SEIZURE AND MOOD STABILIZER MEDICATIONS









Carbamazepine | Tegretol® | Tegretol XR® | Carbatrol® | Equetro®

Dosage form
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

Dosing - 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

Dosing - 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

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

Generic / Price
  • Tegretol® (60 tablets) - YES/$
  • Tegretol XR® (60 tablets) - YES/$
  • Carbatrol® (60 tablets) - YES/$
  • Equetro® (60 capsules) - NO/$$$$

Lab monitoring
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]
Other labs
  • 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.

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
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 indications
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

Side effects
NOTE: Data is from Equetro® PI

Side effect Carbamazepine Placebo
Dizziness 44% 12%
Somnolence 32% 13%
Nausea 29% 10%
Vomiting 18% 3%
Ataxia (Loss of coordination) 15% 0%
Constipation 10% 5%
Itching 8% 2%
Dry mouth 8% 3%
Weakness 8% 4%


Drug Interactions
  • Carbamazepine is a CYP1A2 inducer, a CYP3A4 strong inducer and substrate, and a P-glycoprotein inducer and substrate. Because of this, carbamazepine has a long list of potential drug interaction. See Tegretol PI for more.
  • Delavirdine (Rescriptor®) - DO NOT COMBINE
  • HIV non-nucleoside reverse transcriptase inhibitors - DO NOT COMBINE
  • MAO inhibitors - DO NOT COMBINE
  • Nefazodone - DO NOT COMBINE
  • 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 and carbamazepine may affect P-gp substrates.
  • Oral contraceptives - carbamazepine may decrease the effectiveness of oral contraceptives. Consider alternative birth control.
  • Contraceptive implant (Implanon™) - A study published in 2017 found that carbamazepine reduced levels of etonogestrel below therapeutic levels in patients with contraceptive implants [PMID 28288788]. Alternative birth control should be considered in these patients.
  • 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

Contraindications / Precautions
  • Known allergy to tricyclic antidepressants - DO NOT USE. Carbamazepine is a tricyclic compound. See tricyclic antidepressants for more.
  • 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.
  • Anaphylaxis and angioedema - rare cases of anaphylaxis and angioedema have been reported in patients taking their first or subsequent doses of carbamazepine.
  • 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

Gabapentin | Neurontin® | Horizant® | Gralise®

Dosage form
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

Dosing - 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
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

Dosing - 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

Dosing - 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

Efficacy
Generic / Price
  • Neurontin® - YES/$
  • Horizant® - NO/$$$$
  • Gralise® - NO/$$$$

Lab monitoring
  • 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]

Other
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®

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

FDA-approved indications
Neurontin®
  • Epilepsy - adjunctive therapy in focal seizures with and without secondary generalization
  • Postherpetic neuralgia
Horizant®
  • Restless leg syndrome
  • Postherpetic neuralgia
Gralise®
  • Postherpetic neuralgia

Side effects

Side effect Gabapentin Placebo
Dizziness 28% 8%
Somnolence 21% 5%
Peripheral edema 8% 2%
Diarrhea 6% 3%
Dry mouth 5% 1%


Drug Interactions
  • 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

Contraindications / Precautions
  • 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 Dosing

Lamotrigine | Lamictal® | Lamictal XR® | Lamictal CD® | Lamictal ODT®

Dosage form
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

Dosing - 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
  • Lamotrigine should be titrated slowly to decrease the risk for serious skin reactions
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

Dosing - 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

Generic / Price
  • Lamictal® - YES/$
  • Lamictal CD® (60 tablets) - YES/$
  • Lamictal XR® (30 tablets) - YES/$$$
  • Lamictal ODT® (60 tablets) - YES/$$$

Lab monitoring
  • 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]

Other
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
Lamictal
  • 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
Lamictal XR
  • 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

Side effects

Bipolar trials
Side effect Lamotrigine Placebo
Nausea 14% 11%
Insomnia 10% 6%
Somnolence 9% 7%
Fatigue 8% 5%
Back pain 8% 6%
Adjunctive epilepsy trials (added to other seizure meds)
Side effect Lamotrigine Placebo
Dizziness 38% 13%
Headache 29% 19%
Double vision 28% 7%
Loss of coordination 22% 6%
Nausea 19% 10%
Blurred vision 16% 5%
Somnolence 14% 7%
Rash 10% 5%


