MC

ED

Volume 9

April

HECK

2023

N 26
o

Editorial
Ineffective substances should not be approved

Review

SGLT2 inhibitors should not be used
HPV Vaccines: harmful and ineffective
Tacrolimus ointment: robust risk of malignancy

CONTENTS (April 2023, Vol. 9, No. 26)
Editorial
Ineffective substances should not be approved
Review
SGLT2 inhibitors should not be used
No proof of efficacy both for diabetes and heart failure
HPV vaccines:
Seriously harmful and do not prevent cervical cancer
Adverse Reactions
Tacrolimus ointment:

2
3
10

12

Robust carcinogenicity including malignant lymphoma

MED CHECK

Apr. 2023/ Vol.9 No.26 ・ Page 1

ED
HECK

Ineffective substances should not be approved
Translated from the Editorial in Med Check(in Japanese) Jan. 2023 ; 23 (105)：3

Editorial

M
C

In May 2022, a Japanese law was amended to enact emergency use authorization, which allows

approval of new products as medicines easier. Medicines are not approved unless their efficacy isproven in the previous law. However, in the amended law, they can be approved if the efficacy ispresumed when no other appropriate alternatives were available for serious diseases.
Ensitrelvir (Xocova®, Shionogi), as an anti-viral against SARS-CoV-2 is the first agent which wasapproved under this amended law. According to Med Check’s analysis, the baseline characteristics,
which were crucial for the assessment, was markedly (phase 2a) and significantly (phase 2b) in favorof Xocova. If this bias was adjusted, Xocova may not be effective. Moreover, in the phase 3 trial,
the baseline characteristics were not disclosed. The government must have received the wholedata. However, it granted the emergency use authorization without disclosing the information andpurchased Xocova for 1 million people (worth of 1000 billion yen) despite it did not meet even thecriteria for the emergency use authorization.
An even larger problem is the Omicron bivalent vaccines (against: ancestral ＋ BA1 or BA4/5). Clinical
trials have never been conducted to confirm the prophylactic efficacy of either vaccine against

Editoria

COVID-19. For BA1 vaccines, increase in neutralizing antibody was studied in a small number ofparticipants and antibody against ancestral strain increased most, while anti-BA1 antibody increased

only slightly. For BA 4/5 adapted bivalent vaccines, no increase of neutralizing antibody against
the BA 4/5 was observed. However, it was granted with fast-track approval despite that there wasno difference in increase in neutralizing antibody between BA 4/5 bivalent vaccines and original

monovalent vaccines at all in the published data, and ineffectiveness was presumed or even definite.

As of April 28th, 2023, neither Summary Bases for Approval nor Review Report by the Japanese
regulator for BA4/5 bivalent vaccines have been disclosed. Moreover, it became totally ineffective

against newly emerged BQ.1.1 or XBB.1 (BA5 sublineages) now, but the bivalent vaccines arecontinuously recommended for prophylaxis of COVID-19 by the governments and the World HealthOrganization.

Evusheld®, an antibody cocktail product was approved not only for the treatment but also forprophylaxis of COVID-19, despite its effectiveness was dubious. As of April 28th, all monoclonal
antibody products were revealed ineffective based on the in vitro studies.

A huge amount of national budget has been spent on substances whose ineffectiveness and harm

are presumed or established. Such substances should not be approved because it does not benefit
the public, but pharmaceutical companies, and it does only harm.

Page 2 ・ MED CHECK

Apr. 2023/ Vol.9 No.26

Review
SGLT2 inhibitors should not be used

No proof of efficacy both for diabetes and heart failure
Translated and revised from Med Check (in Japanese) Jul. 2022 ; 22 (102)：83-86

Abstract

Med Check Editorial Team● SGLT2 inhibitors lower blood glucose levels by inhibiting the action of the pump that reabsorbs sodium andglucose in the kidneys (Sodium Glucose Cotransporter 2: abbreviated SGLT2), causing glucose to be excreted
in the urine. In addition to diabetes, some preparations are approved for use in chronic heart failure andchronic kidney disease.
● A total of 11 large-scale randomised, double-blinded controlled trials (RCTs) investigating the long-term
prognosis of patients treated with SGLT2 inhibitors - six in diabetics, four in heart failure patients and one inchronic kidney disease patients - have claimed to reduce hospital admissions for heart failure and reduce allcause mortality.
● However, SGLT2 inhibitors have significant diuretic effect and even with the double blinding method,
the physician can easily know to which the patient was allocated SGLT2 inhibitor group or placebo group,
resulting in incomplete blinding (blinding failure or masking failure). As a result, the outcome may beassessed in favour of SGLT2 inhibitor group and against placebo group. The phenomenon of a sharp increasein events in the placebo group after a point, and a slower increase in the SGLT2 inhibitor group conversely,
may be due to this effect. There were total of 6 such trials (3 in diabetes, 2 in heart failure and 1 in renal
disease).
● There were three trials in which baseline characteristics affecting prognosis were biased in favour of the
SGLT2 inhibitor group, although signs of blinding failure were not clear. The hazard ratio (HR) for all-cause
mortality was adjusted by the odds ratio of important baseline characteristics in these 3 RCTs. There were
2 RCTs which had neither biased baseline characteristics nor clear signs of blinding failure. Meta-analysis
was performed using a total of 5 RCTs above. Combined HR for all-cause mortality was 1.01. This means that
SGLT2 inhibitors were not at all effective to reduce all-cause mortality.
● The blinding failure also has a significant impact on the registration of adverse events. Genital infections
and ketoacidosis were reported more frequently in SGLT2 inhibitors irrespective of blinding failure. On
the other hand, lower limb amputations, fractures and urinary tract infections were reported with similarfrequency in both groups in RCTs with sings of blinding failure, while these events were more frequently
reported in SGLT2 inhibitor group in RCTs without conspicuous blinding failure.
Conclusions: SGLT2 inhibitors should not be used for diabetes, heart failure and renal failure.

Keywords:
Randomized controlled trials, all-cause mortality, biased baseline characteristics, masking (blinding) failure, heart failure, renal injury,
genital infections, ketoacidosis, lower extremity amputation, fracture

MED CHECK

Apr. 2023/ Vol.9 No.26 ・ Page 3

Review
Introduction

SGLT2 inhibitors increase urine output by up to l L/day

We assessed SGLT2 inhibitors as 'Do not use for

In a study with tofogliflozin, an SGLT2 inhibitor, urine

diabetes or heart failure' in Med Check No101 [1].

output increased by an average of approximately 600 mL per

In this issue, the rationale is explained in detail.

day after use, from 1300 mL before use to approximately

Diabetes-related medical society guidelines recommend

1900 mL (standard deviation 437 mL), and the frequency of

the use of SGLT2 inhibitors to reduce cardiovascularurination increased approximately times per day (from 5.6

events in type 2 diabetes patients with or at high risk of

to 8.4 times) [18]. The data (average increase and the standard

cardiovascular disease or heart failure [2,3]. The American

deviation) indicate that there may be some patients with

Diabetes Association's 2022 guidelines [3] recommend SGLT-

more than 1000 mL of urine volume increase. If the urine

2 inhibitors on the basis of the results of a number of large

volume and the frequency of urination also increase by thisrandomised controlled trials (RCTs) [4-11]. Subsequently,

much, it is easy for the patients themselves and their doctors

three large RCTs [12-14], as well as two systematic reviews

to guess whether a placebo or a new product was used.

