Issues in the interchangeability of generic drugs: part I

Pharmaceutical industries patent their drugs and have the exclusive right to sell them during the first years of marketing. During these years, the industry profits for the investments they made during the development. After expiration of the term of patent, other industries will often market this drug in generic versions.

The application for marketing authorisation for generic drugs is limited compared with the application for innovator drugs. Generic drugs should comply with the regulations as described in the Directive 2001/83/EC ‘Community code relating to medicinal products for human use’.(1) One of the major requirements for non-biological generic drugs is that bioequivalence is similar to the innovator drug in healthy volunteers. The 90% confidence interval of both the area under curve (AUC) and the maximum concentration (Cmax) should be 80-125% of the original drug. From 2010 onwards, drugs with a small therapeutic window required the 90% confidence intervals within 90 to 111.1 (100 divided by 90)% of the original drug.(2) With these bioequivalence rules and other applicable legislation, the innovator drug and the generics should be interchangeable in clinical practice.

Hospital pharmacists will generally select the most suitable and most cost-effective generic drug that is available on the market. For drugs that are dispensed frequently, producers are asked for tenders for the upcoming period. By contracting producers for a certain term, further reduction in prices is achieved. The drawback of this system is that the generic drugs used in the hospital will change periodically from one brand (generic or innovator) to another. Drug shortages, for example as a result of manufacturing problems or recalls, will also result in changes in brands. In contrast to the switches due to contracting, drug shortages will result in sudden and unexpected switching, making the process more complex. Although the similarity in bioequivalence and other parameters has been bound by strict regulations, there is still debate as to whether they are actually interchangeable. Concerns have been described in the literature about the similarity in effectiveness and the occurrence of side effects.(3,4)

For certain drugs with a small therapeutic window, minor differences in bioequivalence might have a major impact on clinical outcomes. For these drugs, switching from one brand to another may result in either failure of therapy or the occurrence of side effects. The drug classes that have been mentioned in this context are the anticonvulsants, immunosuppressive drugs, thyromimetics, anti-arrhythmics and heart glycosides.(5) These issues have been described extensively in the literature.

Beside the differences in bioequivalence, other differences between the drugs also exist. In the majority of changes, these differences do not have an effect on the clinical application. However, in a minority of changes, these seemingly subtle differences may have consequences and potentially impact patient safety. We analysed our experiences after the introduction of new generic drugs in the academic hospital pharmacy of the Erasmus MC (Rotterdam, The Netherlands) and Stichting Apotheek der Haarlemse Ziekenhuizen (SAHZ, Pharmacy Foundation of Haarlem Hospitals) serving two teaching hospitals (Kennemer Gasthuis, Haarlem and Spaarne Ziekenhuis, Hoofddorp, The Netherlands). These analyses were performed to improve the contracting process.

We composed a checklist to avoid similar problems, and this checklist has been published.(6) The items mentioned in this article and in the checklist are also used as specification parameters during the contracting process. This article is the first in a short series. In part I, we will describe the problems we encountered with differences in the active ingredient between the same drug of various brands, and differences in the excipients used. Part II will describe the problems due to differences in labelling, packaging, preparation and instructions accompanying the drug. The final article will present a guideline for purchasing drugs and accompanying switches that we prepared from the results of these analyses. The issue of biosimilars, the equivalence of biological drugs that are derived from a living organism, is much more complex, and is outside the scope of these articles.

For the manufacturing of dexamethasone solutions, such as injection fluids, dexamethasone disodium phosphate is used because of its solubility, whereas for tablet forms, dexamethasone base is used. We encountered problems with the salt forms of dexamethasone ampoules after switching between different presentations. At the Erasmus MC, we manufactured ampoules in the hospital pharmacy, with the amount of dexamethasone given as dexamethasone disodium phosphate. After commercial ampoules were introduced on the market, we switched to these commercial ampoules. However, the declaration used for these ampoules was the amount of dexamethasone as dexamethasone base. The amount of dexamethasone in both ampoules was identical, but the labels mentioned 5mg dexamethasone disodium phosphate and 3.8mg dexamethasone base, respectively. Although the labelling itself was correct, it is difficult for physicians and nurses to understand that these amounts are the same.

