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Published on 2 October 2013

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Issues in the interchangeability of generic drugs: part II



In the second article of this three-part series, the problems related to labelling, packaging and the instructions accompanying the drug, when switching between different brands of the same drug, are discussed 
Hylke Jan Kingma PharmD
Matthijs Becker PharmD PhD
Pharmacy Foundation of Haarlem Hospitals, Haarlem, The Netherlands
Nicole Hunfeld PharmD PhD
Department of Hospital Pharmacy, Erasmus MC, Rotterdam, The Netherlands
Ruud van der Hoeven PharmD
Pharmacy Foundation of Haarlem Hospitals, Haarlem, The Netherlands
After expiration of the patent term of innovative drugs, generic variants are often introduced on the market. The introduction of more than one producer results in price competition and cost savings. A requirement is that the generic drugs and the original drugs are mutually exchangeable.
Regulations from the government warrant that the various brands have similar properties, including similarity in the plasma levels reached after administration.(1) However, differences do exist between these drugs. Most of the differences may seem irrelevant in clinical practice, but a number of problems when switching between generic drugs have been encountered. In the last issue of Hospital Pharmacy Europe, we described the problems related to differences in formulation, such as differences in salt form of the active ingredient and differences in the excipients used. In this issue, we describe the problems related to labelling, packaging and the instructions accompanying the drug, when switching between different brands of the same drug. The experiences are from three hospitals in The Netherlands, one academic centre (Erasmus MC, Rotterdam) and two teaching hospitals (Kennemer Gasthuis, Haarlem and Spaarne Ziekenhuis, Hoofddorp).
The most obvious difference between different brands of the same drug is the packaging. The printing of the packaging is most often in the layout of the drug manufacturer. Clinicians need to become familiar with the new packaging after a switch. If they search on brand name while the generic name is stocked and vice versa, they might not find the correct drug. There is also the risk of unconsciously picking the wrong drug if they are too familiar with the layout of the package. For patients, these changes may lead to even bigger problems in the home situation.
Patients will often be more familiar with the packaging of a certain drug rather than its name. If two different labels of the same generic drug are dispensed, patients may not recognise them as being the same, leading to the risk of using both drugs simultaneously. This is especially the case when both the brand name and a generic version are dispensed, because the names differ on the packages. In these cases, the risk of patients not recognising that these drugs are essentially the same is even greater. Healthcare providers within the hospital should pay attention to these risks when admitting or discharging patients, or when the patient switches from the dispensing pharmacy. They should discuss the actual medication and ensure that the patient has fully understood the information given.
In some cases, the differences between various brands of the same drugs are small. Similarity of both primary and secondary packaging can lead to errors when preparing or administering medication. For example, we stock two different strengths of sufentanil ampoules in the hospital phamacy:
10 microgram/2ml and 50 microgram/1ml. We signed a purchasing contract with a generic supplier for these ampoules. The differences between the 10 microgram/ 2ml and the 50 microgram/1ml ampoules were small, as can be seen in Figure 1. The only differences were the size of the ampoules (1ml versus 2ml), and the colour marking on the ampoules, although the latter intended for identification during the production process and not for the end-user. The layout and size of the packages were similar. The therapeutic consequences of a potential error were considered to be too great and we decided to purchase the original ampoules, which had sufficient differentiation in presentation between the various strengths.
We encountered similar problems when we purchased diclofenac for injection. The original manufacturer used clear glass ampoules. After signing a new purchasing contract, this time with one of the generic suppliers, the anaesthesiology department reported patient safety issues, because that supplier used brown glass ampoules. The generic diclofenac ampoules resembled the suxamethonium chloride ampoules too closely. The generic product was maintained in stock and a medication safety letter was issued to all medical staff concerned. Interestingly, the introduction of the same brown glass diclofenac ampoules in another hospital did not result in reports of patient safety issues, although they too used the same suxamethonium chloride ampoules.
Correct and readable labelling of a drug is essential for its safe use. For some pharmaceutical presentations, such as ampoules, limited text can be printed on the label. However, the essential information, including the name of the drug, the concentration and volume, batch number and the expiration date should be included in such a way that reading it at a glance poses no problem. We substituted a drug because it was temporarily unavailable on the Dutch market. We imported the drug and found that only the brand name used in that country (which was different to that used in The Netherlands) was printed on the ampoules and not the drug name. Therefore, the Dutch physicians and nurses did not recognise these ampoules as such; moreover, the concentration of the drug was not given on the ampoules.
Storage conditions
Storage conditions sometimes differ between different brands of the same drug. When we switched to a different brand of epinephrine ampoules, we found that the new ampoules required refrigeration, whereas the previous ampoules could be stored at room temperature. Although the concentration and the excipients of the ampoules were identical, the stability testing performed by the pharmaceutical industry at that time was insufficient to warrant storage at room temperature. Epinephrine ampoules are also used in emergency kits and storage in a refrigerator is not an option in this case. After receiving stability information from the manufacturer, we modified the expiration date on these ampoules manually.
