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Drug Dosage form Dosage Generic/Price Lab monitoring
NOTE: Reference ranges may vary by lab
Other Mechanism of Action/
FDA-approved indication
Side Effects
P = % of patients on placebo who experienced side effect
Drug Interactions Precautions/
Contraindications
Carbamazepine

(Tegretol®)
(Tegretol XR®)
(Carbatrol®)
(Equetro®)
Tegretol® tablet
  • 100 mg
  • 200 mg
  • 300 mg
  • 400 mg

Tegretol®, Epitol®
chewable tablet

  • 100 mg
  • 200 mg

Tegretol XR®
extended-release tablet

  • 100 mg
  • 200 mg
  • 400 mg

Carbatrol® capsule
  • 100 mg
  • 200 mg
  • 300 mg

Equetro® capsule
  • 100 mg
  • 200 mg
  • 300 mg
  • 400 mg
Epilepsy     

Tegretol®
  • Starting - 200 mg twice a day
  • Maintenance - 800 - 1200 mg a day
  • Max - 1600 mg a day
  • Increase dose at intervals of one week by 200 mg/day, given in 3 - 4 divided doses

Tegretol XR®, Carbatrol®, Equetro®
  • Starting - 200 mg twice a day
  • Maintenance - 800 - 1200 mg a day
  • Max - 1600 mg a day
  • Increase dose at intervals of one week by 200 mg/day, given in 2 divided doses

Trigeminal neuralgia     

Tegretol®, Tegretol XR®, Carbatrol®
  • Starting - 100 mg twice a day
  • Maintenance - 400 - 800 mg a day
  • Max - 1200 mg a day
  • Increase dose by 200 mg/day, given in 2 divided doses

Equetro®
  • Starting - 200 mg once daily
  • Maintenance - 400 - 800 mg a day
  • Max - 1200 mg a day
  • Increase dose by 200 mg/day, given in 2 divided doses

Bipolar     

Equetro®
  • Starting - 200 mg twice a day
  • Max - 1600 mg a day
  • Increase dose by 200 mg/day, given in 2 divided doses
Tegretol®
YES/$-$$

Tegretol XR®
YES/$$-$$$

Carbatrol®
YES/$$-$$$

Equetro®
NO/$$$$
Levels
  • Routine monitoring is recommended to maintain a therapeutic level and prevent toxicity
  • Levels should be drawn within an hour of the next dose (trough) [3,4,5]
  • Therapeutic levels (alone): 4 - 12 mcg/ml [4]
  • Therapeutic levels (with other antiepileptics): 4 - 8 mcg/ml [3]
  • Potential Toxic: > 12 mcg/ml [3]

Pharmacokinetics
  • Drug half-life is highly variable since it induces its own metabolism. Enzyme induction is usually complete after 3 - 5 weeks of therapy. [1]
  • Initial half-life: 25 - 65 hours
  • Half-life after 3 - 5 weeks (adults): 12 - 17 hours [1]
  • Time to steady state (initial dosing): 5 - 13 days [5]
  • Time to steady state (chronic dosing): 2 - 5 days [5]

Other
  • Carbamazepine is 75% protein bound. Free (unbound) carbamazepine levels may be useful in cases where protein binding may be altered (e.g. uremia, liver disease). [5]
  • Carbamazepine-10,11 epoxide is the major active metabolite of carbamazepine. Carbamazepine-10,11 epoxide levels may be helpful when signs of toxicity are present but carbamazepine levels are normal. [5]
  • Check for HLA-B*1502 allele in at-risk patients (see HLA-B*1502 allele prevalence for more)
  • CBC before therapy. Periodically thereafter.
  • LFTs before therapy. Periodically thereafter.
  • Thyroid tests periodically.
Tegretol®
  • Take with food

Tegretol XR®
  • Take with food
  • Do not crush, cut, or chew tablet
  • Nonabsorbable tablet coating may be seen in stool. This is normal.
  • When converting from Tegretol® to Tegretol XR®, the total daily dose remains the same

Equetro®
  • Equetro® is not rated bioequivalent
  • May take without regard to food
  • May open capsule and sprinkle beads on food. Do not chew beads.

Carbatrol®
  • May take without regard to food

Mechanism of action
  • Binds to voltage-dependent sodium channels
  • Inhibits action potentials (nerve-firing)

FDA-approved indication(s)

Tegretol®, Tegretol XR® Carbatrol®, Equetro®
  • Epilepsy - focal seizures, generalized tonic-clonic seizures, mixed seizure types. Does not appear to be effective for absence seizures.
  • Trigeminal neuralgia

Equetro®
  • Bipolar I - acute mania or mixed episodes
  • Dizziness - 44%, P - 12%
  • Somnolence - 32%, P - 13%
  • Nausea - 29%, P - 10%
  • Vomiting - 18%, P - 3%
  • Ataxia (Loss of coordination) - 15%, P - 0%
  • Constipation - 10%, P - 5%
  • Itching - 8%, P - 2%
  • Dry mouth - 8%, P - 3%
  • Weakness - 8%, P - 4%

  • NOTE: Data is from Equetro® PI
  • Delavirdine (Rescriptor®) - DO NOT COMBINE
  • HIV non-nucleoside reverse transcriptase inhibitors - DO NOT COMBINE
  • MAO inhibitors - DO NOT COMBINE
  • Nefazodone - DO NOT COMBINE
  • Carbamazepine is a CYP1A2 inducer, a CYP3A4 strong inducer and substrate, and a P-glycoprotein inducer and substrate.
  • CYP3A4 inhibitors and inducers - may affect carbamazepine levels
  • CYP3A4 substrates - carbamazepine may decrease levels of CYP3A4 substrates
  • CYP1A2 substrates - carbamazepine may decrease levels of CYP1A2 substrates
  • P-glycoprotein inducers/inhibitors/substrates - carbamazepine is a P-gp inducer and substrate. P-gp drugs may affect carbamazepine levels.
  • Oral contraceptives - carbamazepine may decrease the effectiveness of oral contraceptives. Consider alternative birth control.
  • Warfarin - carbamazepine may decrease the effectiveness of warfarin
  • Clomipramine - carbamazepine may increase blood levels of clomipramine
  • Lamotrigine - carbamazepine may decrease lamotrigine levels by 40%. Lamotrigine may increase carbamazepine levels. See lamotrigine for details on dosing.
  • Phenytoin - carbamazepine may increase or decrease phenytoin levels
  • Valproic acid - carbamazepine may decrease levels of valproic acid by 50%. Valproic acid may affect carbamazepine levels.
  • Topiramate - carbamazepine may decrease topiramate levels by 40%
  • Oxcarbazepine - carbamazepine may decrease oxcarbazepine levels by 40%
  • Primidone - carbamazepine may decrease primidone levels
  • Lithium - combination may increase neurotoxic effects. Consider lower doses of each drug.
  • Chloroquine - may antagonize the activity of carbamazepine
  • Mefloquine - may antagonize the activity of carbamazepine
  • Isoniazid (INH) - may increase risk of hepatotoxicity
  • Neuromuscular blocking agents (vecuronium, etc.) - patients on carbamazepine may be more resistant to effects
  • Known allergy to Tricyclic antidepressants - DO NOT USE. Carbamazepine is a tricyclic compound.
  • Pregnancy - DO NOT USE
  • Hepatic porphyria - DO NOT USE
  • Osteoporosis - carbamazepine may affect vitamin D metabolism which can lead to osteoporosis
  • Serious skin reactions - including SJS, DRESS, and TEN
  • HLA-B*1502 allele - carriers of HLA-B*1502 allele have a higher risk of serious skin reactions. See HLA-B*1502 allele prevalence for more.
  • HLA-A*3101 allele - carriers of HLA-A*3101 allele have a higher risk of serious skin reactions. It is more common in Asian, Japanese, Europeans, and others.
  • Decreased blood cells - carbamazepine has been associated with aplastic anemia and agranulocytosis. These reactions are rare.
  • Thyroid tests - carbamazepine may affect thyroid function tests. Incidence is not well-defined.
  • Suicide - seizure medications have been associated with an increased risk of suicide
  • Low sodium (hyponatremia) - carbamazepine may cause SIADH
  • Glaucoma - carbamazepine may cause pupil dilation
  • Abrupt discontinuation - may increase risk of seizure frequency
  • Liver disease - consider reducing dose; no specific recommendation given
  • Kidney disease - effect unknown; no recommendation given

