week 5- Drugs used in Epilepsy and TDM

Question 1

how is epilepsy manage? drugs, failed

Answer 1

• Anti-epileptic treatment is individualised to the patient dependant on type of seizure, other medication, sex and preference
• given a care plan agreed by patient and care giver
• anti-epileptic therapy only started after diagnosis unless special case
• aim is monotherapy less chance of SE and interactions with other medication, start low titrate up
• if 1st AED fails switch to another after having titrated up
• if 2nd fails then combination is considered only monotherapy cant control symptoms

Question 2

what are some of the therapeutic drug monitoring for epilepsy drugs? need for blood test?

Answer 2

• This is relevant in managing epilepsy in certain circumstances and
with certain medications (but not all AEDs).
• Regular blood tests are not generally recommended and should only
be undertaken if it is clinically needed and recommended by the
specialist.
• Generally, the main reasons for doing a blood test would be(1):
• To identify non-adherence
• Investigate suspected toxicity
• Adjustment of phenytoin doses
• Managing interactions with other medication
• For specific clinical conditions – e.g. organ failure, pregnancy

Question 3

what are some points to be aware of with AEDs? sympotms?

Answer 3

-some ppl have suidicidal thoughts, if patients have change in mood or dissress should seek help
-Antiepileptic hypersensitivity syndrome though very rare is associated with
some AEDs and can be fatal and the drug should be stopped immediately if
symptoms occur
-Many of the AEDs in the BNF mention patients may need vitamin D
supplementation if they are immobile for long periods of time, or have
inadequate sun exposure or dietary intake.

Question 4

what are some antiepileptic drugs?

Answer 4

• Sodium Valproate
• Carbamazepine
• Ethosuximide
• Lamotrigine
• Levetiracetam
• Phenobarbital
• Phenytoin

Question 5

what are the cautions when using soduim valporate with women of child bearing age ?

Answer 5

• can cause birth defects and development disorder

- should prescribe to women

Question 6

what is the primary indication of sodium valoprate?

Answer 6

-first line for ppl not of child bearing potnetial or PPP for Generalised Tonic-clonic seizures, Absence Seizures, Myoclonic seizures, Tonic or Atonic seizures, Can be used as a 1st line agent in Focal seizures if other AEDs are not suitable or not tolerated
• Potential 1st line agent for Dravet’s syndrome, Lennox-Gastaut syndrome
• Adjunctive to other AEDs in certain epilepsies.

other indications
• Migraine prophylaxis (unlicensed)
Mania in Bipolar disorder (either as sodium valproate or as semi-sodium valproate)

Question 7

what are some adverse effects of sodium valporate?

Answer 7

• Nausea, weight gain

* Transient elevation of LFTs, blood dyscrasias alopecia (hair loss), Liver toxicity and pancreatitis (v.rare).

Question 8

what are the pharmokinetics of sodium valporate?

Answer 8

• Crosses into through the placenta (therefore causing birth defects or developmental disorders)
• Half-life ranges between 8-20hours (Usually shorter in children)
• Metabolised through the liver mainly via glucuronidation(5)
• Enzyme Inhibitor of a few CYP enzymes (6)

Question 9

what are some of the monitoring needed for using sodium valporate?

Answer 9

• Liver function tests are conducted before starting Sodium valproate, and within 6months of starting
treatment.
• Full blood count done as well before starting treatment to ensure no potential for bleeding.
• Blood dyscrasias
• Liver disorders – jaundice, and other non-specific symptoms that could be sudden in onset – general
tiredness/lethargy/drowsiness/or loss of strength, anorexia, swelling (sometimes associated with
repeated vomiting and abdominal pain)
• Pancreatitis (5)

Question 10

what is the primary indication for carbamazepine?

Answer 10

• 1st Line – focal seizures, other types of epilepsy that include benign epilepsy with centrotemporal spikes,
Panayiotopoulos syndrome or late-onset childhood occipital epilepsy (Gastaut type).
• Can be considered in generalised tonic clonic seizures (but be aware it can exacerbate myoclonic and
absence seizures – if these are present this is not suitable)
• Adjunctive in focal seizures

other indictaion
• Prophylaxis in Bipolar disorder unresponsive to lithium
• Trigeminal neuralgia
• Adjunct to acute alcohol withdrawal (unlicensed)
• Diabetic neuropathy (unlicensed)

Question 11

what are some adverse side effects of carbamazepine?

