June 23, 2001
Comment
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 ( 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