Drug Dosage form Dosage Generic/Price Lab monitoring
NOTE: Reference ranges may vary by lab
Other Mechanism of Action/
FDA-approved indication
Side Effects
P = % of patients on placebo who experienced side effect
Drug Interactions Precautions/
Contraindications
Gabapentin

(Neurontin®)
(Horizant®)
Neurontin® tablet
  • 100 mg
  • 300 mg
  • 400 mg
  • 600 mg
  • 800 mg

Neurontin® capsule
  • 100 mg
  • 300 mg
  • 400 mg

Horizant® tablet
  • 300 mg
  • 600 mg

Gralise® tablet
  • 300 mg
  • 600 mg
Neurontin®
    Epilepsy (adjunctive therapy for focal seizures)
    • Starting: 300 mg three times a day
    • Maintenance: 900 - 1800 mg a day
    • Max: 3600 mg a day
    Postherpetic neuralgia
    • Starting: 300 mg on day 1, then 300 mg twice a day on day 2, then 300 mg three times a day on day 3
    • Maintenance: 900 - 1800 mg a day
    • Max: 1800 mg a day
    Diabetic neuropathy (off-label)
    • Starting: 100 - 300 mg one to three times a day
    • Target: 900 - 3600 mg/day
    • See diabetic neuropathy for more

Horizant®
    Restless leg syndrome
    • 600 mg once daily at 5PM
    Postherpetic neuralgia
    • Initial: 600 mg a day for 3 days, then 600 mg twice a day
    • Maintenance: 600 mg twice a day
    • Kidney disease - see Horizant® PI for specific recommendations

Gralise®
    Postherpetic neuralgia
    • Initial: Starter pack (titrates to 1800 mg/day)
    • Maintenance: 1800 mg once daily with evening meal
    • Kidney disease - see Gralise® PI for specific recommendations

Neurontin® dosing in kidney disease
    See Neurontin® PI for specific recommendations
    • CrCl 30 - 59 ml/min: 400 - 1400 mg/day
    • CrCl 15 - 29 ml/min: 200 - 700 mg/day
    • CrCl < 15 ml/min: 100 - 300 mg/day
Neurontin®
YES/$

Horizant®
NO/$$$$
Gralise®
NO/$$$$
Levels
  • The value of routine monitoring has not been established
  • Levels may be useful to measure compliance and check for toxicity
  • Ideally, levels should be drawn before the morning dose [4]
  • Therapeutic level (not well-defined): 4 - 16 mcg/ml [3]

Pharmacokinetics
  • Half-life: 5 - 7 hours
  • Time to steady state: 1 - 2 days [2]
Neurontin®
  • May take without regard to food
  • May cut or break tablet. Unused half-tablet should be taken at next dose. Half-tablets not used within several days should be discarded.
  • May cause false-positive urine protein test

Horizant®
  • Take with food
  • Do not crush, cut, or chew tablet
  • Not interchangeable with Neurontin®

Gralise®
  • Take with evening meal
  • Do not crush, cut, or chew tablet
  • Not interchangeable with Neurontin®

Recent studies
Mechanism of action
  • Mechanism not entirely understood
  • Binds to voltage-activated calcium channels
  • Inhibits action potentials (nerve-firing)

FDA-approved indication(s)

Neurontin®
  • Epilepsy - adjunctive therapy in focal seizures with and without secondary generalization
  • Postherpetic neuralgia

Horizant®
  • Restless leg syndrome
  • Postherpetic neuralgia

Gralise®
  • Postherpetic neuralgia
  • Dizziness - 28%, P - 8%
  • Somnolence - 21%, P - 5%
  • Peripheral edema - 8%, P - 2%
  • Diarrhea - 6%, P - 3%
  • Dry mouth - 5%, P - 1%
  • Antacids - may decrease gabapentin absorption. Take gabapentin at least 2 hours after antacids.
  • Naproxen - may increase gabapentin levels
  • Hydrocodone - gabapentin may decrease hydrocodone levels, and hydrocodone may increase gabapentin levels
  • Morphine - morphine may increase gabapentin levels
  • Cimetidine - may increase gabapentin levels
  • Anaphylaxis and angioedema - have occurred in patients taking gabapentin. May occur at any time during therapy.
  • Suicide - seizure medications have been associated with an increased risk of suicide
  • Abrupt discontinuation - may increase risk of seizure frequency
  • Liver disease - gabapentin does not undergo liver metabolism; no dose adjustment necessary
  • Kidney disease - see Dosage

Drug Dosage form Dosage Generic/Price Lab monitoring
NOTE: Reference ranges may vary by lab
Other Mechanism of Action/
FDA-approved indication
Side Effects
P = % of patients on placebo who experienced side effect
Drug Interactions Precautions/
Contraindications
Lamotrigine

(Lamictal®)
(Lamictal XR®)
(Lamictal CD®)
(Lamictal ODT®)
Lamictal® tablet
  • 25 mg
  • 100 mg
  • 150 mg
  • 200 mg

Lamictal XR®
extended-release tablet

  • 25 mg
  • 50 mg
  • 100 mg
  • 200 mg
  • 250 mg
  • 300 mg

Lamictal CD®
chewable tablet

  • 2 mg
  • 5 mg
  • 25 mg

Lamictal ODT®
orally disintegrating tablet

  • 25 mg
  • 50 mg
  • 100 mg
  • 200 mg
Lamictal®     

Epilepsy
  • Typical range: 100 - 500 mg/day given in 2 divided doses
  • The Lamictal® PI gives specific recommendations for titration and dosing with other anticonvulsants

Bipolar
  • Target dose: 200 mg/day
  • The Lamictal® PI gives specific recommendations for titration and dosing with other anticonvulsants

Lamotrigine should be titrated slowly to decrease the risk for serious skin reactions
Lamictal XR®     

Epilepsy
  • Typical range: 200 - 600 mg once daily
  • The Lamictal XR® PI gives specific recommendations for titration and dosing with other anticonvulsants

Lamotrigine should be titrated slowly to decrease the risk for serious skin reactions
Lamictal®
YES/$

Lamictal CD®
YES/$$

Lamictal XR®
YES/$$$$

Lamictal ODT®
YES/$$-$$$
Levels
  • The value of routine monitoring has not been established
  • Monitoring levels may be useful in pregnancy (clearance increased by 65%), with concomitant oral contraceptives, and to assess compliance or toxicity
  • Level should be drawn right before next dose (trough) [5]
  • Therapeutic trough level: 2 - 20 mcg/ml [3]

Pharmacokinetics
  • Half-life: 25 - 33 hours [5]
  • Time to steady state: 2 - 7 days [5]
Lamictal®
  • May take without regard to food
  • Orally disintegrating tablet should be placed on the tongue. May swallow with or without water after dissolves.
  • Chewable tablets may be swallowed whole, chewed, or mixed with water or diluted fruit juice.

