507 - Lecture 3: ASM Adverse Effects & Monitoring

PDAT 507

What are some dose-dependent adverse effects of ASMs?

Somnolence, fatigue, dizziness, visual changes, nystagmus (rapid eye movement), ataxia, tremor, nausea, cognitive difficulties, behavioral changes

They are extensions of actions of the CNS

What are some characteristics of dose-dependent adverse effects of ASMs?

• AEs are dose-related/more prominent at higher C_plasma

• Symptoms are qualitatively similar among ASMs

  • Variability among ASMs and individuals on same ASM

• AEs can occur at lower C_plasma with ASM polytherapy (multidrug)

• Observed if pt starts at too high of a dose or increasing dose too rapidly

How do we manage dose-dependent AEs with ASMs?

• Start low/increase dose slowly

• Avoid large dose changes

• If possible, avoid polytherapy

• Adjust administration schedule

• If the AEs are occurring at time of peak C_plasma:

  • Switch to extended release products

  • More frequent dose administration

  • Administer with food

• Reduce total daily dose

What are neuropsychiatric AEs observed with ASMs?

• Cognitive problems: difficulty thinking, impaired memory or comprehension, slowed mental processing, word finding difficulties

• Behavioral changes: anxiety, hyperactivity, irritability, altered mood

The Cognition/Behavioral Effects seen in ASMs are worsened by?

Severity increased by:

• Higher C_plasma

• Polytherapy

Phenobarbital shows greater negative effects on cognitive performance and behavior in which populations?

Adults and children

What are some recommendations to minimize the cognitive/behavioral effects of ASMs?

• Avoid polytherapy if possible

• Use lowest effective dose and C_plasma

• Avoid chronic use of ASMs such as phenobarbital if possible, especially in children

• Consider newer ASMs (e.g.: LGT, OXC, LAC) in patients experiencing cognitive/behavior problems

What cognitive/behavioral effects do the newer ASMs have?

• Newer ASMs

  • Lamotrigine, Oxcarbazepine, and Lacosamide → minimal effects on behavior and cognition

  • Levetiracetam → minimal effects on cognition, but may alter behavior (aggression, anxiety, irritability)

  • Topiramate, Zonisamide:

    • impaired thinking, behavioral change observed

    • Severity is increased when starting at too high of a dose or increasing too rapidly

  • Topiramate → Word finding difficulties

What’s one special adverse effect found with use of Topiramate?

Word finding difficulties

What’s the relationship between suicidality and ASMs?

• Higher rates of suicide among individuals with epilepsy

• However, the methodology of the studies make it unclear whether or not the ASMs are causative of the higher rate of suicidality

  • In general, monitor for depression or unusual changes in behavior

What idiosyncratic AEs are associated with ASMs?

• Skin rash (most common): CBZ, LAC, LTG, OXC, PHT

  • 40-60% cross reactivity

• SJS/TEN: CBZ, LAC, LTG, OXC, PHT

• Aplastic anemia: CBZ, PHT

• Hepatotoxicity: CBZ, LTG, PHT, VPA

• Pancreatitis: VPA

• DRESS: CBZ, LAC, LTG, OXC, PHT

  • DRESS = drug reaction with ↑eosinophils and systemic symptoms

  • TEN = Toxic epidermal necrolysis

What are some characteristics of idiosyncratic AEs with ASMs?

• Unpredictable

• Not dose related

• Usually occur during the 1-3 months of therapy

• Can be life threatening

• Dependent on chemical characteristics of the drug & patient specific factors

• All ASMs (except three) are associated with idiosyncratic reactions

Which ASMs are NOT associated with idiosyncratic AEs?

Gabapentin

Levetiracetam

Pregabalin

What are the idiosyncratic reactions of ASMs caused by?

• Can be due to the structure of the ASM (aromatic bene ring)

• Can be due to having a direct toxic metabolite (such as Valproic acid)

• Can also be due to patient specific risk factors

  • Underlying defects in fatty acid or amino acid metabolism

  • Children < 2 years

  • Concurrent tx with enzyme inducing ASMs, which enhance the formation of 2-n-propyl-4-pentenoic acid

Which structure of ASMs can cause idiosyncratic reactions? What kind of reaction is it?

• Aromatic benzene ring of ASMs

• Aromatic rings cause delayed hypersensitivity reactions

  • Rash, fever, increased eosinophils, lymphadenopathy, hepatitis

Which ASMs contain an aromatic ring?

Carbamazepine, Lamotrigine, Oxcarbazepine, Phenytoin (CLamOP)

• Cross reactivity occurs in 40-60% among aromatic ASMs (meaning if a patient has a reaction to one, likely that the patient will experience it with the other aromatic ASMs)

What is the mechanism for which AEs occur with aromatic ASMs?

Immune mediated, drug-specific activation of cytotoxic T-cells

• Either the drug directly (non-hapten) activates cytotoxic T-cells

• OR, the reactive metabolite of the drug covalently binds to cellular macromolecules (hapten formation)

Immunological Hypothesis of Aromatic ASMs

What is a cause of increased susceptibility of idiosyncratic SEs with aromatic ASMs?

Genetic variability in immune response

Which gene/population was seen to have idiosyncratic reactions with Carbamazepine?

Individuals with HLA-B*1502 (primarily individuals of Han Chinese, Thailand, Malaysia, and India) were found to have higher rates of AEs with CBZ.

• Specifically, SJS and TEN

• Make sure to genotype individuals with Asian descent!

