Sodium valproate: balancing benefits and risks especially in people of childbearing potential

[Music] Welcome to the Australian Prescriber Podcast, an independent no-nonsense podcast for busy health professionals.

I'm Dhineli Perera, your host for this episode. And today, I get the delightful opportunity to chat to Dr Dan McLaughlin about the use of sodium valproate in people of childbearing potential. Dan is a Brisbane neurologist and epileptologist, and his studies have led him to have a particular interest in the pharmacology of anti-seizure medications and emerging options in anti-seizure medications. Dan is the chair of the Epilepsy Society of Australia's Drug and Devices Subcommittee. A warm welcome to you, Dan.

Thank you very much and thanks for the invitation to speak with you.

You're very welcome. So Dan, maybe you can start us off with some background about sodium valproate and the indications it is used for in Australia.

Sodium valproate's most commonly known by a brand name of Epilim, but there's several generic preparations available. It's been used for more than 50 years around the world as a treatment for epilepsy and, probably within 15 to 20 years of its introduction, was found to be the most effective agent for one of the commonest epilepsy syndromes, the generalised epilepsies. These are the ones that produce tonic-clonic seizures, which some people may recall as grand mal, absent seizures, also known as petty mal.

But in addition, myoclonic seizures, tonic seizures and drop attacks. So a wide range of spectrum of activity. Soon after it was introduced, problems were recognised as adverse effects and later the issue of its effects on pregnancy and the development of the child became apparent, initially with the condition of spina bifida. By the time this was happening, the medication was the most commonly prescribed medicine for epilepsy in Australia.

And in many other parts of the world, similar prescribing figures would've been the case. It took some 10 or 15 years after this was widely recognised so we're now about 2010 to realise the extent of the changes that occurred was such that the prescribing patterns started to change. And in the last 5 years, valproate's fallen from being the most commonly prescribed of the anti-seizure medicines to the third most common.

And the reason is pretty obvious when you realise that the first and second are levetiracetam and lamotrigine. These medications have been found to have efficacy in a number of seizure types that certainly approximates that of Epilim or valproate, except perhaps in the generalised epilepsies where valproate still appears to have better efficacy, but it's the adverse effect profiles of levetiracetam and lamotrigine that has led to their popularity.

And in particular the awareness being driven by the fact that these 2 medicines are considered the safest anti-seizure medicines to take during pregnancy. There's been a major change in the shift of the use of valproate and it seems to reflect pretty good clinical common sense.

Wonderful. Well, that's a really great intro for us. What is it used for these days then if it's not for epilepsy?

Outside epilepsy, it has an important role in treatment of bipolar disorder where it's a comparable drug to lithium in that condition. It became apparent more than 30 years ago that it could be used as a preventive drug in people with frequent migraine attacks and it approximates with a later introduced drug topiramate in its efficacy. It has some other uses that are probably less important.

Okay. So given the limited scope of its use, would you say it is still a widely used drug of choice?

The fact that it's the third most common says yes, there's a role for it. For many men, it's a very appropriate first-line drug for treatment of their epilepsies. There are very active refractory epilepsies in childhood and infancy where valproate is used, although not really commonly in children under the age of 2, but it still has a valuable role to play there. And in older patients at appropriate doses, it's a very well-tolerated medicine and very effective against seizure disorders that develop late in life.

So then when it does come to adverse effects, I guess it's a really tricky tightrope to walk when you're treating something that's not going to be a short-term use. Balancing the need for the awareness with the need to not scare patients off being compliant with their medications, what would you say are the most important adverse effects and their incidence that clinicians should be aware of?

When valproate started, the discussion is initially with what are the most common things that might occur? Because that's the one you want that person and their family or carers to bear in mind. So when it's first started, things that it's useful for them to know of is there's a small risk of nausea. It's probably less than one in 30 people, but it's helpful to know if it happens in that person taking the medication after mealtimes will usually resolve the issue.

A few people feel mild sedation when it starts, probably one in 20. That disappears over 1 to 2 weeks and is never overly troublesome. In older patients, reduction in concentration of memory might just occur so they're worth noting. About 1 in 100 people will get a very fine tremor of their hands, but remember this is occurring in someone who's just started medicine for a seizure disorder and having unwanted movements can be a bit alarming. They can be reassured that it's mild, it won't get troublesome. And if needed, the dose reduced or the drug removed will resolve the issue.

Then the important side effects are the ones with the potential that could cause death, that could cause you to be so severely ill that you end up in hospital. And with valproate, there's a unique one of liver injury, hepatotoxicity. And this condition, once it was recognised, initially put the brakes on the more widespread introduction of the drug. Over a period of 15 years research, a pattern emerged that this was an uncommon condition. So overall, we'd say one in 20,000 people commencing the drug are at risk for it. It occurs much more commonly if you are young, hence the restricted use amongst children, particularly under the age of 2.