Lamictal XR®
  • May take without regard to food
  • Do not crush, cut, or chew tablet
Mechanism of action
  • Mechanism not entirely understood
  • May inhibit voltage-dependent sodium channels
  • Inhibits action potentials (nerve-firing)

FDA-approved indication

  • Epilepsy (adjunctive therapy) - in focal seizures, generalized tonic-clonic seizures, and generalized seizures of Lennox-Gastaut syndrome
  • Epilepsy (monotherapy) - in patients with focal seizures who are converting to lamotrigine from other seizure therapies
  • Bipolar I - as maintenance therapy
Data from bipolar trials
  • Nausea - 14%, P - 11%
  • Insomnia - 10%, P - 6%
  • Somnolence - 9%, P - 7%
  • Fatigue - 8%, P - 5%
  • Back pain - 8%, P - 6%

Data from adjunctive trials (added to other seizure meds)
  • Dizziness - 38%, P - 13%
  • Headache - 29%, P - 19%
  • Double vision - 28%, P - 7%
  • Loss of coordination - 22%, P - 6%
  • Nausea - 19%, P - 10%
  • Blurred vision - 16%, P - 5%
  • Somnolence - 14%, P - 7%
  • Rash - 10%, P - 5%
Oral contraceptives
See Lamictal® PI for specific dosing recommendations
  • Estrogen-containing oral contraceptives - estrogen-containing oral contraceptives may decrease lamotrigine levels by 50%
  • Levonorgestrel - lamotrigine may decrease levonorgestrel levels

Other seizure medications
See Lamictal® PI for specific dosing recommendations
  • Carbamazepine - carbamazepine may decrease lamotrigine levels by 40%. Lamotrigine may increase carbamazepine levels.
  • Phenobarbital - phenobarbital may decrease lamotrigine levels by 40%
  • Primidone - primidone may decrease lamotrigine levels by 40%
  • Phenytoin - phenytoin may decrease lamotrigine levels by 40%
  • Topiramate - lamotrigine may increase topiramate levels
  • Valproate - valproate may more than double lamotrigine levels

Other meds
  • Rifampin - rifampin may decrease lamotrigine levels by 40%
  • Olanzapine - olanzapine may reduce lamotrigine levels
  • Lopinavir/ritonavir - may decrease lamotrigine levels by 50%
  • Atazanavir/lopinavir - may decrease lamotrigine levels by 32%
  • Serious skin reactions - including SJS, DRESS, and TEN. Seen in 0.3% of patients. Concomitant valproate may increase risk.
  • Suicide - seizure medications have been associated with an increased risk of suicide
  • Abrupt discontinuation - may increase risk of seizure frequency
  • Aseptic meningitis - lamotrigine may increase the risk of aseptic meningitis
  • Liver disease
    • Mild (Child-Pugh A) - no dose adjustment necessary
    • Moderate-to-severe (without ascites) - reduce dose by 25%
    • Severe (with ascites) - reduce dose by 50%
  • Kidney disease - use with caution, no specific recommendations given

Drug Dosage form Dosage Generic/Price Lab monitoring
NOTE: Reference ranges may vary by lab
Other Mechanism of Action/
FDA-approved indications
Side Effects
P = % of patients on placebo who experienced side effect
Drug Interactions Precautions/
Contraindications
Levetiracetam

(Keppra®)
(Keppra XR™)
(Spritam®)
Keppra® tablet
  • 250 mg
  • 500 mg
  • 750 mg
  • 1000 mg

Keppra XR®
extended-release tablet

  • 500 mg
  • 750 mg

Spritam®
tablet for oral suspension

  • 250 mg
  • 500 mg
  • 750 mg
  • 1000 mg
Epilepsy     

Keppra®, Spritam® (Adults and children weighing > 40 kg)
  • Initial - 500 mg twice a day
  • Max - 1500 mg twice a day
  • Increase dose by 1000 mg a day at 2 week intervals to the recommended daily dose of 3000 mg

Keppra XR™ (Adults and children ≥ 12 years old)
  • Initial - 1000 mg once daily
  • Max - 3000 mg once daily
  • Increase dose by 1000 mg a day at 2 week intervals to the recommended daily dose of 3000 mg

Dosing in kidney disease     
  • CrCl 50 - 80 ml/min: 1000 - 2000 mg a day
  • CrCl 30 - 49 ml/min: 500 - 1500 mg a day
  • CrCl < 30 ml/min: 500 - 1000 mg a day

Keppra®
Yes/$$

Keppra XR™
Yes/$$-$$$

Spritam®
NO/$$$$
Levels
  • The value of routine monitoring has not been established
  • Monitoring levels may be useful in kidney disease, pregnancy (increased clearance), and to assess compliance or toxicity
  • Levels should be drawn immediately before the next dose (trough) [4]
  • Reference interval: 10 - 40 mcg/ml [3]

Pharmacokinetics
  • Half-life: 6 - 8 hours [1]
  • Time to steady state: 2 days [1]
Keppra®
  • May take without regard to food
  • Do not crush, cut, or chew tablet
  • The effectiveness of doses lower than 3000 mg/day has not been studied

Keppra XR®
  • May take without regard to food
  • Do not crush, cut, or chew tablet

Spritam®
  • May take with or without food
  • Spritam disintegrates in the mouth when taken with a sip of water
  • May also be dissolved with a small amount of water in a cup and swallowed
Mechanism of action
  • Mechanism not entirely understood
  • May work by binding synaptic vesicle protein SV2A, inhibiting exocytosis
  • Inhibits action potentials (nerve-firing)

FDA-approved indications
Keppra®
  • Adjunctive therapy for partial onset seizures - adults and children ≥ 4 years
  • Adjunctive therapy for myoclonic seizures - adults and children ≥ 12 years with juvenile myoclonic epilepsy
  • Adjunctive therapy for generalized tonic-clonic seizures - adults and children ≥ 6 years

Spritam®
  • Adjunctive therapy for partial onset seizures - adults and children ≥ 4 years weighing more than 20 kg
  • Adjunctive therapy for myoclonic seizures - adults and children ≥ 12 years with juvenile myoclonic epilepsy
  • Adjunctive therapy for generalized tonic-clonic seizures - adults and children ≥ 6 years

Keppra XR®
  • Adjunctive therapy for partial onset seizures - adults and children ≥ 12 years
Data from adjunctive trials (added to other seizure meds)