[15,16] have been published; a systematic review by

SGLTs include SGLT1 and SGLT2; SGLT1 is present

Giugliano et al [16] meta-analysed a total of 11 RCTs [4-14].

in the gastrointestinal tract and in almost every organ,

However, these RCTs on which the society based

including liver, lungs, heart, brain, spinal cord, testes,

its recommendation include the empagliflozin RCT [4]prostate, colon, bronchi, spleen, uterus and pancreas. SGLT2

which Med Check editorial team described as 'trial results

is also present in many organs other than kidneys such aswere unreliable' (April 2015) [17]. We also questioned

testes, cerebral arteries, cerebellum, cerebrum, thyroid gland

the reliability of other RCTs, therefore we conducted

and liver etc. It is involved in neurological functions [17].

a comprehensive review of RCTs on SGLT2 inhibitors
including 5 RCTs [4-8] in the Cochrane systematic review

All-cause mortality is shown in this analysis[15] and six more [9-14], for a total of 11 RCTs [4-14].

I n m o s t R C Ts ' h o s p i t a l i s a t i o n f o r h e a r t f a i l u r e
or cardiovascular death' was the primary endpoint.
'Hospitalisation' as an endpoint is vulnerable to performance

Figure 1: Reported meta-analysis results of large-scale RCTs of SGLT2 inhibitors*Combined hazard ratios (HRs) and their 95% confidence intervals (95% CI) are based on Giugliano et al.[16].
Baseline characteristics: ○= no serious bias, × = biased (p<0.1),
Signs of blinding failure: ○= unremarkable, ∆ = possible, × = probable ~ pronounced
Eligibility for inclusion for meta-analysis: ○= eligible, × = ineligible, ♦ = eligible after adjusting hazard ratio by odds ratio as bias in the baselinecharacteristics,
DM:Diabetes, CVD: cardiovascular diseases, HF:heart failure, Red.: reduced, Pres.: preserved R: renal disease, CKD: chronic kidney disease.

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Apr. 2023/ Vol.9 No.26

or detection bias which is likely to be strongly influenced by

We investigated the extent of bias in the baseline

blinding failure as mentioned above for SGLT2 inhibitors.

characteristics and signs of blinding failure in the

Therefore, in this issue, we will conduct a meta-analysis on

studies and then, categorised as follows:.

'all-cause deaths' as the primary outcome, which the Med

Bias in the baseline characteristics:.

○ = not serious ×=biased (p<0.1).

Check editorial team places the greatest emphasis [19].
However, it is also noted that even all-cause mortality

Signs of blinding failure:○ =unremarkable,....

as an endpoint is never completely free from the influence△=possible, ×=probable ~ pronounced..

of blinding failure, as arbitrary drop-out of people who

Eligibility of inclusion for meta-analysis:○= eligible,

are likely to die can reduce the increase in mortality.

×= ineligible, ♦=eligible after correcting hazard ratio
by odds ratio as bias in the baseline characteristics.

Results of syste matic re views

The results of ref. 12) and 14), where baseline

The results of the meta-analysis of 11 RCTs by Giugliano

characteristics had neither serious bias nor serious sign ofet al. were shown in Figure 1. Five of these RCTs, reference

blinding failure (○ or △), the HRs for all-cause mortality were4) to 8), were addressed in the Cochrane review: with 4) and

0.99 and 1.00 respectively; this means SGLT2 inhibitors do not5) in diabetes patients and 6) to 8) in heart failure patients.

reduce all-cause mortality in appropriately conducted trials.

Apart from the Cochrane reviews, references 9)-12)
were studies in diabetes patients, 13) in chronic kidney

Bias in baseline characteristics and its adjustment.

disease (CKD) patients, and 14) in heart failure patients

Biased important baseline characteristics affecting outcome

with relatively preserved cardiac function (called thewith a p-value of less than 0.1 are summarised in Table 1.

EMPEROR-P study using the initial P for preserved).

In the EMPEROR-R study (empagliflozin) [7] in patients

The overall risk of all-cause mortality was reportedwith severe heart failure, the proportion of subjects withby a Cochrane review [15] with an odds ratio (OR) of

a left ventricular ejection fraction (LVEF) below 30%,

0.84 (95%CI: 0.74,0.96, p=0.01) and by Giugliano et al

meaning severe heart failure, was lower in the empagliflozin[16] with a hazard ratio (HR) of 0.87 (0.81,0.94) (Figuregroup (71.8%) than in the placebo group (74.6%) (OR:1). However, these results included an RCT [4] (HR:0.65)

0.87: 0.75-1. 00, p=0.054) , favouring the empagliflozin

which Med Check Editorial team criticised [20].

group. The difference in baseline characteristics would.

be statistically significant (p=0.0499) if the empagliflozin

Selection of appropriate studies:

Figure 2:Typical examples showing a sign of blinding failure in RCTs

A: Excerpt from Ref. 22: The number of mild asthma attack decreased in both groups until the 5th week. However from the 6th week, it suddenly increased in the placebogroup and as a mirror image suddenly decreased in the ketotifen group. There may be blinding failure and possibly as a result, data may be manipulated. A similar patternoccurred frequently in a “randomised controlled trial” in the 1980s in Japan.
B: Reading off the graph for the approximate percentage of hospitalisation for heart failure and calculating the odds ratio for the placebo group to the empagliflozingroup every 6 weeks, the lowest odds ratio was 0.69 (95% CI 0.29- 1.60) at week 30 to 36, with a maximum odds ratio of 9.92 (2.16-45.57) at week 42 to 48, followed by 4.44
(2.21-8.90) at week 0 to 6. The ratios of odds ratios for week 42 to 48 and week 0 to 6 compared with that of week 30 to 36 were 14.5 (95%CI: 2.5-82.7) and 6.5 (95%CI:2.219.3), respectively. These indicate that the relative risk of hospitalisation for heart failure in empagliflozin to placebo greatly changed, especially at the start and the end of thestudy.