Drug Interactions
NOTE: Below are general guidelines. See Lamictal® PI for specific dosing recommendations
Oral contraceptives
  • Estrogen-containing oral contraceptives - estrogen-containing oral contraceptives may decrease lamotrigine levels by 50%
  • Levonorgestrel - lamotrigine may decrease levonorgestrel levels by about 20%
Other seizure medications
  • 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. The effects of lamotrigine on valproate levels are inconsistent.
Other meds
  • UGT inhibitors and inducers - UGT is the enzyme that is responsible for the metabolism of lamotrigine. UGT inhibitors and inducers may affect lamotrigine levels. Strong and moderate inducers of CYP3A4 are also known to induce UGT, and these drugs may also decrease lamotrigine levels.
  • OCT2 substrates - lamotrigine is an inhibitor of OCT2. Exposure to OCT2 substrates may be increased when given with lamotrigine.
  • Rifampin - rifampin may decrease lamotrigine levels by 40%
  • Olanzapine - olanzapine may reduce lamotrigine levels
  • Lopinavir/ritonavir - may decrease lamotrigine levels by 50%
  • Atazanavir/ritonavir - may decrease lamotrigine levels by 32%

Contraindications / Precautions
  • 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
  • Pregnancy - pregnancy category C. The effects of lamotrigine on the developing fetus are unknown. An observational study found no significant link between lamotrigine and orofacial cleft and clubfoot (see pregnancy studies for more).
  • Aseptic meningitis - lamotrigine may increase the risk of aseptic meningitis
  • Hemophagocytic lymphohistiocytosis (HLH) - HLH is a rare syndrome that causes an uncontrolled immune response. HLH typically presents with persistent fever (> 101°). Other symptoms include rash, enlarged liver and spleen, cytopenias, lymphadenopathy, unusual bleeding, and mental status changes. Untreated HLH can be fatal. Lamotrigine has been associated with rare cases of HLH.
  • 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

Levetiracetam | Keppra® | Keppra XR™ | Spritam®

Dosage form
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

Dosing - 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

Generic / Price
  • Keppra® (60 tablets) - YES/$
  • Keppra XR™ (60 tablets) - YES/$
  • Spritam® (60 tablets) - NO/$$$$

Lab monitoring
  • 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]

Other
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

Side effects
NOTE: Data is from adjunctive trials when levetiracetam was added to other seizure meds

Side effect Levetiracetam Placebo
Weakness 15% 9%
Somnolence 15% 8%
Headache 14% 13%
Infection 13% 8%
Dizziness 9% 4%


Drug Interactions
  • Levetiracetam is not extensively metabolized
  • There are no known significant drug interactions

Contraindications / Precautions
  • 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
  • Behavioral changes - in trials, 13% of adults and 38% of pediatric patients reported behaviorall changes when taking levetiracetam compared to 6% and 19% of adult and pediatric patients on placebo. Behavioral changes included aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, and hyperkinesia.
  • Pregnancy - pregnancy category C. The effects of levetiracetam on the developing fetus are unknown. An observational study found no significant link between prenatal levetiracetam exposure and cognition in children (see pregnancy studies for more).
  • Psychosis - in trials, psychotic symptoms were reported in 1% of adults and 2% of pediatric patients taking levetiracetam
  • Abrupt discontinuation - may increase risk of seizure frequency
  • Hematological abnormalities - minor hematologic abnormalities have been seen in patients taking levetiracetam. Abnormalities include decreases in white blood cells, neutrophils, and red blood cells; decreases in hemoglobin and hematocrit; and increases in eosinophil counts. A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders.
  • Serious skin reactions - serious skin reactions including DRESS syndrome have been reported
  • Liver disease - no dose adjustment necessary
  • Kidney disease - see Dosing

Oxcarbazepine | Trileptal® | Oxtellar XR®

Dosage form
Trileptal® tablet
  • 150 mg
  • 300 mg
  • 600 mg
Oxtellar XR® extended-release tablet
  • 150 mg
  • 300 mg
  • 600 mg

Dosing - Epilepsy
Trileptal® (Monotherapy)
  • Initial: 300 mg twice a day
  • Maintenance: 600 mg twice a day
  • Max: 1200 mg twice a day
  • Increase by 300 mg/day every third day
Trileptal® (Adjunctive therapy)
  • Initial: 300 mg twice a day
  • Maintenance: 300 - 600 mg twice a day
  • Max: 600 mg twice a day
  • Increase by 600 mg/day at weekly intervals
Oxtellar XR® (Adjunctive therapy)
  • Initial: 600 mg once daily
  • Maintenance: 1200 - 2400 mg once daily
  • Max: 2400 mg once daily
  • Increase by 600 mg/day at weekly intervals
  • Take on an empty stomach
Pediatric dosing

Generic / Price
  • Trileptal® (60 tablets) - YES/$
  • Oxtellar XR® (30 tablets) - NO/$$$$

Lab monitoring
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]
Other labs
  • Monitoring sodium levels may be appropriate in patients at increased risk of hyponatremia

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

Other
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 indications
Trileptal®
  • Epilepsy - monotherapy or adjunctive therapy for partial seizures in adults and children
Oxtellar XR®
  • Epilepsy - adjunctive therapy for partial seizures in adults and children

Side effects

Side effect Oxcarbazepine Placebo
Dizziness 22% 6%
Nausea 16% 12%
Headache 13% 10%
Diarrhea 7% 2%
Upper respiratory infection 7% 0%
Other
  • