Bioequivalence and labelling of medicines with regard to generic substitution

Updated 07 February 2012

When companies apply for authorisation of generic medicinal products, the authorities impose a number of general and specific requirements on the results of bioequivalence studies which the companies submit with their generic application.

The requirements apply to both authorisation of generic medicinal products, and the subsequent labelling with regard to generic substitution on the Danish market. The general labelling requirements on substitution apply regardless of whether the generics are authorised based on bioequivalence or therapeutic equivalence.

Requirements for the results of bioequivalence studies – acceptance limits

In bioequivalence studies, the 90 % confidence interval for the ratio of the test and reference products for AUC and Cmax, respectively, must generally be contained within the acceptance level 80.00-125.00 %. If substances have a narrow therapeutic index, the acceptance interval may need to be narrowed. The Guideline on the Investigation of Bioequivalence (CPMP/QWP/EWP/1401/98 Rev. 1/Corr) is used to assess whether authorisation of generics can be granted based on bioequivalence against e.g. the Brand Leader.

In the opinion of the Danish Medicines Agency, the 90 % confidence intervals for the ratio of the test and reference products should include 100 %, regardless that the acceptance limits are within 80.00-125.00 % or a narrower interval. Deviations are usually only accepted if it can be adequately proved that the deviation has no clinically relevant impact on the efficacy and safety of the medicinal product.

For a number of substances or therapeutic classes, the Danish Medicines Agency has considered that therapeutic problems might occur in relation to substitution of the medicinal products. The Danish Medicines Agency has tightened the bioequivalence limits for these products with regard to automatic substitution, or has terminated generic substitution for some medicines completely, please see table 1. The list reflects the current situation, and the need for adjustments may arise as specific cases emerge.

Table 1: Acceptance limits for generic substitution



Acceptance limits for AUC and Cmax



90.00-111.11 %



90.00-111.11 %



Cannot be substituted

Vitamin K antagonists


90.00-111.11 %

Antiepileptics apart from levetiracetam and benzodiazepines

(But NOT N03AX14 and N03AE)

90.00-111.11 %

Certain immunosuppressants:





Cannot be substituted



90.00-111.11 %

Centrally acting anorectics


90.00-111.11 %

Tricyclic antidepressants


90.00-111.11 %

Criteria for labelling generics with regard to substitution

Substitution can be made between synonymous medicinal products of the same strength and, usually, of the same pharmaceutical form (exceptions are listed below), and where a direct therapeutic equivalence or bioequivalence is documented. All medicinal product groups and substances are included in the substitution system.

Substitution can be made between tablets and capsules with systemic effect and immediate release, and various salts of active substances, although the authorised indications may be different. Creams, ointments and the like are only mutually substituted if their compositions are identical (incl. perfumes and preservatives).

The Danish Medicines Agency does not allow generic substitution of preparations for which automatic substitution may present a risk of incorrect use or other problems that could affect patient compliance. Examples of such situations are listed in table 2 below.

Table 2: Situations involving a high risk of compliance issues

Prolonged-release products Are only substituted if the same dosage intervals are indicated in the SPCs
Single dose versus multiple dose container Are not substituted
Different strengths Are not substituted
Different times of ingestion, e.g. in connection with food Are not substituted
Products that need to be reconstituted by the patient before use Are only substituted if the products are prepared in the same way
Tablets/capsules (soluble, effervescent, chewable, orodispersible) or otherwise for use in the oral cavity, etc. Are generally not substituted unless special circumstances apply
Nasal sprays, inhalation products, eye drops, etc. Can only be substituted if the devices for administration are the same.

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