It made almost breaking news in the Romanian media the
information that doctors from the Emergency Clinical Hospital for Children “St
Mary” from Iasi (the main city in the North East of Romania) were using Viagra
to treat two children for pulmonary hypertension. The first individuals seemingly
shocked by what they conceived to be a preposterous extravagance were the
Romanian journalists, who continued to crunch the story for several days. In
their glorious fight for the truth, they – rightfully so – asked for the
opinion of the Romanian National Agency for Medicines and Medical Devices (ANMDM),
who through its communication staff stated that “Viagra has as the only
indication the erectile dysfunction and the product is contraindicated in
children less than 18 years”. The President of the Romanian College of
Physicians (CMR), prof. Vasile Astărăstoaie, expressed a different view. He first stated that the product
was initially conceived for the field of cardiology and only later it was
discovered that it has an effect on sexual dysfunctions, and then continued:
“If the doctors in the children hospital uses it for that treatment, it means
that they know what they are doing”.
The media was happy to report on this scandal, whose
importance for the public health was grossly exaggerated and was soon forgotten.
Other stories - as great as this one - were waiting to be brought to the
impatient consumer of news. I have found this story as being of interest for a
number of reasons:
1. The most instructive part of this short-lived scandal seems
to me to be that Romanian people discovered that there is life in sildenafil
beyond Viagra. They learned that the active ingredient in Viagra has a benefit
in pulmonary hypertension, a disease often with a fatal course. It was a pity
that the journalists were so obsessed with the Viagra part of the story that
they hardly mentioned the suffering, pain and sorrow associated with the
progressively worsening of this disease still incurable in many cases.
2. But I also see in this story a peculiar case of atypical
off-label use, which I find very interesting from the regulatory perspective. As
the representatives of the NMA stated, this is clearly a case of off-label use.
I should stress here that in EU, as in the USA, off-label use does not
necessarily mean illegal use. As it has been suggested (at least in the USA,
but I find the argument valid also in our geo-political region) - and I will
spare myself of the effort of finding the exact reference here, as I read it a
few years ago -, what is essential in judging the legality and conformity of a
case of off-label use with the standard of care is the efficacy and safety of a
product in a defined indication (irrespective of the fact that a product is
authorized or not by a regulatory authority in that specific indication) and
the strength of the evidence for both safety and efficacy.
Or, in this case, a
reading of the EPARs for the two products (Viagra and Revatio) shows that the
two are essentially one and the same, with very few “cosmetic” differences: “
The only differences between Viagra tablets
and Revatio tablets are the replacement of the blue dye in the film-coat with
additional titanium oxide to give a white film-coat, and a change in the tablet
shape and debossing.”
According to the same authoritative source, “Several
strengths of conventional
immediate release white
film-coated round biconvex
tablets containing
sildenafil citrate were
studied in development
for potential commercial
presentation. All these strengths
were prepared from a common blend of the active substances, which is
qualitatively, and quantitatively equivalent to the blend used to produce
Viagra tablets.”
Moreover, in the case of Revatio, children do not swallow
directly the tablets, but a suspension prepared by the pharmacist according to
the instructions provided in the product information (SmPC). The suspension is
prepared in the same way irrespective of the dose, as the latter is adjusted by
modifying the volume to be administered. Another difference not mentioned in
the first sentence quoted above from the EPAR is the tablet strength: 25 mg for
Viagra, 20 mg for Revatio. Not a huge one, positively. “The recommended dose in
patients ≤ 20 kg is 10 mg (1 ml of compounded suspension) three times a day and
for patients > 20 kg is 20 mg (2 ml of compounded suspension or 1 tablet)
three times a day.” I should state here that according to the EPAR for the
variation concerning the paediatric indication of sildenafil, “The
“formulation” intended for
authorisation is an
oral suspension formulation which
is extemporaneously prepared by a pharmacist from the 20 mg tablet using
Ora-Sweet and Ora-Plus diluents to reach a concentration of 10 mg/ml. The applicant has shown that there are minor
differences in relative bioavailability among the 10 mg tablet strength and the
other strengths that are likely due to nonlinearity of PK of sildenafil. In any
case, these differences are not considered to be of clinical significance.”
