GS legal status of supply

Due to the minimal risk, these medicinal products do not require advice from a chemist or pharmacist. The MEB does not easily assign GS status. Whether a medicinal product qualifies for GS status of supply is currently only evaluated following a request from a marketing authorisation holder.

Based on section 4.2 of the Medicines Act Regulation, the MEB will categorize a medicinal product as GS if:

1. At least five years of experience have been gathered in the Union or in the United States of America with the active substance in the medicinal product as an OTC medicinal product.
2. The risk of damage resulting from use of the medicinal product is negligible.
3. There are no signs of abnormal use.
4. The number of units per pack is relatively small.
5. The package and patient information leaflet warn for potentially risky situations.

Since 9 December 2011, a sixth criterion has been added:

•  The availability of advice from a chemist or pharmacist is not required.

The 6 criteria or not assessed separately by the MEB, but examined together against the backdrop of actual use and experience with the product. In case of relatively very low risk, the risk of use of the medicinal product is considered negligible (criterion b). This criterion is also not assessed separately by the MEB, but examined together against the backdrop of actual use and experience with the product. The overall social context of experience with and knowledge about the product is important in answering the question of whether the risk of damage is negligible; the effects of broad and easy access are also taken into account (considering the effects of scale and intensity of use of the product). For example, a medicinal product containing a substance that is itself not harmless may still be suitable for the GS category if social use is such that the practical risk of harm is negligible. The risk is determined not only by the active substance but also factors including dose, pack size, additional information and who it is offered to. A good example is the legislation surrounding paracetamol.

Package size

In order to qualify for GS status of supply, it may be necessary to limit the package size in the AV category compared with the PDO packages. Reasons for doing so may include:

• if there is an inherent risk of the active substance or excipient in case of long-term use (e.g. iodine and ibuprofen);
• if there is a risk that an impending (acute) underlying condition will not be recognized in time (for example loperamide and ambroxol).

The degree of limitation depends on the risk and will have to be substantiated case by case in order to ensure the criterion of negligible risk of harm is met for use of the medicinal product.

General principles

For medicinal products, a distinction must be made between medicinal substance and use. The MEB authorizes a medicinal product if said product has a positive balance between efficacy and harmfulness and can be used in relative safety. By supporting careful use, based on good information, the goal is to avoid potential risks for patients.

Additionally, the MEB also feels the user has personal responsibility. Dealing with the risks of over-the-counter medicinal products is no different from dealing with the risks of other activities or products, such as pesticides or cleaning agents, from a user perspective. Every user is personally responsible for using the medicinal product according to the instructions in the leaflet.

At all times, patients may decide to obtain an over-the-counter medicinal product via a pharmacist or local chemist because of, for example, individual additional risks. It is important that any users be able to assess risk based on criteria and information provided upon purchase. This may be realized by listing additional information on the packaging and the leaflet present in the pack. The MEB is further of the opinion that pack size and dosage are potential handholds for further limiting the potential risk of unintended use of over-the-counter medicinal products if said products are also available outside of the pharmacy and chemist. The potential for unintended use is then limited physically. A limitation of dosage and pack size does contribute to a limitation of unintended use, but according to the MEB offers no guarantee (for example, an individual could buy multiple packages at the same time or one after the other within a short time) and therefore cannot replace the information in the leaflet and on the packaging, but solely supplement it.

The answer to the question of whether a certain medicinal product entails a negligible risk cannot be found in national or international cut-offs or models from which 'negligibility' may be derived, but is the resultant of a broad evaluation weighing numerous factors that must be viewed in context. These vary from relationships with other criteria and experience with and knowledge about the medicinal product to the circumstances under which and to whom the medicinal product is offered. It is important to balance advantages (per indication) and disadvantages (undesirable effects), and determine whether risks can be minimized and if so, how. Within this context, it is relevant to note the MEB has mandate inclusion of a warning in the leaflets for all over-the-counter medicinal products that they should be used for no more than 14 days (shorter in some cases) without consulting a doctor. The MEB will therefore have to balance the potential risks for each substance to determine whether the risks are negligible. Based on all relevant aspects, a risk profile is created for the medicinal product and authorized indications. For relatively very low potential risk, the risk becomes negligible, as intended in section 4.2 of the Medicines Act under b.

Determining risk profile

In determining a risk profile and whether a medicinal product meets the set criteria, the evaluation examines the Summary of Product Characteristics (SmPC) as a source document, as this is a summary of all data included in the marketing authorization dossier and reflects the most recent state of knowledge. In addition to the SmPC, other specific sources available to the MEB are consulted, such as recent publications, the Lareb database, EudraVigilance (European database), etc.

