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2016

-The Informed Prescriber

N4

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Memantine (brand name: Memary)
An NMDA antagonist, memantine may induce neurotoxicity

Cochrane team criticises ECDC's draft
advice on oseltamivir use
CONTENTS （April 2016, Vol. 2, No. 4）
Editorial:“Talk about harm, not risk”

2

New Products
Memantine (brand name: Memary): No value for dementia

3

An NMDA antagonist, memantine may induce neurotoxicity
Too many withdrawn cases due to adverse reactions

Dutasteride (Zagallo®) for Androgenetic alopecia:
Good in theory, too harmful in practice: cancer, sexual dysfunctions,
suicideReview
Cochrane team criticises the ECDC experts' draft advice
on oseltamivir use:

7

13

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Editorial“Talk about harm, not risk”
Translated from the editorial in Med Check-TIP (in Japanese) Mar. 2016 ; 16 (64):30

On February 21st, Dr. Andrew Herxheimer

he pointed at his bald head and asked me “Howdied, aged 90 years. In 1962, he launched the

do you call this in Japanese?” I answered him

Drug and Therapeutic Bulletin (DTB) in Britain,“atama”. Then pointing at his head, he said “kara-an independent drug bulleting which receives

atama” and grinned mischievously.

no support from pharmaceutical companies. He

Dr. Herxheimer has been respected by manyleft behind great achievements in establishingpeople. He was still clearheaded, and working

and promoting the International Society of Drugactively until he passed away unexpectedly. In a

Bulletins (ISDB), of which the Med Check TIP

way, it might have been an ideal departure.

is a member. The principal role of independent

We pray his soul may rest in peace.

drug bulletins is “promoting rational use of

In this issue, we featured a new indication

medicines” which has led to today’s “evidence“male pattern baldness” of “dutasteride”,

based medicine”. In the Cochrane Collaboration,

5- α -reductase inhibitor. We have fundamental

he led discussion on conditions for maintaining

questions after reviewing it. Based on the

independence from pharmaceutical companies,

package insert, it is indicated for “androgenic

and also was an opinion leader in discussing

alopecia”. However, is “male pattern baldness”

harms.

really a disease? Does it really need to be

Dr. Andrew Herxheimer said frequently “Talktreated?

about harm, not risk” when he discussed on

TAMIYA, Jiro, an actor who committed suicide

benefits and harms of medicines. These words

at the age of 43, was distressed about his sparse

impressed me the most. He explained “Very often

hair. Reportedly, he underwent hair implantation

people use the word risk when they mean harm,

every year in Britain, and suffered from its severe

and this causes ambiguities and confusion.” Hecomplications such as migraine and memory

proposed four dimensions for both benefits andimpairment. In those days, another actor

harms as follows:advertised wigs on TV and immediately lost his

1. Its nature, described by its quality, its

job offers. However, nowadays advertising hairintensity, and its time course (onset, duration andtonics or wigs does not seem to affect actors’

reversibility).

popularity. Male-pattern baldness is also a proof

2. The probability that it will occur.

of high sexual function in males.

3. Its importance to the person experiencing it.

Is alopecia (sparse hair) a “disease” which

4. How the benefit can be maximised or the harm

is more serious than harms such as sexual

prevented or minimised.

impairment, cognitive impairment, depression,“Risk” is a “probability of harm” and only one ofsuicide, and high-grade prostate cancer induced

the aspects of harms. His idea is referred in theby dutasteride?

Chapter 8 of the ISDB manualDoctors and pharmacists should provide(http://www.isdbweb.org/documents/uploads/

appropriate information to persons who are

manual_full_text.pdf ).

distressed about “hair loss” to help them makeAndrew was a man of humor as well. More than
20 years ago, during the ISDB summer school anda right decision and protect them from more
serious harms.

general meeting in Japan, we came to talk about

Once again, we should think deeply about the“karaoke” (orchestral music without song). Whenwords of Dr. Herxheimer: “Talk about harm, notI explained that “kara” means “empty” in English,risk” reminding his head and thought.

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New Products
Memantine (brand name: Memary):

No value for dementia

An NMDA antagonist, memantine may induce neurotoxicity
Too many withdrawn cases due to adverse reactions
Translated from Med Check-TIP (in Japanese) Mar. 2016 ; 16 (63):3-7

Abstract●Memantine (brand name: Memary), which was launched in 2011, increases dopamine and acetylcholine likean antiparkinsonism agent, amantadine.
●Based on the result from an animal experiment, the manufacturer claims that memantine has neuroprotective
property. However, memantine causes neuronal necrosis in the cingulate cortex, which is involved in cognitionand emotion, at the dose close to the human clinical dose. It also induces neurotoxicity at the dose which isclaimed to improve cognitive abilities. Donepezil (brand name: Aricept), which is often used in combination
with memantine, potentiates this neurotoxicity.
●In patients with moderate to severe dementia, memantine used for 24 weeks is reported to have improved
their symptoms. However, it was confirmed ineffective in an important endpoint. In a follow-up study
conducted after the clinical trial, a half of the patients who were on the medication

discontinued the treatment

within 2 years. Adverse event was the reason for the discontinuation in about a half of the cases. Despite the
manufacturer’s claim, long-term efficacy and safety have not been established.