In the light of the above and provided that the right dose
is administered in children, it seems unlikely that a real problem of safety or
efficacy will affect the administration of Viagra in children as compared to
Revatio. But before jumping to the conclusion that this story was just much ado
about nothing, I would still like to discuss two other points.
3. As I stated above, prof. Astărăstoaie was right, the
doctors knew what they were doing. But a question still remains: why did they choose
Viagra over Revatio? Is it because they didn’t know that there is a product
specifically approved for this indication? Why would a pharmacist accept
compounding a suspension in an improvised way when there is a (semi-)validated
(by the MAH) method of doing so with a slightly different product specifically
approved for children? If I was a journalist (which I am not), these were the
questions I would have asked; not with the judgmental tone and conceit typical
in my sweet country for most journalists, but with a real and sincere
curiosity. I first supposed that it might have been the price, but it seems
unlikely. The wholesale price (without VAT) per tablet is almost identical for
Viagra 25 mg and Revatio 20 mg (20.78 RON for the former, 20.82 for the
latter). There are cheaper generics available, approved for erectile
dysfunction, which might justify their off-label use by some financially
constrained hospitals, but the media reports were about Viagra and not its
generics. If not the price, then what was the reason? Mere ignorance?
4. The representatives of the Romanian College of Physicians
(CMR) stated in that context that “The treatment of pulmonary hypertension with
Sildenafil has been used for a number of years and is recommended in the
guidelines and protocols accepted in USA and Europe”
. This
has been indeed the case, but last in year in August, FDA recommended “that
Revatio (sildenafil) not be prescribed to children (ages 1 through 17)”, based
on a clinical trial showing that in paediatric patients at higher doses there
was an increased risk of death, while at low doses the product is not effective
(Barst RJ, Ivy DD, Gaitan G, et al., Circulation 2012;125:324-334). The
representatives of CMR made clear that regulatory bodies such as the National
Medicines Agency are not competent to regulate medical practice (an idea which
in the United States has been repeatedly confirmed in courts), and that
therefore off-label use should be the responsibility of the medical doctor (a view
which I share, as long as a clear warning of the regulatory body has not been
duly issued). Anyway, FDA is in the USA and we are in Europe, where Revatio
still has an approved indication in children. And this is the last point I
would like to shortly discuss. Here we are again in the old pattern beautifully
expressed by Blaise Pascal: “
A strange
justice that is bounded by a river! Truth on this side of the Pyrenees, error
on the other side.” (In this case one should say truth on this side of the
ocean, error on the other side).
In September 2011, CHMP adopted an opinion based on which
the SmPC was updated with a warning that “Higher than recommended doses should
not be used in paediatric patients with PAH”. This was initiated following a
recommendation of the Data Monitoring Board, seemingly in relation with the
same study on which FDA based its warning. Who is right and who is wrong? Or,
more correctly, what are the arguments against the use in children and what are
those in its favour? This would have seemed to me a sensible discussion of
substance. The European authorities considered that the benefits of sildenafil are
still outweighing the risks in the paediatric population; FDA deemed the risks
higher than the potential benefits.
As I stated in a similar context, it depends on the way one
looks at the data, because (like many other trials) this STARTS-2 trial is
imperfect and affected by uncertainties and limitations. As the Scientific
Leadership Council of the PHA (Pulmonary Hypertension Association) has pointed
out, “
The results from the STARTS-2 trial
do not account for the differences in disease severity at the time of
enrollment or subgroups of PAH children who might respond more favorably. With
respect to long-term survival, there was no control group (untreated group) for
comparison. The overall survival for the sildenafil treated patients is very
favorable compared to historical controls (untreated patients reported in
previous studies). Survival is also favorable in current cohorts of treated
patients despite the reported association between high dose sildenafil and
increased mortality.”
But it is widely known that historical controls are very unreliable, so the
first argument has not much weight. As for the second, I have not seen the data
to form an informed judgment. I think that a thorough discussion of the two
opposing views in an academic journal should be more than welcome.