MED CHECK

Apr. 2023/ Vol.9 No.26 ・ Page 5

Review
Table 1: Examples of biased baseline characteristics (P< 0.1)

DM: diabetes mellitus, LVEF:left ventriclar ejection fraction, ASCVD: atherosclerotic cardiovascular diseases, HF: heart failure, CVD: cardiovascular disease, CKD: chronic kidney diseasegroup had even one more person with LVEF below 30%.

failure 'RCT', which occurred frequently in Japan in

In the VERTIS-CV study (elzugliflozin, not approved in

the 1980s, was the ketotifen RCT [21] (Figure 2A) .

Japan) [5] in diabetic patients, 'insulin users' (indicating

Of the six RCTs, the DAPA-CK study of dapagliflozin

relatively severe diabetes) were significantly less[13] included patients with chronic kidney disease

assigned to the elzugliflozin group (OR: 0.91, p = 0.036).

(CKD) . There was a trend (OR: 0.87: p=0.0999) in favour

In the CANVAS study [9] in diabetic patients, threeof the dapagliflozin group (OR: 0.87: p=0.0999) in cases

important baseline characteristics favoured canagliflozinof reduced (<30 ml/min/1.73 m2) (e-GFR) , the mostgroup; history of atherosclerotic cardiovascular disease with

important laboratory measure of renal function (Table 1)

OR 0.89 (p=0.0096), history of cardiovascular disease with OR:

In a carcinogenicity animal study [23] in rats treated with

0.92 (p=0.046) and manifest albuminuria had an OR of 0.85

dapagliflozin for two years, chronic nephropathy increased(p=0.028), all of which were lower in the canagliflozin group.

in a dose-dependent manner, significantly approximately

Biased baseline characteristics was corrected by calculating

doubling at the lowest dose (4.3 times the human dose). No

the ratio of the ORs (HR instead of OR of total mortality

dose has been identified that does not exacerbate nephropathyby the OR of important biased baseline characteristics) and(Appedix 2). Chronic nephropathy with dapagliflozin has been

its 95% confidence interval using Kolassa's method [21].

described as a degenerative disease specific to male rats, but
at high doses chronic nephropathy also occurs in females

Signs of blinding failure

and may be exacerbated in humans with renal impairment.

A total of six trials with a profound sign of blinding

The indication of dapagliflozin for chronic renal

failure were identified, including the EMPA-REG trial

impairment is based on this DAPA-CK study, but a substanceby Zinman et al. [4], a typical example was shown inwith renal impairment is used for renal impairment. What

Figure 2B. Another typical example of sings of blinding

possible explanation can be offered for this discrepancy?

Figure 3: Meta-analysis results of all-cause mortality using eligible RCTs
*a: Adjusted for history of ASCVD, *b: Adjusted forinsulin use, *c: Adjusted for LVEF ≤ 30.
Pooled odds ratio for all-cause mortality in diabetes
mellitus (ref. 9,5,12) was 1.00 (95%CI: 0.90, 1.11),
Pooled odds ratio for all-cause mortality in heart
failure (ref. 7,14) was 1.02 (95%CI: 0.90, 1.15).
ASCVD: atherosclerotic cardiovascular disease, LVEF:
left ventricular ejection fraction.

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Apr. 2023/ Vol.9 No.26

SGLT2 inhibitors do not reduce all-cause mortality
by adjusting serious bias in baseline characteristics

Adverse reactions to SGLT2 inhibitors
There are known some adverse reactions to SGLT2

Figure 3 showed the results of the meta-analysis of

inhibitors: genital infections, urinary tract infections,

total mortality in the relatively unproblematic RCTs. We

ketoacidosis, lower limb amputation, fractures,

synthesised two RCTs [12,14] with no sign of blinding

dehydration and stroke. These adverse reactions were

failure in all-cause mortality without serious bias inr e p o r t e d f r o m s p o n t a n e o u s l y a n d R C Ts s u b m i t t e dimportant baseline characteristics, plus three RCTs

to the monitoring system, while carcinogenicity was[5,7,9] that corrected for OR of baseline characteristics.

also suspected from animal studies [17,20, 24-26].

C o n s e q u e n t l y, t h e c o m b i n e d o d d s r a t i o w a s 1 . 0 1 .

In most RCTs, genital infections were reported more

Each RCT and the two systematic reviews emphasised

frequently in the SGLT2 inhibitor group. However, therethat SGLT2 inhibitors reduced the risk of heart failure,are very many reports of urinary tract infections, generalcardiovascular disease and renal failure and reduced

infections, lower limb amputations and fractures, whererisk of hospital admissions, mainly due to heart failure.

there were no significant differences. Blinding failure may

However, there was no difference at all in total mortality,

also influence reports of adverse events. Therefore, a meta-

indicating an increase in deaths from other cause.

analysis was performed separately for the five RCTs with no

The RCT by Anker et al [14] (EMPEROR-P) was adequate,

noticeable signs of blinding failure and the six RCTs with

with no signs of blinding failure or serious bias in baseline

signs of blinding failure, and the results were shown in Table 2.

characteristics. In this trial, the cause of death for all deaths

In the six cases with significant signs of blinding failure,

were published. It shows that there were 13 (0.43%) deaths

genital tract infections and ketoacidosis were significantly

from trauma in the empagliflozin group compared to 2 (0.07%)

more common in the SGLT2 inhibitor group, while urinary

in the placebo group, with a significant OR of 6.51 (95%CI: 1.5,

tract infections, fractures and lower limb amputations all

28.9, p = 0.0045). The mechanism by which trauma leads toshowed little difference from the placebo group. However,death is not fully known, but it is suspected to be related to thein five RCTs without apparent signs of blinding failure, theadverse effects of SGLT-2 inhibitors that have ever been noted

overall OR was 3.50 (p<0.0001) for genital tract infection,[17, 24-26]. These include that SGLT2 inhibitors can lead to

2.12 (p=0.0016) for ketoacidosis, 1.12 (p=0.0005) for urinary

severe infections [23], that they can cause a high incidence

tract infection, 1.26 (p<0.0001) for fracture and 1.36 (p=0.0016)

of blood flow failure that forces lower limb amputation

for lower limb amputation All were reported significantly[24] and that they can cause high incidence of fractures.

more frequently for SGLT2 inhibitors, and these were

In any case, the cause of death for all deaths

considered to be adverse reactions due to SGLT2 inhibitors.

i n o t h e r R C Ts n e e d s t o b e p u b l i s h e d i n o r d e r t o

In the CANVAS study [9], a HR of 1.97 (p<0.0001)

know what the most common causes of death could

for lower limb amputation was reported almost twice

be involved other than cardiovascular disease.

as high. Even in the five cases where signs of blinding
failure were less obvious, it should be considered that

Table 2: Combined odds ratio of adverse events, by sign of blinding failure*a: Pooled odds ratio by fixed model. *b: OR=1.21(0.86, 1.71, p=0.279) by Random model *c: OR = 1.84 (0.67, 1.5.02, p = 0.236) by Random model, *d:Including results specific to genital fungal infections.
*e: Amputation was not described in the RCT by Zinman et al. [4] (with signs of blinding failure).

