Medication used for Epilepsy

Anticonvulsants indicated for use in partial seizures are the medical treatment of choice. Patients generally require many years of treatment, so consideration of side effects is important. While most of the anticonvulsants are in pregnancy category C or D, the risk of medication to the fetus must be weighed against the risk of maternal seizures to the fetus. Because of the risk of level fluctuations, patients should not switch between brand and generic anticonvulsants, and if a generic is used, patients should receive the same generic formulation consistently.

Drug Category: Anticonvulsants -- These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

Drug Name	Carbamazepine (Tegretol, Tegretol XR, Carbatrol) -- First-line agent for partial seizures with or without secondary generalization; particularly effective in treatment of nocturnal motor/dystonic frontal lobe seizures; potential hematologic and other adverse effects; blood monitoring recommended. Available as tablets, extended release tablets, extended release capsules, and suspension. Patients who are not using extended release form often require tid dosing.
Adult Dose	200 mg PO qd or bid initially; increase by 200 mg weekly as needed; maximal recommended dose 1200 mg/d in divided doses, although higher doses may be required in patients on other enzyme-inducing drugs
Pediatric Dose	Small children frequently require suspension <6>6-12 years: 100 mg PO bid or half tsp qid; increase as needed by 100 mg/d, up to a maximum of 1000 mg/d in divided doses >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; history of bone marrow depression; MAOIs within last 14 d
Interactions	Danazol may increase serum levels significantly within 30 d (avoid whenever possible); do not coadminister with MAOIs; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; may decrease primidone and phenobarbital levels (their coadministration may increase carbamazepine levels)
Pregnancy	D - Unsafe in pregnancy
Precautions	Do not use to relieve minor aches or pains; caution with increased intraocular pressure; obtain CBCs and serum iron at baseline prior to treatment, during first 2 months, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness

Drug Name	Phenytoin (Dilantin Kapseals, Dilantin Infatabs) -- Available as tab, cap, infatab, and susp. First-line agent for partial seizures; advantages include quickly achieving therapeutic level and possibility of once daily dosing (Dilantin Kapseals), which increases compliance.
Adult Dose	Some patients require oral loading to attain therapeutic level quickly; phenytoin can be loaded as 1 g divided in 3 doses (400 mg-300 mg-300 mg) at 2-h intervals; maintenance dose of 300 mg/d should be started 24 h after loading; if patients are not to be loaded, initiate dosing at 300 mg/d, as tid, bid, or qd; further dosage increase should be based on response to treatment; because of zero order kinetics, increase by 30 mg or 50 mg IV administration should be reserved for situations such as status epilepticus or for patients with IV access only; IV loading dose is 15-20 mg/kg; fosphenytoin is more expensive than IV phenytoin, but does not cause tissue necrosis or irritation when extravasated and may be given IM
Pediatric Dose	<6 st="on">PO in 2-3 divided doses; maintenance dose is 4-8 mg/kg >6 years: May require adult dosing
Contraindications	Documented hypersensitivity; sinoatrial block; second- and third-degree AV block; sinus bradycardia; Adams-Stokes syndrome
Interactions	Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase toxicity Barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate may decrease effects May decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, valproic acid
Pregnancy	D - Unsafe in pregnancy
Precautions	Rapid IV infusion may result in death from cardiac arrest, marked by QRS widening Perform blood counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue use if skin rash appears and do not resume use if rash is exfoliative, bullous, or purpuric; caution in acute intermittent porphyria and diabetes (may elevate blood glucose level); discontinue use if hepatic dysfunction occurs

Drug Name	Valproic acid, divalproex sodium (Depakote, Depakene, Depacon) -- Available as tablets, capsules, syrup, sprinkles, injection. Although considered first-line agent for treatment of primary generalized epilepsy, indicated for partial seizures as well, particularly for patients with secondary generalization. Must be used cautiously in women of childbearing age; has limited use in young children because of risk of hepatic failure, which may be fatal.
Adult Dose	10-15 mg/kg/d PO in divided doses; increase by 5-10 mg/kg/d every wk; usual maximum dose 60 mg/kg/d Alternatively, 20 mg/min IV 60-min infusion; faster rates have been used
Pediatric Dose	<2>>2 years: Administer as in adults
Contraindications	Documented hypersensitivity; hepatic disease/dysfunction
Interactions	Cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may reduce levels significantly; in children, salicylates decrease protein binding and metabolism of valproate; may result in variable changes of carbamazepine concentrations with possible loss of seizure control; may increase diazepam and ethosuximide toxicity (monitor closely); may increase phenobarbital and phenytoin levels while either may decrease valproate levels; may displace warfarin from protein-binding sites (monitor coagulation tests); may increase zidovudine levels in HIV-seropositive patients
Pregnancy	D - Unsafe in pregnancy
Precautions	Thrombocytopenia and abnormal coagulation parameters have occurred; risk of thrombocytopenia increases significantly at total trough plasma concentrations >110 mcg/mL in females and >135 mcg/mL in males; determine platelet counts and bleeding time before initiating therapy, at periodic intervals, and prior to surgery; reduce dose or discontinue therapy if hemorrhage, bruising, or hemostasis/coagulation disorder occurs; hyperammonemia may occur, resulting in hepatotoxicity; monitor patients closely for appearance of malaise, weakness, facial edema, anorexia, jaundice, and vomiting; may cause drowsiness

