Antiepileptic

Question 1

Barbituates

Answer 1

MOA= Prolong inhibitory postsynaptic potential by the duration of GABA-induced cell membrane hyperpolarisation.

2. Epilepsy, including simple and complex partial seizures, generalised tonic-clonic seizures, neonatal and febrile seizures, to follow the use of short acting benzodiazepines to treat status epilepticus.
   Phenobarbital (phenobarbitone) is utilised as a second line medicine in the tx of partial seizures.
3. Phenobarbital: Adult, oral 60–240 mg once daily at bedtime.

OTHER STUFF: 30mg tabs, 30 mg once daily at night PO, increasing by 30 mg every 3 to 4 weeks to 90 mg once daily at night PO. Maximum 240 mg at night PO

Primidone: 250mg tabs. 125mg once daily at night PO increasing up to maximum 750 mg twice daily PO. (1.5g D)

4. • avoid in pts w/hypersensitivity to phenytoin or carbamazepine.
     - renal fn
     - hepatic fn
     - ↓ BMD (LONG-TERM USE)
     - vitD and Ca2+ levels
     - Induces CYP3A4 enzymes which results in ↑ metabolism of oestrogens and progesterone, this may make hormonal contraception unreliable or cause breakthrough bleeding. Use Copper IUD, Levonorgestrel IUD or medroxyprogesterone depot or high dose COCs.
     - plasma levels if required
     - ↑ levothyroxine metabolism
     - ↑ risk of resp depression
5. • Sedation (goes away w/time), impaired cognition, depression, confusion, rash.
     - LABELs 1, 2- alcohol, 5, 9
     - vitD and Ca2+ to prevent osteomalacia and osteoporosis (long-term)
     - frozen shoulder,
     - can cause SJS. If any rash develops within 8 weeks of phenobarbital (phenobarbitone) therapy, it should be ceased immediately.

Question 2

Carbamazepine (Tegretol), Oxcarbazepine (Trileptal)

Answer 2

1. Antiepileptic
2. Epilepsy focal seizures, bipolar disorder
3. Switching to CR= ↑ total daily dose
   WITH FOOD
   Epilepsy
   400mg-1.2 g daily in 2 or more doses.

Bipolar disorder
Initially 400mg daily in divided doses; ↑ gradually according to response, up to 1.6 g daily.

Oxcarbazepine
600mg–2.4g daily in 2 doses.

4. • induces enzymes
   • ↑ levothyroxine metabolism
   • ALLELES that ↑ risk of SJS and skin reactions.
   • hepatic fn
   • women OCP
   • complete blood count before tx and periodically
   • monitor for skin reactions
   • BMD monitoring - vitD and Ca2+ levels
   • TDM
     Can induce its own metabolism (auto-induction). When initiating treatment, increase dose slowly to allow for this (may take 2–4 weeks to reach steady state).
   • Oxcarbazepine= Na+ levels
   • bone marrow depression occurs
5. drowsiness until tolerance develops
   dizziness, blurred vision
   - severe skin reactions
   - DRESS
   - vitD and Ca2+ to prevent osteomalacia and osteoporosis (long-term)
   - LABELs: A (CR), B, 12 (at start), 2, 5, 18, 9
   SMURFBB
   - Tell your doctor immediately if rash, sore throat, fever, mouth ulcers, bruising or bleeding occur.

Question 3

Lacosamide (Vimpat)

Answer 3

1. Antiepileptic
2. Epilepsy focal seizures with or without secondary generalisation
3. Monotherapy: Age >16 years
   Oral/IV: 100-300mg BD.
4. C/I 2nd or 3rd-degree AV block as lacosamide may prolong the PR interval. Use cautiously in severe cardiac disease or other cardiac conduction abnormalities.
   - renal fn
   - hepatic fn
   - women

5.dizziness, headache, N&V, diplopia, blurred vision, tremor, abnormal coordination, drowsiness, fatigue, nasopharyngitis, injection site reactions
nystagmus, 1st-degree AV block
bradycardia, AF, atrial flutter, DRESS, SJS, TEN
- LABELs: 12 (at start), 2, 9

Question 4

Lamotrigine (Lamictal, Lamitan)

Answer 4

1. Antiepileptic
2. Epilepsy focal seizures, bipolar disorder
3. 100–200 mg daily in 1 or 2 doses.
4. Tx w/valproate—increases lamotrigine’s concentration, necessitating lower lamotrigine dose; also increases risk of severe skin reactions.
   - hepatic fn
   - vision changes
   - Severe skin reactions HIGHEST RISK!
   – START LOW DOSE BC OF THIS.
   IF THERES BEEN AN INTERRUPTION IN TX FOR MORE THAN 2 WEEKS NEED TO RETRITRATE– CHECK PRODUCT
5. LABELs: 1, 9, 21
   - Tablets may be swallowed whole, chewed or dispersed in a small volume of water.
   - May ↑ effects of alcohol.
   - drowsiness, dizziness or blurred vision
   - Tell dr immediately if you develop a RASH, FEVER OR SWOLLEN GLANDS.

