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The Antiepileptic Drug Page

Directory

• carbamazepine (Tegretol)
• clonazepam (Klonopin)
• ethosuximide (Zarontin)
• felbamate (Felbatol)
• fosphenytoin (Cerebyx)
• gabapentin (Neurontin)
• lamotrigine (Lamictal)
• phenobarbital (Luminal)
• phenytoin (Dilantin)
• primidone (Mysoline)
• topiramate (Topamax)
• valproate, sodium divalproex (Depakene, Depakote)
• vigabatrin (Sabril)
• References and disclaimer
• Povratak na pocetnu stranicu

carbamazepine (Tegretol)

Dose range

• Adults: 600 to 2,000 mg per day
• Children: 10 to 40 mg/kg per day
• Comment: Optimal individual maintenance doses will be determined by clinical response; initial doses are lower; pharmacokinetic interactions may affect dosage requirements.

Regimen

• Three to four times per day; two times per day for sustained release preparation, Tegretol XR

Pharmocokinetics

• Hepatic elimination by oxidation, aromatic hydroxylation, and N-glucuronidation
• Half life 5-20 hours
• Some clinically relevant pharmacokinetic drug interactions:
• Carbamazepine induces the metabolism of cyclosporine A, tricyclic antidepressants, and warfarin (Coumadin)
• Carbamazepine induces the metabolism of oral contraceptive agents, including ethinyl estradiol and levonorgestrel, with the potential for breakthrough bleeding and contraceptive failure
• Carbamazepine levels are increased by the calcium-channel blockers verapamil and diltiazem, erythromycin and other macrolide antibiotics,isoniazid, cimetidine (Tagamet), and propoxyphene (Darvon).
• Carbamazepine increases phenytoin metabolism to a variable degree
• Carbamazepine increases primidone biotransformation to phenobarbital
• Carbamazepine increases metabolism of valproate, ethosuximide, and lamotrigine
• Carbamazepine metabolism is increased by phenytoin, phenobarbital, primadone, and felbamate.
• Felbamate increases carbamazepine epoxide levels
• Comment: Steady-state values for the half life of carbamazepine are reached only after complete hepatic autoinduction, which occurs after approximately one month of carbamazepine administration.

Adverse effects

• Dose related: Double vision, Dizziness, Nausea, Headache
• Idiosyncratic: Rash, Leucopenia
• Comment: All antiepileptic drugs are potentially teratogenic. An increased incidence of neural tube defects has been shown to occur with carbamazepine.

Efficacy:

• Partial seizures
• Secondarily generalized seizures

External Carbamazepine Link 1
External Carbamazepine Link 2
External Carbamazepine Link 3 (adverse cutaneous reactions)
External Carbamazepine Link 4
External Carbamazepine Link 5

clonazepam (Klonopin)

Dose range

• Adults: 2-4 mg per day
• Children: 0.1-0.3 mg/kg per day
• Comment: Optimal individual maintenance doses will be determined by clinical response; lower initial doses may reduce somnolence.

Regimen

• Two to three times per day

Pharmacokinetics

• Hepatic elimination by nitroreduction and acetylation
• Half life 20-40 hours
• Pharmacokinetic drug interactions are uncommon, but administration of hepatic enzyme inducing agents such as carbamazepine, phenobarbital and phenytoin may lower clonazpeam levels somewhat.

Adverse effects

• Dose related: Drowsiness, Ataxia, Irritability
• Idiosyncratic: Rash, Leucopenia
• Comment: All antiepileptic drugs are potentially teratogenic.

Efficacy:

• Myoclonic seizures
• Absence seizures
• Partial seizures
• Secondarily generalized seizures

External Clonazepam Link 1
External Clonazepam Link 2 (adverse cutaneous reactions)
External Clonazepam Link 3

ethosuximide (Zarontin)

Dose range

• Adults: 500-1250 mg per day
• Children: 10-60 mg/kg per day
• Comment: Optimal individual maintenance doses will be determined by clinical response.

