numbness in hands
and feet, slurred speech, losing consciousness andhemiplegia.
Possible sign of abdominal bleeding: nausea, vomiting,diarrhea, discomfort in the stomach and stomachache.
[allergic symptoms] dyspnea (possibility of anaphylaxis
and interstitial pneumonia), fever, sore throat andsevere urticaria※ See your doctor as soon as possible if you have:yellow skin, any rash and urticaria■ If you notice any sign of other possible adverse
effects (side effects), please ask your doctor or apharmacist.
Med Check TIP

MED CHECK - TIP AUGUST 2015 / Vol.1 No.2 ・ Page 23

New Products

Lubiprostone (Amitiza)
Too harmful and expensive for general use as a laxative
Translated from Med Check TIP (in Japanese) 2015; 15 (May:#59); 55-57.

Abstract:
Lubiprostone is the most recent laxative to be marketed in the last thirty years, but it is not superior to conventional
laxatives in benefits. While the manufacturer emphasizes its specific effect on chloride channel-2 (ClC-2), lubiprostonealso has prostaglandin properties. Because both prostaglandin receptors and ClC-2 are widely present in the human
body, lubiprostone may cause various adverse reactions. The drug was approved at a time when its prostaglandin
properties, including the effect of its active metabolite 15-hydroxyl-lubiprostone, had not been sufficiently investigated.
A recent study reported that lubiprostone itself may constrict intestinal circular smooth muscle. Studies with guinea
pigs found that lubiprostone increased spontaneous abortion (resorption) at doses as low as one fifth the clinical dose.
The mechanism by which the drug induces abortion/resorption can be explained by its effect as a prostaglandin and
ClC-2 agonist on the uterine muscle. In addition, dyspnea occurred in 2% to 3% of patients treated with lubiprostone;
this is unacceptable for the treatment of constipation. Finally, the drug is very expensive. We conclude that lubiprostone
is not appropriate for use as a laxative.

What is lubiprostone?
Lubiprostone is structurally similar to prostone, abicyclic fatty acid compound derived from prostaglandin
E1 (PGE1) [1]. The manufacturer of the drug states thatlubiprostone opens a chloride channel-2 (ClC-2) of the small
intestinal mucosa, thereby increasing fluid secretion to thelumen, softening the stool, and inducing bowel movements,
thus alleviating constipation [2-4]. However, lubiprostonealso acts as a prostaglandin analogue [1] (described indetail below) and ClC-2 is present in almost all body cells
systemically, including the central nervous system [5]. Henceit may cause adverse reactions systemically.
Lubiprostone (trade name: Amitiza) was approved by
the FDA in 2006 for the treatment of chronic idiopathic
constipation (CIC) in patients aged 18 years and older[6]. Lubiprostone is now approved for the treatment of
CIC and constipation associated with opioids (excluding
diphenylheptane opioids such as methadone) in adults [6,7].
Lubiprostone is also indicated for constipation connectedwith irritable bowel syndrome in women aged 18 years andolder. In 2012, lubiprostone was approved as a laxative for
CIC in Japan [2]. The recommended dosage of 24 micrograms
twice daily is the same as that in the USA [3].
Activation of ClC-2 and function as a prostaglandin
Lubiprostone is claimed to be a specific activator of ClC-2
in the small intestinal mucosa. The Japanese versions of
the package insert and interview form for lubiprostone
do not mention its prostaglandin effects [3]. The AMITIZA(lubiprostone) official website (www.amitiza.com/) does not
mention these either. Only limited information is available
regarding the prostaglandin-like effects of lubiprostone, in
the Summary Basis of Approval (SBA) and a review of the

Page 24 ・ MED CHECK - TIP AUGUST 2015 / Vol.1 No.2

drug by the Pharmaceuticals and Medical Devices Agency(PMDA) [2]. The SBA [2a] states:“Effects of lubiprostone on prostaglandin receptors (EP1, EP2,
EP3, and FP) were investigated using the longitudinal smoothmuscle of the ileum of guinea pigs (for EP1), the circular smoothmuscle of the ileum of guinea pigs (for EP2), the seminal ductof guinea pigs (for EP3), and the iris sphincter of beagle dogs
(for FP). Lubiprostone was found to cause almost no activationof EP1 and FP, but exerted a weak activation effect on EP2
and EP3. Agonist activity in terms of IC50 of lubiprostone
on EP2 and EP3 was less than 1/10 that of misoprostol.
These results indicate that agonist activity of lubiprostone on
prostaglandin receptors is weak; hence, no clinically significant
pharmacological effect is likely to be induced via thesereceptors.”