diplopia, blurred vision,
dizziness, ataxia, headache, somnolence, hyperkinesia, nausea, vomiting, maculopapular rash
alopecia

Question 5

Phenytoin (Dilantin)

Answer 5

1. Antiepileptic
2. Epilepsy, including simple and complex focal (partial) seizures, and generalised tonic-clonic seizures
   Status epilepticus (IV)
   Seizure prophylaxis in neurosurgery, seek specialist advice
3. Epilepsy
   Usual range= 200-500mg daily in 1 or 2 doses.

Initially 4-5mg/kg daily in 1 or 2 doses. ↑ by 30mg daily once every 2 weeks according to clinical response and plasma concentration.
- Dose can be ↑ by 100mg daily if total plasma phenytoin conc is 5mg/L or less, but by no more than 30 mg daily if concentration is higher.

Status epilepticus
IV 15-20mg/kg. An additional dose of 5 mg/kg may be given after 12 hours if necessary.
Child, IV 15–20 mg/kg.

Dose Equivalence
100mg phenytoin sodium= approximately 92mg phenytoin.
Capsules/injections=phenytoin sodium.
Tablets/oral liquid= phenytoin.

4. Monitoring points for phenytoin
   • P= p450 and interactions
   • H=hirsutism = coarsening of female facial feature
   • E= enlarged gums (gingival hypertrophy)
   • N= eye condition nystagmus
   • Y=yellow= jaundice
   • T= teratogenic
   • O=osteomalacia and rickets bone problems
   • I= iron and electrolytes
   • N= neuropathy
   D= diabetes risk of hyperglycaemia
   - ↑ levothyroxine metabolism
   - test for alleles that ↑ risk of SJS and skin reactions.
5. • LABEL 5, 9, 12, A
     - May increase the effects of alcohol.
     - Visit your dentist regularly; gingival hyperplasia.
     - This medicine can cause nausea, vomiting, constipation, enlargement of the gums, taste disturbances, dizziness, insomnia, drowsiness and headaches.
     - If you develop a fever, rash, itchy skin, sore throat, mouth ulcers, unusual bruising or bleeding, joint pains, or yellow skin or eyes, tell your doctor immediately.
     SMURF BB
     - ‘purple glove’ syndrome IV
     - To prevent enlarged gums, practise good dental hygiene (including gum massage, frequent brushing and regular dental check-ups) while you are taking this medicine.

Question 6

Levetiracetam (Keppra, Levi), Brivaracetam (Briviact)

Answer 6

1. Antiepileptic
2. Epilepsy all seizures, Monotherapy of focal with or without secondary generalisation, Adjunctive therapy of all.
   Brivaracetam= focal
3. Monotherapy Age >16 years
   Oral/IV, initially 250mg-1.5g BD.

Adjunctive therapy Adult, child >50 kg
Oral/IV, initially 500mg-1.5g BD.

Brivaracetam
Oral/IV, initially 25–50 mg twice daily; adjust dose according to response. Maintenance dose 25–100 mg twice daily.
Hepatic impairment, initially 25 mg twice daily; maximum 75 mg twice daily.

4. • Learning disability, history of psychiatric problems—↑ risk of behavioural A/Es.
     - renal impair= Levetiracetam
     - hepatic impair= Brivaracetam
     - once seizures are controlled using levetiracetam as adjunctive therapy, consider its use as monotherapy
5. Behavioural effects= depression, emotional lability, hostility, aggression, agitation, anxiety and nervousness.
   - drowsiness, weakness, dizziness, h/ache, vertigo, insomnia, amnesia, ataxia, diplopia, anorexia
   - alopecia, SJS, TEN, thrombocytopenia, AKI, hypersensitivity incl; angioedema, anaphylaxis & DRESS.
   LABELs: 1, 9

Question 7

Valproate (Epilim)

Answer 7

1. Antiepileptic
2. Primary generalised epilepsy (including absence, tonic-clonic, myoclonic and atonic seizures), and simple and complex focal (partial) seizures
   Bipolar disorder
   Accepted: Prevention of migraine when other treatments have failed
3. Epilepsy= Initially, oral 600mg daily in 2 doses; increase every 3 days by 200 mg daily according to response.
   Maintenance, oral/IV 1–2 g (20–30 mg/kg) daily in 2 doses; maximum 2.5 g daily.
4. TDM if required
   Correlation between plasma concentrations and therapeutic effect is poor; dose should be adjusted according to clinical monitoring.
   - complete blood count (including platelets) before start tx
   - routine monitoring of liver aminotransferase concs does not predict the rare occurrence of hepatic failure
   - BMD, Ca2+ and vitD= valproate appears to reduce BMD and may increase fracture risk
   - hepatic fn
   - women
5. Crushable tablet/oral solution: 9, 10a, 12†, 13, 21, B; enteric-coated tablet: 9, 10a, 12†, 13, 21, A, B
   WITH FOOD ↓ to reduce stomach upset.
   - ↑ effects of alcohol.