It has resulted in the erroneous administration of 5mg dexamethasone base instead of 5mg dexamethasone disodium phosphate, an overdose of approximately 30%. A comparable issue occurred at the Spaarne Ziekenhuis and Kennemer Gasthuis when a commercial supplier of dexamethasone disodium phosphate 5mg/ml ampoules changed the declaration of the drug on the label. This supplier previously stocked two strengths of dexamethasone ampoules: dexamethasone disodium phosphate 5mg = 1ml ampoules; and dexamethasone 20mg = 1ml ampoules. The declaration of the dexamethasone disodium phosphate 5mg = 1ml ampoules was changed to dexamethasone 4mg = 1ml in order to create uniform declarations of the drug on the labels. In order to safely introduce injectables with altered declarations on the label, hospital medication protocols should be checked. It is the legal duty of hospital pharmacists to inform healthcare providers and patients about the correct use of the drug. In the Spaarne Ziekenhuis and Kennemer Gasthuis, more than 100 hospital medication protocols had to be changed. These changes require efficient communication between the hospital pharmacy, physicians and nurses.

The policy in other hospitals may also have an impact when patients are transferred from one hospital to another. Caffeine is used for treating apnoea in newborns. At that time, it was not available in The Netherlands as a commercial product and therefore was produced in several hospital pharmacies, including the SAHZ serving the Spaarne Ziekenhuis. Recently, a commercial product has been introduced on the market and some of the hospitals switched to this drug. A major difference is that the ampoules manufactured in hospital pharmacies contain caffeine base, whereas the commercial product contains caffeine citrate, and is labelled as such. The commercial product contains 20mg/ml caffeine citrate, which corresponds to 10mg/ml caffeine base. Two different dosing regimens are given in the Dutch guidelines for paediatric dosing, one for caffeine citrate and one for caffeine base, with a twofold difference between them.(7) A newborn was transferred from a nearby hospital where he had been treated with caffeine citrate. In our hospital, the formulary uses caffeine base.

The physician erroneously used the dose prescribed in the first hospital as caffeine citrate while prescribing the base, thereby resulting in a twofold overdose of caffeine. The prescribed drugs are checked daily by a pharmacist and this error was noted during medication verification in the hospital pharmacy within 24 hours. The pharmacist contacted the physician and the dose was corrected. The erroneous higher dosage was administered only once; no toxic effects were noted and no therapeutic drug monitoring was performed. This difference in labelling poses the serious threat of a twofold over- or under-dose, especially because physicians and nurses are not familiar with the difference in the citrate and base. In this case, the paediatricians should have been informed about the introduction of a new presentation on the market with a different dosing regimen. Although we did not introduce this presentation in our hospital, the policy in other hospitals can imply that physicians in our hospital are confronted with it.

In the selection process of generic drugs, the role of excipients is often disregarded, although differences could have an impact. A notable situation was the introduction of gemcitabine as an infusion concentrate. We previously used a powder for solution for injection and an advantage of an infusion concentrate is that the solvent step is omitted during preparation of the drug. After the introduction of the new gemcitabine concentrate, we received complaints from the treating physicians that patients appeared to be drunk after administration of the gemcitabine infusion. The infusion concentrate contained ethanol as co-solvent, because the solubility of gemcitabine in water is insufficient. We calculated that the amount of ethanol that was given to an average person with each administration corresponded with around two glasses of beer. This amount was unacceptable to us and we switched back to the powder for solution for injection.

Differences in excipients without pharmacologic activity may seem irrelevant. However, in the case of hypersensitivity to these excipients, these differences may have important implications. Levothyroxine tablets (25μg) are registered and available under two different brand names in The Netherlands: Euthyrox® and Thyrax®. Thyrax tablets contain indigo carmine (5,5′-indigodisulfonic acid sodium salt; also known as indigotine or E132) as colourant. Indigo carmine can cause allergic reactions, such as rash (urticaria), itching, bradycardia and hypotension. When switching between these formulations, the risk of allergic reactions should be considered.(8)

Also, the lactose content of the tablets may cause a problem in patients who are lactose intolerance. Although it is stated in the literature that the amount of lactose in tablets and capsules is not sufficient to cause gastrointestinal problems, some patients do complain after taking tablets containing lactose.(9) This implies that generic drugs not containing lactose are requested for these patients.

In children, other issues may play a role. In some pharmaceutical liquids, small quantities of ethanol are used as co-solvent. These quantities are harmless in adults, but the effect of these small quantities of ethanol on the development of children is unknown and, therefore in our opinion, an unacceptable risk. A number of drugs contain benzyl alcohol as preservative. Benzyl alcohol is contraindicated in children under the age of four years because they are unable to metabolise it.(10) If given in large amounts, the metabolite can accumulate in the central nervous system, with serious consequences including metabolic acidosis, vasodilation, paralysis, seizures, respiratory depression and death.

