E-drug: Strength of Fixed Dose Combinations
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Last summer I got much help from E-druggers on my request on
strength indication of carbidopa/levodopa. Thank you very much!
My findings are published in the last issue of the Pharmaceutical
Journal in the UK.
www.pharmj.com/Editorial/20010623/comment/spectrum.html
The full text of the article follows below.
Stein Lyftingsmo
Hospital Pharmacy of Elverum, Norway
e-mail: sjappe@apotek.no
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The Pharmaceutical Journal Vol 266 No 7153 p851
June 23, 2001
Why strength of a medicine is not the sum of its parts and needs
regulation.
By Stein Lyftingsmo
Medicines with more than one active substance usually lack an
indication of strength on the packaging. Descriptive words like
"forte" and "plus" are not strength indications. In fact, a lack of a
numeric strength indication in the product name is a kind of hidden
code for health professionals, telling them that the medicine has
more than one active ingredient.
In most countries, the strength of single substance medicines must
be indicated clearly, close to the product name. I have not been
able to find any country that demands strength to be indicated with
numerals in the product name of medicines with more than one
active substance, or "fixed drug combinations" (FDCs). With an
increasing number of FDCs and different strengths of the same
FDC, the risk of medication errors is rapidly growing. And with the
increasing globalisation of the medicines market and parallel
importation of medicines, the lack of a standard is becoming
apparent.
Medicines for patients with Parkinson's disease is a case in point. In
Norway, the difficulties for these patients were dramatically
increased when the Norwegian medicine reimbursement system
changed in favour of parallel imported medicines.
I decided to post a message on two e-mail listings
(e-drug@healthnet.org and the Pharmweb Regulatory Affairs
Discussion Forum) asking about the strength indications of
carbidopa/levodopa combinations. I got answers from 15 countries,
and I had more detailed communications with four of them. Then I
looked more thoroughly on the shelves of the pharmacy where I
work. I was shocked by what I found.
Sinemet was chosen as an example of a product name well known
in many countries, and with several strengths and formulations. The
responses I received indicated that Madopar would have been an
equally good (or bad) example. Sinemet is extensively parallel
imported to several North European countries. It has six different
formulations (two of them are controlled release tablets) on the
Norwegian market, but only two of them have strength indicated
with numerals.
In July 2000, there were 10 different parallel imported Sinemet
packages on the drug wholesalers' list in Norway, not counting
different package sizes.
In the United Kingdom and several other countries some "strengths"
of Sinemet are indicated by the sum of the milligrams of the two
active substances, eg, Sinemet 110.
In France the "strength" can be indicated by the milligrams of only
one of the two active substances, eg, Sinemet 100.
In 17 varieties of Sinemet the strength is either not shown in the
product name or is not clearly indicated.
Why should we make things more difficult for patients who already
have enough difficulties keeping things in order?
Renitec Comp (enalapril) and Zestoretic (lisinopril) are FDCs without
strength indication (other than in the list of ingredients). Both
contain 20mg of ACE inhibitor and 12.5mg of diuretic. More or less
they compete for the same patients on the Norwegian market. Both
have a weaker variety but the product names do not show that one
manufacturer reduced the ACE inhibitor, whereas the other reduced
the diuretic in the weaker version.
In Norway, Cozaar Comp (losartan and diuretic) had a stronger
variety (from the same manufacturer) named Fortzaar. Fortzaar has
now changed its name to Cozaar Comp Forte, still without strength
indication. In some countries even Fortzaar Mite is marketed.
Supposedly that is a weaker variety of the stronger variety of
Cozaar Comp.
Augmentin has a strength of 125/31 of amoxicillin/clavulanic acid,
and Augmentin-Duo is 400/57. But here "Duo" does not mean
double at all.
In some cases there seem to be disagreement whether an ingredient
is active, or to be regarded as an excipient.
In the Nordic countries the clavulanic acid in Bremide (synonymous
with Augmentin) is only mentioned in the list of ingredients, and the
strength is indicated only for amoxicillin.
Protamin sulphate with insulin is another example. In the Nordic
countries NovoNordisk expresses it as part of the isophane insulin
complex (Insulin Mixtard 30/70). Hoechst/Aventis only mentions it
as an excipient (Insuman Comb 25). Lilly does both (Humalog Mix
25).
My strong personal view is that both clavulanic acid and protamine
sulphate are active ingredients.
There are at least four different problems here. All of them need to
be internationally standardised. First, ingredients need to be
classified as active or non-active. Second, the product name needs
to indicate if the medicine is a combination product (FDC). Third, a
way needs to be found of indicating strength in FDCs. And, fourth,
a way needs to be found to indicate different strengths of the same
FDC. FDCs are more complex than single substance medicines.
Each substance has its mechanisms of action and elimination, and
possible adverse reactions. In addition there are both the wanted
and unwanted interactions. It is also more difficult to identfy the
source of unwanted effects.
An FDC ought to be specially labelled to inform the patient that it is
a combination product. It is not sufficient to mention the
substances in the list of ingredients. Most patients will not be able
to tell from the substance name whether it is an active or
non-active ingredient.
Indicating "strength" with the sum of two different substances (eg,
Sinemet 110) is as erroneous as adding horses and jockeys. A
one-number "strength" also gives an impression of only one active
ingredient. Similar arguments can also be held against ignoring one
of the ingredients (like in Sinemet 100).
The strength of an FDC should indicate both the number of active
ingredients, and the respective amounts. Values separated with a
solidus (eg, Sinemet 10/100, Rifater 50/120/ 300) seem to be
being established as an internationally acceptable way of doing it. I
believe that omitting the units for FDCs (mg, mg/ml, international
units) will not increase the risk of medication errors.
Manufacturers of FDCs with three or more active ingredients, could
perhaps be allowed to print "combination" or "multi ingredient" or
an equivalent expression in the product name, given that the active
substances are sufficiently specified in the list of ingredients. But
that is only if the FDC is marketed in one variety. If the FDC is
marketed in more than one variety, the strength should always be
indicated in the product name for each active ingredient.
Medicines regulatory authorities must issue regulations, and
medicine manufacturers must adjust their quality standards in this
matter.
Stein Lyftingsmo is manager of the hospital pharmacy in Elverum,
Norway
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