Another example is lidocaine–epinephrine ampoules. Drugs are usually stored at room temperature (15–250C), in the refrigerator (2–80C) or in the freezer (<180C). A new brand of lidocaine–epinephrine ampoules required storage below 150C. An option was to store these ampoules in the refrigerator. However, the number of refrigerators on wards and in the hospital pharmacies is limited and the lidocaine–epinephrine ampoules needed considerable space in these refrigerators, so we decided to store them at room temperature with a shorter shelf life.
There are many systems available for the administration of drugs, such as infusion sets for parenteral drugs and inhalation systems for pulmonary drugs. In most cases, compatibility between drug and instrument is obvious. However, an unforeseen incompatibility was discovered after the introduction of a generic variant of human immunoglobulin. The opening of the vial was too small to puncture the vial with both a spike and a vent needle. A new infusion system had to be introduced with the spike and vent needle combined, to make administration of these immunoglobulins possible.
The preparation process can differ between generic drugs. The introduction of a new generic drug should be accompanied simultaneously by the introduction of the accompanying protocols. Errors in a mismatch between the protocol and the drug could potentially result in both under- and overdosing. Differences in the amount of fluid used to dissolve the drug, or differences in concentration, are potential causes of these errors for both oral liquid and parenteral drugs. For oncolytics and other drugs with a small therapeutic window, these errors may result in serious adverse patient outcomes. For these drugs, the simultaneous introduction of adjusted protocols is even more important and measures should be taken to ensure that all drugs from the previously used manufacturer are discarded at the same time. Because of extensive checking and strict enforcement of these protocols, these errors have not occurred in our pharmacies.
Substitution of drugs in the hospital formulary frequently leads to changes in the primary package. Barcodes on the primary package are used for medication administration registration in some hospitals. The patient and drug package is identified through barcode scanning and checked automatically by a computer system. The introduction of new packages without a barcode could disturb this process. Gradual introduction of new packages will also pose challenges when a barcode on the primary package is present, because two different barcodes for the same drug will be present on wards. Changing from a unit dose package to a strip or a bottle of tablets can make identification of an individual unit impossible. On unit dose packages, the drug name, strength, batch number and expiry date are present. Missing one or more of these parameters makes the unique identification of the medication upon administration impossible. Also, reshipment to pharmacy and reimbursement of surplus medication is not possible.
Route of administration
Ampoules for injection can be administered in various ways, for example, through intravenous, intramuscular and spinal routes. Various excipients, such as antioxidants and preservatives, have been associated with neurotoxicity after spinal administration.(2) If a certain drug is used for spinal administration, special attention should be paid to the excipients used. Also, problems may arise between drugs containing the same excipients. A few years ago, we switched from branded diclofenac (Voltaren®) to generic diclofenac: both are virtually identical with respect to the excipients. The product information of the branded diclofenac mentioned that both intravenous and intramuscular administration was possible; however, the generic version mentioned only the intravenous administration. This resulted in confusion for physicians and nurses and the intramuscular administration of these diclofenac ampoules was actually off-label. In the meantime, the intramuscular administration has been added to the product information of the generic diclofenac.
Most switches of generic drugs are introduced in the clinic without problems. However, a minority will result in issues, as described in this article and our previous article. If these issues are not foreseen before introduction in the clinic, the problems that arise will have to be solved unexpectedly and could result in patient harm. This reactive policy requires much effort and the costs of these efforts might outweigh the initial benefits. We previously published a checklist that is used to foresee potential problems before introduction and to potentially avoid them.(3) This checklist will help to identify the majority of potential problems in advance.
Switching between various brands of a drug can result in cost savings. To make a valid decision for a switch, it is necessary to consider all the consequences and the work involved to cope with them before, and not after, the decision. If not, the introduction of a different brand of the same drug may give unforeseen problems. Also, potential harm to patients cannot be excluded without a thorough investigation in advance. Solving these problems will require teamwork from pharmacy personnel and clinicians. Pharmacists have an important role in supervising these switches because they are the drug specialists in the hospital and are responsible for both purchasing and dispensing. The examples given in this and the previous article will help minimise these problems. A proactive approach with the help of a checklist, instead of a reactive approach, will be beneficial and will save unexpected costs, reduce complaints and, most importantly, reduce patient harm. In our final article, we will present a guideline for purchasing drugs and accompanying switches. Because of government- and healthcare insurance-driven needs to cut costs in drug dispensing, such an approach is vital to maintain both cost effective and safe administration of drugs in and from hospitals.
Key points
  • For (price) competition between generic drugs, mutual exchangeability is a requisite.
  • Minor differences between generic drugs may in some instances result in problems after switching between these drugs.
  • The issues due to differences in labelling, packaging and instructions are discussed in this article.
  • Identification of these problems before introduction in clinical practice will save unexpected costs, reduce complaints and reduce patient harm.
  • Pharmacists have an important role in supervising switches, because they have the knowledge and responsibility for both purchasing and dispensing.
  1. EU directive 2001/83/EC ‘Community code relating to medicinal products for human use’. (accessed 8 August 2013).
  2. Hodgson PS et al. The neurotoxicity of drugs given intrathecally (spinal). Anesth Analg 1999;88:797–809.
  3. Becker ML et al. Switching to different generic medicines: a checklist for safety issues. Eur J Hosp Pharm 2013;20(2):74–7.

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