Published: 6 June 2024

Publications

A reminder: generic medicines, bioequivalence and switchability

Published: 6 June 2024
Prescriber Update 45(2): 44–46
June 2024

Generic medicines and bioequivalence

Generic medicines are required to be the same as innovator or ‘brand-name’ medicines in dosage, safety, effectiveness, strength, stability and quality, as well as in the way they are made.¹

During the pre-market approval process, Medsafe assesses evidence provided by sponsors to show that their generic medicine is bioequivalent to the innovator. Bioequivalence studies are small clinical trials that generally involve single doses given to healthy volunteers. Medicines are bioequivalent if the rate and extent of absorption of the active ingredient into the bloodstream (bioavailability) meet internationally agreed criteria for similarity.^2–4

Bioequivalence means a patient can expect to experience the same safety and efficacy when starting on either an approved generic or the innovator (brand name) medicine. Bioequivalence is not required to be checked between generics. However, because the difference between generics and the innovator is so small, patients would not normally experience any difference in efficacy or safety.

Bioequivalence and switchability

An innovator medicine can generally be substituted with an approved generic and vice versa because of the comparable bioavailability demonstrated through bioequivalence studies. However, these studies are not designed to investigate patients’ suitability to change from one brand to another during their treatment (‘switchability’).

For most medicines, patients can switch between approved brands during treatment without issue. However, switching between different brands should ideally be avoided for some specific medicines. A medicine’s switchability may be affected by its therapeutic index or pharmacokinetics, or the patient population. For example, medicines with a narrow therapeutic index are often carefully titrated to a safe and effective dose for individual patients, and small changes can have a clinically meaningful impact on efficacy. In some patients or for certain medicines, formulation or significant manufacturing changes can affect the patient’s response, despite the demonstration of bioequivalence between the old and new medicine.

Other non-pharmacological factors may influence a patient’s experience when changing medicine brands. These could include preconceptions of generic medicines or concerns about change in general, resulting in the patient experiencing and reporting real side effects, as commonly seen in patients taking placebos in clinical trials. However, there are also other reasons that patients may feel a difference in effect between brands (eg, infection), and it can be difficult to determine the cause of an adverse event seemingly linked to a brand switch.

Changes to the Pharmac-funded medicine supplier or supply chain issues may lead to an unavoidable brand change for the patient. If changing a difficult-to-switch medicine is necessary and/or a patient expresses concerns about a change, prescribers should take extra care, including counselling, monitoring and dose adjustment.

Anti-epileptic medicines

Anti-epileptic medicines (AEMs) as a medicine class can cause difficulties when switching patients between brands. Medsafe recommends that prescribers follow the UK Medicines and Healthcare products Regulatory Agency’s (MHRA) advice regarding AEMs, which places them in three categories based on switchability.⁵

Category 3 medicines (eg, levetiracetam, gabapentin) generally have high bioavailability and a wide therapeutic index, meaning that switching is relatively straightforward. Whereas patients taking category 1 medicines (eg, phenytoin, phenobarbital) should remain on the same brand, as clinically relevant differences between brands can occur despite bioequivalence being shown.⁵ Recent New Zealand experience supports this advice, with many patients experiencing difficulties when the funded lamotrigine brand (a category 2 AEM) was changed in 2019,⁶ and when the formulation of the brand name phenytoin medicine Dilantin was altered.⁷

Levothyroxine and Eltroxin reformulation

Levothyroxine is another example where brand switching is not recommended if avoidable, with dose changes of the same brand also requiring careful monitoring and titration. This is largely due to the medicine’s complex pharmacokinetic profile and narrow therapeutic index, meaning that slight differences in bioavailability and serum levels have clinically relevant impacts. This lack of switchability was highlighted in New Zealand in 2007 when the Eltroxin brand of levothyroxine was reformulated by the manufacturer. Despite bioequivalence being successfully demonstrated between the old and new formulations, many patients reported issues following the change.^8,9 Similar experiences were also reported in Denmark and France.¹⁰

Medsafe recently assessed and approved another minor formulation change for Eltroxin, which will be implemented from June 2024. While most patients will not experience any issues with the change, prescribers should carefully monitor patients when changing them to the new formulation.

For information about this change refer to:

• the manufacturer’s Dear Healthcare Professional letter (PDF, 2 pages, 98 KB)
• Pharmac’s information about the change
• the Eltroxin data sheet for dose titration and monitoring advice.

More information

Medsafe publishes copies of Dear Healthcare Professional letters sent to healthcare professionals by medicine manufacturers and sponsors. These may include information supply chain issues and brand substitutions.

Refer to the Pharmac website for:

• supply issues, discontinuations and brand changes
• the Community Schedule and the Hospital Medicines List
• consultations and decisions, including tender results.

References

1. Food and Drug Administration. 2021. Generic drug facts 1 November 2021. URL: www.fda.gov/drugs/generic-drugs/generic-drug-facts (accessed 6 May 2024).
2. European Medicines Agency. 2010. Guideline on the Investigation of Bioequivalence. Doc Ref: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **, 20 January 2010. URL: www.ema.europa.eu/en/investigation-bioequivalence-scientific-guideline (accessed 3 May 2024).
3. Medsafe. 2017. The Medsafe Files – Episode Four: New Medicines Assessment (Part 2). Prescriber Update 38(3): 43–4. URL: www.medsafe.govt.nz/profs/PUArticles/September2017/TheMedsafeFiles4NMAssessment.htm (accessed 3 May 2024).
4. bpac^nz. 2007. What is bioequivalence. Best Practice Journal SE: 12–16. URL: bpac.org.nz/BPJ/2007/March/bioequiv.aspx (accessed 3 May 2024).
5. Medicines and Healthcare products Regulatory Agency. 2017. Antiepileptic drugs: updated advice on switching between different manufacturers’ products. Drug Safety Update 11(4): 5. URL: www.gov.uk/drug-safety-update/antiepileptic-drugs-updated-advice-on-switching-between-different-manufacturers-products (accessed 3 May 2024).
6. Medsafe. 2019. Update on suspected adverse reaction reports to lamotrigine after changing brands 20 December 2019. URL: www.medsafe.govt.nz/safety/Alerts/Lamotrigine.asp (accessed 3 May 2024).
7. Medsafe. 2019. Phenytoin (Dilantin capsules formulation change) – How did it affect patients? Prescriber Update 40(2): 29–30. URL: www.medsafe.govt.nz/profs/PUArticles/June2019/Phenytoin-Dilantin-capsules-formulation-change.htm (accessed 7 May 2024).
8. Medsafe. 2013. Eltroxin formulation change 4 July 2013. URL: www.medsafe.govt.nz/hot/alerts/EltroxinInfo.asp (accessed 3 May 2024).
9. bpac^nz. 2007. Eltroxin (levothyroxine formulation change). Best Practice Journal 15: 48–51. URL: bpac.org.nz/BPJ/2008/August/eltroxin.aspx (accessed 3 May 2024).
10. Fliers E, Demeneix B, Bhaseen A, et al. 2018. European Thyroid Association (ETA) and Thyroid Federation International (TFI) joint position statement on the interchangeability of levothyroxine products in EU countries. European Thyroid Journal 7(5): 238–42. DOI: 10.1159/000493123 (accessed 7 May 2024).