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Home > Companies > Authorisation of medicinal products > Guidelines and forms >

Bioequivalence and labelling of medicinal products with regard to generic substitution

- Information to applicants for marketing authorisation for medicinal products.

This note sets out a number of general and specific requirements the Danish Medicines Agency has in relation to results of bioequivalence studies submitted in marketing authorisation applications for generic medicinal products. 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 on the basis of bioequivalence or therapeutic equivalence.

Requirements for the results of bioequivalence studies – acceptance limit
The Note for Guidance on the investigation of bioavailability and bioequivalence (CPMP/EWP/QWP/1401/98) is used to assess whether authorisation of generics can be granted based on bioequivalence against e.g. the Brand Leader. The requirements are that the 90% confidence intervals for the ratio test: reference for both AUC and C max must usually be within 80 – 125%. Where substances have a narrow therapeutic index, this interval may be narrowed.

The Danish Medicines Agency considers that the 90% confidence interval for the ratio test versus reference should include 100% irrespective of whether acceptance limits of 80-125% or narrower are employed. Deviations may be accepted if they can be adequately justified not to have impact on either the overall therapeutic effect or safety profile of the product.

The Danish Medicines Agency also considers that the bioequivalence acceptance limits for immunosuppressives (ATC: L04) must lie within 90-111% as they have a narrow therapeutic index, see Table 1.

For a number of other substances or therapeutic groups, the Danish Medicines Agency considers that authorisation may be granted if the usual acceptance limits (80-125%) are observed, but that therapeutic problems in relation to substitution of the preparations might occur. The bioequivalence limits have therefore been narrowed for such medicinal products when automatic substitution is being considered, cf. Table 1.

Table 1: Acceptance limits

Substance	ATC	Acceptance limits for AUC and C max
Substance	ATC	MA	G-sub
Aminophylline/ Theophylline	R03DA05 R03DA04 R03DB04 R03DA54 R03DA74		90-111%
Lithium	N05AN01		90-111%
Thyroxine	H03AA		90-111%
Wafarin	B01AA03		90-111%
Antiepileptics apart from benzodiazepines	N03 (But NOT N03AE)		90-111%
Immunosuppressives	L04	90-111%	90-111%
Antiarrhythmics	C01B		90-111%
Centrally acting anorectics	A08AA		90-111%
Tricyclic antidepressiva	N06AA		90-111%

MA = marketing authorisation; G-sub = generic substitution

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Criteria for labelling generics with regard to substitution
Substitution can be made with synonymous medicinal products of the same strength and, usually, of the same medicinal product 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 substituted among themselves in so far as their compositions are identical (incl. perfumes and preservatives).

The Danish Medicines Agency does not allow generic substitution of preparations for which automatic substitution may entail a risk of incorrect use or other problems which might affect patients’ compliance. Examples of such situations are listed in Table 2 below.

Table 2: Situations with a large risk of compliance problems

Depot preparations	Are only substituted if the same dosage intervals are indicated in the SPC
Single dose versus multiple dose container	Are not substituted
Different strength indications	Are not substituted
Different times of ingestion, e.g. in connection with food	Are not substituted
Preparations requiring preparatory treatment by patients	Are only substituted if the preparatory treatments are identical
Tablets/capsules to dissolve, chew, melt or for use in the oral cavity, etc.	Are normally not substituted mutually unless special circumstances apply
Nasal sprays, inhalation preparations, eye drops, etc.	Can only be substituted if the devices for administration are identical

For further information, please contact Deirdre Mannion on tel.: +45 4488 9721 or Per Helboe on tel.: +45 4488 9275.

The Danish Medicines Agency, 13 July 2005, updated 8 February 2010

Last updated - 02.09.2010