Questions about AEDs (part 1)

Questions about AEDs (part 1)

Taking medication for epilepsy is much more than just pill-swallowing. Deciding to take anti-epileptic drugs (AEDs) can be a big decision, and you might have lots of questions about how the drugs work before you take that step. In part 1 of Questions about AEDs we look at some common questions, from how the AED is chosen to what monotherapy and polytherapy are.

So, lets start at the beginning - how are AEDs developed?

Section 1 - Trials and testing

Drugs are produced by drug (or pharmaceutical) companies. Researching and developing drugs is a very long, complicated and expensive process. Each step of the process is designed to make sure that the drug is safe for us to use, that it works (does what it says it will do) and that it can be produced in a way to make sure it is consistent (that each pill is the same as the next one). For every drug that is successfully developed there will be many that fail and never make it to a medicine cabinet.

How are drugs developed?

The first stage of developing drugs is to ‘find’ a possible drug. Researchers look for chemical compounds, which might be similar to a drug that already exists, that they think might work for a particular condition.

Once a compound is found the next stage is to do trial it. This involves testing the compound to see if it does the job the researchers expect it to. The first trials might be computer tests (to see whether the compound works in theory). After this, the compound is tested on animals before it is tested on human volunteers. These trials happen in three phases and can take up to six years to complete. Strict guidelines and ethical standards make sure that drug trials are fair, accurate, thorough and give enough information about the drug to know whether it works.

Tests include checking that the drug is safe (and doesn’t cause illness) by testing them on people who do not have the condition (for example testing AEDs on people who do not have epilepsy).

Some drug tests (or trials) are ‘double-blind randomised controlled’ trials. This means that, of a group of volunteers, half are chosen at random to take the drug and the other half take a placebo. Randomly selecting who takes the drugs and who takes the placebo means that the researchers cannot chose who they think will respond best to the drug or treat them different to the volunteers taking the placebo.

‘Double blind’ means that neither the volunteer nor the researcher knows who has the real drug and who has the placebo. After a certain length of time (which depends on the individual trial) the drugs are ‘crossed over’ – the volunteers are switched from one treatment to the other. So if a volunteer was taking the placebo they will be swapped on to the ‘real’ treatment and if they were taking the ‘real’ treatment they will be swapped to the placebo.

During these trials, the researcher will see how well the drug works and also whether it has any common or predictable side effects. The ideal is to develop a drug that is as effective as possible with the least side effects. The benefits of taking the drugs are compared to the risk of side effects and the risk from not treating the condition. A drug would only be licensed if the benefits out-weight the risks.

Licensing drugs

Once a drug is discovered, tested, works and is safe, the next stage is to license it. Once a drug is licensed it can be prescribed and used. Drugs are licensed either by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK, or the European Medicines Evaluation Agency (EMEA) in the European Union. Licensing can take two to three years.

Once a drug has been licensed it can be manufactured and appear in shops or pharmacies. Getting to this stage can take 12 years!

There are different types of licence:

1. ‘controlled’ drugs (C) have very strict regulations about how they are used (for example, morphine)
2. ‘prescription-only’ drugs (POM) are only available on prescription (including AEDs
3. ‘over-the-counter’ drugs (OTC) can be bought in a shop without a prescription (like aspirin and paracetamol)

Note: sometimes drugs are prescribed ‘off license’ or for something they do not have a license for. For example, some AEDs are licensed for particular seizure types and not other seizure types. But the AED may be prescribed to someone who has seizures that it is not licensed for, if it is thought to be helpful.

The young, the old and the pregnant

Drug trails have to be ethical: certain groups of people are not allowed to be have drugs tested on them. This includes children, people aged 60 and over, and pregnant women. There are many reasons for this. Children are not able to understand the possible risks of taking trial drugs and so can’t give their consent (willing agreement) to drug trials. Similarly, unborn babies can be put at risk if the mother takes trial drugs.

The ways that drugs are handled by the body (absorbed and removed) in children, pregnant women and older people can be different to adults in general. Once a drug has been licensed for adults (from 18 – 60 years), further tests are needed for these groups of people: testing first with older people and then with children.

Unfortunately the effects of the drug on pregnant women and their unborn child cannot be seen until it starts to get used, but new drugs will not normally be prescribed to pregnant women until they have been thoroughly tested in other groups. Once a pregnant woman is prescribed a new drug, she will be very closely monitored.