  • Weakness - 15%, P - 9%
  • Somnolence - 15%, P - 8%
  • Headache - 14%, P - 13%
  • Infection - 13%, P - 8%
  • Dizziness - 9%, P - 4%
  • Levetiracetam is not extensively metabolized
  • There are no known significant drug interactions
  • Hypersensitivity reactions - levetiracetam may cause hypersensitivity reactions including angioedema and anaphylaxis. Reactions may occur with the first dose or at any time during treatment.
  • Suicide - seizure medications have been associated with an increased risk of suicide
  • Abrupt discontinuation - may increase risk of seizure frequency
  • Decrease in blood cells - decreases in blood cells including agranulocytosis have been reported
  • Serious skin reactions - serious skin reactions including DRESS syndrome have been reported
  • Liver disease - no dose adjustment necessary
  • Kidney disease - see dosage

Drug Dosage form Dosage Generic/Price Lab monitoring
NOTE: Reference ranges may vary by lab
Other Mechanism of Action/
FDA-approved indications
Side Effects
P = % of patients on placebo who experienced side effect
Drug Interactions Precautions/
Contraindications
Oxcarbazepine

(Trileptal®)
(Oxtellar XR®)
Trileptal® tablet
  • 150 mg
  • 300 mg
  • 600 mg

Oxtellar XR®
extended-release tablet

  • 150 mg
  • 300 mg
  • 600 mg
Epilepsy     

Trileptal®
  • Initial - 300 mg twice a day
  • Maintenance - 600 mg twice a day
  • Max - 2400 mg a day
  • Increase by 300 mg/day every third day
  • Dosed twice a day

Oxtellar XR®
  • Initial - 600 mg once daily
  • Maintenance - 1200 - 2400 mg a day
  • Max - 2400 mg a day
  • Increase by 600 mg/day at weekly intervals
  • Dosed once daily
Trileptal®
YES/$$

Oxtellar XR®
NO/$$$$
Levels
  • The value of routine monitoring has not been established
  • Monitoring may be useful in liver disease and to assess compliance or toxicity
  • Oxcarbazepine is rapidly metabolized to its active metabolite, 10-hydroxy-carbamazepine (MHD). Blood assays measure MHD.
  • Levels should be drawn immediately before next dose (trough) [5]
  • Reference interval (MHD): 3 - 35 mcg/ml [4]

Pharmacokinetics
  • Half-life (MHD): 9 hours [1]
  • Time to steady state (MHD): 2 - 3 days [1]

Other
  • Monitoring sodium levels may be appropriate in patients at increased risk of hyponatremia
Trileptal®
  • May take without regard to food

Oxtellar XR®
  • Take on empty stomach, 1 hour before or 2 hours after a meal. Food increases absorption and risk of side effects.
  • When converting from Trileptal® to Oxtellar XR®, higher doses of Oxtellar XR® may be necessary
  • Do not crush, cut, or chew tablet
Mechanism of action
  • Mechanism not entirely understood
  • Inhibits voltage-sensitive sodium channels
  • Inhibits action potentials (nerve-firing)

FDA-approved indication(s)

Trileptal®
  • Epilepsy - monotherapy or adjunctive therapy for partial seizures in adults

Oxtellar XR®
  • Epilepsy - adjunctive therapy for partial seizures
  • Dizziness - 22%, P - 6%
  • Nausea - 16%, P - 12%
  • Headache - 13%, P - 10%
  • Diarrhea - 7%, P - 2%
  • Upper respiratory infection - 7%, P - 0%
  • Fatigue and somnolence were also common at higher doses (20% of patients)
  • Side effects increase with higher doses
  • Oxcarbazepine is a CYP2C19 inhibitor and CYP3A inducer
  • CYP2C19 substrates - oxcarbazepine may increase levels of CYP2C19 substrates
  • CYP3A4 substrates - oxcarbazepine may decrease levels of CYP3A4 substrates
  • Oral contraceptives - oxcarbazepine may decrease ethinyl estradiol and levonorgestrel levels by up to 50%. Use alternative birth control
  • Carbamazepine - may decrease oxcarbazepine levels by 40%
  • Phenobarbital - may increase phenobarbital levels by 14%. Oxcarbazepine levels may decrease by 25%
  • Phenytoin - may increase phenytoin levels by 40%. Oxcarbazepine levels may decrease by 30%
  • Valproic acid - oxcarbazepine levels may decrease by 18%
  • Felodipine - oxcarbazepine may decrease felodipine levels by 28%
  • Verapamil - verapamil may decrease oxcarbazepine levels by 20%
  • Cyclosporine - oxcarbazepine may decrease cyclosporine levels
  • Known hypersensitivity to oxcarbazepine or eslicarbazepine (Aptiom) - DO NOT USE
  • Carbamazepine sensitivity - oxcarbazepine is structurally related to carbamazepine. 25 - 30% of patients with a history of reaction to carbamazepine will have a reaction to oxcarbazepine.
  • Low sodium (hyponatremia) - oxcarbazepine may cause hyponatremia in up to 2.5% of patients. More common during first 3 months of treatment.
  • Serious skin reactions - including SJS, DRESS, and TEN have been reported. Patients carrying the HLA-B*1502 allele may be at increased risk. See HLA-B*1502 allele prevalence for more.
  • Suicide - seizure medications have been associated with an increased risk of suicide
  • Abrupt discontinuation - may increase risk of seizure frequency
  • Pregnancy - oxcarbazepine levels may decrease during pregnancy
  • Angioedema and anaphylaxis - rare
  • Thyroid hormone - may affect thyroid hormone levels
  • Seizure exacerbation - oxcarbazepine may exacerbate seizures in some patients, particularly children
  • Liver disease
    • Mild to moderate (Child-Pugh A/B) - no dose adjustment necessary
    • Severe (Child-Pugh C) - has not been studied, use caution
  • Kidney disease
    • CrCl < 30 ml/min - initiate at one-half the usual dose (300 mg/day); increase slowly

Drug Dosage form Dosage Generic/Price Lab monitoring
NOTE: Reference ranges may vary by lab
Other Mechanism of Action/
FDA-approved indications
Side Effects Drug Interactions Precautions/
Contraindications
Phenobarbital Phenobarbital tablet
  • 15 mg
  • 16.2 mg
  • 30 mg
  • 32.4 mg
  • 60 mg
  • 64.8 mg
  • 97.2 mg
  • 100 mg
Epilepsy
  • 50 - 100 mg two to three times a day

Sedative
  • 30 - 120 mg a day given in 2 or 3 divided doses
Phenobarbital
Yes/$-$$
Levels
  • Routine monitoring is recommended to maintain a therapeutic level and prevent toxicity
  • Levels may be drawn at any time (random) [4]
  • Therapeutic levels: 15 - 40 mcg/ml [3]
  • Potentially Toxic: > 40 mcg/ml [3]

Pharmacokinetics
  • Half-life: 84 - 108 hours [3]
  • Time to steady state: 11 - 29 days [5]

Other
  • It may be beneficial to monitor liver function tests periodically
  • Phenobarbital is a C-IV controlled substance
Mechanism of action
  • Binds to GABA receptors
  • Causes membrane hyperpolarization
  • Inhibits action potentials (nerve-firing)

FDA-approved indication(s)

  • Treatment of seizures

  • Sedative
  • NOTE: The incidence of phenobarbital side effects is not well-defined