S/Es= drowsiness, dizziness, nausea, abdo pain,diarrhoea. May ↓/disappear w/ continued use.
If you develop severe abdominal pain, vomiting, loss of appetite, yellow skin or eyes, weakness and lack of energy, swelling of the face, or unusual bruising or bleeding, seek immediate medical attention.

While you are taking this medicine, your appetite may increase; you may need help with your diet to avoid weight gain.

Stop tx promptly if:

• loss of seizure control, anorexia, vomiting, ataxia, impaired consciousness, jaundice or oedema (may indicate hepatitis or pancreatitis)
• smx of hypersensitivity
• spontaneous bruising or bleeding occurs (may indicate thrombocytopenia, effect on clotting factors or hepatotoxicity)

LABELs: 9, 10a, 12†, 13, 21, A, B

Question 8

Topiramate (Topamax)

Answer 8

2. Focal (partial) seizures with or without secondary generalisation, generalised tonic-clonic seizures (monotherapy or adjunctive treatment)
   Seizures associated with Lennox-Gastaut syndrome (adjunctive treatment)
   Prevention of migraine
3. Daily doses of 50 mg or more should be taken in 2 doses.

Epilepsy monotherapy= 50mg BD. Max 500mg daily. (100-500mg daily in 2 doses)

Migraine prevention= initially 25mg @ bedtime, 25-50mg BD.

4. Hx of psychiatric disorders—topiramate is associated with many psychiatric adverse effects.
   - Renal fn= halve initial dose
   - Metabolic acidosis- Topiramate weakly inhibits renal carbonic anhydrase.
   - stop tx ASAP if acute onset of ↓ visual acuity or ocular pain occur
   - monitor for ↓ sweating & hyperthermia, esp in hot weather; risk is ↑ if combo w/other drugs w/this effect, eg anticholinergics.
   - measure serum bicarbonate conc at baseline and periodically during tx; if metabolic acidosis develops and persists, reduce dose or stop topiramate.
5. Avoid alcohol as it may worsen some of the side effects of topiramate.
   LABELs: 1, 9, 12 (start), 21, A
   - Tell your doctor immediately if your eyesight changes or you have eye pain.
   - Make sure you drink enough water every day, especially if you have had kidney stones in the past.
   - Topiramate may reduce or prevent sweating which may affect your body’s ability to cool down, especially in hot weather. Tell your doctor if this happens to you.

Question 9

Ethosuximide

Answer 9

Ethosuximide is used to treat absence seizures. It does not prevent generalised tonic-clonic seizures (which may coexist, particularly in juvenile absence epilepsy) and should not be used alone in patients with mixed seizure types.

2. Absence seizures
3. Adult, child >6 years
   Oral, initially 250mg BD; ↑ gradually by 250mg daily every 4–7 days according to response. Maintenance 20–40 mg/kg daily in 2 doses; max 1.5g daily.
4. • Mixed seizure types—ethosuximide may unmask tonic-clonic seizures.
5. This medicine may cause drowsiness or dizziness; if affected, do not drive or operate machinery.

Ethosuximide may also increase the effects of alcohol.

Contact your doctor immediately if fever, sore throat, mouth ulcers, bruising or rash develop.

Do not stop taking this medicine suddenly unless your doctor tells you to.

anorexia, nausea, vomiting, epigastric pain, weight loss, hiccup, drowsiness, dizziness, ataxia, headache, euphoria

Rare (<0.1%)
depression, psychosis, rash, Stevens-Johnson syndrome, multi-organ hypersensitivity syndrome, systemic lupus erythematosus, leucopenia, agranulocytosis, aplastic anaemia, pancytopenia

Question 10

Vigabatrin ↑↓△

Answer 10

2. Epilepsy, in particular complex focal (partial) seizures, not controlled satisfactorily by other antiepileptic drugs (adjunctive treatment). Do not use if alternative treatments have not been tried.
3. 2–4 g daily in one or two doses.
4. Hx of psychiatric disorders—↑ risk of psychiatric A/Es.
   Myoclonic and absence seizures—↑ risk of seizures.
   Eyes= Not recommended in patients with pre-existing visual field defect. Males may be at greater risk of visual field defects. Pts should be able to perform visual field testing.
   - Visual field defect, in particular visual field constriction, occurs in 20–40% of patients; it may be asymptomatic and is usually irreversible.
   - Visual tests before starting, and every 6 months during tx.
   Renal fn (increased risk of CNS adverse effects).
5. Common A/Es: diplopia, fatigue, sedation, headache, memory impairment, abnormal thinking, insomnia, nervousness, dizziness, depression, hallucinations, psychosis, weight gain, arthralgia, anaemia, peripheral neuropathy, tremor, alopecia
   Vigabatrin may make you feel drowsy or dizzy; if affected, do not drive or operate machinery.
   LABELs: 9, 12†, 21, A
   This medicine may also increase the effects of alcohol.