Regimen

• Two to three times per day

Pharmacokinetics

• Elimination: Hepatic (80%) oxidation; Renal (20%)
• Half life 30-60 hours
• Ethosuximide is not protein bound
• Some clinically relevant pharmacokinetic drug interactions:
• Half life decreased by concomittant administration of hepatic enzyme inducing agents such as carbamazepine, phenytoin or phenobarbital
• The half life of ethosuximide may be increased by valproate
• Ethosuximide has little or no effect on the pharmacokinetics of other antiepileptic drugs

Adverse effects

• Dose related: Nausea, hiccups, anorexia
• Idiosyncratic: Rash, SLE
• Comment: All antiepileptic drugs are potentially teratogenic.

Efficacy:

• Absence seizures

felbamate (Felbatol)

Dose range

• Adults: 2400-4600 mg per day
• Children: 40-60 mg/kg per day
• Comment: Optimal individual maintenance doses will be determined by clinical response; initial doses are lower; pharmacokinetic interactions may affect dosage requirements.

Regimen

• Three times per day

Pharmacokinetics

• Elimination is both renal, and hepatic by hydroxylation and glucuronidation
• Half life 15-20 hours
• Some clinically significant pharmacokinetic drug interactions:
• Felbamate increases phenytoin, phenobarbital and valproate levels
• Felbamate decreases carbamazepine concentration but increases the concentration of carbamazepine epoxide
• Felbamate levels are decreased by phenytoin, and carbamazepine, but valproate has little effect

Adverse effects

• Dose related: Anorexia, Weight loss, Headaches, Insomnia
• Idiosyncratic: Aplastic Anemia, Liver failure
• Comment: All antiepileptic drugs are potentially teratogenic.

Efficacy:

• Partial seizures
• Secondarily generalized seizures
• Generalized seizures
• Absence seizures
• Myoclonic seizures
• Lennox-Gastaut syndrome
• Comment: Use of felbamate is restricted by an FDA advisory because of the risk of idiosyncratic side effects.

External Felbamate Link 1
External Felbamate Link 2
External Felbamate Link 3
External Felbamate Link 4 (adverse cutaneous reactions)

fosphenytoin (Cerebyx)

This agent is not currently approved for use in the United States. Information on this agent will be posted when this occurs.

gabapentin (Neurontin)

Dose range

• Adults: 900-4800 mg per day
• Children: 15-30 mg/kg per day
• Comment: Optimal individual maintenance doses will be determined by clinical response; lower initial doses may reduce ataxia or somnolence.

Regimen

• Three times per day

Pharmacokinetics

• Renal elimination
• Half life 5-7 hours
• Gabapentin does not have significant pharmacokinetic drug interactions and is not significantly protein bound.

Adverse effects

• Dose related: Dizziness, Ataxia, Somnolence, Weight Gain
• Idiosyncratic: Rash
• Comment: All antiepileptic drugs are potentially teratogenic.

Efficacy: Approved as use as an add on treatment in adults for

• Partial seizures
• Secondarily generalized seizures

Lamotrigine (Lamictal)

Possible mechanism of action:

• Blockade of voltage sensitive sodium channels.
  
  

Pharmacokinetics

• Oral bioavailability: 98 %
  
• Protein binding: 55 %
  
• Elimination by hepatic N-glucuronidation
• Half life ~26 hours
• Some clinically relevant pharmacokinetic drug interactions:
• Half-life prolonged by valproate
  
• Half-life shortened by carbamazepine, phenytoin, phenobarbital, primidone
  
  

Efficacy: Approved for use as add on treatment for

• Partial seizures
  
• Absences and atypical absences
  
• Lennox-Gastaut syndrome
  
• Tonic and atonic seizures
  
  

Side effects:

• Dose Related: Diplopia, Somnolence, Dizziness, Ataxia, Insomnia
• Idiosyncratic: Rash--The risk of rash is decreased by lower initial doses.
• Comment: All antiepileptic drugs are potentially teratogenic.

