Classic AEDs

John M. Pellock, MDProfessor and Chairman

Division of Child NeurologyVirginia Commonwealth University

Medical College of Virginia HospitalsRichmond, Virginia

Older AEDs

Phenobarbital (1912)

Phenytoin (1938)

Ethosuximide (1960)

Carbamazepine (1974)

Valproic acid (1978)

Bromides

Benzodiazepines

First-Line Therapy Early 20th Century

Mattson RH et al. N Engl J Med 313:145, 1985

VA Cooperative Study

Toxicity of Classic AEDs

M de Silva (Lancet 1996) randomized 167 children with partial or tonic-clonic seizures

6 of 10 children assigned to phenobarbital had behavioral or cognitive adverse events

Only 15 children had adverse effects requiring withdrawal

Phenytoin: 2 with drowsiness; 1 each skin rash, hirsutism and blood dyscrasia

Carbamazepine: 1 each drowsiness and blood dyscrasia

VPA: 1 each behavioral and tremor

Classic Drugs are Equally Effective

AED Selection

Seizure type and syndrome

Neonatal seizures

Infantile spasms

Generalized epilepsies

Partial-onset

AED efficacy

AED toxicity

Need for monitoring

Ease of dosing and compliance issues

Underlying medical conditions

Medication interactions

Urgency of initiating therapy

Cost

Carbamazepine

Carbamazepine

Dose: 10-35 mg/kg/day (bid-qid)

Elimination

>85% hepatic

Major pathway CYP3A4

Active metabolite 10-11 epoxide, metabolized by epoxide hydrolase (may be increased out of proportion to total level)

Autoinduction

Clearance can increase by 300% over first 3-5 wks

May need 3 to 4x / day dosing in children

Carbamazepine: Adverse Effects

10% with transient leukopenia

Risk of aplastic anemia and agranulocytosis 5-8x risk in general population Mid-1980s, 31 cases thrombocytopenia 10 cases agranulocytosis 27 cases aplastic anemia 8 cases pancytopenia

Rash reported in 17% pts; 10% have been life-threatening Incidence of rash increased with age: 5% at 0-6 yrs, 15.4% at >7 yrs

Hepatotoxicity 20 cases of clinical significance reported by mid-1980s Hepatotoxicity reversible, but recurs with re-administration of drug

Dose related neurotoxic effects: dizziness, somnolence, ataxia, diplopia, blurred vision, nausea

Carbamazepine: Drug Interactions

Enzyme inducer Effects on thyroid and sex hormones Effects on vitamin D metabolism

Multiple drug interactions

Increase CBZ Azole antifungals, cimetidine, delaviridine, diltiazem,

clarithromycin, erythromycin, fluoxetine, INH, NNRTIs, omeprazole, PIs, propoxyphene, verapamil, caffeine, grapefruit juice

Decrease CBZ FBM, desmethyldiazepam, PB, PHT, loxapine

Increase epoxide levels FBM, VPA

Levels rise with CBZ

Chlorothiazide, MAO inhibitors, lithium, perphenazine, acenocoumarol, digitalis glycosides, furosemide and INH

No significant clinical interaction

Phenobarbital, primidone

Levels decrease with CBZ

Antipsychotics (haloperidol, alprazolam, clozapine, trazadone – clinically insignificant with olanzapine)

Azole antifungals, calcium chennel blockers, cyclosporine, FBM, VPA, narcotics, neuromuscular blockers, NNRTIs, oral contraceptives, PIs, theophylline, TGB, tricyclics, VPA, warfarin, ZNS

Benzodiazepines

Carbamazepine: Drug Interactions

Schachter S. Exp Opin Invest Drugs 8:1, 1999

Oxcarbazepine Metabolic Pathway:No Epoxide, No Autoinduction

NH2O

NH2O

O

NH2O

OH

NH2O

Gluc O

NH2O

O

NH2O

OH OH

Oxcarbazepine

Carbamazepine

Reduction Conjugation

Oxidation Hydrolysis

MHD

10, 11-Epoxide

No autoinduction

Autoinduction

N N

NN N

N

Oxcarbazepine: Pediatric Adjunctive Therapy Trial

Glauser TA et al. Neurology 54:2237, 2000

41%

27%

4%

22%

7%

1%0

15

30

45

60

Oxcarbazepine (n=135)