MED CHECK

Apr. 2023/ Vol.9 No.26 ・ Page 7

Review
they are not completely free from the effects of blinding
failure and that the actual harm should be even greater.

Conclusion
S G LT 2 i n h i b i t o r s s h o u l d n o t b e u s e d f o r
diabetes, nor for heart failure and renal failure.

Appendix 1: Dapagliflozin rat carcinogenicity study for 2 years

A. Chi2 for linear trend: male: p=0.0002, total: p=0.0002 and significant, female: p=0.070. 0.5 mg/kg males and total had odds ratio of 2.23 (p=0.008),
and 1.81 (p=0.018) compared with control group respectively. Female 2 mg/kg group had a significant odds ratio of 3.98 (p=0.011) compared withthe control group. The male 0.5 mg/kg group is only 4.3 times the human dose in terms of blood concentration (AUC). Chronic nephropathy isconsidered to be a degenerative disease specific to male rats, but it also occurred in female rats at high doses, and the possibility of exacerbating
renal disorders in humans cannot be denied.
B. Trend analysis by Chi2 for linear trend: p<0.0001 for males, females and total. 0.5 mg/kg males, females, totals (versus the control group) were all
significant with odds ratios of 10.8 (p<0.0001), 3.8 (p=0.0001), 8.8 (p<0.0001), respectively. In the male 0.5 mg/kg group, the blood concentration (AUC)
conversion was only 4.3 times the human dose. Manufacturer explain that the hypertrophy and vacuolization in the adrenal gland is those in thezona glomerulosa which is the aldosterone secreting site. However, hypertrophy of the zona fasciculata were observed even at the lowest dose in
the empagliflozin toxicity tests (Appendix 2) and they did not report the findings in the zona fasciculata in the Dapagliflozin toxicity test. Hence, it isunreliable that dapagliflozin does not cause hypertrophy of the fasciculus. Based on the data from the Toxicity, Summary Bases of Approval of
Dapagliflozin

Appendix 2:Adrenal lesion in rat 6 month toxicity test of Empagliflozin

In a 6-month toxicity study of empagliflozin in rats, not only vacuolization of the zona glomerulosa which is the aldosterone-secreting site(A), but also hypertrophy of the zona fasciculata which is the glucocorticoid-secreting site (B) is observed with very high proportion evenat the lowest dose (30 mg/kg) for both males and females (p<0.0001) compared with all zero in the control groups.
Based on the data from the Toxicity, Summary Bases of Approval of Empagliflozin

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Apr. 2023/ Vol.9 No.26

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Review

HPV Vaccines
Seriously harmful and do not prevent cervical cancer
Translated and revised from Med Check(in Japanese) Mar. 2023 ; 23 (106)：34
Med Check Editorial TeamThe active recommendation of HPV(human papillomavirus)

vaccine [2]. Even on the basis of this data, the incidences

vaccines, or so-called “cervical cancer vaccines ” wasof various symptoms increased by 28-fold in the vaccinatedonce suspended in 2013, but was resumed in April, 2022

group as compared with the unvaccinated group [25].

in Japan[1]. The main reasons for the resumption were theresults of studies showing that the various symptoms observed

Neurological symptoms increased over 5-fold in theafter vaccination were also observed in unvaccinated wemen

Danish study[2] and that the vaccine contributed to a decrease in cervical

The Danish epidemiological study published in September,cancer [3]. However, as Med Check has discussed in detail

2020, investigated intractable neurological symptoms after[4-25], the vaccine is certainly harmful, while there is novaccination, such as complex regional pain syndrome (CRPS),

evidence to prove the reduction in cervical cancer. This article

chronic fatigue syndrome (CFS) or postural orthostatic

summarises the critical investigations of the data which thetachycardia syndrome (POTS). The authors concluded thatdecision for the resumption was based on.

there was no significant increase [29].
However, by our calculation adjusting these results forAll-cause mortality increased 5-fold after vaccination

the rate ratio (0.22, 95%CI:0.03-1.54) within one week from

We conducted a meta-analysis of randomized controlled-

vaccination which is estimated from the reported data,

trials (RCTs) for HPV vaccine involving women aged 25-40

adjusted rate ratio was significantly increased more than 4.0

years [26-28 9-11]. As a result, risk ratio of all-cause mortality

after 3 months or more than 5.0 after 6 months.

was 5-fold as compared with the controlled group, suggestinghigh toxicity of the vaccine.

Real reason for lower cancer incidence in vaccinee
HPV vaccine cannot prevent nor reduce non-HPV-related

Severe disability increased 47-fold after vaccination incancer. However, in the Finish study [30], the incidence

the Nagoya study

rate ratio of non-HPV-related cancer overall, including

Med Check editorial team calculated the risk of HPV

breast cancer and thyroid cancer, comparing vaccinatedvaccine after adjusting for the health status before vaccination,with unvaccinated was 0.43. This result suggests that thebased on the raw data of Nagoya study, which involved

unvaccinated women were originally sicklier, and had 2.3-

about 700,000 women aged 25-40 years [25]. The result

fold (1/0.43) higher tendency to have cancer as compared withshowed that those who experienced severe disability, suchthe vaccinated women. For a fair comparison, adjustment

as becoming dependent on a walking stick or wheelchair,must be made: the incidence of cervical cancer in theincreased by 47-fold in the vaccinated group as comparedunvaccinated group is divided by 2.3. The adjusted resultwith the unvaccinated group. Moreover, loss of ability toshows no significant difference between the vaccinated andremember fundamental Kanji (Chinese characters indispensable

unvaccinated groups (see [25] for more details).

for life in Japan), loss of ability to perform simple calculations,

The Swedish study [31] also reported that the risk of cervicalloss of ability to walk normally, weakness in the hands andcancer was reduced. However, after the same adjustment asfeet also increased by 25-fold, 16-fold, 11-fold, and 9.2-fold,above, no effect of the vaccine was observed [25].

respectively [13].
Japan’s Mistry of Health, Labour and Welfare (MHLW)The British study was also biased

disclosed data that provide “evidence” for the safety of HPV

The British study [3] reported that HPV vaccination offered

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Apr. 2023/ Vol.9 No.26

to women aged 16-17 years, 14-15 years, 12-13 years the18) Web MedCheck No174 (2016.10.15) Deteriorates cognitive and motor

risk reduction of cervical cancer by 34%, 62%, and 87%,19) Web MedCheck No177 (2018.03.08) Symptoms after HPV vaccination (inrespectively, by comparing with earlier cohorts that were noteligible for HPV vaccination. However, after the adjustment,functions(in Japanese)
Japanese)20) Hama R et al. efficacy and harm of HPV vaccine. The Informed Prescriber
2013：28(2):17-27(in Japanese)．

there was no difference in women aged 14 years and older21) Hama R et al. Risk of autoimmune diseases after HPV vaccination. The[25]. Even in women aged 12-13 years, there was only a slight22) Hama R. Cochrane review should be revised due to overlooked trials, toxicity

difference when the adjustment was made based on the healthstudies with serious healthy-vaccinee effect. Rapid response (on 8. Sept. 2018)

condition prior to the vaccination. The study authors attributed
the unmarked decrease in women aged 14 year or older to that