  • Drowsiness
  • Sedation
  • Nausea
  • Paradoxical excitement
  • Phenobarbital is an enzyme inducer and therefore has many potential drug interactions
  • CYP3A4 substrates - phenobarbital is a CYP3A4 strong inducer. Phenobarbital may lower blood levels of CYP3A4 substrates.
  • CYP1A2 substrates - phenobarbital is a CYP1A2 weak inducer. Phenobarbital may lower blood levels of CYP1A2 substrates.
  • CYP2B6 substrates - phenobarbital is a CYP2B6 inducer (class uncertain). Phenobarbital may lower blood levels of CYP2B6 substrates.
  • CYP2C9 substrates - phenobarbital is a CYP2C9 weak inducer. Phenobarbital may lower blood levels of CYP2C9 substrates.
  • P-glycoprotein substrates - phenobarbital is a P-glycoprotein inducer. Phenobarbital may lower blood levels of P-glycoprotein substrates.
  • Valproic acid - phenobarbital may decrease levels of valproic acid by 50%. Valproic acid may increase phenobarbital levels.
  • Lamotrigine -phenobarbital may decrease lamotrigine levels by 40%. See lamotrigine for details on dosing.
  • Oxcarbazepine - may increase phenobarbital levels by 14%. Oxcarbazepine levels may decrease by 25%
  • Canagliflozin - phenobarbital may decrease canagliflozin levels
  • Porphyria - DO NOT USE
  • Respiratory distress - DO NOT USE
  • Osteoporosis - phenobarbital may affect vitamin D metabolism which can lead to osteoporosis
  • Serious skin reactions - including SJS, DRESS, and TEN have been reported
  • Abuse and addiction - phenobarbital has abuse and addiction potential
  • Suicide - seizure medications have been associated with an increased risk of suicide
  • Abrupt discontinuation - may increase risk of seizure frequency
  • Liver disease
    • Mild-to-moderate disease (Child-Pugh A/B): use caution, no specific dosage recommendations given
    • Severe (Child-Pugh C): - DO NOT USE
  • Kidney disease - use caution; no specific recommendations given

Drug Dosage form Dosage Generic/Price Lab monitoring
NOTE: Reference ranges may vary by lab
Other Mechanism of Action/
FDA-approved indications
Side Effects Drug Interactions Precautions/
Contraindications
Phenytoin

(Dilantin®)
(Phenytek®)
Phenytoin capsule
  • 30 mg
  • 100 mg
  • 200 mg
  • 300 mg

Phenytoin
chewable tablet
  • 50 mg

Dilantin® capsule
  • 30 mg
  • 100 mg

Phenytek® capsule
  • 200 mg
  • 300 mg
Epilepsy     

Standard dosing
  • Initial - 100 mg three times a day
  • Maintenance - 100 mg three to four times a day
  • Lab monitoring should be used to guide dosing

Once-a-day dosing
  • Patients stable on phenytoin may wish to change to once-a-day dosing with entire daily dose taken at bedtime
  • Once-a-day dosing is only recommended with Dilantin® brand-name capsules

Loading dose
  • Three doses (400 mg - 300 mg - 300 mg) administered at 2 hour intervals
  • Maintenance dosing starts 24 hours after last loading dose
Phenytoin
Generic - $

Dilantin®
Brand - $$

Phenytek®
Brand - $$

Levels
  • Routine monitoring is recommended to maintain a therapeutic level and prevent toxicity
  • Phenytoin metabolism is nonlinear. The enzyme responsible for its metabolism can become saturated and blood levels may increase exponentially. After saturation, small increases in dosage can lead to large increases in blood levels.
  • For most patients, the relation of the blood draw to the last dose will not matter [4]
  • Frequency of lab monitoring will depend on the patient and their concomitant medical conditions/meds

Phenytoin, Total
  • Therapeutic level: 10 - 20 mcg/ml [5]

Phenytoin, Free
  • Therapeutic level: 1 - 2 mcg/ml [5]

Total vs Free Phenytoin
  • Phenytoin is 90% bound to plasma protein
  • Only free phenytoin is biologically active
  • Typically, total phenytoin levels are measured
  • In conditions where binding kinetics may be altered (ex. kidney disease, concurrent protein-bound medications, liver disease, pregnancy, postpartum), free phenytoin levels may be helpful

Pharmacokinetics
  • Average half-life at steady state: 22 hours (range 7 - 42 hours) [1]
  • Time to steady state: 7 - 10 days [1]
Hypoalbuminemia
  • Because phenytoin is 90% bound to plasma protein, phenytoin levels should be corrected in patients with low albumin levels
  • Corrected Phenytoin = Total phenytoin (mcg/ml) / (0.2 x Albumin[g/dl] + 0.1)
Phenytoin
  • Take at the same time each day
  • Food may alter absorption. Best to take on an empty stomach.

Signs of toxicity
  • Nystagmus
  • Loss of coordination
  • Mental status changes
Mechanism of action
  • Inhibits voltage-dependent sodium channels
  • Inhibits action potentials (nerve-firing)

FDA-approved indication(s)

  • Epilepsy - generalized tonic-clonic and psychomotor (temporal lobe) seizures

  • Prevention of seizures with neurosurgery
NOTE: The incidence of phenytoin side effects is not well-defined

  • Somnolence
  • Drowsiness
  • Dizziness
  • Nystagmus
  • Nausea
  • Coarsening of facial features
  • Gingival hyperplasia - overgrowth of gum tissue
  • Increased hair growth
  • Delavirdine (Rescriptor®) - DO NOT COMBINE
  • Phenytoin is a CYP2C19 and CYP2C9 sensitive substrate. It is a CYP3A4 strong inducer and a CYP1A2 moderate inducer. It has the potential for a large number of drug interactions. See phenytoin PI for complete list.
  • CYP3A4 substrates - phenytoin may decrease levels of CYP3A4 substrates
  • CYP1A2 substrates - phenytoin may decrease levels of CYP1A2 substrates
  • CYP2C19 inhibitors and inducers - CYP2C19 inhibitors and inducers may affect phenytoin levels
  • CYP2C9 inhibitors and inducers - CYP2C9 inhibitors and inducers may affect phenytoin levels
  • Highly protein-bound drugs - phenytoin is highly protein-bound. Other highly protein-bound drugs (ex. valproic acid, acetazolamide, aspirin, salicylic acid, phenylbutazone, ceftriaxone, nafcillin, sulfamethoxazole) may displace phenytoin and increase its activity.
  • P-glycoprotein substrates/inducers/inhibitors - phenytoin is a p-glycoprotein inducer and substrate. Phenytoin may affect other p-glycoprotein drugs, and p-glycoprotein inducers and inhibitors may affect phenytoin
  • Valproic acid - phenytoin may decrease levels of valproic acid by 50%. Valproic acid may affect free phenytoin levels.
  • Lamotrigine - phenytoin may decrease lamotrigine levels by 40%. See lamotrigine for details on dosing.
  • Carbamazepine - carbamazepine may increase or decrease phenytoin levels
  • Topiramate - phenytoin may decrease topiramate levels by 48%. Topiramate may increase phenytoin levels.
  • Oxcarbazepine - may increase phenytoin levels by 40%. Oxcarbazepine levels may decrease by 30%
  • Digoxin - phenytoin may decrease digoxin levels
  • Furosemide - phenytoin may decrease the effect of furosemide
  • Canagliflozin - phenytoin may decrease canagliflozin levels
  • Antacids and acid-suppressing drugs (famotidine, PPIs, etc.) - Drugs that suppress stomach acid may affect phenytoin levels. In most cases, phenytoin levels will decrease.
  • Pregnancy - DO NOT USE
  • Porphyria - DO NOT USE
  • Lymphadenopathy (enlarged lymph nodes) - phenytoin has been associated with cases of benign lymphadenopathy
  • Osteoporosis - phenytoin may affect vitamin D metabolism which can lead to osteoporosis
  • Carbamazepine sensitivity - phenytoin is structurally related to carbamazepine. Patients sensitive to carbamazepine may cross-react with phenytoin.
  • Barbiturate sensitivity - phenytoin is structurally related to barbiturates. Patients with barbiturate sensitivity may cross-react with phenytoin.
  • Serious skin reactions - including SJS, DRESS, and TEN have been reported
  • CYP2C9 alleles - carriers of CYP2C9 alleles (specifically the CYP2C9*3 allele) have a higher risk of serious skin reactions (PMID 25096692).
  • HLA-B*1502 allele - carriers of HLA-B*1502 allele have a higher risk of serious skin reactions. See HLA-B*1502 allele prevalence for more.
  • Decreased blood cells - phenytoin has been associated with decreased blood cells. These reactions are rare.
  • Suicide - seizure medications have been associated with an increased risk of suicide
  • Abrupt discontinuation - may increase risk of seizure frequency
  • Liver disease - because liver disease can affect plasma protein levels, free phenytoin levels should be monitored closely
  • Kidney disease - because kidney disease can affect protein-binding kinetics, free phenytoin levels should be monitored closely