Answer 11

• Drowsiness, dry mouth, nausea, vision disorders
• Blood disorders – leucopenia, eosinophilia, thrombocytopenia
• Hyponatraemia
• Skin disorders

Question 12

what are the pharmacokinetcis of carbamazepine?

Answer 12

• Enzyme inducer – induces multiple CYP enzymes in the liver.
• Has multiple formulations (immediate release tablets, MR release, liquid. However different
preparations are NOT bioequivalent(7)
• It is metabolised in the liver and its clearance can be affected not only by other drugs causing enzyme
induction/inhibition but also by autoinduction of its own metabolism – thus altering the half-life of the
drug after continued administration(7,8).
• Interacts with other AEDs

Question 13

what is the monitoring needed for carbamazepine?

Answer 13

• Pre-treatment screening is necessary in patients of Han Chinese or Thai origin for the allele HLA-B*1502
allele – due to the increased risk of Steven-Johnson Syndrome in patients with this allele(9).
• Plasma concentration for optimum response 4-12mg/L measured after 1-2 weeks
• Manufacturer recommends blood counts, liver and renal function tests – however the actual value of
these tests is not known(9)
• Monitor for any blood dyscrasias, liver or skin disorders

Question 14

wha are some AED that are related to carbamazepine?

Answer 14

-Oxcarbazepine
• Analogue of carbamazepine. It is a prodrug that is converted in the liver into its active metabolite.
• Is a weak enzyme inducer of CYP enzymes (CYP3A4 and 3A5); also enzyme inhibitor of CYP2C19
• Patients that are allergic hypersensitivity to carbamazepine have a 25-30% chance of experiencing
a similar reaction to oxcarbazepine.
• Has more linear pharmacokinetics – no self-induction of metabolism(10)

-Eslicarbazepine
• Like that of Oxcarbazepine – weak inhibitor and inducer of certain CYP enzymes
• Does not affect its own metabolism or clearance
• Long half-life therefore once daily dosing(11)
• Risk of hypersensitivity reactions
• Similar side effects to oxcarbemazepine – but can also prolong the PR interval and therefore
caution should be used in associated medical conditions(12).

Question 15

what are the primary indications, other indications, adverse effects , pharmacokinetcis and monitoring for ethosuximide?

Answer 15

-primary indication
1st Line for absences seizures, childhood absence epilepsy, and other absence epilepsy syndromes(1).
- Adjunctive for absences seizures and other absence epilepsy syndromes
- It is also licensed for myoclonic seizures(2) .

Adverse side effects
Other indications - None
- GI discomfort (nausea, vomiting, diarrhoea, constipation), anxiety, sleep disturbances, behavioural disorders, ataxia
(uncoordinated movements and balance), drowsiness.
- Blood disorders, rash (Steven-Johnson syndrome)

Notable pharmacokinetics

• Absorbed well orally, metabolised in the liver(13).
• Available in soft capsule or syrup forms.
• Generally, there is no notable interactions with other AEDs (14, 15).

Monitioring
- Monitor for any blood dyscrasias:
oPatients/carers should be told how to recognise the signs – to seek medical attention if they experience a fever, rash,
mouth ulcers, bruising or bleeding develop(16)
- Monitor for suicidal behaviours
Patients/carers should report any signs or symptoms of suicidal thoughts or behaviour. (13)

Question 16

what are the primary indications, other indications, adverse effects , pharmacokinetcis and monitoring for lamotrigine?

Answer 16

primary indication
-1st Line and can be used as an adjunctive for Focal Seizures, generalised tonic-clonic seizures, absence seizures (if
ethosuximide or sodium valproate not suitable/tolerated), idiopathic generalised epilepsy. Also benign epilepsy
with centrotemporal spikes, Panayiotopoulos syndrome or late-onset childhood occipital epilepsy (Gastaut type).(1)

other indication
- Bipolar disorder (monotherapy and as an adjunctive)

adverse SE
- Dizziness, drowsiness, headache dry mouth, diplopia (double vision), rash (more common when given with other AEDs or in too rapid dose titration), hypersensitivity syndrome, suicidal ideation, blood disorders. (17)

Notable pharmacokinetcis
-When given with drugs that are hepatic enzyme inducers or inhibitors, the half life of the drug is altered.
Therefore, dosage of the drug needs to be adjusted to accommodate for this.(11)
- Does induce its own metabolism but does not affect other AEDs pharmacokinetics(17).

monitoring
-Counselling of patients around (17)
oSkin reactions – to report signs and symptoms of a rash or hypersensitivity syndrome immediately to the their doctor
-Bone marrow failure – anaemia, bruising or infection

Question 17

what are the primary indications, other indications, adverse effects , pharmacokinetcis and monitoring for levetiracetam?