Dosage:

Adolescents and adults:

• If added to valproate monotherapy: 25 mg daily for two weeks, then 50 mg daily for two weeks, then titrate up to 150 mg twice daily.
  
• If added to carbamazepine, phenytoin,phenobarbital or primidone: Initial dose 50 mg twice daily, subsequent increases up to 100 - 200 mg twice daily.
  
  

Infants and children:

• If added to valproate monotherapy: initial dose 0.5 mg/kg/day, final maintenance dose of 1 - 5 mg/kg/day.
  
• If added to carbamazepine, phenytoin, phenobarbital, or primidone: initial doses 2 mg/kg/day, with subsequent increases to 5 - 15 mg/kg/day.
  
• Comment: Optimal individual maintenance doses will be determined by clinical response.

phenobarbital (Luminal)

Dose range

• Adults: 30-180 mg per day
• Children: 2-8 mg/kg per day
• Comment: Optimal individual maintenance doses will be determined by clinical response; initial doses are lower; pharmacokinetic interactions may affect dosage requirements.

Regimen

• Once per day

Pharmacokinetics

• Elimination is both renal, and hepatic by parahydroxylation and conjugation to glucuronic acid
• Half life 65-110 hours
• Some clinically relevant pharmacokinetic drug interactions:
• Phenobarbital levels are significantly increased by valproate
• Phenobarbital levels may be mildly increased by acetazolamide, phenylethylacetylurea and methsuximide
• Phenobarbital lowers levels of valproate, and may cause mild lowering of carbamazepine levels
• Interactions between phenobarbital and phenytoin are mild and inconsistent
• Chloramphenicol elevates phenobarbital levels
• Quinine and phenothiazines lower phenobarbital levels
• Phenobarbital decreases levels of theophylline, chloramphenicol, doxicycline, warfarin (Coumadin), cimetidine, cyclosporine, digoxin, and chlorpropamizine
• Phenobarbital increases metabolism of oral contraceptive agents potentially leading to breakthrough bleeding and contraceptive failure

Adverse effects

• Dose related: Somnolence, Hyperactivity, Depression
• Idiosyncratic: Rash, SLE
• Comment: All antiepileptic drugs are potentially teratogenic.

Efficacy:

• Partial seizures
• Secondarily generalized seizures
• Myoclonic seizures

phenytoin (Dilantin)

Dose range

• Adults: 200-600 mg per day
• Children: 5-10 mg/kg per day
• Comment: The half life of phenytoin is concentration dependent due to nonlinear kinetics.
• Comment: Optimal individual maintenance doses will be determined by clinical response; lower initial doses may reduce ataxia or somnolence; pharmacokinetic interactions may affect dosage requirements.

Regimen

• Once or twice per day

Pharmacokinetics

• Elimination is nearly entirely hepatic by oxidation, hydroxylation, and glucurinidation
• Half life 10-60 hours
• Some clinically relevant pharmacokinetic drug interactions:
• Phenytoin levels are decreased by vigabatrin
• Phenytoin levels may be decreased, increased or unchanged in an unpredictable fashion by phenobarbital or carbamazepine
• Phenytoin decreases the levels of carbamazepine, lamotrigine, and valproate, and increases biotransformation of primidone to phenobarbital
• Phenytoin increases metabolism of oral contraceptives and dexamethasone (Decadron)
• Phenytoin decreases levels of theophylline, quinidine, cyclosporin, digitoxin, and chloramphenicol
• Phenytoin has variable effects on warfarin (Coumadin)
• Phenytoin levels are increased by amiodarone, diltiazam, isoniazid, sulfonamides, fluconazole, cimetidine, and phenylbutzone
• Total phenytoin levels decreased, but free phenytoin levels may be increased by valproate, diazoxide and high doses of acetylsalicylic acid (Aspirin)

Adverse effects

• Dose related: Nystagmus, Ataxia, Gingival hyperplasia
• Idiosyncratic: Rash, blood dyscrasia, dyskinesias
• Comment: All antiepileptic drugs are potentially teratogenic.