Drug Name	Gabapentin (Neurontin) -- Indicated for use in partial seizures with and without secondary generalization; has relatively few drug interactions and adverse effects.
Adult Dose	300 mg PO bid or tid; may be increased weekly up to 1800-2400 mg/d in divided doses; some patients require doses as high as 3600 mg/d or higher; renally excreted, dosage adjustment necessary for patients with renal dysfunction
Pediatric Dose	<12>>12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids may significantly reduce bioavailability (administer at least 2 h following antacids); may increase norethindrone levels significantly
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in severe renal disease

Drug Name	Lamotrigine (Lamictal) -- Newer agent, effective for partial seizures with or without secondary generalization. Main side effect of concern is rash, which may be severe.
Adult Dose	Dosing depends on coadministration of other anticonvulsants, specifically valproate; see dosing instructions for specific guidelines; slow titration recommended to prevent rash
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Acetaminophen increases renal clearance, decreasing effects; similarly, phenobarbital and phenytoin increase lamotrigine metabolism, causing decrease in lamotrigine levels; valproic acid increases half-life
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Serious or life-threatening rash, more likely children and patients on valproate; while many other adverse effects reported, all are infrequent or rare

Drug Name	Levetiracetam (Keppra) -- Newer agent, effective for partial seizures with or without secondary generalization. Few adverse effects, no drug-drug interactions. Does not require blood monitoring, although slight decreases in RBC and WBC counts have been reported.
Adult Dose	500 mg PO bid, increase additional 1000 mg/d in divided dosing every 2 wk to maximum recommended daily dosage of 3000 mg; slower titration may be better tolerated by some patients; no IV form available; requires adjustment for impaired renal function
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Somnolence, coordination abnormalities, and behavioral abnormalities may occur; requires adjustment for impaired renal function

Drug Name	Oxcarbazepine (Trileptal) -- Indicated as monotherapy or adjunctive therapy in treatment of partial seizures with or without secondary generalization. Mechanism of action similar to that of carbamazepine, without metabolism to epoxide. Active metabolite MHD (monohydroxy derivative). If patient being converted from carbamazepine to oxcarbazepine, the inducing effect of carbamazepine on cytochrome P-450 enzymes will be reduced, and other AEDs may need adjustment. No IV form available. If added to phenytoin, may elevate phenytoin levels by as much as 20%.
Adult Dose	Monotherapy: 150 mg or 300 mg PO bid initially; dose may be increased by 300 mg/d q3d; maximum recommended daily dose of 1200-2400 mg in divided dosing; elderly patients may require slower titrations
Pediatric Dose	Approved for use as adjunctive therapy in children aged 4-16 years Initiate at 8-10 mg/kg PO, generally not to exceed 600 mg/d in divided dosing; target dose based on weight 20-29 kg: 900 mg/d 29-39 kg: 1200 mg/d >39 kg: 1800 mg/d
Contraindications	Documented hypersensitivity
Interactions	Increases phenytoin level; may interact with oral contraceptives, calcium channel blockers
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hyponatremia may be clinically significant with sodium <125;>