Section 2 – Types of drugs

There are many different anti-epileptic drugs: some are brand versions some are generic, some are first line and some are second, some are taken as monotherapy and some as polytherapy. But what do all these terms mean?

Patents

Like many inventions, new drugs are patented. This patent is the legal right the drug company has to be the only company to make that drug for a certain length of time (usually 20 years). During this time no other drug company can make it. Because developing a new drug costs so much, the company has time ‘on patent’ to try and recover some of these costs by selling their drug at a price that reflects the cost of development.

When the drug comes ‘off-patent’ (after the 20 years), other companies can make their own versions of the drug. These versions are called generic (see below). Because other companies have not had the cost of developing the drug from scratch, their versions can be cheaper than the original versions.

What do ‘brand’ and ‘generic’ mean?

AEDs often have two names: a brand (or trade) name and a generic name.

All drugs have an active ingredient. The generic name of a drug is the name of that active ingredient, and all drugs with the same active ingredient will have the same generic name. Generic names start with a lower case letter such as paracetamol and ibuprofen. Generic AEDs include sodium valproate and carbamazepine.

Some AEDs also have a brand name. The brand name is often the name given by the drug company that developed it, and starts with a capital letter. For example, a brand name for sodium valproate is Epilim, and carbamazepine is Tegretol.

Some drugs have many brand names or are sold by different companies under the generic name. For example, ibuprofen is sold as the branded ‘Neurofen’, and also as ‘ibuprofen’ by Boots, Tesco’s and Sainsbury’s. With AEDs, sodium valproate may be sold as generic ‘sodium valproate’ or branded ‘Epilim’, and carbamazepine as ‘carbamazepine’ or ‘Tegretol’.

Are all forms of a drug exactly the same?

All drugs with the same generic name, or with different trade names but the same generic name, have the same active ingredient. However, the amount of active ingredient may vary a little. And there is more to a drug than just the active ingredient: there are other ingredients such as colourings and binding ingredients. These other ingredients may differ from one form of the drug to another. It’s a bit like soup: all forms of tomato soup contain tomatoes but some contain cream and others contain milk, some have salt and some don’t.

In some cases, the other ingredients can affect how the drug is absorbed in the body and its bioavailability. With AEDs this can be quite important: one particular form of an AED may be effective in stopping seizures for an individual but another form of the same drug might not work as well. This could result in seizures happening. For this reason it is recommended that you take the same form of the same AED (whether branded or generic) all the time.

My AEDs look different to normal – why is this?

If your drugs look different to normal, there could be several reasons for this.

• The drug company could have changed how the drug looks.
• You could have a parallel import of your drug. This is when the drug is made outside the UK and brought back into the country. Some drug companies make their drugs, under strict guidelines, in other countries. Often this is not a problem, but the company may not be able to guarantee how the drug has been stored and this could affect how it works. Some parallel imports have different packaging to UK versions and may not have patient information leaflets in English.
• You may have been given a different form of the drug - for example, if you usually take a branded form and have been given a generic form, or have been given a different generic form to usual. If your prescription only has the generic name of the drug, a pharmacist can give you any form of the drug with that generic name. However, if your prescription has the brand name of a drug, the pharmacist has to give you that brand.

It is often wroth checking that your drugs are the right ones before you leave the pharmacy. If you find out that you don’t have the right drug once you get home, your pharmacist may not be able to change them. They can’t guarantee that you haven’t ‘tampered’ with them, and so they can’t give them to someone else. If you are concerned for any reason, you could talk to your pharmacist and explain the situation.

What does ‘chrono’ mean?

Some drugs are called ‘chrono’ or ‘retard’ (for example, Epilim chrono or Tegretol retard). Chrono and retard mean ‘slow-release’. If your drug is a slow-release form, the active ingredient is released in your digestive system more slowly, than non-chrono forms of that drug. This prolongs its absorption and means that you don’t have to take it as often as other forms.

What are ‘first-’ and ‘second- line’ AEDs?

AEDs are licensed to use for controlling particular types of seizures. ‘First-line’ and ‘second-line’ refers to how AEDs are selected and used for the treatment of epilepsy and particular types of seizures.