Informed Prescriber: 2013：28(5)：89-99．(in Japanese)of adjuvant, mortality in mid-adult women and lack of discussion on observational
to "The Cochrane HPV vaccine review was incomplete and ignored important
evidence of bias" by Jørgensen et al:
https://ebm.bmj.com/content/ebmed/23/5/165.full.pdf

they might have already been exposed to HPV (or might have23) Hama R Benefits and Harms of HPV Vaccine-Evidence-based

experienced sexual intercourse). However they never mentioned24) Resuming HPV vaccine is very dangerous. MedCheck 2022: 22 (99): 20-21.

the healthy vaccinee effect which may be extreme in women
aged 12-13 years then those aged 14 years or older.

Updates, Sexual Health, 2021: 20 (4): 41-59. (in Japanese)(in Japanese)25) MedCheck editorial team. Resuming HPV vaccination is dangerous.
MedCheck in English 2022: 8(No23): 3-10.
https://www.npojip.org/english/MedCheck/Med%20Check%20TIp-23-2022-04.pdf
26) Skinner SR, Szarewski A, Romanowski B, Garland SM, Lazcano-Ponce E,

Conclusions
HPV vaccine is not only ineffective, but harmful.
The immunization with the vaccine should besuspended.

Salmeron J. Efficacy, safety, and immunogenicity of the human papillomavirus
16/18 AS04- adjuvanted vaccine in women older than 25 years: 4-year interim
follow-up of the phase 3, double-blind, randomised controlled VIVIANE study.
Lancet 2014;384(9961): 2213–27. PMID: 25189358
27) Wheeler CM, Skinner SR, Del Rosario-Raymundo MR, Garland SM,
Chatterjee A, Lazcano-Ponce E, et al. Efficacy, safety, and immunogenicityof the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older
than 25 years: 7-year interim follow-up of the phase 3, doubleblind, randomised

References
1) Haruyama R, Obara H, Fujita N. Japan resumes active recommendations of
HPV vaccine after 85 years of suspension. Lancet Oncol. 2022 Feb;23(2):197198. doi: 10.1016/S1470-2045(22)00002-X.PMID: 35114115
2) Sobue T et al. Epidemiological study on evaluation of effectiveness and safetyof cervical cancer vaccine: 2016 Report for MHLW grant.
3) Falcaro M, Castañon A, Ndlela B et al. The effects of the national HPV
vaccination programme in England, UK, on cervical cancer and grade 3 cervicalintraepithelial neoplasia incidence: a register-based observational study.
Lancet. 2021 Dec 4;398(10316):2084-2092. PMID: 34741816
4) Med Check No 52：Learn more about vaccines, the benefits and harms of
HPV vaccines, 2013.10 (in Japanese)5) Med Check No 53：Learn more about vaccines, Part2: Hepatitis B, Japanese
encephalitis, adjuvant 2014.01 (in Japanese)
6) MedCheck No57: About the epidemiological study on the harm of HPV vaccine

controlled VIVIANE study. Lancet Infectious Diseases 2016;16(10):1154-68.
PMID: 27373900
28) Castellsagué X, Munoz N, Pitisuttithum P et al. End-of-study safety,
immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18)
recombinant vaccine in adult women 24 to 45 yers of age. British Journal ofCancer 2011;105(1):28–37. PMID: 21629249
29) Hviid A, Thorsen NM, Valentiner-Branth P, Frisch M, Mølbak K. Association
between quadrivalent human papillomavirus vaccination and selected
syndromes with autonomic dysfunction in Danish females: population based,
self-controlled, case series analysis. BMJ. 2020 Sep 2;370:m2930. doi:
10.1136/bmj.m2930.PMID: 32878745
30) Luostarien T, Apter D, Dillner J, et al. Vaccination protects against invasive
HPV-associated cancers. Int J. Cancer 2018;142:2186-2187. PMID: 29280138
31) Lei J, Ploner A, Elfström KM, et al. HPV Vaccination and the Risk of Invasive
Cervical Cancer. N Engl J Med. 2020 Oct 1;383(14):1340-1348. PMID:
32997908(in Japanese)
7) MedCheck No62: Intractable disease after HPV vaccination (in Japanese)
8) MedCheck No65: HPV Vaccine Damage and "Healthy vaccinee Bias” (inJapanese)
9) MedCheck No77: Suzuki's paper shows the harm of HPV vaccine (inJapanese)10) MedCheck No80: HPV vaccine increases mortality: Cochrane data (inJapanese)11) MedCheck Editorial team. Harm of HPV vaccine: Latest information andexamination of epidemiological studies. MedCheck in English. 2015: 1 (No.1):9-14.
https://www.npojip.org/english/MedCheck/Med%20Check-TIP%2001-4-25.pdf12) MedCheck Editorial team. Symptoms after HPV vaccine: typical “frailty
exclusion bias” in Nagoya study. MedCheck in English. 2016: 2(No 5): 18-21.
https://www.npojip.org/english/MedCheck/Med%20Check-TIP%2005-08-08.pdf
13) Web MedCheck No163 (2013.11.18) HPV (cervical cancer) vaccine isdangerous. (in Japanese)
14) Web MedCheck No164 (2014.01.28) Thorough verification of HPV vaccine(inJapanese)
15) Web MedCheck No165 (2014.01.29) Possibility of 1 in 100-200 serious
reactions(in Japanese)
16) Web MedCheck No166 (2014.01.29) Resuming recommended vaccination isextremely dangerous(in Japanese)17) Web MedCheck No167 (2014.02.28) International Symposium on Harm(inJapanese)

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Apr. 2023/ Vol.9 No.26 ・ Page 11

Adverse Reactions
Tacrolimus ointment for atopic dermatitis
Robust carcinogenicity including malignant lymphoma
Translated and revised from Med Check(in Japanese) Mar. 2023 ; 23 (106)：42-44
Med Check Editorial Team

Abstract● When approval for tacrolimus ointment 0.03% for pediatric atopic dermatitis was reviewed in 2003, Japan’s
Ministry of Health, Labour and Welfare (MHLW) included cancer risk in “Red-Box Warnings” of the package insert
to impose obligation on doctors to provide the information to patients, after MedCheck’s petition against its
approval.
●However, in 2021, the caution level was downgraded from “Red-Box Warnings” to “Precautions” in the package
insert. The reason for this change was that no malignant tumor, including skin cancer, had been observed in atreatment outcome study in Japan.
●United States followed the strict measure in Japan and warned of carcinogenicity, resulting in drastic decreasein use, and many epidemiological studies were conducted. By meta-analyzing these studies, it was found thatincidences of malignant lymphoma and leukemia in the tacrolimus group were twice (all ages including adults)
and 46 times (children) as high as those in the control group.
●The person-years observed in the Japanese study, which the MHLW’s decision was based on, was only 1/140 of
those in all epidemiological studies abroad. In such a small-scale study, it is natural that rare cancer like malignant
lymphoma, would not be detected. The explanation in the package insert, “no malignant tumor was reported” iserroneous.
Conclusions: Tacrolimus ointment increases malignant lymphoma and leukemia especially in children.