Drug Name	Topiramate (Topamax) -- Indicated for adjunctive treatment of partial seizures with or without secondary generalization, and for tonic-clonic seizures. Approved for adults and for children aged 2-16. Has multiple mechanisms of action.
Adult Dose	25-50 mg/d PO for 1 wk, then increase by 25-50 mg/d every wk in bid dosing to therapeutic dose of 200-400 mg/d
Pediatric Dose	1-3 mg/kg/d PO for 1 wk, then increase by 1-3 mg/kg/d PO every 1-2 wk to target dose of 5-9 mg/kg/d taken bid
Contraindications	Documented hypersensitivity
Interactions	Phenytoin, carbamazepine, and valproic acid can decrease levels significantly; reduces digoxin and norethindrone levels; carbonic anhydrase inhibitors may increase risk of renal stone formation and should be avoided; use with extreme caution concurrently with CNS depressants since may have an additive effect in CNS depression, as well as other cognitive or neuropsychiatric adverse events
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Risk of developing kidney stone increased 2-4 times that of untreated population; risk may be reduced by increasing fluid intake; caution in renal or hepatic impairment

Drug Name	Zonisamide (Zonegran) -- Indicated for adjunctive treatment of partial seizures with or without secondary generalization. Evidence that is effective in myoclonic and other generalized seizure types as well.
Adult Dose	100 mg/d PO for 2 wk, then increase by 100 mg/d every 2 wk to maximum of 400 mg/d; may be given qd or bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May increase serum carbamazepine levels; carbamazepine may increase concentrations; phenobarbital may decrease levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause drowsiness, weight loss, ataxia, nausea, and slowing of mental activity

Drug Name	Tiagabine (Gabitril) -- Indicated for adjunctive treatment of partial seizures with or without secondary generalization. Mechanism of antiseizure action unknown. Believed to be related to ability to enhance activity of GABA, major inhibitory neurotransmitter in CNS.
Adult Dose	Begin at 4 mg/d PO for 1 wk, increase by 4-8 mg/d per wk to maximum of 56 mg/d in 2-4 daily doses
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Cleared more rapidly in patients treated with carbamazepine, phenytoin, primidone, or phenobarbital than in patients who have not received these drugs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Patients receiving valproate monotherapy may require lower doses or slower dose titration for clinical response; moderately severe to incapacitating generalized weakness has been reported following administration of tiagabine in as many as 1% of patients with epilepsy; weakness may resolve after reduction in dose or discontinuation of tiagabine; tiagabine should be withdrawn slowly to reduce potential for increased seizure frequency

Drug Name	Pregabalin (Lyrica) -- Structural derivative of GABA. Mechanism of action unknown. Binds with high affinity to alpha2-delta site (a calcium channel subunit). In vitro, reduces calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. FDA approved for neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and as adjunctive therapy in partial-onset seizures.
Adult Dose	75 mg PO bid or 50 mg PO tid initially; if needed, may increase dose to maximum of 600 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May cause additive effects on cognitive and gross motor functioning when coadministered with drugs that cause dizziness or somnolence
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Discontinue gradually (over a minimum of 1 wk) to minimize increased seizure frequency in patients with seizure disorders; may cause insomnia, nausea, headache, or diarrhea with abrupt withdrawal; common adverse effects include dizziness, somnolence, blurred vision, weight gain, and peripheral edema; may elevate creatinine kinase level, decrease platelet count, and increase PR interval; doses >300 mg/d associated with higher rate of adverse effects and treatment discontinuation; decrease dose with renal impairment (ie, CrCl <60>

Further Outpatient Care:

• Patients require frequent office visits during the titration and adjustment phase of anticonvulsants.

• Examination should include evaluation for excessive nystagmus, tremor, and ataxia.

• Baseline and follow-up blood testing may be needed.

• When seizure free on maintenance dose of medication, patients may be asked to come for follow-up 1-3 times a year.

• Patients who are seizure free for 2-5 years may be considered for a trial of medication withdrawal, depending on the individual case.

In/Out Patient Meds:

• Folate should be added to the anticonvulsant regimen of female patients of childbearing age.

Deterrence/Prevention:

• Frontal lobe epilepsy may be an early or late aftermath of head trauma. Measures should be taken to prevent head injury, including mandatory use of seat belts and bicycle helmets.

• Use of prophylactic anticonvulsants following head trauma has not demonstrated a decrease in the development of epilepsy.

Medical/Legal Pitfalls:

• Failure to diagnose the episodes as epilepsy, misdiagnosis as a psychiatric or parasomniac condition

• Driving restrictions

• Certain states have mandatory reporting of seizures by physicians to the motor vehicle authorities (eg, Department of Motor Vehicles [DMV]).

• Even in states that do not have mandatory reporting, physicians must document that the patient is aware of driving restrictions.

• Patients must be aware of the potential risks of pregnancy and epilepsy/anticonvulsants. Women of childbearing age who are taking anticonvulsants should be given folate supplementation.

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