Placebo (n=128)

% o

f P

atie

nts

Decrease in Seizure Frequency

>50% >75% 100%

Safety of Oxcarbazepine: Hyponatremia

Incidence of clinically significant hyponatremia

(Na <125 mmol/L) in clinical trials: 2.5%

Most (79%) were receiving concomitant Na-depleting medications

Hyponatremia usually asymptomatic

TRILEPTAL® prescribing information

Safety of Oxcarbazepine: Hypersensitivity

25-30% hypersensitive to CBZ will experience similar reaction to OXC

Prevention of hypersensitivity reactions

Ask about prior adverse experiences with CBZ

If patient has history of hypersensitivity with CBZ, use OXC only if benefit justifies risk

Discontinue OXC immediately if signs or symptoms

of hypersensitivity develop

TRILEPTAL® prescribing information

Dosing Guidelines:Pediatric Adjunctive Therapy

Approved product labeling recommendations

Starting dose: 8-10 mg/kg/day (not to exceed 600 mg/day); titrate to target dose over 2 wks

Target dose based on weight 20-29 kg 900 mg/day 29.1-39 kg 1200 mg/day >39 kg 1800 mg/day

Clinical experience

Improved tolerability with lower starting dose and slower titration

Starting dose: 4-5 mg/kg/day increased weekly by 4-5 mg/kg/day to target dose of 20 mg/kg/day in approximately 4 wks

Phenobarbital

Used in neonatal seizures, and potentially useful for severe epilepsy acknowledging its cognitive, depressive, and behavioral side effects

Formulations: 30, 60, and 100 mg tabs; 20 mg / 5 mL elixir

Doses Half-life

Neonates, 3-4 mg/kg/day 43-217 hrs

Infants, 4-5 mg/kg/day

Children, 2-3 mg/kg/day 35-73 hrs

Adults, 0.5-1 mg/kg/day 56-140 hrs

Slow taper to discontinue

Phenobarbital: Adverse Effects

Neurotoxic effects Sedation, dizziness, mood change,

insomnia, hyperkinesia (children, elderly) Cognitive dysfunction

Others Osteomalacia Peripheral neuropathy Dupuytren’s contraction Frozen shoulder

Idiosyncratic Skin rash Hepatotoxicity Blood dyscrasia

Phenobarbital: Drug Interactions

Increase PB levels: FBM, MSM, VPA

Phenytoin may increase or decrease levels

Phenobarbital decreases blood levels

Antipsychotics, azole antifungals, CB, CBZ, cyclosporine, FBM, LTG, narcotics, NNRTIs, oral contraceptives, PHT, PIs, steroids, TGB, theophylline, TPM, tricyclics, VPA, warfarin, ZNS

Dosing Guidelines:Pediatric Adjunctive Therapy

Approved product labeling recommendations

Starting dose: 8-10 mg/kg/day (not to exceed 600 mg/day); titrate to target dose over 2 wks

Target dose based on weight 20-29 kg 900 mg/day 29.1-39 kg 1200 mg/day >39 kg 1800 mg/day

Clinical experience

Improved tolerability with lower starting dose and slower titration

Starting dose: 4-5 mg/kg/day increased weekly by 4-5 mg/kg/day to target dose of 20 mg/kg/day in approximately 4 wks

Phenytoin

Phenytoin

Pediatric doses mg/kg/day Half-life, hrs

Neonate 4-6 3-140

Poor absorption 15-20

3 mo-3 yr 6-10 1.2-31.5

4-6 yrs 5-7

7-9 yrs 4-7

>10 yrs 4-6 6-60

Volume of distribution: 0.7-1.2 (neonates)