There are some other risk factors for it occurring, and these usually relate to associated illnesses, particularly the need to take other anti-seizure medicines, but some rare congenital disorders of liver function are at risk, and there is an association with mental impairment or significant intellectual impairment, but the mechanism for that is not clear and I suspect relates more that the epilepsy that person suffers tends to be more refractory to treatment.

There's a prodrome before the illness is reflected in blood tests. The person becomes unwell, typically nausea, feeling off colour, almost like coming down with the flu. And then within another few days, jaundice makes itself known, they start feeling particularly ill. And if the drug is not withdrawn, then liver failure symptoms predominate with drowsiness, and if the drug's continued, death ensues. This syndrome occurs in the first 6 months of use.

Because of its rarity, regular blood test monitoring won't reliably identify who's at risk. There is a role for blood test monitoring, but not just trying to obviate this condition. It's better that the problem be highlighted earlier on so that if it occurs, either the person or the people around them recognise it, get them to attend a doctor and hopefully, have the drug immediately discontinued.

With its recognition and a change in its prescribing profiles, we now have safety data in older adults over 30 where the risk is about one in a hundred thousand. So it becomes more palatable for that person to take the medicine on, whereas risks of one in a thousand in young children are clearly serious limitations on the drug. The other significant serious adverse effects, pancreatitis occurs uncommonly, but it clearly does relate to the drug and this can occur at any time during the period of treatment with the medication.

Can't give you a risk factor for how often it occurs, but it is a close association. They are the major adverse effects that we cover with the medication at that stage.

And I guess the way that that's communicated to the patient is particularly important because it could be quite alarming to hear some of those things, but highlighting the incidence of being one in 100,000 for an adult with the hepatotoxicity, it does, as you said, make it more palatable. So while our clinicians can be aware of it, the way it's communicated to the patient is particularly important too.

It has a role, but not as far-reaching as doctors 40 years ago appreciated. Some early smaller studies suggested dose ranges between 50 mg/L, 100 mg/L [was] associated with good outcome. Later work, however, showed that wasn't quite the case. And in fact, the large studies showed that in 50% of people who take valproate to suppress their seizures, they will have blood serum concentrations below the 50 mg/L mark for most of the time they're treated with it with good seizure control. So it lets you know that there isn't a proper correlation because of the serum concentration and the efficacy. And so essentially, its biochemical actions in the brain don't correlate with how much is present in the blood.

Excellent. Thank you for that. And that's great to know that it's not really a correlate for efficacy. Something useful for clinicians to keep in mind when ordering levels. Now, if we zoom in on the teratogenicity of the neurodevelopmental risks for sodium valproate and maternal exposure, what are the risks and some management strategies you'd suggest to mitigate them?

The drug's initial teratogenic effect identified was an increased risk of spina bifida. And this was uncommon but clearly associated. And while that was being studied, registries measuring the outcomes of children born to mothers taking antiepileptic drugs were being established. One of the first was in Australia. And over a period of 15 to 20 years, these registries gained more and more data of outcome amongst these children.

And when the registries got together, with the European Registry, a number of important features were found. Additional malformations became apparent, including hypospadias in males, low birth weights. And in around 2010, it became clear that when these children became 5 or 6 years of age and cognitive function could be measured, they didn't achieve as well as comparable groups of children who were treated with the medication carbamazepine.

And that area has been focused on and there's a significant risk of impaired intellectual development. There's a significant increase in the risk of autism and other neurodevelopmental disorders including attention deficit disorder are also increased. The skeletal malformations and the spina bifida had a dose related phenomena become apparent, but unfortunately the ones related to brain development and the neurodevelopmental aspects of it, a lower dose where the drug is safe to be given during pregnancy can't be established.

So over time, the shifts being from we'll use lower doses, to we'll avoid using this medication as a treatment for women who are wanting to have children or might have children. And as that was happening, the options suddenly became available that we did have levetiracetam establish itself and lamotrigine establish themselves as being safe to take in pregnancy.

And so they gradually became the first-line choices for women in that situation. In some parts of the world, the advice is very prescriptive, is that it [valproate] should not be provided to them unless 2 treating neurologists agree that it is needed for control of their epilepsy. Some patients will be trialled on levetiracetam and lamotrigine and the drugs are ineffective and that Epilim is the only one that provides them with seizure control.

In that setting, we use the drug [valproate] at its lowest dose. We advise the person of these risks and make sure that they're properly informed. Essentially, the advice currently is omit prescribing the medication as initial treatment. If it's thought it might be needed, time to refer on to a neurologist in the area to guide the treatment advice for that person.

Wonderful. Well, that really answers my next question in terms of circumstances where the benefit of sodium valproate outweighs the risks. It seems to be consistent even internationally that it's really only going to be used in that situation where the first-line agents are proving to be ineffective or not working for the patient. I will ask though, when it comes to male-mediated teratogenesis due to the paternal use of valproate, this is a newer adverse effect to be reported.

Could you walk us through the retrospective cohort study and its methodological limitations that led to such a controversial conclusion?