Efficacy:

• Partial seizures
• Secondarily generalized seizures

External Phenytoin Link 1
External Phenytoin Link 2
External Phenytoin Link 3 (adverse cutaneous reactions)
External Phenytoin Link 4

primidone (Mysoline)

Dose range

• Adults: 500-1250 mg per day
• Children: 5-20 mg/kg per day
• Comment: Optimal individual maintenance doses will be determined by clinical response; initial doses are lower; pharmacokinetic interactions may affect dosage requirements.

Regimen

• Three times per day

Pharmacokinetics

• Elimination by hepatic transformation by ring scission to phenylethylmalonamide (PEMA) and oxidation to phenobarbital; elimation is then primarily renal
• Half life 8-15 hours
• Some clinically relevant pharmacokinetic drug interactions:
• Carbamazepine increases biotransformation to phenobarbital (minor)
• Carbamazepine levels decreased by primadone
• Phenytoin increase phenobarbital levels and decreases primadone levels
• Phenytoin levels decreased by primadone
• Valproate increases primadone and phenobarbital levels
• Clonazpam increases primadone levels
• Ethanol and isoniazid increase primadone levels
• Primadone decreases warfarin (coumadin), cyclosporine, digitoxin, and theophylline

Adverse effects

• Dose related: Somnolence, Ataxia, Depression
• Idiosyncratic: Rash, SLE
• Comment: All antiepileptic drugs are potentially teratogenic.

Efficacy:

• Partial seizures
• Secondarily generalized seizures
• Myoclonic seizures

topiramate (Topamax)

This agent is not currently approved for use in the United States. Information on this agent will be posted when this occurs.

valproate, sodium divalproex (Depakene, Depakote)

Dose range

• Adults: 750-4000 mg per day
• Children: 15-70 mg/kg per day
• Comment: Optimal individual maintenance doses will be determined by clinical response; initial doses are lower; pharmacokinetic interactions may affect dosage requirements.

Regimen

• Three to four times per day

Pharmacokinetics

• Elimination is almost entirely hepatic by several conjugation and oxidative reactions.
• Half life 5-15 hours
• Some clinically relevant pharmacokinetic drug interactions:
• Valproate increases phenobarbital, lamotrigine, felbamate, and ethosuximide levels
• Valproate decreases total phenytoin levels, but increases free phenytoin levels
• When valproate is administered with primidone, both primidone and phenobarbital levels may increase
• Valproate levels are decreased by carbamazepine, phenobarbital and phenytoin
• Valproate levels are increased by felbamate
• Valproate does not increase clearance of oral contraceptive agents

Adverse effects

• Dose related: Weight gain, Hair loss, Tremor
• Idiosyncratic: Liver failure, Pancreatitiis, Thrombocytopenia
• Comment: All antiepileptic drugs are potentially teratogenic. An increased incidence of neural tube defects has been shown to occur particularly with valproate.

Efficacy:

• Partial seizures
• Secondarily generalized seizures
• Generalized seizures
• Absence seizures
• Myoclonic seizures
• Lennox-Gastaut syndrome

External Valproate Link 1
External Valproate Link 2
External Valproate Link 3 (adverse cutaneous reactions)
External Valproate Link 4

vigabatrin (Sabril)

This agent is not currently approved for use in the United States. Information on this agent will be posted when this occurs.

References and Disclaimer

References

The most comprehensive reference on the properties of antiepileptic drugs is Antiepileptic Drugs, Fourth Edition Levy, R.H.; Mattson, R.H.; and Meldrum, B.S.; Raven Press, 1995. Some of the information on this page comes from this source.

Disclaimer

We make no claims for the accuracy of the information on this page, and will not be held legally responsible for its contents. Any discussion of specific antiepileptic medications does not constitute an endorsement of those agents or of the pharmaceutical companies which manufacture them.