Answer 17

primary indication
1st Line focal seizures (after carbamazepine and Lamotrigine), myoclonic seizures,
- Adjunctive in focal seizures, generalised tonic-clonic seizures, myoclonic seizures
- In tertiary care it can be used as an adjunctive in absence seizures(1)

other indications
none

adverse SE
Drowsiness, dizziness, anxiety, GI discomfort, asthenia (lack of energy), insomnia, behavioural abnormalities
(aggression, irritability), rash.
- Uncommon/rare – suicidal behaviours, thrombocytopenia, leukopenia (18)

Notable pharmcokinetics
- Oral bioavailability is almost 100% with linear pharmacokinetic profile, allowing plasma levels to be more
predictable, therefore plasma monitoring is not needed.
- It is not extensively metabolised in the body, and a large proportion is excreted through the kidneys unchanged.
Some of the drug is metabolised through hydrolysis and does not involve the CYP450 hepatic isoforms.(19)

monitoring
-None except for general counselling of AEDs.

Question 18

what are the primary indications, other indications, adverse effects , pharmacokinetcis and monitoring for phenobarbital?

Answer 18

primary indications
-NICE recommends its use as an adjunctive in refractory focal seizures and benign epilepsy with centrotemporal
spikes, Panayiotopoulos syndrome or late-onset childhood occipital epilepsy (Gastaut type) recommended only in a
tertiary care setting by a specialist (1)
- It is licensed for all epilepsy types except typical absence seizures but as stated, NICE recommends it only in certain
circumstances. Also used in status epilepticus as IV form (20).

other indication
-none

adverse SE
-AED hypersensitivity syndrome (Steven-Johnson syndrome), bone fracture and bone disorders, blood disorders, folate deficiency, drowsiness, suicidal behaviours, hepatic disorders. (21)

notable pharmacokinetics
-Metabolism of the drug varies in neonates and also in children. It is partly metabolised in the liver, and some is
excreted unchanged from the kidneys.(21)
- Crosses the placenta barrier and is present in breast milk
- Enzyme inducer of CYP450 enzymes (potent)

monitoring
- Optimum plasma concentration levels of phenobarbital are 15-40mg/L however due to tolerance occurring with
phenobarbital, these measuring these levels may not be as useful as with other AEDs(20).
- Monitor for suicidal behaviours
- Skin reactions – to report signs and symptoms of a rash or hypersensitivity syndrome immediately to their doctor

Question 19

what are the primary indications, other indications, adverse effects , pharmacokinetcis and monitoring for phenobaarbital?

Answer 19

primary indications
-NICE recommends its use as an adjunctive in refractory focal seizures and benign epilepsy with centrotemporal
spikes, Panayiotopoulos syndrome or late-onset childhood occipital epilepsy (Gastaut type) recommended only in a
tertiary care setting by a specialist (1)
- It is licensed for all epilepsy types except typical absence seizures but as stated, NICE recommends it only in certain
circumstances. Also used in status epilepticus as IV form (20).

other indication
-none

adverse SE
-AED hypersensitivity syndrome (Steven-Johnson syndrome), bone fracture and bone disorders, blood disorders, folate deficiency, drowsiness, suicidal behaviours, hepatic disorders. (21)

notable pharmacokinetics
-Metabolism of the drug varies in neonates and also in children. It is partly metabolised in the liver, and some is
excreted unchanged from the kidneys.(21)
- Crosses the placenta barrier and is present in breast milk
- Enzyme inducer of CYP450 enzymes (potent)

monitoring
- Optimum plasma concentration levels of phenobarbital are 15-40mg/L however due to tolerance occurring with
phenobarbital, these measuring these levels may not be as useful as with other AEDs(20).
- Monitor for suicidal behaviours
- Skin reactions – to report signs and symptoms of a rash or hypersensitivity syndrome immediately to their doctor

Question 20

what are the primary indications, other indications, adverse effects , pharmacokinetcis and monitoring for phenytoin?