Other ASMs seen are Lamotrigine, Oxcarbazepine, and Phenytoin

What should we do to manage/prevent idiosyncratic rxns with ASMs?

• For aromatic ASMs:

  • Note past reactions to other aromatic ASMs

  • Genotype for HLA-B*1502 in Asian population

• For Lamotrigine

  • Children are at higher risk than adults

  • Check if patient is concurrently using Valproic acid

  • Check if starting dose is too high

  • Note past reactions to other aromatic ASMs

  • Genotype for HLA-B*1502 in Asian population

Skin rash is commonly seen in which ASMs? Is there cross reactivity?

Carbazepine, Lamotrigine Oxcarbazepine Phenytoin (CLamOP)

• Yes, cross-reactivity is SUPER common (40-60%), don’t swap for another aromatic ASM

What are characteristics of skin rashes with ASMs?

• Mostly mild, macular-papular rash

• Reversible on d/c of ASM, resolution in 1-2 weeks

• Rare, but can progress to SJS or TEN

What are signs/symptoms of possible serious skin reactions?

• Fever

• Lymphadenopathy

• Mucus membrane involvement

• ↑ eosinophils

• Abnormal liver function tests

• Facial edema

• Blisters

• Painful dermatitis

How do we manage skin rash rxns from aromatic ASMs?

• First, Stop ASM

• Administer antihistamines for symptomatic relief

• Re-examine within 24 hrs

• If oral ulceration, blistering, fever, facial edema, or lymphadenopathy → immediate assessment and/or admit to hospital for further management

• If possible, delay starting new ASM for 3-7 days & Cover with Benzodiazepines

• If causative ASM was an aromatic ASM, avoid use of other aromatic ASMs due to possible cross-reactivity

A patient presents with a skin rash after starting a new antiseizure medication: can we start a new ASM rightaway? Which drug do we use to cover the patient’s seizures?

No, wait 3-7 days for the drug to clear out of the patient (remember Habibi’s comment about losing that 2nd line option)

Cover with benzodiazepines in the meantime (i.e. lorazepam, alprazolam)

If patient experiences skin rash with aromatic ASMs, what are acceptable alternatives?

Levetiracetam

Pregabalin

Topiramate

Valproic acid

Which ASMs have weight gain as an adverse effect?

Carbamazepine

Gabapentin

Pregabalin

Valproic acid

Which ASMs have weight loss as an adverse effect?

Topiramate

Zonisamide

Which ASMs do not affect weight?

Levetiracetam

Lamotrigine

Oxcarbazepine

Phenyotin

Lacosamide

What adverse effect is seen more often in patients with epilepsy taking ASMs?

• Bone fractures (osteoporosis, osteomalacia)

• 2-6x higher incidence of bone fractures (bone health impacted) in patients with epilepsy

What’s a special patient population in which we have to manage carefully?

Pregnant patients with epilepsy

• Women may experience increased seizure frequency

• Causes: sleep deprivation, noncompliance, pregnancy-induced PK changes, hormonal changes

ASMs and teratogenicity

ASMs can be toxic to the fetus!

• Incidence of major congenital malformations (MCM)

• Congenital anomalies:

  • CV malformations(0.2-2.5%)

  • Cleft lip/palate (0.5-2%)

  • Skeletal abnormalities(1%)

  • Developmental delay (0.5%)

• Neural tube defects (spina bifida)

Which ASM is highly associated with teratogenicity and is contraindicated in pregnancy?

Valproic acid (Depakote)

• 2-3x higher frequency of major congenital malformations vs other ASMs

• Higher risk of spinal bifida vs other ASMs

• Higher frequency of postnatal cognitive/developmental problems

What are risk factors for teratogenicity with ASMs?

• Higher ASM serum concentrations

• ASM polytherapy

• Family history of birth defects

• Use of valproic acid!!!

If a patient wants to become pregnant, how should we manage epilepsy in pregnant patients?

• Reassess need for ASM treatment

• If ASM is still required:

  • Select most appropriate ASM, considering potential for MCM (major congenital malformation)

  • Avoid VPA

  • Monotherapy at lowest effective dose

  • Measure plasma concentration when dose optimized

    • Significant PK changes occur due to pregnancy

What should we counsel patients prior to becoming pregnant?

• Contraception

  • CBZ, OXC, PHT, TPM induce metabolism of hormonal contraceptives

• Counsel concerning risks

• Start folate > 3 months before conception (minimum of 1mg daily in epilepsy)

When should we monitor ASM plasma concentrations?

• To guide dosage adjustments

• Identify individual’s therapeutic range

• Determine cause for loss of seizure control or toxicity

• Evaluate consequences with addition/removal of concurrent drug

• Assess compliance

When interpreting ASM plasma concentrations, what should we think about?

• When the last dose given?

• Is the concentration at steady-state?

• Is the patient compliant?

• What is the response at this concentration?

• Are there any recent changes to illness or drugs?

Plasma concentrations of ASM is lower than expected: what could be some causes?

• Noncompliance

• Lab error

• Inconsistent sampling times

• Steady-state not reached

• PK changes

  • change in drug formulation (Affecting extent & rate of absorption)

  • Reduced plasma protein binding

  • enhanced metabolism

  • Increased renal excretion

Plasma concentrations of ASM is higher than expected: what could be some causes?

• Noncompliance

• Lab error

• Inconsistent sampling times

• PK changes

  • change in drug formulation (increased extent & rate of absorption)

  • Decreased metabolism

  • Reduced renal excretion