Keywords:
Protopic, malignant tumor, malignant lymphoma, leukemia, immunosuppressantConditions for approval is to inform cancer risk
I n M a y, 2 0 0 3 , t a c r o l i m u s o i n t m e n t 0 . 0 3 %(Protopic®Ointment) for pediatric refractory atopic dermatitis

was discussed for approval at the pharmaceutical affairs
council. Med Check submitted a petition againt the approvalof the product, because the risk of cancer including malignant
lymphoma increased in the animal toxicity studies [1].
The council meeting was supposed to be short as it wasusually just for reporting. However, as a result of substantial
discussion, 4 strict conditions were added [2]: one of which isto provide information on carcinogenicity to users, although
Protopic® Ointment for Pediatric (0.03%) was approved (SeeTable 1). Moreover, the obligation to provide the information
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Apr. 2023/ Vol.9 No.26

was also imposed on Protopic® Ointment for adults [3].

Table 1: Four conditions for approval (summary of ref. [3])1.Provide information on carcinogenicity to patients:“Carcinogenicity” be stated in the “Red-Box Warning”
of the package insert. The pharmaceutical company
make leaflets for patients. Doctors be thorough withinformed consent.
2.Prescription be restricted to doctors who haveexpertise in atopic dermatitis.
3.Prescription record be given to patients
4.Carcinogenicity test be reconducted (at the dose lower
than 0.03%)

Adverse Reactions
Figure 1：Utilization trends before and after the warnings in US [4]Black-Box Warnings issued later in the U.S.

Warnings against carcinogenicity was removed

In the U.S., 400,000-500,000 prescriptions for

In Japan, in the package insert revised on June 21, 2021

pimecrolimus, a drug with the same indication as Protopic®,[5], the information on the carcinogenicity was moved fromused to be issued monthly [4]（Figure 1）. However, in March“Red-Box Warnings” to “Important Precautions”. This

2005, the U.S. Public Health Advisory Committee issued

change was made based on that no malignant tumor including

a document to inform potential cancer risk of these drugs,

malignant lymphoma and skin cancer, had been reported in aand the number of prescriptions drastically decreased. It was

long-term Japanese post-marketing surveillance, and in long-issued probably based on the investigation in response to theterm epidemiological studies abroad no increased risk ofstrict measure taken in Japan [4].

cancer was observed related to the use of tacrolimus.

However, since the number of prescriptions increased again

However, this small size of study in Japan [6] cannot

within less than a year, the committee mandated a “Black-Box

detect cancer development and the results of many

Warning” label, which the highest level of caution, and issued

large epidemiological studies in the world have been

a warning letter to parents, and the number of prescriptions

misinterpreted and the association between Protopic®

decreased to one-fifth to one-fourth of that before the warning

use and cancer risk is completely ignored.

(Figure 1). The Black-Box Warning label has been maintainedin the U.S. since then.

Malignant lymphoma doubled for all ages
The latest systematic review [7] meta-analyzed 10 cohorts
from 5 studies [8-12] and reported that combined risk ratio

Figure 2: TCIs use and risk of malignant lymphoma (Meta-analysis results as reported by Lam et al [7], adjusted for TCS use)

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Apr. 2023/ Vol.9 No.26 ・ Page 13

Table 2: Person years of follow-up in the European JOELLE study [13]versus TCS groups, and (3) TCS versus
untreated groups.
Person-years of follow-up are shown in
Table 2. Total person-years for TCI was
almost half million in total including
146,561 for children and 2.9 million forcomparators including 2 million TCS
users and 0.9 million untreated persons.
As shown above, in addition tocomparing tacrolimus ointment andfor malignant lymphoma and leukemia of topical calcineurin

TCS, the risk of TCS was compared with untreated group.

inhibitors (TCIs: tacrolimus or pimecrolimus) compared with

Therefore, it was possible to compare the risk of tacrolimus

control was 1.86 (95% CI: 1.39-2.49, p<0.001) (Figure 2). This

ointment with untreated group indirectly.
Figure 3 shows the incidence rate of malignant lymphoma

result is robust.
Incidence of malignant lymphoma per 100,000 person-years

per 10,000 person-years so that it can be easily compared with

was 0 (0/189,798 person-years) with untreated children [13], 2

the Japanese survey. Incidence rate are shown by age group(children) or 10 (all ages) in control groups (including topical(children and adults) and by product (tacrolimus ointment alone,corticosteroid users) and 15 (all ages including children) or 3.0 to

combined TCI, and TCS group).

10.4 (children) in TCI (immunosuppressant) users.

Without treatment, none of the children developed
malignant lymphoma during 190,000 person-years of follow-

Children have 46 times higher risk compared withup, which is more than 30 times the Japanese survey (less thanno treatment

6,000 person-years). However, with tacrolimus ointment, theThere is a very large-scale study done in Europe called

incidence was about 1.0 in 10,000 person-years.

JOELLE study [13]. The data of this study was not used in

Figure 4 shows the degree of risk of TCIs expressed as

the meta-analysis in the Figure 2 by the systematic review

odds ratios. Children treated with tacrolimus ointment were[7], because the main comparisons were the two topicalestimated to be 46 times more likely to develop malignant

calcineurin inhibitors (tacrolimus or pimecrolimus) and topicallymphoma compared with untreated group.

corticosteroids (TCS) with moderate- to high-potency.
In this study, children (0-17 years) and adults (≥18 years) were

All studies are large-scale except in Japan

divided into following groups and followed up: (1) Tacrolimus

When Med-Check reviewed tacrolimus in 2010[4], anointment (Protopic®) versus TCS groups, (2) Pimecrolimus

epidemiological study conducted by Harvard University

Figure 3: TCIs use and risk of malignant lymphoma（European JOELLE study, by age group including comparison with untreated）

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Apr. 2023/ Vol.9 No.26

Adverse Reactions
Figure 4：TCIs use and risk of malignant lymphoma（European JOELLE study, by age group including comparison with untreated）

with fund from the manufacturer [8], and a study conducted

12 years, between March 2004 and March 2016. It excluded

independently from the manufacturer [9] had been published.