Delirium is a symptom. Dementia is a disease.
Dementia is a syndrome – usually of a chronic orprogressive nature – in which there is deterioration incognitive function (i.e. the ability to process thought)
beyond what might be expected from normal ageing. It
affects memory, thinking, orientation, comprehension,
calculation, learning capacity, language, judgement and theability to perform everyday activities. Consciousness is notaffected [1]. Dementia is characterized by “a condition inwhich cognitive function which once developed normallydeteriorate persistently because of acquired brain disease,affecting the patients’ daily and social lives. It is observed
when consciousness is preserved” (definition by the JapaneseSociety of Neurology Guideline (2010) [2]).
[1] WHO: Media centre Dementia, Fact sheet No362 (March
2015) http://www.who.int/mediacentre/factsheets/fs362/en/
To complement the definition above, “because of acquired
brain disease” and “persistently” are very important factors
in distinguish it from delirium, which is characterized bytransient cognitive impairment [1-7].
Both dementia and delirium cause impairment in cognition

and memory, and disturb judgement and behavior which arenecessary for social life. Among different types of memory,both disrupt short-term memory in particular, and thus thepatients forget instantly what they heard just a while ago.
When they worsen, they lead to delusion and hallucination.
These are common to both delirium and dementia [1-7].
Nevertheless, it should be emphasized again that delirium isa transient symptom while dementia is a disease of persistentand progressive nature that accompanies “acquired brain
diseases”
Medicines for dementia
In Japan, as many as 38 kinds of anti-dementia agents,
named as “cerebral circulation improving agents” or “cerebral
metabolism improving agents”, had been approved fortreatment of dementia in the past [8-10]. Between 1998
and 1999, most of them were taken off the market. None of
the medicines approved in or before 1998 still hold a clear
indication for treatment of dementia today.
Currently, only 4 medicines are indicated for treatment ofdementia like in other countries; namely donepezil (brand
name: Aricept etc.); cholinesterase inhibitors, galantamine

MED CHECK - TIP April 2016 / Vol.2 No.4 ・ Page New Products
Table ：Approved products for dementia（as of March, 2016）*a: All are indicated for “suppressing the progress of dementia symptoms in dementia of the Alzheimer’s type”. It is important to note thatthese indications do not mean “controlling the progress of dementia itself”, but “transiently suppressing the dementia symptoms.” All the
medicines, except for donepezil, have restriction by severity in Japan.
*b：Among the donepezil preparations, Aricept was approved for treating Lewy body dementia in September 2014 in Japan.
NMDA-R: NMDA receptor(Reminyl) and rivastigmine (Rivastouch, Exelon Patch); and an
NMDA receptor antagonist (NMDA antagonist), memantine(Memary) (Table).
Cholinesterase inhibitors are expected to activate mental
activities by increasing acetylcholine in the brain. Memantine
is expected to exhibit the similar effect by inhibiting NMDA
receptors which glutamate acts on, and paradoxicallyincreasing dopamine and acetylcholine.
Expectation for memantine
When the brain is acutely damaged by cerebral infarction
or trauma, glutamate accumulates around NMDA receptors
in the damaged brain tissue, inducing excitotoxicity in thebrain. In such a condition, NMDA antagonists are reported toprevent glutamate from accumulating in the receptors andprotect the nerves [11]. Reasoning from this line of evidence,
it has been hypothesized that glutamate, by chronic low-grade
overstimulation of NMDA receptors, may contribute to theneuropathology of Alzheimer’s disease (AD), and that drugs
that block NMDA receptors might be neuroprotective in AD[12].
An NMDA antagonist, memantine induces neurotoxicity.
On the other hand, memantine induces neurotoxicity.
According to the information submitted for approval ofmemantine [11], the medicine protected against neuronopathy
in rats at 1.7 mg/kg and 3.3 mg/kg in human equivalent dose
(HED: Note 1, [13]). Meanwhile, HED of non-observed effectlevel (NOEL) in rats is 0.17-0.25 mg/kg, and is lower than thehuman clinical dose（0.4 mg/kg= 20 mg/50 kg. Furthermore,
HED of 25 mg/kg, the dose at which necrosis was caused in
the retrosplenial cortex and cingulate cortex, was 4 mg/kg.
HED (2 mg/kg) of NOEL, at which no necrosis was observed,
was only 5 times higher than the clinical dose (0.4 mg/kg.)
This indicates that the dose that demonstrates protective
effect (1.7-3.3 mg/kg）and the dose that causes toxicity (4mg/kg）are almost the same. The manufacture explains thepathogenic mechanism as follows [11].