Report any new vision problem to your doctor.

Do not stop taking this medicine suddenly unless your doctor tells you to.

You will need to have regular eye tests while you are taking this medicine.
This medicine can cause drowsiness, dizziness, headaches, nausea, abdominal pain and weight gain.
If you develop any changes in your eyesight or vision, tell your doctor

Question 11

Zonisamide

Answer 11

2. Focal (partial) seizures with or without secondary generalisation (adjunctive treatment or monotherapy)
3. Monotherapy: 100mg OD for 2 weeks, then 200mg OD for 2 weeks, then 300mg OD. Max 500mg daily.
   Adjunctive therapy: 25mg BD for 1 week, increasing gradually to 300-500mg daily in 1-2 doses.
4. Sulfonamide allergy—contraindicated (possible cross-sensitivity).
   Risk factors for nephrolithiasis (eg hypercalciuria, personal or family history)—increase risk of nephrolithiasis; ensure adequate hydration (see Metabolic acidosis).

Predisposition to acidosis (eg renal or severe respiratory disease, status epilepticus)—may increase risk of metabolic acidosis.

History of psychiatric disorders, eg depression, psychosis—zonisamide is associated with psychiatric adverse effects.

5. LABELs: 1, 5, 9, 21, A
   This medicine can cause loss of appetite, weight loss, nausea, abdominal pain, diarrhoea or constipation, double vision, dizziness and insomnia.
   It can also reduce sweating (particularly in children), which may affect the body’s ability to cool down, especially in hot weather. If this happens, tell your doctor.
   If you develop a rash, fever, severe muscle pain or weakness, vomiting, rapid breathing, palpitations, or severe pain in the abdomen or lower back, seek immediate medical attention.
   Additional information:
   Make sure you drink plenty of water every day, especially before and during exercise, and avoid exposure to high temperatures

Question 12

Li

Answer 12

2. Prev of manic/depressive eps in bipolar disorder
   Tx of acute mania
   Schizoaffective disorder and chronic schizophrenia (rarely used)
   Accepted
   Augmentation for tx-resistant depression
3. 250-1000mg daily in divided doses (every 12 hours if using Quilonum SR®) for 2 weeks, then adjust dose according to serum concentration.
4. TDM=Li levels= measure 5-7 days after starting tx and after each dose △ until stabilised, then every 3 months.
   Electrolytes= Na+ , Ca2+ (parathyroid)
   Renal fn(more frequently if unstable)= nephrotoxicity
   Thyroid and parathyroid fn AND clinical signs and smx of THYROID dysfn
   Cardiac fn= ECG, BP, HR etc.
   Weight
   Hormone concs
   Monitor pt for worsening of depressive smx and/or emergence of suicidality, esp during initial months of therapy and at dose changes.
   Diabetes insipidus greatly ↑ risk of Li toxicity.
   Hyponatraemia (eg vomiting, diarrhoea, diuretics, dehydration, Addison’s disease)= ↑risk of Li toxicity, avoid.

Psoriasis—may be exacerbated or precipitated by lithium.

Tx w/drugs that contribute to serotonin toxicity= likelihood of serotonin toxicity may be ↑; avoid combo or monitor clinical course carefully.

5. LABEL: 5, 13, 21, A, B
   Do not take tablets with a hot drink.
   Do not stop Li tx abruptly.
   You will need to have regular blood tests while you are taking this medicine.
   Maintain a normal diet with regular salt and fluid intake. Avoid low-salt diets and heavy exercise that causes excessive sweating because these may lead to increased lithium levels.
   Avoid sodium bicarbonate (found in products such as indigestion medicines, eg Salvital®, and products like Ural® or Citravescent®) as it makes lithium less effective.

Drink more non-alcoholic fluid during hot weather to avoid toxicity.

If the level of lithium in your blood becomes too high, you may get lithium toxicity.

Be alert for signs and smx of Li toxicity esp during illness, exercise&low salt, if you start needing to urinate frequently, or develop extreme thirst, severe diarrhoea, vomiting, blurred vision, weakness or drowsiness, stop taking this medicine and seek immediate medical att.

S/Es= nausea, diarrhoea, muscle weakness and dizziness. These often decrease or disappear w/ continued use. Can also cause a metallic taste, loss of appetite, constipation, headaches and weight gain.