109 patients and followed 1221 patients for average 4.8 years

In these studies, non-immunosuppressant-user (control)(5816 person-years) . As a result, it concluded that no skingroup was followed for about 220,000 person-years [8]cancer nor other malignant tumor was observed, emphasizing

and 2,400,000 person-years [9]. On the other hand, topicalthat the drug was safe. However, the study is defective and not

immunosuppressant groups were followed for 160,000 person-

reliable as it has no control group and the criteria for selecting

years[8] and 90,000 person-years[9], 250,000 person-years in

1330 patients and the reason for excluding 109 patients aretotal.

not explained.

Med-Check meta-analyzed these 2 reports and found that

The revised package insert states that in a long-term post-

the risk ratio for malignant lymphoma and leukemia was 2.2

marketing surveillance in Japan, no malignant tumor, such

(p=0.0003). The person-years covered by the epidemiologicalas malignant lymphoma and skin cancer, has been reported,

study which included later studies[10-13] was about 816,000

referring to the above study as evidence.

for the treatment groups and over 6,200,000 for the control

However, it is natural that no malignant tumor, such asgroups (including untreated group) . In the studies whichmalignant lymphoma, occurred as the total person-year

separately reported for children, the total person-year was

was only 5816 in this study. Moreover, based on the vital

214,000 [10-13]. This is more than 36-times of that in thestatistics in population aged 0-14 years in 2019, the mortality

Japanese study (5816 person-years)[6]. In two very large studies

rate per 100,000 person-years of malignant tumor is 2.02

in which results were not separately reported for children

for all sites, 0.57 for hematological malignancies and 0.09

and adults, more than a half of the participants were adults [8]for all malignant lymphoma. Therefore, it is natural that noor their average age was 37 years old [9].

malignant tumor was found in 5816 person-years of children.
o Although 234 study sites were Japan’s leading institutions

Japanese study was small

with the dermatologist and the follow-up was conducted for

The title of the paper published in the Japanese Journal

12 years starting right after the launch, the study ended upof Dermatology October 2022 issue by the Japanese

as a very small-scale study, following only 1221 patients.

Dermatological Association [6] is the “long-term post-

However, in the statement which is issued by the Japanesemarketing surveillance in Japan.” Is it worth to be theDermatological Association issued in December 2003 andevidence base?

is titled “To patients who now uses or will use tacrolimus

Tacrolimus ointment for pediatrics (Protopic®Ointment)

ointment (Protopic® Ointment)” [11], it is mentioned “safety

0.03% was launched in December, 2003. The study involved

has suddenly become an issue” and “it was sparked when an

1330 patients with atopic dermatitis aged 2-12 years, whoorganization submitted a request to the Ministry of Health,used the ointment and were registered in 231 institutions forLabour and Welfare”. This suggests that unlike in the U.S., the
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Apr. 2023/ Vol.9 No.26 ・ Page 15

Figure 5: Incidence rate of malignancies after heart transplantationprescription of tacrolimus was largely restricted as the strict

the risk of cancer persists into the future [4].

condition was imposed at approval.
Conclusions

The reason for revision is inaccurate and false
Even if strict restriction was imposed, 1221 is too small
for the number of patients followed by the study. In addition

Tacrolimus ointment increases the incidencesof malignant lymphoma and leukemia especially inchildren.

to this fact, unknown inclusion criteria and no control groupwell indicate that the methods which makes the association
between tacrolimus and cancer undetectable was intentionallyused.
The statement in the package insert “no malignancies havebeen reported with Protopic®“ is based on a single small
study with no power to detect malignancies and misrepresents
the truth. On the other hand, systematic reviews and otherstudies showed a definite result that malignant lymphoma andleukemia had doubled for overall age and 46 times more riskof malignant lymphoma in children aged less than 18 years
compared with no treatment. Therefore, the statement “in along-term overseas epidemiological study, potential risk ofcancer did not increase due to the use of the drug” is false as
malignant lymphoma and leukemia are malignant tumors.

Malignant tumor drastically increases after 10
years of use
In the previous studies, the duration of follow-up is around4 years at most. However, according to the result of a longterm observation for more than 10 years after tacrolimus use
for organ transplantation, all cancers, including malignant
lymphoma, drastically increased after 10 years (Figure5)[4,14,15].
If tcrolimus is used in childhood, it should be considered that
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Apr. 2023/ Vol.9 No.26

Warnings or precaution of Package insert of Protopic ointment
Red-Box Warnings (before June 21, 2021)
In a mouse carcinogenicity study, increased lymphoma
is obser ved related to the persistent high bloodconcentration. In addition, although the association withthe use of the drug is unclear, lymphoma and leukemia
have been reported clinically. When using this drug, theinformation should be provided to patients or proxies andmake sure they understand the risk.
Revised on June 21, 2021:“Red-Box Warnings” weredeleted, “precautions” were added as belows [5]:There is a potential carcinogenic risk due to theimmunosuppressive effect of this drug. In a long-term postmarketing surveillance in Japan for 0.03% formulation,no malignant tumor, such as malignant lymphoma andskin cancer, has been reported, and in a long-term
epidemiological study abroad, no increased risk of cancer
was observed related to use of this drug. On the other
hand, although the association with the use of the drug is
unclear, lymphoma and skin cancer have been reported.
When using this drug, the information should be provided
to patients or proxies and make sure they understand therisk.

Adverse Reactions
References

4) Hama R, Tacrolimus Topical (Protopic Ointment) and Carcinogenesis, The
Informed Prescriber (TIP) 2010: 25(4): 50-57.

1) Web MedCheck No18-27,29,31,34-36 https://www.npojip.org/contents/sokuho/1.html

5) December 8, 2021 PSEHB (Pharmaceutical Safety Division, Pharmaceuticala) Web MedCheck No36: 2003.10.10 What is “carcinogenicity of Protopic ointment” ?

and Environmental Health Bureau) Notification No.1208 No. 1 Attachment 1

https://www.npojip.org/sokuho/031010.htmlb) Web MedCheckNo35: 2003.10.09 Approval information for Protopic ointment
is disclosed. https://www.npojip.org/sokuho/031009.htmlc) Web MedCheckNo34: 2003.10.08 From Aug/Sept.issue of TIP: The Informed
Prescriber: A 16-year-old malignant lymphoma case discovered while using
Protopic ointment. https://www.npojip.org/sokuho/031008-2.htmld) Web MedCheckNo33: 2003.10.08 Yomiuri Report; Protopic Ointment Sidehttps://www.info.pmda.go.jp/kaiteip/20211208A001/01.pdf
6) Otsuki M et al. Long-term safety and efficacy of 0.03% pediatric tacrolimus
ointment (Protopic® ointment) for pediatric atopic dermatitis -Final report ofa survey on long-term special use -Journal of the Japanese Dermatological
Association 2022: 132 (10), 2327-2338.
7) Lam M, Zhu JW, Tadrous M, Drucker AM. Association Between TopicalCalcineurin Inhibitor Use and Risk of Cancer, Including Lymphoma,

effects? Malignant lymphoma, 16-year-old girl, progression related to

Keratinocyte Carcinoma, and Melanoma: A Systematic Review andimmunosuppression? https://www.npojip.org/sokuho/031008-1.html

