Bioequivalence and labelling of medicines with regard to generic substitution

Updated 05 July 2019

Substitution can be made between synonymous medicinal products of the same strength and, usually, of the same pharmaceutical form, if a direct therapeutic equivalence or bioequivalence is documented. All medicinal product groups and substances are included in the substitution system. However, the Danish Medicines Agency does not allow generic substitution of products if automatic substitution could result in risks of incorrect use or other patient problems.

When a company applies for a marketing authorisation for a generic medicinal product and the Danish Medicines Agency in this connection considers generic substitution, the results of the bioequivalence studies must comply with several requirements. In addition, there are a number of general criteria for the labelling of generics intended for substitution.

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 %, however, in special circumstances, e.g. for substances with a narrow therapeutic index, the acceptance interval may be narrowed to 90.00-111.11 %.

This appears from the Guideline on the Investigation of Bioequivalence (CPMP/QWP/EWP/1401/98 Rev. 1/Corr), which is used to assess whether authorisation of generics can be granted based on bioequivalence against e.g. the Brand Leader.

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. For this reason, 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

Substance

ATC

Acceptance limits for AUC and Cmax

Aminophylline/Theophylline

R03DA05
R03DA04
R03DB04
R03DA54
R03DA74

90.00-111.11 %

Lithium

N05AN01

90.00-111.11 %

Thyroxine

H03AA

Cannot be substituted

Vitamin K antagonists

B01AA

Cannot be substituted

Phenytoin
Carbamazepine
Valproate
Other antiepileptics

N03AB02
N03AF01
N03AG01
Other N03

Cannot be substituted
Cannot be substituted
Cannot be substituted
90.00-111.11 %

Certain immunosuppressants:
Cyclosporine
Tacrolimus

L04AD01
L04AD02

Cannot be substituted

Antiarrhythmics

C01B

90.00-111.11 %

Centrally acting anorectics

A08AA

90.00-111.11 %

Tricyclic antidepressants

N06AA

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 products if automatic substitution could result in risks of incorrect use or other problems affecting patient complianceExamples 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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