However, smooth muscle contractility was found to be
20 % in 100 nM lubiprostone compared with 70 % in 100
nM misoprostol. Furthermore, Chan et al. [1] reported thatlubiprostone caused the circular smooth muscle of the mousesmall intestine to contract at a concentration equal to or
higher than 10 nM, and that contraction disappeared when
an EP1 antagonist was administered. These results suggestthat the prostaglandin-like effect of lubiprostone differs from
species to species. This may be interpreted as indicating thatinter-individual variation in the prostaglandin-like effect ofthe drug is very large in humans, making it difficult to predictwhether lubiprostone will induce prostaglandin-like effects inany particular individual.
Lubiprostone induces abortion/resorption
The manufacturer notes that although lubiprostone
does not induce abortion directly, it can induce fetal

death, abortion, or other fetal abnormalities. The PMDA
acknowledges the applicant’s explanation, but states thatprostaglandin-like effects of the drug cannot be excluded
as a cause of harmful influences on the embryo/fetus
and reproductive function of parental animals. Therefore,
lubiprostone is contraindicated in pregnant or possiblypregnant women.
Two abortifacient studies using guinea pigs clearly showedthat lubiprostone induced abortion [4]. Table 1 extracts theresults relating to abortion/resorption from these studies. In
Study 1, abortion occurred in 2 of 9 animals and one diedmicrogram/kg). (See Table 1.) In Study 2, abortion occurredin 2 of 29 animals (7% ) at the minimum dose of
1 microgram/kg (HED = 0.2 microgram/kg). There were nocases of abortion/resorption in 58 animals in the control
groups of Studies 1 and 2.
Figure shows the estimated abortion/resorption curve and
95 % confidence interval for the logistic regression analysisof the data from Studies 1 and 2. The odds increase ratio
was 1.057 (95 % confidence interval: 1.030 to 1.085), whichindicates a 5.7 % increase in abortion per 1 microgram/kg
dose of lubiprostone.

Table 1: Oral abortion study using guinea pigs (data from FDA [4])*a： Resorption refers to abortion in animals. Late resorption refers to intrauterine death.
*b： 24 animals each were included in the “no treatment” and “only vehicle” control groups.
*c： 5 μ g/kg for a guinea pig is equivalent to 1.1 μ g/kg for a human (HED=1.1 μ g/kg); hence
this was approximately the usual daily dose (48 μ g/day) for a woman weighing 45 kg. A HED of
1 μ g/kg for a guinea pig is far lower than the usual daily dose.
*d： Satellite tests were conducted using 5 guinea pigs in each dose group.
Data of *a and *d were used to perform a logistic regression analysis (see results in Figure 1).

Figure : Dose-response relation between lubiprostone and abortion/resorption: logistic
regression analysis and 95% confidence interval (shadow area)*Logistic regression analysis was performed using the data from Study 1 (including late resorption,
which corresponds to human intrauterine death) and Study 2 (including satellite study). The shadow
area represents the 95% confidence interval.

MED CHECK - TIP AUGUST 2015 / Vol.1 No.2 ・ Page 25

New Products
in late resorption at the minimum dose of 5 microgram/kg
lubiprostone (HED = human equivalent dose = 1.1
ClC-2 exists in uterine muscle, respiratory organs,and central nervous system
The principal activity of ClC-2 is to regulate passive
movement of chloride ions. Chloride channels regulatepassive movement of inorganic anions (I-, Br-, F-, and others)
and organic anions (NO3-, HCO3-, glutamate, aspartic acid,and others); hence they are also called anion channels.
The manufacturer of lubiprostone claims that the drug’s main effect is on ClC-2 specifically located in the intestine.
However, ClC-2 exists widely in the human body, including in
the central and peripheral nervous system, cardiac muscle,epithelial cells, smooth muscle, and exocrine glands. ClC-2
plays an important role in smooth muscle contraction,
cardiac contraction, fluid secretion from the epithelium,
and regulation of cell volume [5]. Recently, ClC-2 was foundto be present in the uterine smooth muscle and it may
cause contraction of the uterus [8]. Thus, it is likely thatlubiprostone is a “ClC-2 activator,” which means that it has
pharmacological effects on the whole body.
Lubiprostone-induced abort ion/resorpt ion can be
explained by the drug’s action both as a prostaglandin in
the form of an M3 metabolite and/or as a ClC-2 agonist
on uterine muscle contraction. Either of these mechanisms
can explain lubiprostone’s abortifacient effect. Above all,the abortifacient effect of lubiprostone may also occur inhumans.
The characteristics of lubiprostone as a prostaglandinsuggest that it has properties that dilate blood vessels andaffect the function of nerve cells. Due to its antiplatelet
and dilatation effects as a prostaglandin, administration of
lubiprostone may be harmful for patients who are alreadyusing anti-coagulants and/or antiplatelets, particularly theelderly.
Active metabolite (M3) is absorbed and exerts systemic
effects
It is claimed that lubiprostone acts locally in the intestine.
Although lubiprostone is not detected in the blood, its
metabolite (15-hydroxy-lubiprostone: M3), which is as active
as lubiprostone, appears in the blood and exerts systemic
effects. The mean half-life of M3 at the standard dose of
48 micrograms was found to be 3.91 ± 4.65 hours in two