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The Cingulate cortex neurons have Ach (acetylcholine）
receptors, muscarinic receptors, and the release of Ach around thereceptors is regulated by GABAergic neurons. On GABA neurons,
NMDA receptors are present. When NMDA receptor channel
antagonists suppress the NMDA receptors on the GABAergic
neurons, GABA can no longer regulate the release of Ach.
Therefore, by administrating memantine, the NMDA receptors on
GABAergic neurons are suppressed, causing the persistent releaseof Ach. The excessive Ach is believed to induce histological damage
in the cingulate cortex neurons.
This explanation clearly states that while NMDA antagonists
protect the nerves, they also damage the nerves. However,
it is inadequate because it misses out another important
point. When the NMDA receptors on the GABAergic neurons
are suppressed, it leads to the excess of not only Ach, butalso dopamine, inducing even more intense excitotoxicity
to the neurons [12, 14] (Figure 1). At the effective dose
sufficient to improve cognitive abilities, memantine exhibited
mild neurotoxicity [12, 14]. When it was combined with
donepezil, the toxicity was potentiated [12]. Therefore, theprotective effect on nerves which the manufacturer claims isquestionable. The cingulate gyrus, where memantine causes
necrosis, plays an important role in emotion, learning, andmemory [15]. In addition, NMDA antagonists cause memory
and behavioral impairment at a much lower dose than thedose which exhibits the protective effect [12, 14].
Decreased function of NMDA receptors is deeply related tothe onset of schizophrenia [16-18] and also is an underlying
factor of pathogenesis of Alzheimer’s disease. NMDA
antagonists deteriorate the decreased function of NMDA
receptors even further, lowering the function of inhibitory
neurons. This activates excitatory neurons and induces
excitotoxicity [12, 13, 16].
Figure 1 shows the explanation about the pathogenic
mechanism of Alzheimer’s disease and the effects ofmemantine by the manufacturer as well as that by the Med
Check TIP.

Figure 1 ： Pathogenesis of dementia （AD） and action of memantine

Clinical efficacy is confirmed only up to week 24
In a double-blind randomized controlled trial (RCT),
memantine 20 mg or placebo were given to 432 patientswith moderate to severe dementia of the Alzheimer’s type
(Note 2) for 24 weeks. In the memantine group, the dose wasincreased weekly by 5 mg increments from 5 mg/day to 10
mg/day and 15 mg/day in the first 3 weeks followed by 20
mg/day for 21 weeks (total 24 weeks).
The difference in change in score on the SIB-J (Note 3),
which is designed to evaluate cognitive function in severer
dementia, between the two groups (primary outcome: at 24
weeks) was 4.53 points and significant (p=0.0001). In the
final evaluation, the significant difference was also confirmed(p<0.0001) [11]. In another double-blind controlled trial,
although the evaluation of cognitive function significantly
improved on the SIB-J, a dose-response was not observed on
the ADCS ADL-J (Note 3) in the primary outcome (change inscore at 24 weeks: comparing before and after the treatment).
The ADCS ADL-J evaluates activities of daily living which are
more important in a real life. The result of a parallel-groupcomparison showed no significant difference between theplacebo and memantine 20 mg/day groups (sample size: 260,p=0.8975）[11]. The parallel-group comparison which was
conducted as the secondarily analysis should have been a
primary analysis.

Figure 2 ： Cumulative proportion (%) of withdrawn after memantine use

Three major reasons: adverse events, poor compliance, consent withdrawn．
All reasons other than three major reasons, the followings were reported: no need oftreatment, inadequate alternatives/monitoring, did not visit, contravene exclusion criteria,difficult to visit, institutionalization, and others
Editor’s note 1：Because it is hard to believe that dementia was relieved, it is strange that
medication was considered to be unnecessary. It could be either the patients originally did notneed the medication or they switched to other medicines. Details are unknown.
Editor’s note 2：It is not clear what “inadequate alternative/monitoring” means.

