Adverse effects of ASMs

Question 1

[Dose/Plasma concentration-related adverse effects]

4 broad classes of dose-related ADRs

Answer 1

• CNS
• GI
• Psychiatric
• Cognition

Dose related ADRs are usually the main limiting factor in epilepsy treatment

Severity and frequency of these ADRs vary amongst ASMs

Question 2

[Dose/Plasma concentration-related adverse effects]

CNS side effects include:

Answer 2

• Somnolence
• Fatigue
• Dizziness
• Visual disturbances (double/blurred vision)
• Nystagmus (vision condition, uncontrolled eye movement)
• Ataxia (poor muscle control, clumsy movement)
• Mental changes
• Coma

Question 3

[Dose/Plasma concentration-related adverse effects]

GI side effects include:

Which drugs more a/w these SEs?

Answer 3

• Nausea
• Vomiting

Carbamazepine
Valproate

Phenytoin

Question 4

[Dose/Plasma concentration-related adverse effects]

Psychiatric side effects include:

Which drugs more a/w these SEs?

Answer 4

• Behavioural disturbances (irritability, aggression, mood changes)

Levetiracetam

Question 5

[Dose/Plasma concentration-related adverse effects]

Cognition side effects include:

Which drugs more a/w these SEs?

Answer 5

• Speech fluency
• Psychomotor slowing
• Memory

Topiramate

Question 6

[Dose/Plasma concentration-related adverse effects]

Hyponatremia is a possible dose-related ADR of which drug?

Answer 6

Carbamazepine

Question 7

[Dose/Plasma concentration-related adverse effects]

When are dose-related ADRs most prominent?

Answer 7

• Higher ASM concentrations
• More frequent and occur at lower plasma conc. in pt receiving ASM combi therapy (due to additive neurologic effects)
• Mostly occur during initiation of therapy, but may disappear as tolerance develops

Question 8

[Dose/Plasma concentration-related adverse effects]

Mitigation of dose-related ADRs

Answer 8

1. Initiate at low dose, titrate slowly
2. Avoid large dose changes
3. Restrict therapy to one drug only
4. Adjust administration schedule

• largest dose at bedtime to avoid SEs during daytime
• divide daily dose into smaller doses given more frequently
• sustained-release formulations to achieve baseline level throughout the day
• reduce total daily dose (if clinically safe)

Question 9

[Idiopathic/hypersensitivity-related adverse effects]

Which ASMs are associated with hypersensitivity ADRs?

Answer 9

All current ASMs (except some 2nd gen ASMs) have been a/w development of rare (<0.1%) but serious idiosyncratic reactions

Question 10

[Idiopathic/hypersensitivity-related adverse effects]

When are hypersensitivity ADRs most likely to occur?

Answer 10

Most likely occur in first few months of therapy

Question 11

[Idiopathic/hypersensitivity-related adverse effects]

Name the reactions that may occur

Answer 11

• Blood dyscrasias (aplastic anemia, agranulocytosis)
• Hepatotoxicity
• Pancreatitis
• Lupus-like reaction
• Exfoliative dermatitis
• TEN/SJS
• Hyperammonemia

Question 12

[Idiopathic/hypersensitivity-related adverse effects]

• ASMs a/w blood dyscrasias

Answer 12

Blood dyscrasias

• All ASMs can cause blood dyscrasias
• Carbamazepine (Aplastic anemia)
• Valproate (possibly)

Question 13

[Idiopathic/hypersensitivity-related adverse effects]

• ASMs a/w Hepatotoxicity

Answer 13

Hepatotoxicity

• 1st gen ASMs: phenytoin, valproate, carbamazpine

Question 14

[Idiopathic/hypersensitivity-related adverse effects]

• ASMs a/w Pancreatitis

Answer 14

Pancreatitis

• Sodium valproate

Question 15

[Idiopathic/hypersensitivity-related adverse effects]

• ASMs a/w TEN/SJS

Answer 15

• Carbamazepine
• Phenytoin
• Lamotrigine

Question 16

[Idiopathic/hypersensitivity-related adverse effects]

• ASMs a/w hyperammonemia

Answer 16

Hyperammonemia

• Sodium valproate

=> Hyperammonemia encephalopathy (drowsiness, lethargy, changes in level of consciousness, slowing cognition, neurological deficits)

Question 17

[Chronic adverse effects]

Characteristics of chronic ADRs

Answer 17

• Due to long-term ASM therapy
• Tend to be drug-specific, not directly related to plasma conc. of ASM
• Usually not life-threatening, but might affect QoL

Question 18

[Chronic adverse effects]

Gingival hyperplasia

Answer 18

Phenytoin

Question 19

[Chronic adverse effects]

Hirsutism

Answer 19

Phenytoin

• common in children and young adults

Question 20

[Chronic adverse effects]

Alopecia

Answer 20

Sodium valproate

Question 21

[Chronic adverse effects]

What neurological effects may occur, and due to which ASMs?

Answer 21

Peripheral neuropathy

Phenytoin tx at high doses

• may experience sensory loss
• may or may not improve with decrease in ASM dose
• may respond with folate supplementation (low evidence, in folate deficiency)

Carbamazepine

Phenobarbital

Question 22

[Chronic adverse effects]

What metabolic effects may occur, and due to which ASMs?

Answer 22

1. Increased weight gain

• Sodium valproate - reverses spontaneously with discontinuation of treatment

2. Anorexia and weight loss

• Topiramate - reversible with discontinuation

Question 23

[Chronic adverse effects]

What endocrine effects may occur, and due to which ASMs?