Drug Dosage form Dosage Generic/Price Lab monitoring
NOTE: Reference ranges may vary by lab
Other Mechanism of Action/
FDA-approved indications
Side Effects
P = % of patients on placebo who experienced side effect
Drug Interactions Precautions/
Contraindications
Pregabalin

(Lyrica®)
Pregabalin capsule
  • 25 mg
  • 50 mg
  • 75 mg
  • 100 mg
  • 150 mg
  • 200 mg
  • 225 mg
  • 300 mg
Neuropathic pain/Postherpetic neuralgia
  • Starting - 150 mg a day given in two or three divided doses
  • Maintenance - 150 - 300 mg a day
  • Max - 300 mg a day

Fibromyalgia
  • Starting - 75 mg twice a day
  • Maintenance- 300 - 450 mg a day
  • Max- 450 mg a day

Epilepsy
  • Starting- 150 mg a day given in two or three divided doses
  • Maintenance- 150 - 600 mg a day
  • Max- 600 mg a day

Kidney disease
See Lyrica® PI for specific recommendations in kidney disease
Lyrica®
NO/$$$$
Levels
  • The value of routine monitoring has not been established
  • Monitoring may be useful to assess compliance or toxicity
  • A normal reference range for pregabalin has not been established [5]

Pharmacokinetics
  • Half-life: 6 hours
  • Time to steady state: 1 - 2 days [2]
  • May take without regard to food
  • Pregabalin is a Schedule-V controlled substance
Mechanism of action
  • Mechanism not completely understood
  • Binds to alpha2-delta site on voltage-gated calcium channels
  • Inhibits action potentials (nerve-firing)

FDA-approved indication(s)

  • Epilepsy- as adjunctive therapy in partial seizures
  • Postherpetic neuralgia
  • Diabetic peripheral neuropathy
  • Fibromyalgia
  • Neuropathic pain associated with spinal cord injury
  • Dizziness- 30%, P - 8%
  • Somnolence- 23%, P - 8%
  • Weight gain - 9%, P - 2%
  • Blurred vision - 7%, P - 2%
  • Peripheral edema - 6%, P - 2%
  • Dry mouth - 5%, P - 1%
  • Weakness- 5%, P - 2%
  • Pregabalin does not undergo significant liver metabolism
  • Glitazones (Actos® and Avandia®) - Pregabalin may potentiate the fluid retention that is seen with glitazones
  • Angioedema (swelling of the mouth, face, and tongue) - pregabalin has associated with rare cases of angioedema
  • Heart failure - pregabalin may worsen fluid retention in some patients
  • Creatine Kinase elevation - pregabalin may cause an increase in CK values in some patients. Significant increases are rare.
  • Decreased platelet count - pregabalin may cause a decrease in the platelet count. Significant decreases are rare.
  • PR interval prolongation - pregabalin may prolong the PR interval. An increase in heart block has not been demonstrated.
  • Abuse potential - pregabalin may have abuse potential
  • Suicide - seizure medications have been associated with an increased risk of suicide
  • Abrupt discontinuation - may increase risk of seizure frequency
  • Liver disease - pregabalin does not undergo significant liver metabolism; no dose adjustment necessary
  • Kidney disease - see Lyrica® PI

Drug Dosage form Dosage Generic/Price Lab monitoring
NOTE: Reference ranges may vary by lab
Other Mechanism of Action/
FDA-approved indications
Side Effects
P = % of patients on placebo who experienced side effect
Drug Interactions Precautions/
Contraindications
Topiramate

(Topamax®)
(Trokendi XR®)
(Qudexy® XR)
Topiramate with phentermine

(Qsymia®)
Topamax® capsule
  • 15 mg
  • 25 mg

Topamax® tablet
  • 25 mg
  • 50 mg
  • 100 mg
  • 200 mg

Trokendi XR®
extended-release capsule

  • 25 mg
  • 50 mg
  • 100 mg
  • 200 mg

Qudexy® XR
extended-release capsule

  • 25 mg
  • 50 mg
  • 100 mg
  • 150 mg
  • 200 mg

Qsymia®
phentermine(mg):topiramate(mg) capsule

  • 3.75 : 23
  • 7.5 : 46
  • 11.25 : 69
  • 15 : 92
Epilepsy
    Topamax®
    • Epilepsy titration schedule - Topamax PI
    • In general, adult dosing starts at 25 - 50 mg a day (given in two divided doses) and increases by 50 mg a day at weekly intervals
    • Max dose epilepsy - 400 mg a day
    • Topamax is dosed twice a day
    Trokendi XR®
    • Epilepsy titration schedule - Trokendi PI
    • In general, adult dosing starts at 50 mg once daily and increases by 50 mg a day at weekly intervals
    • Max dose epilepsy - 400 mg a day
    • Trokendi XR is dosed once daily
    Qudexy® XR
    • Epilepsy titration schedule - Qudexy PI
    • In general, adult dosing starts at 50 mg once daily and increases by 50 mg a day at weekly intervals
    • Max dose epilepsy - 400 mg a day
    • Qudexy XR is dosed once daily

Migraine prevention (≥ 12 years old)
    Topamax®
    • Starting: 25 mg in the evening
    • Target: 50 mg twice a day
    • Increase daily dose by 25 mg at weekly intervals
    Qudexy® XR and Trokendi XR®
    • Starting: 25 mg once daily
    • Target: 100 mg once daily
    • Increase daily dose by 25 mg at weekly intervals

Weight loss
    Qsymia®
    • See Qsymia® dosing for complete guidelines
    • Starting - 3.75/23 mg once daily for 14 days
    • Maintenance- 7.5/46 mg once daily
    • Max- 15/92 mg once daily
Topamax®
YES/$