In a long-term follow-up, a half of thepatients withdrew within 2 years
Another study [17] was conducted tofollow-up 702 participants involved in arandomized controlled trial for moderate tosevere dementia of the Alzheimer’s type for along time (memantine was used for average798.1 days, maximum 3,373 days) after thetrial (RCT). The study reported as follows:

Incidence of adverse events was 71.0% to88.9%, and incidence of side effects was 5.6%
to 32.1% by every 52-week period and there wasno association observed between the incidencesand duration of use nor between long-term use
and particular side effects. The main reason for
discontinuation was “adverse events.” Manycases of adverse events and discontinuation
were reported, which occurred because ofchanges in environment of home care andinstitutionalization as a result of the progressof an underlying disease. The MMSE scores
gradually declined. The study suggested that noproblem in tolerability was identified in a longterm use of memantine and that it can inhibit thedeterioration of cognitive function in a long-term.

MED CHECK - TIP April 2016 / Vol.2 No.4 ・ Page New Products
We review the relevance of this interpretation. Figure
2 i n d i c a t e s t h e c u m u l a t i ve p r o p o r t i o n ( N o t e 4 ) o f
discontinuation by the reasons of discontinuation. The figure
was reconstructed based on the data from the reference 17.
The conclusion of the study, “there is no problem intolerability”, is based on that the proportions of adverse
events that led to discontinuation were 12 % in the firstyear, and 4.3 % to 11 % in the subsequent years, and did notincrease. However, in the cumulative proportion, 48 % of thepatients discontinued for some reason, and in about a half ofthe cases, adverse events were involved. This clearly showsthat there was a problem in tolerability.
Symptoms were likely to improve in patients who continued thetreatment for a long-term
The study report the data as if memantine protected therapid progression of the disease by comparing the resultsfrom the CERAD study which was conducted in the U.S. before
donepezil and memantine were introduced. In the CERAD
study, the MMSE scores rapidly declined from 10 points
before the treatment to 1.6 points at 2 years. On the other
hand, the data in this study showed that the MMSE scores
before the treatment was 9.7 points and it declined to 6.3
points at 2 years, 3.4 points at 5 years, and 2.9 points at 7
years.
However, the number of patients followed decreased
substantially from 702 in the beginning to 351 at 2 years,
52 at 5 years, and only 19 at 7 years. Because longer theduration, more patients discontinued the treatment due to“institutionalization”, patients who discontinued had severer
symptoms with more complications while patients who
continued were healthier with relatively milder symptoms
and less complications. The effect of withdrawal of severer
patients, not the effect of memantine, obviously contributed
to the slower decline of the MMSE scores.

Conclusion ： Memantine should not be used in patients withdementia of the Alzheimer’ s type at any stage.

References
1) WHO: Media centre Dementia, Fact sheet No362 (March 2015)
http://www.who.int/mediacentre/factsheets/fs362/en/
2) The Japanese Society of Neurology、Guideline for management of dementia
2010 (in Japanese) http://www.neurology-jp.org/guidelinem/nintisyo.html
3) American Psychiatric Association DSM-IV-TR（2000)、
DSM-5(2013)DSM-IV-TR(2000):
4) Hama R、You may falsely be “dementia”? Gentoh-sha.2010
5) Med Check No27、”Dementia and delirium” 2007
http://www.npojip.org/contents/book/mag027.html
6) Therapeutic Guidelines Australia，translated by The Informed Prescriber and
JIP，Therapeutic Guideline “Psychotropic, 4th and 5th ed” (in Japanese)，
NPO Japan Institute of Pharmacovigilance (JIP)，2004
http://www.npojip.org/contents/book/book006.html
7) ibid、supplement 6 for translated edition: pharmacological treatment of senile
dementia (pp300～307, in Japanese)
http://www.npojip.org/contents/book/ book006.html
8) Editorial board, What does it mean that Calcium Hopantenate was designated asa “powerful drug” ? (in Japanese) The Informed Prescriber: 1989: 3 (3): 17-21.
9) Yanagi M, Hashimoto K, Umeda T, Takamoto E. Limitations of “global
improvement scale” as a tool of efficacy assessment (in Japanese).
The Informed Prescriber 1995: 10(3): 21-24.
10) Cancellation of “anti-dementia agents”: so called “drugs for improvement ofbrain circulation and/or brain metabolism” (in Japanese).
The Informed Prescriber: 1998: 13 (6): 55-58.
11) Japanese information for approval of memantine (a. examination results、
b.summary basis of approval (SBA),c. label,d. Interview form (in Japanese).
http://www.pmda.go.jp/PmdaSearch/iyakuSearch/
12) Creeley CE, Wozniak DF, Nardi A, Farber NB, Olney JW. Donepezil markedly
potentiates memantine neurotoxicity in the adult rat brain.
Neurobiol Aging. 2008 Feb;29(2):153-67.
13) U.S. Department of Health and Human Services, FD, CDER,
Guidance for Industry-Estimating the Maximum Safe Starting Dose in
Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers,
2005 accessed on 09/06/2015
http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf
14) Creeley C, Wozniak DF, Labruyere J, Taylor GT, Olney JW.
Low doses of memantine disrupt memory in adult rats.