women. The fact that the standard deviation was greaterthan the mean indicates a large variation among individuals.
Moreover, the area below the curve for women was 1.5 times
greater than that for men because M3 has a longer half-life
in women [2a].
Clinical studies
A Pu b M e d s e a r c h u s i n g t h e t e r m “ l u b i p r o s t o n e /meta analysis”retrieved 4 articles on chronic idiopathic
constipation (CIC), 2 articles on irritable bowel syndrome(IBS), and one article on opioid-induced constipation(accessed on April 16, 2015). The result of a meta-analysis
of RCTs showed that the risk of failure to respond to therapy
were 45.1 % and 66.9 % in the lubiprostone and placebogroups, respectively [9].
The risk ratio of failure to respond to lubiprostone was
0.67 (95 % CI: 0.56, 0.8; NNTB: 4). In a Japanese study,
approximately 60% of CIC patients attained defecation within
24 hours and the number of bowel movements increased
significantly after lubiprostone administration [2a].
The risk ratio (RR) for adverse events was 1.79 （95 ％ CI:
1.21, 2.65; NNTH: 4） according to the results of the metaanalysis [9]. In particular, the RRs for diarrhea and vomiting
were 4.5 (95％ CI: 1.3 to 15.5) and 7.3 (95％ CI: 3.8, 14.1),
respectively [9].
Regarding adverse reactions, the SBA [2a] reported thatwhen lubiprostone was used at a dosage of 48 microgram/day for 3 to 4 weeks, nausea occurred in 24.4% to 43.8% ofcases, headache in 6.7% to 12.5% of cases, dizziness in 5.0%
to 9.4% of cases, and diarrhea in 4.2% to 6.7% of cases. For
the placebo group, the corresponding figures were 0.0 %to 6.8% , 4.2% to 12.1% , 0.8% to 3.0% , and 0.0% to 1.6% ,respectively. Adverse reactions, including laboratory test
abnormalities, were reported in 62% of cases in the domestic
clinical trials. Major reactions included diarrhea (30 % ofcases), nausea (23 % ), and dyspnea (1.6 % ). The package
insert for Amitiza notes that the dose should be reduced forpatients with moderate to severe liver abnormality or severe
kidney failure. Results of animal experiments point to therisk of fetal abnormality and tumorigenesis. In a foreign
study, dyspnea was observed in 3% of patients, and some had
to discontinue lubiprostone use because of repeated episodes[10].

Table 2. Meta-analysis results of RCTs of laxatives for chronic idiopathic constipation [ref 9]*Osmotic laxatives included polyethylene glycol and lactulose; the stimulant laxative was picosulfate.
RR= risk ratio; 95% CI = 95% confidence interval
NNTB = number needed to treat for an additional beneficial outcome; NNTH = number needed to treat for an additional harmful
outcomePage 26 ・ MED CHECK - TIP AUGUST 2015 / Vol.1 No.2