Trokendi XR®
NO/$$$$

Qudexy® XR
NO/$$$$

Qsymia®
NO/$$$$
Levels
  • The value of routine monitoring has not been established
  • Monitoring levels may be useful to assess compliance or toxicity
  • Levels should be drawn immediately before the next dose (trough) [5]
  • Therapeutic range: 5 - 20 mcg/ml [4]

Pharmacokinetics
  • Half-life (Topamax): 21 hours [1]
  • Time to steady state (Topamax): 4 days [1]

  • Half-life (Trokendi XR): 31 hours [1]

  • Half-life (Qudexy XR): 56 hours [1]
  • Time to steady state (Qudexy XR): 5 days [1]

Other
  • Baseline and periodic serum bicarbonate levels are recommended
  • Ammonia levels in patients also taking valproic acid may also be useful
  • Topiramate may cause decreased phosphorus levels (6% of patients)
  • Topiramate may cause increased alkaline phosphatase levels (3% of patients)
Topamax®
  • May take without regard to food
  • Topiramate tablets have a bitter taste. Do not break to avoid taste.
  • Topamax® sprinkle capsule may be opened and sprinkled on food. Do not chew.

Trokendi XR®
  • Do not take Trokendi XR® within 6 hours of alcohol consumption, either before or after. Alcohol affects the release of the drug and may increase blood levels.
  • May take without regard to food
  • Swallow capsule whole. Do not open and sprinkle on food.

Qudexy® XR
  • Capsules may be opened and sprinkled on soft food. Swallow whole, do not chew food.
  • May take without regard to food

Qsymia®
  • May take without regard to food
  • Avoid taking in the evening to avoid insomnia
  • When discontinuing 15/92 mg dose, take every other day for 1 week to avoid precipitating seizure
  • Providers and pharmacies must register in the Qsymia REMS program to prescribe
Mechanism of action
  • Mechanism not completely understood
  • Blocks voltage-dependent sodium channels
  • Augments GABA activity
  • Antagonizes glutamate receptors
  • Inhibits carbonic anhydrase enzyme
  • Inhibits action potentials (nerve-firing)

FDA-approved indication(s)

Topamax® and Qudexy® XR
  • Partial onset and generalized tonic-clonic seizures (monotherapy) - in patients ≥ 2 years old
  • Partial onset and generalized tonic-clonic seizures (adjunctive) - in patients ≥ 2 years old
  • Lennox-Gastaut syndrome (adjunctive) - in patients ≥ 2 years old
  • Migraine headache prevention (12 years of age and older)
Trokendi XR®
  • Partial onset and generalized tonic-clonic seizures (monotherapy) - in patients ≥ 6 years old
  • Partial onset and generalized tonic-clonic seizures (adjunctive) - in patients ≥ 6 years old
  • Lennox-Gastaut syndrome (adjunctive) - in patients ≥ 6 years old
  • Migraine headache prevention (12 years of age and older)
Qsymia® (with phentermine)
  • Chronic weight management in patients with BMI ≥ 30, or ≥ 27 with one weight-related comorbidity
  • Paresthesia (typically tingling of the extremities) - 49%, P - 6%
  • Fatigue- 19%, P - 11%
  • Decreased appetite - 14%, P - 6%
  • Nausea- 14%, P - 8%
  • Change in taste - 12%, P - 1%
  • Dizziness- 12%, P - 10%
  • Diarrhea- 11%, P - 4%
  • Weight loss - 11%, P - 1%
  • Memory problems - 11%, P - 2%
  • Concentration problems - 10%, P - 2%
  • Somnolence - 10%, P - 5%
  • Blurred vision - 4%, P - 2%
  • Topiramate is a CYP2C19 weak inhibitor and CYP3A4 weak inducer
  • Phenytoin - phenytoin may decrease topiramate levels by 48%. Topiramate may increase phenytoin levels.
  • Carbamazepine - carbamazepine may decrease topiramate levels by 40%
  • Valproic acid - combination may lead to hyperammonemia, encephalopathy, and hypothermia (see precautions)
  • Oral contraceptives - topiramate may decrease oral contraceptive levels and their effectiveness
  • Digoxin - topiramate may decrease digoxin levels
  • Hydrochlorothiazide (HCTZ) - HCTZ may increase topiramate levels
  • Metformin - topiramate may cause metabolic acidosis in which case metformin would be contraindicated
  • Pioglitazone (Actos®) - topiramate may decrease pioglitazone levels
  • Glyburide - topiramate may decrease glyburide levels
  • Lithium - topiramate may increase lithium levels
  • Amitriptyline - topiramate may increase amitriptyline levels
  • Diltiazem - topiramate may decrease diltiazem levels, and diltiazem may increase topiramate levels
  • Carbonic anhydrase inhibitors - topiramate may potentiate the effect of zonisamide, acetazolamide, and dichlorphenamide. This may increase the risk of metabolic acidosis and kidney stones.
  • Pregnancy - DO NOT USE. May increase risk of cleft lip and/or cleft palate (oral clefts) and being small for gestational age.
  • Visual changes - topiramate has been associated with a syndrome of acute myopia and angle closure glaucoma. Typically occurs within the first month of therapy.
  • Visual field defects - topiramate has been associated with visual field defects. The defects typically resolve when therapy is discontinued.
  • Non-anion gap metabolic acidosis - may occur because of renal bicarbonate loss secondary to carbonic anhydrase inhibition
  • Hyperammonemia and encephalopathy - may raise ammonia levels and cause encephalopathy. Risk is higher when taken with valproic acid.
  • Kidney stones - may increase risk of kidney stones because of decreased urinary citrate excretion
  • Hypothermia - may occur when taken with valproic acid
  • Decreased sweating - may cause decreased sweating that leads to body temperature elevation
  • Bleeding - in placebo-controlled trials, topiramate was associated with an increased risk for bleeding (4.5% vs 3% for placebo)
  • Suicide - seizure medications have been associated with an increased risk of suicide
  • Abrupt discontinuation - may increase risk of seizure frequency
  • Liver disease - topiramate levels may be increased. Use caution.
  • Kidney disease
    • CrCl < 70 ml/min: use one-half the usual adult dose

Drug Dosage form Dosage Generic/Price Lab monitoring
NOTE: Reference ranges may vary by lab
Other Mechanism of Action/
FDA-approved indications
Side Effects
P = % of patients on placebo who experienced side effect
Drug Interactions Precautions/
Contraindications
Valproic acid

(Depakene®)
Divalproex sodium

(Depakote®)
(Depakote ER®)
Valproate sodium

(Depacon®)

Valproic acid is available in the forms above. Each form delivers an equivalent amount of valproate ion, the active ingredient.
Depakene® capsule
  • 250 mg

Depakote® tablet
  • 125 mg
  • 250 mg
  • 500 mg

Depakote®
sprinkle capsule

  • 125 mg

Depakote ER®
extended-release tablet

  • 250 mg
  • 500 mg

Depacon® injection
  • 100 mg/ml
General dosing recommendations
  • Depakote® is dosed twice a day
  • Depakote ER® is dosed once a day
  • Depakene® is dosed 2 to 3 times a day