Meta-analysis. JAMA Dermatol. 2021 May 1;157(5):549-558.

e) Web MedCheckNo31: 2003.08.09 2 papers related to "Protopic Ointment"
published in the July issue of TIP https://www.npojp.org/sokuho/030809.htmlf) Web MedCheckNo29: 2003.08.03 Here we disclose the data on animal
carcinogenicity test results which Fujisawa reluctant to disclose
https://www.npojip.org/sokuho/030803.htmlg) Web MedCheckNo27: 2003.07.31 Sunday Mainichi reports on the dangers

doi: 10.1001/jamadermatol.2021.0345.PMID: 33787818
8) Schneeweiss S, Doherty M, Zhu S, et al. Topical treatments withpimecrolimus, tacrolimus and medium- to high-potency corticosteroids, andrisk of lymphoma. Dermatology. 2009;219(1):7-21. doi:10.1159/000209289
9) Hui RL, Lide W, Chan J et al. Association between exposure to topicaltacrolimus or pimecrolimus and cancers. Ann Pharmacother. 2009 Dec; 43(12):of Protopic Ointment in detail https://www.npojip.org/sokuho/030731.html

1956-63. doi: 10.1345/aph.1M278. Epub 2009 Nov 10.PMID: 19903860h) Web MedCheckNo26: 2003.07.19 Protopic ointment for children Approved10) Margolis DJ, Abuabara K, Hoffstad OJ,Wan J, Raimondo D, Bilker WB.

with strict conditions (Ministry of Health, Labor and Welfare)https://www.npojip.org/sokuho/030718.htmli) Web MedCheckNo25: 2003.07.10 Concentration-cancer incidence

Association between malignancy and topical use of pimecrolimus. JAMA
Dermatol. 2015;151(6):594-599. doi:10.1001/ jamadermatol.2014.4305
11) Cai SCS, LiW, Tian EAL, Allen JC, Tey HL. Topical calcineurin inhibitors

relationship perfectly matches the theoretical curve.

in eczema and cancer association: a cohort study. J Dermatolog Treat. 2016;

https://www.npojip.org/sokuho/030710.html

27(6):531-537. doi:10.3109/09546634.2016. 1163317j) Web MedCheckNo24: 2003.07.03 We submitted a new “petition” tothe chairman of the pharmaceutical affairs council.
https://www.npojip.org/sokuho/030703.htmlk) Web MedCheckNo23: 2003.06.27 The pharmaceutical affairs council

12) Deleuran M, Vestergaard C, Volund A et al. Topical calcineurin inhibitors,
topical glucocorticoids and cancer in children: a nationwide study. Acta Derm
Venereol. 2016;96 (6):834-835. doi:10.2340/00015555-2392 PMID: 26934868
13) Castellsague J, Kuiper JG, Pottegard A, et al. A cohort study on the risk

recognize well the carcinogenicity of Protopic. But why they approved it?

of lymphoma and skin cancer in users of topical tacrolimus, pimecrolimus,

https://www.npojip.org/sokuho/030627.html

and corticosteroids (Joint European Longitudinal Lymphoma and Skin Cancerl) Web MedCheckNo22: 2003.06.26 The pharmaceutical affairs council outrage:
Approved Dangerous Protopic Ointment.
https://www.npojip.org/sokuho/030626.html

Evaluation – JOELLE study). Clin Epidemiol. 2018;10:299-310.
doi:10.2147/CLEP.S146442
14) Working Group for the Use of Topical Tacrolimus, Committee for Atopicm) Web MedCheckNo21: 2003.06.25 Additional information for the “petition”

Dermatitis Treatment, Japanese Dermatological Association, “Letter to the user

againt approval of protopic ointment: One month use increases lifetime cancer

or future user of Tacrolimus Ointment (Protopic® Ointment)” (2023.12.12)

by 5-folds. https://www.npojip.org/sokuho/030625.html

https://www.dermatol.or.jp/modules/publicnews/index.php?content_id=2n) Web MedCheckNo20: 2003.06.19 Submission of petition against approval ofProtopic Ointment. https://www.npojip.org/sokuho/030619.htmlo) Web MedCheckNo19: 2003.06.17 Who's to blame if a person get cancerfrom Protopic Ointment? https://www.npojip.org/sokuho/030617.htmlp) Web MedCheckNo18: 2003.06.12 Protopic Ointment is Dangerous—
Carcinogenic Risk, Especially for Children
https://www.npojip.org/sokuho/030612.html
2) Web MedCheckNo23: 2003.06.27 The pharmaceutical affairs council
recognize well the carcinogenicity of Protopic. But why they approved it?
https://www.npojip.org/sokuho/030627.html
3) Web MedCheckNo26: 2003.7.19 Protopic ointment for children Approved withstrict conditions (Ministry of Health, Labor and Welfare)https://www.npojip.org/sokuho/030718.html

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2023

Vol.9

No.26

HECK

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD)Managing Editor: SAKAGUCHI, KeikoE d i t o r i a l S t a f f : N A K A N I S H I ,Ta ke a k i ( P h a r m a c i s t ) ; TA K A N O,
Yo s h i h i ko ( M D [ p e d i a t r i c i a n ] / P h a r m a c i s t ) ; U M E DA , Ta d a h i t o(MD[psychiatrist]) ;YANAGI, Motokazu (MD) ; YASUDA, Yoshinobu(Pharmacist); WATANABE, Shintaro (MD)Page 18 ・ MED CHECK

Apr. 2023/ Vol.9 No.26

Translators: NAKAMURA, Akari
Advisors:HONZAWA,Tatsuo (MD[GP]) ; IKEDA,Akiko (Pharmacist) ;KIM,Mieko (Pharmacist) ; KUDO,Shino (Pharmacist) ; MITA,Yasuko(Pharmacist) ; MUKAI, Junji (Pharmacist) ; SUMIDA, Sachie (MD[Dermatologist]); TERAOKA, Akio (Pharmacist) ; TOI, Chihiro (Pharmacist);
WADA,Masahide (MD[GP])Editorial Officer: SAKAGUCHI, Keiko
Production Team: UMEKI, Yukiko; SAKAGUCHI, Keiko; MATSUMOTO,
Koji
Information Technology (IT): KURODA, Akira (Systems Engineer)
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