Comparison of lubiprostone and conventional laxatives
There is no hard data with which to compare lubiprostone
and conventional laxatives as no studies have compared
the two drugs directly. As shown in Table 2, the effect of
lubiprostone is similar to that of conventional laxatives.
However, adverse reactions, including nausea, headache, anddyspnea, cannot be ignored. In addition, Amitiza is expensive:
the standard dosage of 24 micrograms twice daily costs\322.2 per day, whereas the equivalent dosage of magnesia
tablets costs only \22.4 per day.
The number of the annual users of magnesium oxide isestimated to be approximately 45 million. Fifteen casesof hypermagnesemia due to magnesium oxide use werereported between August 2008 and April 2005 [11].
Because it is excreted efficiently in urine, magnesium does
not accumulate in persons with normal renal function.
However, hypermagnesemia may occur in patients with renal
failure.
The place of lubiprostone in CIC
Constipation is a condition experienced by many people.
The majority do not need to visit a doctor. But if constipation
causes discomfort, a medical examination should be
performed to check for mechanical obstruction of theintestine. When findings from this examination turn out tobe negative, a diagnosis of chronic idiopathic constipation ispossible.
Usually, the physician will advise a patient to increase
ingestion of dietary fiber—often called bulk laxatives—toincrease stool bulk. If bulk laxatives are ineffective, osmotic
laxatives may be prescribed, including magnesia for generaluse and lactulose for patients with liver damage. If thesemeasures fail, then stimulant laxatives such as picosulfate
and senna may be tried. For patients taking opioids, it isnecessary to use both osmotic laxatives and stimulant
laxatives.

Lubiprostone may be included in the category of osmotic
laxatives, considering its mechanism of action. It is rather
difficult to find a place for lubiprostone in the generalapproach to CIC treatment described above, because its
effect is not superior to that of conventional laxatives andits price is extremely high, to say nothing of its variety ofside effects. When all conventional laxatives fail to treat CIC
successfully, lubiprostone treatment may be considered for
carefully-selected patients, with the exception of women ofchildbearing age. However, it cannot be recommended forgeneral treatment of CIC.
References
1) Chan WW, Mashimo H. Lubiprostone Increases Small Intestinal Smooth Muscle
Contractions Through a Prostaglandin E Receptor 1 (EP1)-mediated Pathway. J
Neurogastroenterol Motil. 2013 Jul;19(3):312-8.
http://www.isdbweb.org/documents/uploads/manual_full_text.pdf
2) Dossiers of approval information of lubiprostone (Amitiza). a)summary basis ofapproval(SBA), b) examination reports by PMDA,
3) Ather information of lubiprostone (Amitia). a) package insert, b)Interview form
4) AFDA new drug pharmacology review
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021908s000_Amitiza_PHARMR.pdf
5) Yoon IS, Jeong SM, Lee SN, et al Cloning and heterologous expression of aCa2+- activated chloride channel isoform from rat brain. Biol Pharm Bull. 2006
Nov;29(11):2168-73.
6) A a) Amitiza approval history: http://www.drugs.com/history/amitiza.htmlb)FDA Approves Amitiza for Opioid-Induced Constipation
http://www.medscape.com/viewarticle/802953
7) Akita T, Kumata T, Fukuda A. Cloride channel 、ictionary for brain science
http://bsd.neuroinf.jp/wiki/(in Japanese)
8) Bernstein K, Vink JY, Fu XW, Wakita H, Danielsson J, Wapner R, Gallos G. Calciumactivated chloride channels anoctamin 1 and 2 promote murine uterine smooth muscle
contractility.
Am J Obstet Gynecol. 2014 Dec;211(6):688.e1-10.
9) Ford AC, Suares NC.Effect of laxatives and pharmacological therapies in chronic
idiopathic constipation: systematic review and meta-analysis. Gut 2011;60(2):209-218.
10) Amitiza (lubiprostone) capsules label - Food and Drug Administration.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021908s005lbl.pdf11) MHLW. Hypermagnesemia induced by magnesium oxide. Pharmaceuticals and medical
devices safety information No.252

Plain Language summary

Lubiprostone: a new product for constipation
Harmful and expensive for general use
It is hard to objectively define “constipation”, because

3 times a week. When one’s stool is smooth and does

the bowel habits are highly individual. However, it

not accompany discomfort, it is not constipation evencould be called “constipation”, when one has discomfort

if the frequency of bowel movement is less than once

because of the following conditions: difficulty in passing

a day. However, it may be often accompanied by somestools, infrequent stools, and/or small, hard stools.

kind of inconvenience and discomfort if one does not

Persons with constipation might also feel the urge tohave a bowel movement for 3 to 4 days.