Epilepsy
  • Initial - 10 - 15 mg/kg/day
  • Maintenance - based on blood levels and response
  • Max - 60 mg/kg/day
  • Increase dose by 5 - 10 mg/kg/week

Migraine
  • Initial - 500 mg a day
  • Max - 1000 mg a day

Mania
  • Initial - 750 mg a day
  • Maintenance - titrate as needed
  • Max - 60 mg/kg/day

Specific dosing recommendations

Converting from Depakote® to Depakote ER®
  • In general, the Depakote ER® dose should be 8 - 20% higher than the total daily dose of Depakote®. See Depakote ER® PI for specific recommendations
Depakote®
YES/$

Depakote ER®
YES/$$$

Depakene®
YES/$
Levels
  • Routine monitoring is recommended to maintain a therapeutic level and prevent toxicity
  • Level should be drawn right before the next dose (trough level)
  • Valproic acid is highly protein bound (> 80%). In conditions where binding kinetics may be altered (ex. kidney disease, concurrent protein-bound medications, liver disease), free valproic acid levels may be helpful [5]

Valproic acid, Total
  • Therapeutic level (epilepsy): 50 - 100 mcg/ml [1]
  • Therapeutic level (mania): 50 - 125 mcg/ml [1]
  • Potential toxicity: > 120 mcg/ml [3]

Valproic acid, Free
  • Therapeutic level: 6 - 22 mcg/ml [3]

Pharmacokinetics
  • Half-life: 9 - 16 hours [1]
  • Time to steady state: 2 - 4 days [2]

Other
  • Liver enzyme tests should be drawn at baseline and periodically thereafter, particularly in the first 6 months
  • Platelet counts and coagulation tests should be measured at baseline and periodically (also before surgery)
  • Valproic acid may cause false-positive urine ketones
  • Valproic acid may alter thyroid function tests
Depakote®
  • May take without regard to food
  • Do not cut, crush, or chew tablets
  • Depakote® sprinkle capsules may be opened and sprinkled on food. Do not chew sprinkles.
  • Medication residue may be seen in the stool. This is not normal. Check level, consider other therapy.

Depakote ER®
  • May take without regard to food
  • Do not cut, crush, or chew tablets
  • Medication residue may be seen in the stool. This is not normal. Check level, consider other therapy.

Depakene®
  • May take without regard to food
  • Swallow capsules whole. Do not open and sprinkle on food.
Mechanism of action
  • Mechanism not entirely understood
  • Increases GABA activity in the brain
  • Inhibits action potentials (nerve-firing)

FDA-approved indication(s)
  • Epilepsy - monotherapy and adjunctive therapy in complex partial seizures, and simple and complex absence seizures
  • Bipolar mania
  • Prevention of migraine headache
  • Nausea - 31%, P - 10%
  • Fatigue/Weak - 20%, P - 9%
  • Somnolence- 17%, P - 5%
  • Upset stomach - 13%, P - 9%
  • Dizziness- 12%, P - 6%
  • Diarrhea- 12%, P - 7%
  • Vomiting- 11%, P - 1%
  • Tremor- 9%, P - 0%
  • Abdominal pain - 9%, P - 4%
  • Weight gain - 8%, P - 2%
  • Hair loss - 7%, P - 1%
  • Lesinurad (Zurampic®) - DO NOT COMBINE. Valproic acid is an epoxide hydrolase inhibitor and it may block the metabolism of lesinurad.
  • Topiramate - combination may lead to hyperammonemia, encephalopathy, and hypothermia (see precautions)
  • Lamotrigine - valproic acid may increase lamotrigine levels. See lamotrigine for details on dosing
  • Carbamazepine - carbamazepine may decrease levels of valproic acid by 50%. Valproic acid may affect carbamazepine levels.
  • Phenytoin - phenytoin may decrease levels of valproic acid by 50%. Valproic acid may affect free phenytoin levels.
  • Phenobarbital - phenobarbital may decrease levels of valproic acid by 50%. Valproic acid may increase phenobarbital levels.
  • Oxcarbazepine - valproic acid may decrease oxcarbazepine levels by 18%
  • Rufinamide - valproic acid may increase levels of rufinamide by up to 70%. When adding valproate to rufinamide, a low starting dose should be used. When adding rufinamide to valproate, a rufinamide dose of < 400 mg/day should be used.
  • Felbamate - felbamate may increase valproic acid levels
  • Estrogen-containing contraceptives - estrogen-containing contraceptives may increase valproic acid clearance and lead to subtherapeutic valproate levels
  • Aspirin - may increase levels of valproic acid (free and total)
  • Highly protein-bound medications - valproic acid may displace highly protein-bound drugs and increase their levels, and vice-versa
  • Rifampin - may decrease valproic acid levels
  • Carbapenem antibiotics (imipenem, etc.) - may decrease valproic acid levels
  • Amitriptyline - valproic acid may increase amitriptyline levels
  • Nortriptyline - valproic acid may increase nortriptyline levels
  • Clomipramine - valproic acid may increase clomipramine levels
  • Primidone - valproic acid may increase primidone levels
  • Propofol - valproic acid may increase propofol levels. Reduce the dose of propofol when combining.
  • Clonazepam - may induce absence seizures when combined
  • Diazepam - valproic acid may increase diazepam levels (free and total)
  • Lorazepam - valproic acid may increase lorazepam levels. Lorazepam dose should be halved when combining.
  • Cholestyramine (Depakene only) - cholestyramine may decrease levels of Depakene. Cholestyramine should be given at least 3 hours after Depakene.
  • Ethosuximide - valproic acid may increase ethosuximide levels
  • Tolbutamide - valproic acid may displace tolbutamide from protein-binding
  • Warfarin - valproic acid may displace warfarin from protein-binding
  • Zidovudine - valproic acid may increase zidovudine levels
  • Mitochondrial DNA disorders (POLG, Alpers-Huttenlocher Syndrome) - DO NOT USE
  • Urea cycle disorders - DO NOT USE
  • Pregnancy - DO NOT USE
  • Liver disease - DO NOT USE
  • Liver failure - cases of liver failure have been associated with valproic acid use
  • Low platelets - valproic acid may cause a decrease in platelets. This is seen at higher blood levels - ≥ 110 mcg/ml in females and ≥ 135 mcg/ml in males.
  • Hyperammonemia and encephalopathy - may raise ammonia levels and cause encephalopathy. Risk is higher when taken with topiramate.
  • Hypothermia - may cause hypothermia. Risk may be greater when taken with topiramate.
  • Serious skin reactions - including SJS, DRESS, and TEN
  • Virus stimulation - valproic acid may stimulate replication of HIV and CMV virus
  • Suicide - seizure medications have been associated with an increased risk of suicide
  • Abrupt discontinuation - may increase risk of seizure frequency
  • Pancreatitis - rare cases of pancreatitis have been reported with valproic acid
  • Brain atrophy - rare cases have been reported
  • Liver disease - DO NOT USE
  • Kidney disease - protein-binding may be decreased. Measure free levels.






  • PRICING

    • $ = 0 - $50
    • $$ = $51 - $100
    • $$$ = $101 - $150
    • $$$$ = > $151

    • Pricing based on one month of therapy at standard dosing in an adult
    • Pricing based on survey of GoodRX.com®, HEB®, and Costco®, [accessed 12/2014]
    • Pricing may vary by region and availability