Note 1：HED (human equivalent dose) is a human doseconverted by body surface area [13]. For example, in mice,
rats, and dogs, 1/12, 1/6 and 1/2 of the dose per body weight
are the HED, respectively. If “No Observed Adverse EffectLevel” (NOAEL) in mice is 120 mg/kg, HED = 10 mg/kg.
Note 2：Moderate to severe dementia were defined as
those with score ≧ 5 and ≦ 14 by MMSE (Mini Mental State
Examination)[18] and with stage ≧ 6a and ≦ 7a by FAST
(Functional Assessment Staging) among the assessment tools
to evaluate the severity of dementia symptoms.
Note 3：SIB-J stands for “severe impairment battery-Japan”[19] and ADCS ADL-J for “Alzheimer Disease Cooperative
Study-Activities of Daily Living inventory-Japan” [20]Note 4：Cumulative proportion is not the proportion ofpatients who discontinued each year among the patients at
risk in each year, but the cumulative proportion of patients
who discontinued since the beginning of the study until theend of each year.

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J Neurosci. 2006 Apr 12;26(15):3923-32.
15) Stevens Windows to the brain
http://neuro.psychiatryonline.org/doi/abs/10.1176/jnp.23.2.jnp121
16) Nakazawa K, Zsiros V, Jiang Z, Nakao K, Kolata S, Zhang S, Belforte JE.
GABAergic interneuron origin of schizophrenia pathophysiology.
Neuropharmacology. 2012; 62(3):1574-83.
17) Kitamura S. et al. Tolerability and effectiveness of long term use of memantine(MemaryⓇ) on moderate to severe dementia of Alzheimer type (in Japanese).
Jap J Geriatrics 2014;51:74-84.
https://www.jstage.jst.go.jp/article/geriatrics/51/1/51_74/_pdf18) MMSE (Mini-Mental State Examination) :http://www.home-school.ne.jp/ brain/mmse-print.pdf
19) SIB (severe impairment battery): http://www.medafile.com/zyweb/SIB.ht
20) ADCS-ADL(Alzheimer's Disease Cooperative Study- Activities of Daily Living Inventory)
http://www.dementia-assessment.com.au/function/adcs-adl_scale.pdf

Dutasteride (Zagallo®) for Androgenetic
Alopecia:
Good in theory, too harmful in practice: cancer, sexual dysfunctions, suicide
Synopsis from Japanese edition of MED-CHECK TIP (No64)

Synopsis● Dutasteride, an ingredient of Zagallo
which is newly approved in Sept 2015
for androgenetic alopecia, has been
already approved and on the market for
prostatic hyperplasia (Avolve®).

Figure 1 ： Metabolism of testosterone, 5 α -reductase and its inhibitors● It is an inhibitor of 5- α reductase
which converts testosterone into thestrongest androgen, dihydrotestosterone(DHT). It also increases estradiol whichis the strongest estrogen and is one of
the strongest carcinogens. (Figure 1)● Treatment for androgenic alopecia
may continue for a long term. Because
the maximal daily dose for alopecia
is the same as that for prostatic
hyperplasia, the same harm with similarrisk ratio can occur as used in prostatic
hyperplasia. Abstract of an article ondutasteride for prostatic hyperplasia [ref8] is shown in the Box1.

Box 1. Abstract of an article on dutasteride for prostatic hyperplasia (ref [8])MED CHECK - TIP April 2016 / Vol.2 No.4 ・ Page New Products
Figure2: Norwood-Hamilton classification for androgenic alopecia and the types
which were tested in the randomized controlled trial of dutasteride● Norwood-Hamilton classification
for androgenic alopecia and the types
which were tested in the randomized
controlled trial of dutasteride areshown in Figure 2.

Table1 ： Increment of number of hair in the pivotal RCT of Zagallo● Hair number at alopecic area
increases by about 10 % (Table 1), but
only 0.5 point out of 7 points increaseson the satisfaction assessment scale(Table 2).

Table2 ： Self assessment of satisfaction in the pivotal RCT *a of dutasteride (Zagallo)

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Table 3: Common adverse reactions to dutasteride in REDUCE trial or adverse events leading to discontinuation of study agents

Figure 3: Study Design of REDUCE Trial and Biopsy [ref 15]● On the other hand, harm such as loss oflibido, erectile dysfunction, ejaculation disorder,
decreased semen volume and gynecomastia
due to decreased male function may occur
based on the adverse reactions reported in the
randomized controlled trial (RCT) of dutasteridefor prostatic hyperplasia (REDUCE trial) (Table 3).
● In the REDUCE trial (Figure 3, Figure 4),8241 patients with prostatic hyperplasia wereassigned to dutasteride or placebo group (Table 4).