pass stools, but they do not come out.
Normal frequency of bowel movement varies amongindividuals. It ranges from 3 times a day to around 2 toWhile various causes lead to constipation, it is mostly
resolved by correcting one’s lifestyle. However, in somecases, other factors may be more the important.
MED CHECK - TIP AUGUST 2015 / Vol.1 No.2 ・ Page 27

Plain Language summary
The stomach and intestines are the pipes that always

intestine. When findings from this examination turnmove and send off their contents. Constipation may

out to be negative, the physician may diagnose that you

occur if the contents of the bowels lose much water andhave chronic constipation.

become hardened; the bowel movement is extremely

Usually, your physician will advise you to increase

decreased; or the intestines are mechanically blocked.

ingestion of dietary fiber to increase stool bulk or

Constipation may also occur if the bowel movements

prescribe a medicine called “bulk laxatives” such as

are suppressed by something inside or outside thecarmellose or Plantago asiatica as an alternative tointestine (e.g., by a cancer), or they are stopped bytaking fiber from food.

medicines. The medicines that easily cause constipation

If bulk laxatives are ineffective, osmotic laxatives,

include tranquilizers, sleeping pills, antidepressants,

which increase water inside the intestine, may becalcium antagonists (a drug to lower high bloodprescribed, including magnesia for general use, andpressure), painkillers of the stomach and antihistamine

lactulose for patients with liver damage. If thesein cold remedies or allergic diseases. An anti-diabetic

measures fail, then stimulant laxatives, such as

medicine, alpha-glucosidase inhibitors, soften stools, andpicosulfate and senna, may be tried. For patients taking

excessive softening may cause paradoxical constipation.

opioids, it is necessary to use both osmotic laxatives andSome changes in life or lifestyle that cause mental strain

stimulant laxatives.

may induce constipation. Some diseases that impairs

Lubiprostone is a very new medicine launched inoxygen intake, such as advanced emphysema, a chronic

Japan in 2013. It increases water inside the intestine

severe lung disease, may worsen movement of theand may be categorized as an osmotic laxative.

bowels and induce constipation.

Lubiprostone also seems to have an action as a class

For the prevention of constipation, the followingof “prostaglandin”, which activates movement of theare important in lifestyle: one should take meals

intestine and uterus. Hence, it may induce abortion ifwith enough fiber and enough water, avoid enduringa pregnant woman takes it. It may cause difficulty indefecation desire, and have moderate physical activities.

breathing in 2 to 4 percent of the persons who take it.

The movement of the bowels becomes most active

Lubiprostone treatment may be considered forparticularly 10 to 30 minutes after breakfast, which may

carefully-selected patients, with the exception of women

be the best time to defecate. It is important to habituateof childbearing age, if all other laxatives failed.

bowel movement every day in this time.

However, it is difficult to find a place for lubiprostone

If you fail to improve constipation by removing

in the general approach to treatment of chronic

medicines that might caused your constipation andconstipation because it is not superior in efficacy andby practicing other preventive measures above, yoursafety compared with conventional laxatives, and its

physician will check for mechanical obstruction of theprice is extremely high.

Page 28 ・ MED CHECK - TIP AUGUST 2015 / Vol.1 No.2

Adverse Reactions
Reactions
Adverse
Propofol-induced death in children: at a Univ. Hospital
Contraindicated for mitochondrial toxicity, withdrawal malignant syndrome suspectedTranslated from Med Check TIP (in Japanese) 2015; 15 (May:#59); 64-65.
Abstract:
An analytical report on a case of the death of a child involving administration of the contraindicated drug “propofol”
was published. The report concluded that “propofol infusion syndrome” was the direct cause of death. It also reported
that the contraindicated drug was used at high doses over a long period. As for the underlying cause of this death,the report pointed out that the physicians and pharmacists involved lacked understanding of the characteristics andpotential harmful effects of the drug.
In propofol infusion syndrome, continuous administration of the drug for at least 48 hours at high doses rapidly
induces cardiac muscle injury that is accompanied by severe metabolic acidosis, rhabdomyolysis, and renal failure,leading to death. Propofol is a mitochondrial toxin. It is used as an ultra-short-acting GABAA agonist for anesthesia.
After administration is discontinued, malignant syndrome may occur because of withdrawal muscle rigidity.
The physicians did not recognize the risk of withdrawal reactions, and the package insert does not mention this risk,
which appears to be due to the characteristics of the drug as a mitochondrial toxin and a GABAA agonist with very
rapid elimination half-life. The contents of the package insert for propofol should be revised to include warning of thesepotential harmful effects.