Sections 4.1 through 4.9 of the SmPC contain the most important information for proper use: 4.1 Therapeutic indications; 4.2 Posology and method of administration; 4.3 Contraindications for use; 4.4 Warnings and special precautions for use (for specific patient groups); 4.5 Interactions with other medicinal products and other interactions; 4.6 Pregnancy and lactation; 4.7 Effects on ability to drive and use machines; 4.8 Undesirable effects; 4.9 Overdose. The information in the patient information leaflet is derived directly from the SmPC and therefore contains all information required by the patient for good and responsible use. Every medicinal product packaging contains a leaflet and this information is therefore available to the user. Any risks and how damage due to these risks may be prevented and limited are clearly described (e.g. users are generally aware of serious renal dysfunction).

Decision tree for risk assessment

Using a decision tree, the key elements of risk are assessed. At each step, the necessity for intervention by a doctor or Pharmacovigilance or additional information for responsible use is evaluated. Good and safe use as well as unintended use (frequency and severity of consequences) are examined. Contraindications and warnings, for example, are evaluated to determine whether they may be recognized and whether it may be assumed that a user knows he has a specific condition for which use of the medicinal product is contraindicated or for which a warning applies. The interactions that may occur are evaluated, along with frequency and severity and how they may be prevented. Interactions that may occur with a prescription only medicinal product are also involved. Furthermore, the existence of any special user groups is evaluated, along with potential risks, e.g. children and pregnant women.

A possible effect on ability to drive is also considered, looking among other things at what various classification systems say about the effects of the active substance on reaction speed and effects on the ability to drive. Examples of active substances for which considerations in this area have played a role are antihistamines (loratadine and ceterizine) and travel sickness medication (cyclizine and cinnarazine).

Furthermore, a great deal of attention is also paid to the potential for undesirable effects, including severity and frequency.

In determining whether a product may be assigned GS status, whether the (rare) undesirable effect is reversible plays a role. In general, undesirable effects that cause permanent, serious damage are incompatible with GS status of supply. In considering legal status of supply, the frequency of the undesirable effect must also be considered. An undesirable effect that is serious but occurs very sporadically may still be compatible with GS status. The legal status of supply (prescription only, PH, PDO or GS) and the incidence of the rare undesirable effect are defining. For example, the incidence of very rare, unpredictable but sometimes severe, often immunological/allergic undesirable effects (such as Stevens Johnson syndrome, bronchospasm, etc.) cannot be avoided. Only in the event of such an undesirable effect will the patient see a doctor. These undesirable effects occur independently of how the patient received the product (prescription only, PH, PDO or GS). A change to the legal status of supply does not contribute to risk minimization in terms of undesirable effects that can occur for all medicinal products and are difficult to 'regulate' due to their unpredictability and rarity. Therefore, a product that may trigger such a response may still be assigned GS status. An example is bromohexine.

Duration of use

When considering whether a product may be given GS status, the duration of use plays a key role. GS medicinal products are only designed for short-term use. Medicinal products that require chronic use or are used preventively for a longer period therefore generally do not qualify for GS status of supply. An example of such a product is Caltrate 600mg/400 I.E. (RVG 103835) which did not receive GS status, as well as Vitango (RVG 101963), a traditional herbal remedy for which the indication does not guarantee short-term/limited use and short-term use is also not useful. The MEB is of the opinion that chronic use is difficult to combine with self care. In general, if complaints persist longer than 14 days, a doctor should be consulted regardless of whether legal status of supply is GS, PDO or PH.

Requesting a GS legal status of supply

Since the changes to the Medicines Act in 2007, the MEB has drafted a list of substances that may, under specific circumstances, qualify for GS legal status of supply. This is not a static document, but one that changes continuously if marketing authorisation holders submit applications for admission of a medicinal product and therefore active substance to the GS category, or if the MEB feels new data warrants changes.

Every time the list is updated, the MEB publishes a new list with comments on the changes.

If a marketing authorisation holder requests GS legal status of supply for a medicinal product with an active substance on the list which meets the conditions on the list, an accelerated procedure will be initiated lasting 30 days, at the end of which GS status is generally assigned. The marketing authorisation holder need not submit any underlying data. However, a specific excipient used in a medicinal product with an active product on the GS list may be reason enough to deviate from the accelerated administrate procedure. This may relate to the amount of a specific excipient used or specific properties of the excipient or relative novelty of the excipient such that more extensive evaluation is required.

If the active substance is not yet on the list or the marketing authorisation holder wishes to submit an application for a substance that is on the list, but the conditions on the list cannot be met, the marketing authorisation holder may submit a type II variation and an individual evaluation will be performed. In such cases, the marketing authorisation holder must submit supporting scientific information and data along with motivation for why the medicinal product may qualify for GS legal status of supply. The marketing authorisation holder must also indicate whether the over-the-counter medicinal product meets the 5 legal criteria a GS medicinal product must meet.