Another co-solvent that could be dangerous in young children is propylene glycol. In contrast to benzyl alcohol, children have an increased metabolism of propylene glycol. It is metabolised into lactate by the liver enzyme alcohol dehydrogenase. Therefore, the risk of causing metabolic acidosis is increased in children and a daily dose of > 200mg/kg, both oral and parenteral, is contraindicated. In adults, the maximum daily dose is 400mg/kg.

The possibility of administering drugs through feeding tubes may differ between drugs of various brands. Losec® MUPS, containing omeprazole, can be dispersed in a small amount of water just before administration. This allows omeprazole to be administered through gastric feeding tubes (G-tubes) with an opening of less than 10 French Gauge (or Charierre). The generic omeprazole pellets obstructed the G-tubes easily. The difference in formulation and excipients between the generic omeprazole and the Losec® MUPS is the cause of this problem. Obstructed G-tubes need to be replaced, causing significant discomfort to the patient and a rise in costs for the hospital. Alternative administration of omeprazole was introduced for patients with gastric feeding tubes.

The selection of the best cost-effective generic drugs may result in cost savings and reduction of healthcare costs. In a minority of cases, introductions of a different generic drug results in unexpected problems, and in some cases may cause patient harm. The costs to solve these problems, both in workforce and in buying alternative drugs, may even transcend the initial savings. The introduction of a switch in generic drugs involves proper selection to consider all the differences and potential consequences, and informing the healthcare providers and patients sufficiently about these differences and potential consequences. In this article, we have described the results from an analyses we performed on unexpected events that we encountered after the introduction of generic drugs, related to differences in the active ingredient and excipients of the drugs. Hospital pharmacists are responsible for both purchasing and dispensing and have an important role in the selection of new generic drugs and the introduction of these drugs in the clinical setting. Although this process is often rather straightforward, minor changes may have large implications, as described here. Our guidelines for purchasing drugs and accompanying switches will be useful for hospital pharmacists to avoid these unexpected events and maintain both cost-effective and safe administration of drugs in and from hospitals.

• Generic drugs should comply with regulations on bioequivalence among others, to make them interchangeable with the innovator drugs and other generics in clinical practice.
• Beside the differences in bioequivalence, other differences do exist. In the minority of changes, they may cause problems in the clinical application.
• We analysed these problems retrospectively, to improve the contracting process and to avoid them in the future. This analysis is described in this short series.
• Differences in the labelling of the active ingredient, for example caffeine base or caffeine citrate, may result in both under- and overdosing.
• Differences in the excipients used, such as ethanol, benzyl alcohol and propylene glycol, should be taken into account.

1. EU Directive 2001/83/EC. ‘Community code relating to medicinal products for human use’.  http://europa.eu/legislation_summaries/internal_market/ single_market_for_goods/pharmaceutical_and_ cosmetic_products/l21230_en.htm (accessed 20 May 2013).
2. European Medicines Agency. Committee for medicinal products for human use (CHMP). Guideline on the investigation of bioequivalence. www.ema.europa.eu/docs/en_GB/document_library/ Scientific_guideline/2010/01/WC500070039.pdf (accessed 20 May 2013).
3. Al Ameri M, Epstein M, Johnston A. Generic and therapeutic substitutions: are they always ethical in their own terms? Pharm World Sci 2010;32:691-5.
4. Simoens S. Generic and therapeutic substitution: ethics meets health economics. Int J Clin Pharm 2011;33:469-70.
5. Platform patient-industry. Generic drug substitution do or don’t [In Dutch: Generieke Geneesmiddelen Substitutie. Wel of niet doen]. www.cbg-meb.nl/NR/rdonlyres/6D81F7C9-B77D-4DEA-AD4A-ED17E35BE8F7/0/120531PIrapport.pdf (accessed 20 May 2013).
6. Becker ML et al. Switching to different generic medicines: a checklist for safety issues. Eur J Hosp Pharm 2013;20(2):74-7.
7. Dutch Knowledge Centre Pharmacotherapy in Children. Children Formulary [In Dutch: kinderformularium]. www.kinderformularium.nl
8. Lareb. Hypersensitivity reactions with Thyrax Duotab® 0.025 mg  [In Dutch: Overgevoeligheidsreacties bij Thyrax Duotab® 0,025 mg]. Geneesmiddelenbulletin 2006;40(11):127-8.
9. de Vries S, Schaafsma E. Lactose in pharmaceuticals does not cause problems [In Dutch: lactose in farmaca geeft geen problemen]. Pharmaceutisch Weekblad 1998;133(16):650.
10. Medicines Evaluation Board (CBG-MEB). Allergy Information. www.cbg-meb.nl/CBG/en/human-medicines/medicinal%20products/Allergy-information/default.htm (accessed 20 May 2013).