Introduction
At Tokyo Women’s Medical University Hospital, during afive-year period up to 2013, 63 children were administeredpropofol, a drug that is contraindicated for use with children.
12 of the 63 children died [1a]. One of these was a 2-yearold boy who died in February 2014 due to an overdose of
propofol [1b,1c]. The Tokyo Women’s Medical University
Hospital Third-party Accident Investigation Committee
investigated the death of this child and published a reportwhich concluded that the direct cause of the death was
propofol infusion syndrome, and not pneumonia [1b].
The report stated that “no purposive medical justification”
could be found for administering propofol, a drug that iscontraindicated for use with children, at high doses over along period. The report concluded that this case represented“a lack of understanding of contraindicated medications.”
The report also highlighted various other issues, including
the decision by the central ICU team of physicians in chargeof postoperative management to administer propofol to thechild, the need for a monitoring system for adverse reactions,lack of appropriate referencing by pharmacists, and poor
coordination between the attending physician and ICU
physicians.
The investigation focused on the death of the child, whose
age was 2 years and 10 months. Propofol was infused for
70 hours. An earlier investigation of the other 11 propofolrelated deaths found that the maximum doses administeredexceeded 4 mg/kg/h in all cases and 10 mg/kg/h in 5 cases;
the usual adult dosage is 0.3-3 mg/kg/h [1].
Propofol is a mitochondrial toxin [2-5]. It has an anesthetic
effect as a GABAA agonist [6-9], and its half-life is extremely
short [10]. If the physicians and pharmacists involved in thecase described above had known these characteristics, theymight not have used the drug. Their lack of knowledge was
the fundamental cause of the fatality. This article examinescharacteristics of propofol that are not mentioned in thereport or in the package insert for the drug.

Overview:
The course of death and investigation of the cause
The following is a direct quote from the Investigation
Committee report [1b].
“Propofol was administered in a 2-year, 10-month oldchild over a long period: 70 hours and 15 minutes. The
total dose administered was 6953.5 mg. (The average
dosing rate over the administration period was 8.1
mg/ kg/h, which is 2.7 times higher than the maximum
rate recommended for sedation of artificially ventilated
adults.) This dosage rate is much higher than the
maximum rate of 4 mg/kg/h over 48 hours that has been
demonstrated to be safe for infants, according to theliterature.
After propofol was discontinued, high fever, increased

MED CHECK - TIP AUGUST 2015 / Vol.1 No.2 ・ Page 29

CK level, metabolic acidosis, and hyperkalemia wereobserved, and rhabdomyolysis developed. Regarding theseverity of rhabdomyolysis, CK level was 10,036 U/L at
resuscitation, and postmortem examination found thatthe lesion of rhabdomyolysis was not extensive, but only
regional.
Therefore, rhabdomyolysis alone could not havebeen the cause of death. This case followed a uniquecourse: sudden cardiac arrest occurred and marked
lactic acidosis developed, followed by hyperkalemia,
arrhythmia, and circulatory failure. This led tounsuccessful cardiopulmonary resuscitation and death.
Moreover, since day 2 of the initial dosing, negative T
waves had been observed. On day 4, not only negative T
waves but also low voltage, a prolonged QRS interval, andventricular tachycardia were observed, suggesting thepossibility of progressive cardiomyopathy. Evidence of
cardiomyopathy was not found at autopsy.
However, circulatory failure, which developed suddenly
after a short time, was refractory to cardiopulmonary
resuscitation, and life support was unsuccessful.
Considering this course, it is highly likely that prolonged
administration of propofol was directly related to thecause of death. Because the symptoms of rhabdomyolysis,high CK level, arrhythmia, heart failure, and lactic
acidosis were observed, it is reasonable to conclude that
propofol infusion syndrome was the direct cause ofdeath.”