Figure 4: Cumulative probability of prostatic cancer in REDUCE trial

MED CHECK - TIP April 2016 / Vol.2 No.4 ・ Page New Products● Among the biopsy population (N 3 or N 4 ), prostatic
cancer of any grade of Gleason score (GS) were significantly
less detected in dutasteride group than placebo group.
However, prostatic cancer with high grade of malignancy(especially of modified GS 8 -10) were significantly more
detected in the dutasteride group than placebo group (Table
4).

Note that 14 patients had high grade of malignant prostatecancer (modified GS: 8-10) in the dutasteride group after
3 to 4 years, while 0 in the placebo group: odds ratio
28, p=0.0001) (Table 5). This fact is not described in the
package insert of products of dutasteride (both Avolve®
and Zagallo®) in Japan.

Table 4 ： Prostatic cancer detected by Gleason score after treatment of prostatic hyperplasia with dutasteride for 4-years

Table 5 ： Prostatic cancer classified
by modified Gleason score after 4-years treatment of prostatic hyperplasia with dutasteride

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Figure 5: Common adverse reactions to finasteride and PRR Based on the FDA’ s
ADR reports (data from http://rxisk.org/)● Common adverse reactions to finasteride and their
proportional reporting ratios (PRR) based on the FDA’s ADR
reports (data from http://rxisk.org/) are shown in the Figure
5. Among them, cognitive disorders (n=1052, PRR=68),
depression (n=1379, PRR=11), suicidal ideation (n=211,
PRR=4.7), suicide completed (n=50, PRR=1.2) are noted. In
addition, not only prostate cancers (n=191, PRR=25) but
also testis cancer (n=34, PRR=84) should be noted.
● Mechanisms based on these psychiatric adverse
reactions such as anxiety, depression and suicidal
reactions may be related to the inhibition of synthesisof neurosteroids which is synthesized from testosterone[30]. Mukai (2008) reported that finasteride dosedependently inhibits the stress-induced elevation of thebrain allopregnanolone (AP) (a potent positive modulatorof the GABA A receptors and one of the most importantneurosteroids), and that a 10 mg/kg dose of finasteride canalmost completely deplete AP in the rat brains [30].

● Although the treatment with Zagallo® is an intervention
to a condition without threat to life, the harm inducedby the treatment with Zagallo® may be life threatening
with a possibility of high malignancy grade prostatic
cancer and suicidal reactions, and may also cause nonlife threatening serious adverse reactions such as sexual
dysfunct ions, cognit ive disorders, psychiatric andneurological reactions.

Conclusion
Hence the harm clearly exceeds benefit.
We do not recommend the use of this agent for
androgenic alopecia.

Box 2: PRR (proportional reporting ratio) and ROR

MED CHECK - TIP April 2016 / Vol.2 No.4 ・ Page 11

References
1) Product information “Zagallo” including examination report by
the regulatory authority (PMDA)
2) Japanese Summary Basis of Approval (SBA) of “Zagallo” (in Japanese):
3) Product information “Avolve” including examination report by PMDA
4) Japanese SBA of “Avolve” (in Japanese)
5) Product information “Propecia” including examination report by PMDA
6) Japanese SBA of “Propecia” (in Japanese)7) Wilson JD et al ed Williams Textbook of Endocrinology 9th ed.
WB Saunders Company, Philadelphia, 1998
8) Hama R, Kimoto Y. A 5- α reductase inhibitor (dutasteride; Avolve)
increases high grade prostatic cancer,
TIP (The Informed Prescriber) 2012: 27(6): 86-91.
9) GSK press release；
http://www.gsk.com/en-gb/media/press-releases/2011/gsk-statement-on-avodartdutasteride-for-prostate-cancer-risk-reduction/10) a) 5 α -reductase inhibitor (5-ARIs): Label change - increased risk of
prostate cancer: http://www.cancerit.jp/3651.htmlb) FDA; 5- α reductase inhibitors: Label Change-Increased Risk of
Prostate Cancer
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMe
dicalProducts/ucm258529.htmc) FDA Drug Safety Communication: 5-alpha reductase inhibitors (5-ARIs)
may increase the risk of a more serious form of prostate cancer
http://www.fda.gov/Drugs/DrugSafety/ucm258314.htm

11) Google search results by “dutasteride prostate cancer” 9470 hits on
June 18 2012a) http://glaxosmithkline.co.jp/press/press/2009_01/P1000553.htmlb) http://www.watarase.ne.jp/aponet/blog/110612.htmlc) http://medical-confidential.com/confidential/2012/07/post-427.html
12) WHO, Classification of Tumours Pathology and Genetics of Tumours of
the Urinary System and Male Genital Organs:
13) Thompson IM et al. The influence of finasteride on the developmentof prostate cancer. N Engl J Med. 2003; 349(3): 215-24.
14) Yao S et al. Serum estrogen levels and prostate cancer risk in theprostate cancer prevention trial: a nested case-control study.
Cancer Causes Control. 2011;22(8): 1121-31
15) FDA Briefing Document; Dec 1 2010); Part 2: for AVODART® (dutasteride)
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/
Drugs/OncologicDrugsAdvisoryCommittee/UCM234934.pdf.