How do they cause this ADR?

Answer 23

Osteomalacia

• Phenytoin
• Phenobarbital
• Carbamazepine

Hepatic enzyme inducers => incr clearance of Vit D => secondary hyperparathyroidism => incr bone turnover => reduce bone density => osteomalacia

Question 24

[Chronic adverse effects]

What haematological effects may occur, and due to which ASMs?

Answer 24

1. Blood dyscrasias

• Nearly all ASMs
• Particularly Carbamazepine for aplastic anemia
• Sodium valproate

2. Megaloblastic anemia (rare <1%)

• Phenytoin (predominantly)
• Phenobarbital
• Carbamazepine

Question 25

[Chronic adverse effects] What neonatal congenital defects may occur, and due to which ASMs?

Answer 25

1. Major malformation risk - *Valproate (high) - *Phenobarbital (high) - dose-dependent risk - *Topiramate (high) - dose-dependent risk - *Phenytoin (moderate) - *Carbamazepine (moderate) - dose-dependent risk 2. Neonetal cognition - *Valproate (high) - *Phenytoin (moderate) - Phenobarbital - Topiramate (emerging data)

Question 26

[Chronic adverse effects] Which ASMs cause suicidal ideations?

Answer 26

- Carbamazepine - Valproate - Lamotrigine - Levetiracetam - Topiramate - Gabapentin - Pregabalin - Oxcarbazepine *Suicidality in epilepsy is multifactorial* *Stopping/refusing to start ASM can result in serious harm and death* *Closer monitoring of symptoms required* *Advice pt not to stop ongoing therapy without discussion with physician*

Question 27

[Hypersensitivity reaction] - Can range from?

Answer 27

mild maculopapular rash SJS TEN AHS - anticonvulsant hypersensitivity syndrome

Question 28

[Hypersensitivity reaction] What are the risk management strategies for the various drugs a/w hypersensitivity reactions?

Answer 28

1. Carbamazepine - PGx testing 2. Lamotrigine - dosing guidance 3. Identify potential cross-sensitivity reaction Also: Phenytoin

Question 29

[Hypersensitivity reaction] Pharmacogenetic testing for Carbamazepine - What allele - Relevant for which population

Answer 29

HLA-B*1502 - Strong association b/w HLA-B*1502 carriers and risk of CBZ-induced SJS/TEN - Relevant for Hans Chinese and other Asian ethnic groups (e.g., Malays, Indians, Thai) - Asians 10x more risk than caucasians *If pt tested positive, avoid both Carbamazepine and Phenytoin*

Question 30

[Hypersensitivity reaction] Lamotrigine risk of serious cutaneous reaction is higher with:

Answer 30

Risk of serious cutaneous reaction is higher with: - High starting doses - Rapid dose escalation - Concomitant valproate (inhibitor)

Question 31

[Hypersensitivity reaction] Comment on Lamotrigine initial dosing guidance

Answer 31

Generally: **slow titration** In patient taking concomitant valproate (an inhibitor), - Lower dose, divide up the higher doses In patient taking concomitant CBZ/PHT/PHB (inducers), - Higher dose, divide up the higher doses

Question 32

[Hypersensitivity reaction] Cross-sensitivity reaction is between ASMs with what structure? List examples of ASMs with this structure.

Answer 32

ASMs with aromatic rings - Hypothesized to be able to form **arene-oxide intermediate**, become immunogenic through interactions with proteins or cellular macromolecules - Carbamazepine - Phenytoin - Phenobarbital - Lamotrigine - Oxcarbazepine

Question 33

SEs of Levetiracetam (IC4)

Answer 33

- (COMMON): Headache, vertigo, cough, depression, insomnia - (IC7) somnolence, asthenia, dizziness, coordination difficulties (esp first 4 weeks) - (IC7) Behavioural disturbances: Irritability, aggression - (RARE): Agranulocytosis, suicide, delirium, dyskinesia

Question 34

SEs of Lamotrigine (IC4)

Answer 34

- (COMMON): Headache, irritability/aggression, tiredness - (IC7) Dizziness, N/V, headache, incoordination, tremor, somnolence, asthenia, headache - (IC7) Rash, SJS/TEN, DRESS - (RARE): Agranulocytosis, hallucination, movement disorders (worsens Parkinson's disease), SJS/TEN, hepatic failure

Question 35

SEs of Topiramate (IC4)

Answer 35

- Cognition dysfunction: psychomotor slowing, speech, memory - Metabolic: weight loss - Neonatal congenital defects: major malformation risk - (IC7) Somnolence, ataxia, fatigue, nausea - (IC7) Glaucoma, hyperammonemia, metabolic acidosis, hyperthermia, paresthesias, renal stones - (COMMON): Depression, somnolence, fatigue, nausea, weight change - (RARE): Neutropenia, mania, tremor, transient blindness, SJS/TEN, hepatic failure

Question 36

Carbamazepine CI

Answer 36

- Hypersensitivity to CBZ or TCA (structurally related) - Concurrent/withing 14 days of discontinuation of MAOi (enhances toxic effect on MAOi) - Avoid use in mod-severe renal impairment

Question 37

Major DDIs of Sodium Valproate

Answer 37

CNS depressants - psychotropics: benzodiazepines, antihistamines, hydroxyzine, opioid agonists, antidepressants, MAOi - alcohol - enhance CNS depressant effects Carbapenems - dcr serum conc. of valproate Lamotrigine - incr serm conc. of lamotrigine - lamotrigine dose reduction needed Salicylate - hepatotoxicity