Saturable metabolism, does not follow linear kinetics

Oral load can be divided into increments of 300-400 mg given every 2-4 hrs

Highly protein bound

VPA can increase free fraction by 0.1% for each mg/mL At VPA levels of 100, free phenytoin can be 20% of total

Phenytoin: Adverse Effects and Drug Interactions

Side effects: nystagmus, ataxia, dizziness, hirsuitism, gingival hyperplasia, peripheral neuropathy, osteomalacia, folate deficiency

Idiosyncratic Skin rash Hepatotoxicity Blood dyscrasia Lymphadenopathy

Increase PHT levels: amiodarone, cimetidine, diltiazem, FBM, fluconazole, fluoxetine, INH, MSM, omeprazole, OXC, PB, ritonavir, ticlopidine, TPM, VPA

Decrease PHT levels: antacids, CBZ, ciprofloxacin, PB, sucralfate

R. DeLorenzo, in Antiepileptic Drugs, 4th Edition

Ethosuximide

Useful for absence attacks of childhood absence epilepsy and for atypical absence

Formulations: 250 mg capsule and 250 mg/5 mL solution

Common pediatric dose: 10-15 mg/kg/day (initial);15-40 mg/kg/day (maintenance) qd – tid

Increased doses can decrease GI side effects

Adverse effects: GI distress, nausea, anorexia, drowsiness, HA, dizziness, hiccups, behavioral changes (rare psychotic reactions)

Idiosyncratic: skin rash, blood dyscrasia

VPA may increase levels; CBZ, PB, PHT decrease levels

Valproic Acid

Valproic Acid

Different spectrum of usefulness (generalized, absence, atonic, myoclonic [Lennox-Gastaut] seizures)

Used in bipolar and schizoaffective disorders

Common pediatric doses: 15-60 mg/kg/day

Elimination: hepatic metabolism (>95%), glucuronidation (20-50%), beta-oxidation (40%), CYP (minor)

Adverse reactions: hepatotoxicity (highest risk in those <2 yrs and on multiple AEDs), pancreatitis, and blood dyscrasia Bleeding with and without thrombocytopenia Osteomalacia Polycystic ovary syndrome (anovulatory cycles) Teratogenicity

Valproate: Drug Interactions

High protein binding

Inhibits biotransformation of PB, ethosuximide, LTG, carbamazepine epoxide, free PHT

Increased levels of CCB, FBM, zidovudine

Increase VPA levels: ASA, FBM, fluoxetine, INH

Decrease VPA levels: CBZ, LTG, PB, PHT, ritonavir

Glauser TA, et al. NEJM 362;9, March 4, 2010

Ethosuximide, Valproic Acid, and Lamotrigine in Childhood Absence Epilepsy

Benzodiazepines

Highly protein bound: 80-90%

Used to treat status

Rectal dizaepam and oral Intensol used to treat prolonged seizures in intractable seizure disorders and clusters; also available for patients with infrequent seizures

Tolerance precludes broad use for chronic seizures

Care must be taken to prevent psychosis and seizure exacerbation during withdrawal

Use of Drug Level Monitoring:Always Have a Question!

Establish “baseline” effective concentrations

Evaluate potential causes for lack of efficacy “Fast metabolizers” Noncompliance

Evaluate potential causes for toxicity

Altered drug utilization as consequence of physiological conditions (puberty, geriatrics)

“Slow metabolizers”

Altered drug utilization as consequence of pathological conditions (renal failure, liver failure)

Drug-drug interactions

Switching AED preparations

Use of Drug Level Monitoring:Always Have a Question!

Evaluate potential causes for loss of efficacy

Altered drug utilization as consequence of physiological conditions (e.g. neonates, infants, young children)

Altered drug utilization as consequence of pathological conditions

Change in formulation

Drug-drug interaction

Judge “room to move” or when to change AEDs

Minimize predictable problems (PHT, VPA)