Answer 20

primary indication
-1st line – no first line indications
• Adjunctive in refractory focal seizures in tertiary care settings; also adjunctive in tertiary care settings to treat benign epilepsy with
centrotemporal spikes, Panayiotopoulos syndrome or late-onset childhood occipital epilepsy (Gastaut type)(1).
• BNF indications states use in tonic-clonic seizures (as well as focal seizures) however NICE guidance does state that if myoclonic or
absence seizures are present phenytoin should NOT be used(1). The BNF also states its use in the prevention of seizures during or
following neurosurgery

other indication
-Trigeminal neuralgia (usually as 2nd or 3rd line and often under a specialist)

adverse SE
-Drowsiness, confusion, hirsutism, gingival hyperplasia (overgrown gums), cerebellar dysfunction, bone and bone marrow
disorders (can affect the hematopoietic system – formation of different blood types of cells resulting in megaloplastic
anaemia, granulocytopenia, etc.)(23)
•Symptoms of Phenytoin toxicity – nystagmus, diplopia, slurred speech, ataxia, confusion and hyperglycaemia

Notable pharmacokinetics
- Highly protein bound (approx. 90%)(11) –
• Clearance of the drug is through the liver but follows non-linear kinetics (saturation of the clearance pathway occurs at
therapeutic dosages) which can have a knock-on effect on the half-life of the drug(11).
• Available in various formulations – IV, capsules, tablets, liquid. NOT all bioequivalent. (22)
• Enzyme Inducer of CYP450

monitoring
- Due to its pharmacokinetic profile monitoring may be needed in certain patient groups or situations where protein
binding may be reduced (in pregnancy, the elderly, when administered with other interacting medications). Free
plasma-phenytoin concentration may be more appropriate(22).
• Monitor for any blood dyscrasias, or skin disorders
• Patients/carers should be told how to recognise the signs – to seek medical attention if they experience a fever, rash,
mouth ulcers, bruising or bleeding develop(22).
• With IV use monitor ECG and blood pressure.(22)

Question 21

what are he 3 different catogeries of AED and how they should be prescribed?

Answer 21

cat 1-Patient’s should be
maintained on a
specific
manufacturer’s
product

cat 2-The need for continued supply of a
particular manufacturer’s product
should be based on clinical judgement
and consultation with patient/carer
taking into account various clinical and
non-clinical factors.

cat 3-Usually unnecessary for patients
to be maintained on a specific
manufacturer’s product as
therapeutic equivalence is
assumed. Non-clinical factors
should be considered though.

Question 22

what drugs in cat 1?

Answer 22

Carbamazepine,
Phenobarbital,
Phenytoin and
primidone

Question 23

what drugs are in cat 2?

Answer 23

Clobazam, clonazepam, eslicarbazapine,
lamotrigine, oxcarbazepine,
perampanel, rufinamide, topiramate,
Sodium valproate, zonisamide

Question 24

what type of drugs can exacerbate epileptic seizures?

Answer 24

• alcohol, prescription and otc drugs can exacerbate seizures
• due to one reason of lowering seizure threshold

Question 25

how do drugs exacerbate epileptic drugs?

Answer 25

• Ways in which drugs can trigger seizures include: • Induction or inhibition of hepatic enzymes by other drugs can alter the pharmacokinetics of AEDs and affect plasma concentrations • Some AEDs can themselves worsen and/or precipitate some types of seizures(1) • Secondary effects of other drugs used for other medical reasons can precipitate seizures – hyponatraemia, serotonin syndrome(2). • Other factors that can affect dose/plasma concentration of AEDs – e.g. renal or hepatic impairment. Or co-administered with interacting drugs or drugs that are cautioned in epilepsy e.g. ciprofloxacin, theophylline(3)

Question 26

what is the aim of AED and withdrawal from them?

Answer 26

A main aim of AED treatment in all patients is to become seizure free, and some patients do achieve this. However, many experience adverse side effects which can affect their quality of life, so withdrawal of treatment is desirable though not always achievable due to fear of seizure recurrence(

Question 27

when can withdrawal and discontinuation of AED occur?