Propofol infusion syndrome and mitochondrial toxin
Propofol was already suspected to be a mitochondrial toxin
in 1993 [11].
Tw o p a t i e n t s w i t h m i t o c h o n d r i a l m y o p a t h y w e r eadministered an anesthetic that contained propofol, andexperienced bradycardia (< 50/min). The patients received
atropine, administration of propofol was discontinued, andboth recovered.
Subsequent studies have identified the direct inhibitory
effect of propofol on energy production in the mitochondria
as an intracellular mechanism in which propofol infusion
syndrome occurs [2-5].
Propofol acts as a mitochondrial toxin by impairing freefatty acid utilization [3,4], reducing cytochrome C oxidase,and impairing coenzyme Q [5] in the mitochondria. The
heart is continuously at work and consumes a large amountof energy. It is therefore susceptible to the effect of a
mitochondrial toxin, such as propofol, and bradycardia andheart failure are easily induced.
In another case, a preterm baby (580 g) began propofol
treatment at an initial dose of 8 mg/kg/h. When the patient’s
weight reached 1380 g, the dose was increased to 60-80 mg/
kg/h infused over 2 hours. After 1 hour, bradycardia (< 100/min), lowered blood pressure (mean arterial blood pressure< 33 mm Hg), and lowered oxygen saturation (85-93% ) wereobserved. Propofol was discontinued after 2 hours, and thepatient’s condition gradually improved [12]. This case showsthat if a higher dose of propofol is infused even for 1 hourPage 30 ・ MED CHECK - TIP AUGUST 2015 / Vol.1 No.2

in patients, such as premature babies and infants, who havesmall reserves of glycogen and need to use fatty acid as
their source of energy, propofol infusion syndrome may be
induced. Concomitant use of catecholamines and/or steroids
is also a risk factor [3].

Ultra-short-acting GABAA agonist:
The possibility of withdrawal malignant syndrome
Propofol is a GABA A agonist [6-9, 13, 14], and its
elimination half-life is extremely short.
According to the package insert of diprivan Injection “Whensingle bolus doses of propofol 1.0, 2.0, and 2.5 mg/kg wereintravenously administered in 6 healthy Japanese adult males,
pharmacokinetics of propofol fit a 3-compartment model,
and all blood concentrations decreased in 3 phases. The halflives of each phase were 2.6 minutes ( α -phase), 51.0 minutes( β -phase), and 365 minutes ( γ -phase).”Both the α - and β -phases were shorter than 1 hour, andthe γ -phase was as short as 6 hours. Elimination half-livesof triazolam and zolpidem, which are regarded as ultrashort-acting hypnotics, are 2.9 hours and 1.8-2.3 hours
respectively, and the half-life of a short-acting hypnotic
brotizolam is about 7 hours. Even the γ -phase of the halflife of propofol is shorter than the half-life of brotizolam.
Short-acting benzodiazepines may induce withdrawal
catatonia - malignant syndrome. A patient discontinued
triazolam and brotizolam for 1 night because he was goingto have a blood sample taken for a medical check-up. At
about 10 a.m. on the following day, the patient experienced
generalized rigidity, and developed catatonia - malignant
syndrome with increased CK level [15].
It should be understood that ultra-short-acting propofol
may develop dependency in an extremely short time, andmay cause malignant syndrome with withdrawal muscle
rigidity and fever.
In fact, it has been reported that when propofol wasadministered for the treatment of typical generalized tonicclonic status epilepticus, withdrawal convulsions occurredas quickly as after 1-2 days [9]. A 41-year-old woman
received propofol for the treatment of status epilepticus,
and the condition was well controlled. On the following
day, propofol was discontinued, and convulsions recurred
after 10 minutes. Because persistent high-frequency coarse
rhythmic shaking was observed, the patient was diagnosed
with status epilepticus, propofol treatment was resumed, andconvulsions subsided. A second trial of propofol withdrawal
was performed with an epileptologist at the patient’s bedside.
Similar convulsive motor activity occurred again, about fiveminutes after discontinuation of propofol treatment, but theconcomitant electroencephalograph (EEG) showed muscle
artefact to be without any ictal activity. Propofol treatment
was not restarted and the patient was sedated with fentanyl.
Based on these findings, the convulsions were considered tohave been caused by propofol withdrawal.
In the fatal case of the child in Tokyo Women’s Medical
University Hospital, although the temporality remains
unclear, the report concluded: “After propofol wasdiscontinued, high fever, increased CK level, metabolic acidosis,
and hyperkalemia were observed, and rhabdomyolysis
developed.” These findings strongly suggest that dependency
on propofol developed rapidly, leading to malignantsyndrome-like pathology, including increased CK level andfever caused by withdrawal muscle rigidity.

Proposal
Propofol is a mitochondrial toxin. Its toxicity may appear
early in patients with severe conditions who have small
glycogen reserves or in patients who are fasting. It isan ultra-short-acting GABA A antagonist, and may cause
withdrawal convulsions or withdrawal catatonia-malignant
syndrome that can lead to rhabdomyolysis.
Warnings of these potential harmful effects should beclearly stated in the package insert for propofol.