16) Andriole GL et al (REDUCE Study Group) Effect of dutasteride on therisk of prostate cancer. N Engl J Med. 2010; 362(13):1192-202.
17) same aa ref 15) Part 1 For Proscar (finasteride).
18) Fujii K. Evaluation of the newborn mouse model for chemicaltumorigenesis. Carcinogenesis. 1991; 12(8): 1409-15.
19) Sýkora I, Vortel V. Comparability of results of postnatal and long-term
tests for carcinogenicity. Neoplasma. 1993; 40: 321-7.
20) Li JJ et al, Relative carcinogenic activity of various synthetic and natural
estrogens in the Syrian hamster kidney. Cancer Research 1983; 5200-4.
21) Li JJ et al. Carcinogenic activities of various steroidal and nonsteroidal
estrogens in the hamster kidney: relation to hormonal activity and cellproliferation. Cancer Research 1995; 55: 4347-51.
22) Lambe M et al. Transient increase in the risk of breast cancer after
giving birth. N Eng1 J Med 1994; 331: 5-923) Bernstein L et al. Correlation of estrogen levels between successive
pregnancies. Am J Epidemio11995; 142: 625-824) McConnell JD et al. The long-term effect of doxazosin, finasteride, andcombination therapy on the clinical progression of benign prostatic
hyperplasia. N Engl J Med 2003; 349: 2387-98

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25) Russo J, Russo IH. The role of estrogen in the initiation of breast
cancer. J Steroid Biochem Mol Biol. 2006;102(1-5):89-96.
26) The Coronary Drug Project Research Group. Findings leading todiscontinuation of the 2.5-mg day estrogen group. JAMA 1973; 226: 652-7
27) GlaxoSmithKline, Briefing Document for ODAC01-December-2010：
Avodart for the Reduction of Risk of Prostate Cancer:
http://www.fda.gov/downloads/Advisor.../UCM234936.pdf28) http://rxisk.org/drugs-a-z/29) National Institute of health Sciences, Safety Information of Medicinal
products (2016): 14 (3) (2016-02-10)30) Mukai Y, Higashi T, Nagura Y, Shimada K. Studies on neurosteroids
XXV. Influence of a 5alpha-reductase inhibitor, finasteride, on rat brainneurosteroid levels and metabolism. Biol Pharm Bull. 2008; 31(9):1646-50.

Review
Cochrane team comments on the ECDC draft
advice on oseltamivir:
Criticising misinterpretation in the draft “Expert Opinion”
ECDC (European Centre for Disease Prevention and Control) announced on February 17 2016 that public consultation
opened [1] on the draft “Expert Opinion on Neuraminidase inhibitors for the treatment and prophylaxis of influenza - Review ofrecent systematic reviews and meta-analyses” [2].
The recent systematic reviews and meta-analyses include the systematic review and meta-analysis by the Cochraneneuraminidase inhibitor team (Cochrane team) [3].
Hama et al [4], on behalf of the Cochrane team, submitted an expert opinion commenting that the draft advice and expert
opinion by ECDC on neuraminidase inhibitors have many limitations including misunderstanding of the most important findingsin the systematic review by the Cochrane team. The comments by Hama et al [4] covered comprehensive issues on the efficacy
and safety of neuraminidase inhibitors, especially of oseltamivir as shown in the contents below.
The Cochrane team’s comments [4] conclude as follows (See Supplementary material in detail):

Conclusion
As ECDC advice and expert opinion on neuraminidase inhibitor have many limitations including
misunderstanding of the most important findings of our systematic review, meta-analysis and discussions.
We strongly recommend that our Cochrane review be re-read .
Findings from epidemiological studies should be taken into account.
Findings from basic sciences are also important to understand the mechanism of efficacy and harm fromneuraminidase inhibitors:
Inhibition of host’s neuraminidase followed by impaired functions of various cell such as immune, metabolic,renal, cardiac and neuronal cells by neuraminidase inhibitors is closely related not only to the symptom relief but
also many adverse effects on various organs.
Central nervous system depressing and stimulating actions of oseltamivir but not zanamivir may be closely
related to abnormal behaviours and sudden death from respiratory failure after oseltamivir use.
Finally, we find it strange that a public body would dismiss the findings of our Cochrane review and align its
conclusions with a pharmaceutically-sponsored meta-analysis for which neither protocol nor assessment of risk ofbias seems to exist.