Answer 27

AED treatment can be discontinued in patients that have been seizure free for at least 2 years(1). • The AED would slowly be withdrawn – over 2-3months but sometimes longer • Patients who are on barbiturates and benzodiazepines – their withdrawal must be much slower (over 6 months) due to withdrawal symptoms and potential seizure recurrence. • If patients are on multiple AEDs – one drug must be withdrawn at a time. • Withdrawal from AEDs should be under the supervision of a specialist, and a plan in place that has been agreed with the patient as to what to do if they start to have seizures again(

Question 28

why do women and girls need to be cautioned and well managed on AED? what should be discussed?

Answer 28

• Women and girls with epilepsy need to be thoroughly counselled and informed about topics such as contraception, pregnancy, breastfeeding and menopause to ensure treatment can be personalised to fit individual needs and (if appropriate) involve carers and close family members(1). • Things discussed may include: • Risk of AEDs in general causing malformations and other developmental disorders in unborn children. Also highlighting the lack of information regarding this with newer AEDs • Risks and benefits of individual AEDs – most

Question 29

what should be counselled and discussed for AED and contracpetion?

Answer 29

Patients need to be counselled on the potential interactions AEDs have with oral contraceptives, and assessment needs to be carried to balance the risks and benefits of treatment(1). This would be dependent on: • Individual AED treatment regimen • Risks and benefits of different contraception methods

Question 30

what are the 2 types of AED?

Answer 30

* Enzyme-inducers | * Non-enzyme inducers

Question 31

what contraception can be used when taking enzyme-inducing AED?

Answer 31

Patients on enzyme-inducing AEDs are able use(1, 5): • Progesterone only depot injections • Levonorgestrel intrauterine device • Cooper-intrauterine device (non-hormonal) • Combined oral contraceptive – reference to guidance in individual SPCs should be looked at. The BNF states only if the ethinylestradiol dose is 50mcg or more daily and use of an extended or tricycling regimen followed by a shortened break (4 days) before restarting (unlicensed).

Question 32

what contraception cant be used when taking enzyme-inducing AED?

Answer 32

* Oral progesterone only pills * Progesterone only implants * Combined oral contraceptives with less than 50mcg of ethinylestradiol.

Question 33

what should be given for management for emergency contraception in epilepsy for enzyme-inducing AED?

Answer 33

In the case of emergency hormonal contraception with enzyme-inducing AEDs(6): • Copper IUD (most effective form of emergency contraception • Levonorgestrel 1.5mg tablets – double dose should be taken to provide cover if Cooper IUD is not suitable or acceptable to patient • Ullipristal Acetate 30mg tablet – NOT appropriate to give!

Question 34

what type of contraception can be taken if you are using non-enzyme inducing AED?

Answer 34

-NORMAL CONTRACEPTION -The main exception is lamotrigine as the combined oral contraceptive reduces the efficacy of lamotrigine

Question 35

what can happen if a patient uses non-enzyme inducing AED and lamotrigine?

Answer 35

• Increase the risk of seizures for the patient during days 1-21 of their cycle, and then during the pill free period there is the risk of toxicity as there is increased exposure to the lamotrigine(6). • A progesterone-only contraceptive Desogesterol is also thought to potentially increase the exposure of Lamotrigine and therefore careful monitoring would be needed

Question 36

what should be done/discussed with patients with epilepsy and preconception?

Answer 36

Preconception • Discuss it with their doctor, for the pregnancy to be planned. • regularly reviewed at routine consultations when talking to patients who are of childbearing potential. • Counselling about the importance of taking AEDs (if appropriate), discussion of the potential risks of AEDs on a developing foetus vs the increased risk of seizures to mother and foetus; also, the possibility of status epilepticus and SUDEP in patients who plan to stop AED therapy(7). • The risk of foetal malformations is related to the type, number and dose of AED • Risk of malformations of the foetus is higher in patients on AEDs • Woman with epilepsy who are pregnant are also at increased risk of SUDEP during pregnancy and just after birth

Question 37

what should be done/discussed with patients with epilepsy and preconception? dosing, risk of changes, unplanned pregnancy

Answer 37

Preconception Discussion of the risks and benefits of potential changes to the dose of the AED and/or the choice of AED (7). • The aim is to be on the lowest effective dose to obtain seizure control before and during pregnancy(1). • Avoid use of polytherapy where possible(1) Taking a supplement containing Folic acid before becoming pregnant • To help prevent neural tube defects – one of the most common congenital malformations associated with women on AEDs(10) – especially sodium valproate • 5mg of folic acid is recommended in women with epilepsy taking AEDs for at least the first trimester If a woman with epilepsy has an unplanned pregnancy, all the above will still need to apply

Question 38

what should be done/discussed with patients with epilepsy and pregnancy?