References
1) a) Asahi Newspaper July 09, 2014: Tokyo hospital gave 16 children excessive doses ofanesthetic agent propofol
accessed on 30/07/2015 available at:
http://ajw.asahi.com/article/behind_news/social_affairs/AJ201407090060b) Tokyo Women's Medical University Hospital:
Examination report on "a post-operative death case from cervical cystic lymphangioma”c) summarized report as the Hospital (in Japanese) accessed on 31/03/2015,
Available at
http://www.twmu.ac.jp/info-twmu/index/news-all/616-20150427.html
2) Wolf A, Weir P, Segar P, Stone J, Shield J. Impaired fatty acid oxidation in propofol
infusion syndrome. Lancet. 2001 24;357(9256): 606-7. Mitochondria
3) Vasile B, Rasulo F, et al. The pathophysiology of propofol infusion syndrome: a simple
name for a complex syndrome. Intensive Care Med.
4) Finsterer J, Segall, L. Drugs interfering with mitochondrial disorders 2010, 33(2): 138-151.

Plain Language summary

Anesthetic-induced deaths in children: at a Univ. Hospital
Contraindicated due to heart toxicity
Abstinence syndrome may be suspected
At Tokyo Women’s Medical University Hospital,
during a five-year period up to 2013, 63 children

to move continuously and requires high energy. The
toxicity to mitochondria could induce patient death.

were administered propofol, an anesthetic drug that is

Propofol also acts like an extremely-short-acting

contraindicated for use with children. Of the 63 children

sleeping pill, far shorter than a typical short-acting

12 died. The third-party to the university hospital

sleeping pills such as triazolam (brand name: Halcion

published a report focusing on the death of the child,etc.) or zolpidem (brand name: Ambien etc.) or alcohol.

whose age was 2 years and 10 months.

Propofol could induce abstinence seizures if it is stopped

The report concluded from the medical aspects that

abruptly, just like after stopping short acting sleeping

the direct cause of the death was “propofol infusion

pills or alcohol. Propofol could induce abstinence

syndrome”, a sort of toxic syndrome due to the drug. The

seizures/muscle contraction far earlier than the short-report stated that “no purposive medical justification”

acting sleeping pill or alcohol. There is a report that

could be found for administering propofol, a drug that is

abstinence seizures occurred following discontinuation

contraindicated for use with children, at high doses overof the drug after the use for one day. Abstinence seizures

a long period.

or continuous muscle contracture may cause fever or

The report also concluded from the aspects ofthe system, that this case represented “a lack ofmuscle destruction followed by pneumonia, kidneydamage and death.

understanding of contraindicated medications” in the

Physicians and pharmacists are not familiar withmedical professionals including attending physicians,

these facts that propofol is toxic to mitochondria andcentral ICU team of physicians, pharmacist. Their poorthat abstinence seizure could induce death, because thecoordination was also highlighted.

package insert of propofol for professionals does not

Propofol is a very toxic substance that impairs

describe them.

mitochondria, an indispensable apparatus for respiration

Warnings of these potentially harmful effects should

and oxygen utilization within a cell. It is especially toxic

be clearly stated in the package insert for propofol toto heart muscle in infants whose nutritional reserve isprevent use in children.

scarce because heart muscle usually consumes oxygen

MED CHECK - TIP AUGUST 2015 / Vol.1 No.2 ・ Page 31

M
C

ED

HECK

The Informed Prescriber
2015

Vol.1

No.2

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD); TANIDA, Noritoshi (MD)Managing Editor: SAKAGUCHI, Keiko
Editorial Staff: NAKANISHI,Takeaki(Pharmacist); OHTSU,
Fumiko.(Pharmacist) ; TAKANO, Yoshihiko(MD[ pediatrician ]/Pharmacist) ; YANAGI, Motokazu (MD); YASUDA, Yoshinobu(Pharmacist)
Translators: NAKAMURA, Akari ; TAKAMACHI, Koji

Page 32 ・ MED CHECK - TIP AUGUST 2015 / Vol.1 No.2

Advisors:HONZAWA,Tatsuo (MD[GP]); IWAMOTO,Kayoko(Pharmacist);KIM,Mieko(Pharmacist); MUKAI, Junji (Pharmacist); SEGAWA,Yusuke;
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