Contents of comments by Cochrane team (Hama et al [4]: See supplementary material in detail):
1. On the analysis methods
1.1. On the principles of analysis methods in general
1.2. For the systematic review of treatment
1.2.1. The population: ITT population should be used for efficacy analysis.
1.2.2. Exclusion or inclusion of high dose groups
1.2.3. All hospitalizations
1.2.4. Pneumonia and bronchitis
1.2.5. Note that reduction of antibody production is related to the mechanism of action of symptom relief
1.2.6. Efficacy in non-influenza ILI
1.3. For the systematic review of prophylaxis: Discussions are needed by taking “false negative effect” into
account both for ECDC advice and for our own.

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2. On the data of individual results.
2.1. Treatment trials
2.1.1. Efficacy: complication especially on serious events leading to treatment withdrawal and hospitalization.
2.1.2. Harm: antibody production, QT interval, cardiovascular events.
2.1.2.1. Antibody production
2.1.2.2. QT interval and other cardiovascular events
2.1.2.3. Psychiatric events, injury and poisoning
2.2. Prophylaxis trials
2.2.1. Efficacy in prophylaxis trials:
2.2.2. Harm in prophylaxis trials:
2.2.2.1. Psychiatric reactions
2.2.2.2. Injury and poisoning
2.2.2.3. Other adverse reactions
2.2.2.3.1. Renal impairment
2.2.2.3.2. Hyperglycemic of diabetic events, and pain in limbs
2.2.2.3.3. Headaches
3. Evidence from non-randomized studies
3.1. Epidemiological studies suggesting neuropsychiatric adverse reactions to oseltamivir:
3.1.1. Prospective cohort studies and their systematic review and meta-analysis.
3.1.2. Proportional reporting ratio for abnormal behaviours especially of fatal outcome.
3.2. Adverse effects on mortality
3.2.1. Observational studies do not support protective effect on mortality
3.2.2. Epidemiological evidence suggesting sudden deterioration leading to death following oseltamivir use:
3.3. Adverse effect on pregnant women, fetus and newborns
4. No discussion on the mechanisms of action and reactions of oseltamivir
4.1. Oseltamivir act on the central nervous system (CNS) both as depressant and as stimulants.
4.1.1. Juvenile (7-day-old) rats and mature rats (intraduodenally and intravenously)
4.1.2. Oseltamivir has hypothermic effect on animals by inhibiting nicotinic acetylcholine receptor.
4.1.3. Oseltamivir induces abnormal behaviours by inhibiting MAO-A.
4.1.4. Oseltamivir has various other effects on CNS such as impairment of sensory system, impairment ofcognition, impairment of alertness other than respiratory depression.
4.2. Oseltamivir has symptom relieving effects by inhibiting host’ s endogenous neuraminidase, not by inhibiting
viral load.
4.2.1 Label of oseltamivir does not state viral load reduction
4.2.2. Experiments indicate inhibition of host’ s endogenous neuraminidase, but not viral load
4.3. Inhibiting host’ s endogenous neuraminidase may be related with adverse effects of NIs
5. Efficacy and effectiveness in risk groups
6. Conflict of Interest
7. Conclusion

References
1) ECDC- Neuraminidase inhibitors for the treatment and prophylaxis of
influenza: public consultation opens: accessed on 2016-02-19, available at:
http://ecdc.europa.eu/en/press/news/_layouts/forms/News_DispForm.
aspx?ID=1362&List=8db7286c-fe2d-476c-9133-18ff4cb1b568
2) ECDC. Draft scientific advice for consultation: ECDC preliminary scientificadvice. “Expert Opinion on Neuraminidase inhibitors for the treatment andprophylaxis of influenza - Review of recent systematic reviews and metaanalyses”: accessed on 2016-02-19, available at:
http://ecdc.europa.eu/en/publications/Publications/neuraminidaseinhibitors-flu-consultation.pdf

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3) Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, et al.
Neuraminidase inhibitors for preventing and treating influenza in healthy
adults and children. The Cochrane database of systematic reviews. 2014;4:
CD008965. accessed on 2016-03-31, available at:
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008965.pub4/full4) Hama R, Jefferson T, Henehgan C. Public Comments on the ECDC’s
Expert Opinion on neuraminidase inhibitors for prevention and treatment
of influenza – review of recent systematic reviews and meta-analyses.
Submitted to ECDC on 2016-3-13, accessed on 2016-04-05 available at:
http://www.npojip.org/english/MedCheck/medchecktip.html

M
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The Informed Prescriber
2016

Vol.2

No.4

Editor-in-Chief: HAMA, Rokuro (MD)
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