Answer 38

Pregnancy • Notify the UK Epilepsy and Pregnancy register • Care of women with epilepsy when pregnant should be shared with the epilepsy specialist and obstetrician/midwife(1). Good communication between them should continue throughout the pregnancy to allow follow up and planning of delivery with the patient(1). • NICE guidance states “Women should be informed that they are likely to have healthy pregnancies but should be aware of the risk of complications during pregnancy and labour are higher in patients with epilepsy” (1) than those without. • Women with epilepsy while pregnant who are taking AEDs should be offered high resolution ultrasound scans to screen for structural anomalies at around 18-20 weeks(1). • Routine drug monitoring of AEDs is not recommended during pregnancy except in clinically appropriate circumstances (e.g. increased frequency of seizures) (1) • Genetic counselling should also be considered if there are known risk factors or fear of inheritance of epilepsy – especially with idiopathic epilepsy and positive family history

Question 39

what should be done/discussed with patients with epilepsy and pregnancy? risk of seizures?

Answer 39

Risk of seizures during pregnancy • NICE guidance states that generally, women with epilepsy are unlikely to experience an increase in seizure frequency while pregnant or during first few months after birth(1). • HOWEVER – patients that have generalised tonic-clonic seizures should be informed that the foetus may be at relative higher risk of harm during a seizure and may depend on seizure frequency(1). • With focal, absence and myoclonic seizures there is no evidence of adverse effects to the foetus unless the mother falls or sustains an injury as a result of the seizure(1). • Risk of seizures during labour is also low however it is currently recommended patients give birth in hospital where there are the facilities for resuscitation and treatment of seizures (10). • Patients would be kept under close observation in hospital, in an open bay (not in a room alone). This is again because of risk of SUDEP.

Question 40

what should be done/discussed with patients with epilepsy and after birth?

Answer 40

After Birth • Babies born to mothers who are on enzyme inducing AEDs are given a 1mg Vitamin K parentally at delivery.(1) • Patients are encouraged to breastfeed as it is generally safe whilst on AEDs – there are exceptions of course and patients also need to be supported in their choice of feeding that suits the patient(1). • Individual SPCs of AEDs should always be consulted • Risk and benefits of breastfeeding whilst on AEDs also should be discussed between the clinician and patient • Also certain safety precautions should be discussed and taken with the patient and/or carer to help reduce accidents and harm to the infant and mother(1, 9): • Bathing, drowning risk • Feeding, sitting down, pillows near • Changing nappies, sitting down • Going outside

Question 41

what is the link between epilepsy and bone health?

Answer 41

• It has long been thought that long term use of AEDs (both enzyme inducing and non-enzyme inducing) increases the likelihood of bone loss, reduced bone density, risk of osteoporosis and fractures (at least in part as a result of seizures)(12). • Enzyme inducers – carbamazepine, phenytoin, primidone; and non-enzyme inducer Sodium Valproate. There have not been enough studies to comment on the effect of newer AEDs and their effect on bone health in patients. • Risk to bone health increased if on multiple AEDs(13) or for long periods of time. • NICE guidance recommends monitoring of Vit D levels of patients on enzyme inducing AEDs every 2-5years.(1) • Other tools that could be used are DXA scans and the FRAX tool (14). • Counselling patients about bone health is important (15)

Question 42

what is the link and risk of epilepsy and driving?

Answer 42

• It is important that patients inform the DVLA if they have an epileptic seizure or blackouts AND stop driving immediately (16). • People who fail to inform the DVLA could be fined up to £1000 and be prosecuted if it results in an accident. • Informing the DVLA can be done online or by filling in a FEP1 form • There are a slightly different set of rules for people who have bus, coach and lorry driver licences.