First-line AEDs are the AEDs that are usually considered first when starting epilepsy treatment. They tend to be used on their own (monotherapy). They include sodium valproate and carbamazepine. Which one is chosen depends on the type of seizures the person has.

Second-line AEDs are AEDs that are usually taken alongside first-line therapy (also called adjunctive therapy) and are therefore they are generally used as polytherapy. They include topiramate and gabapentin. Second-line AEDs also include AEDs that were used as first-line treatments but that are no longer generally considered as a first treatment option when treatment is started.

However, as treatment with AEDs is always individualised, in some cases the neurologist may use his specialist knowledge and decide to put an individuals on monotherapy with a second-line rather than first-line drug.

What is monotherapy?

Monotherapy is taking just one drug (mono = one). If you are on monotherapy you usually take a single first-line drug. If you take more than one drug (either more than on first-line drugs, or first-line and second-line drugs) this is called polytherapy (poly = many).

Neurologists often use monotherapy at the start of epilepsy treatment. Taking just one AED makes treatment simpler: there are no interactions with other drugs; it reduces the chance of getting side effects; and it is clear to see if the drug works or not. If a single AED does not stop your seizures the options are to try a different first line drug, or to add-on a second drug.

Taking more than one drug (polytherapy) means that there may be different side effects from each of the different drugs. Your neurologist will have to consider which side effects may be from which drug. He (or she) will also need to be aware of possible interactions between the drugs, and, if your seizures become better controlled, may find it hard to see which drug is working best.

Out with the old and in with the new?

AEDs can be divided into two groups according to when they where developed and how long they have been around for.

Newer drugs (licensed after 1989) include lamotrigine, gabapentin and topiramate. Older drugs (licensed before 1989) include phenytoin, carbamazepine and sodium valproate.

When you compare the older and newer drugs it is not a simple as ‘newer drugs are better because they have been developed more recently’ or that ‘older drugs are better because they have stood the test of time and are still used’. Again, like most things in the treatment of epilepsy, there are positives and negatives to each.

The positives and negatives about older drugs include:

• Because they have been used over may years the longer-term benefits and side effects are better known
• We know more about how they work and what seizures they are likely to work for
• They are known to be very effective for some people (through many years of experience using them)
• Some have serious side effects or interactions with other drugs.

The positives and negatives about newer drugs include:

• They often have fewer side effects
• They are less likely to interact with other drugs
• They are more expensive (see section on licensing)
• We don’t have the years of experience to know what types of seizures they work best for.

So the decision about which AEDs to choose is more complicated than their age alone.

Choosing AEDs depends on:

• The type of seizures you have
• The AED that is known to work best for that type of seizure

• Your lifestyle. Some side effects are more important to some people than others: for a student, avoiding an AED that affects their concentration may be important, but for a man, taking an AED that can cause menstrual problems won’t be a problem.

Glossary

Active ingredient: the chemical compound in a drug that makes it work (for the reason you take it). For example, the active ingredient in Neurofen is ibuprofen.

Bioavailability: the amount of the active ingredient of a drug that is in your body and ‘available to use’ at the site of action (the place in the body where the drug works).

Drugs: the products that are prescribed to individuals to treat the cause or symptoms of medical conditions. Also called medications.

Drug company: the companies that find, develop, test and manufacture drugs. Also called Pharmaceutical companies.

Licensing: the official process of showing that drugs have been tested and are safe to use.

MHRA (Medicines and Healthcare products Regulatory Agency): the organisation that licenses and regulated medicines in the UK.

Parallel import: drugs that are made outside, and are brought back into, the UK. This is legal between countries in the European Union, and these drugs may be cheaper than versions made in the UK. Also called ‘parallel traded’ drugs.

Patent: this is the legal right a drug company has to be the only company to make the drug they have developed. Patents usually last 20 years and during this time no other company can make the drug.

PIL: Patient Information Leaflet. This is the leaflet that comes with each drug and says what the drug is, how to take it and what the possible side effects are.

Placebo: these are ‘dummy’ drugs that have no active ingredient in them. They are used as controls in drug trials – used to compare the effects of the real drug.

Side effects: an additional and unintended effect of medication. Side effects are not the expected action of the medication (the reason why you take it). Also called adverse effects (although they are not always unwanted).

© Epilepsy Society
November 2008