This really has given many neurologists around the world something to have a deep think about. Having had issues which have really changed the use amongst people of childbearing potential, the thought came perhaps valproate might do this to spermatogenesis and thereby create problems for children born to fathers who'd taken it. A study was initiated by European Medicines [Agency] and it was undertaken by a group who combined data that had been collected from 3 relatively similar studies being conducted in Nordic countries.

These studies had some variation in methodology which creates issues of how do you analyse all the data if it's being collected in different ways? And when it was published, the authors actually did put some caveats on their data saying there are some risk factors for autism and neurodevelopmental disorders which we have not controlled for. However, we think the populations of people checked are enough for us to draw these conclusions.

And the conclusions were quite worrisome. They were finding that neurodevelopmental disorders were being seen 50% more commonly in the children born to fathers who'd been taking it, compared to those who were taking levetiracetam or lamotrigine. This was out of step with some previous information that had been published in this area. Now, when such a big risk factor is suddenly discovered with a drug, it is natural to be cautious.

And this is where the European Medicines [Agency]'s response, the drug should not be used in men under the age of 55 was introduced. So taking the study on face value, they've made what you would regard as an appropriate response. However, a justifiable criticism is a single paper resulting in a widespread change in the use of the medication seemed out of keeping with what's been published as occurring in humans.

That remains a point of discussion. However, within a year, a group on this occasion doing it from a single Nordic country, Denmark, and they had a single methodology study much larger numbers. So they went through registries, identified there'd been over 200,000 live births over a 10-year period. Of those live births, the registry showed that over a thousand had been to fathers who had taken valproate within 3 months of conception.

And when they compared these children to fathers who'd not been exposed to valproate, they didn't identify any increased risk of congenital malformations or neurodevelopmental disorders and specifically not autism spectrum disorder. That's substantial data. They had follow-up from birth to 10 years for age in both the study group and the control group. And I think that is cause to pause about a strict prohibition of it.

A compromised position is the one where we advise the patients that there is an uncertainty in this area. It remains unclear about is this a real problem or not? It is being looked at. European Medicines [Agency] having triggered their warning, triggers a regulatory warning in Australia. And so the TGA [Therapeutic Goods Administration] has notified prescribers that this has been brought up as a risk. It's made a comment that the data is not clearly established, which is the view of the Epilepsy Society [of Australia].

And my thoughts are that we make sure that men taking it and that includes younger males are aware that it is still being established and that we offer them the choice of continuing with the medication, which by that stage for many of them has given them independence in life. Their health is good. They can do things that everybody else can do without the concern that a seizure might strike them down.

As a colleague, Professor Cook, put it: "for an illness that makes you sick for 2 minutes, you suffer for years". So offering alternative drugs to them is appropriate, but at the moment I wouldn't change for what I'm sure of in an individual person, this is working. You feel well. Let's wait for a bit more data.

Interesting. And I think in passing that awareness to the patient, as you said, is quite important, whereas if that young male that's had good control has no intention of having children, then you're right. There's a really questionable need to switch. However, if there is other alternatives that don't have even the question mark of this risk and they do plan on having children or they're in a situation where they might have children in the short term in those situations, if you were the prescriber, would you consider changing?

I'd offer them the choice.

Yeah. Then Dan, do you see sodium valproate as being a medication that is on the way out, that could be retired effectively based on its adverse effect profile that you've mentioned in detail before and its other risk factors, or do you see it still having a really useful role in the management of epilepsy or potentially even refractory epilepsy?

It won't have the role it once had. The safety of 2 agents established for each of more than 20 years is gradually going to dominate our prescribing practices as they currently stand. Where it will be used in the long term really becomes hypothetical because in the long term, there are some other advances in therapies for epilepsy that are going to make taking tablets twice a day not a primary choice. I think we'll see a change in therapeutics where longer acting therapeutic treatments will develop.

Whether they are control of irritable central nervous system networks by a monoclonal antibody. There's a corollary already that migraine attacks can be suppressed by this type of therapy very effectively, or will our advances in epilepsy step straight through to modifying either gene problems or problems that have developed between the gene and the manufacturer of nerve cells in a more direct way?

So my guess is that over time, valproate will be used less and less because it will get replaced by better medications, but not quite completely. Neurology at the moment there's a number of medicines we use that have been used for more than 50 years and look as if they'll continue to be used for a lot longer yet.

Wonderful. Well, as always, I have many more questions to ask, but unfortunately, that's all we've got time for today. Thank you so much for joining us, Dan.

Thank you very much for the opportunity, Dhineli.

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Dr Dan McLaughlin's article, 'Sodium valproate: balancing benefits and risks especially in people of childbearing potential', is available on the Australian Prescriber website. The views of the hosts and the guests on the podcast are their own and may not represent Australian Prescriber or Therapeutic Guidelines. Dan is the chair of the Epilepsy Society of Australia's Drugs and Devices Committee.

He was co-author of the Epilepsy Society of Australia's position statements on 'Generic [Drug] Use in Epilepsy' and 'Valproate Use in Man and Offspring Risk'. I'm Dhineli Perera, and thanks for joining us on the Australian Prescriber Podcast.

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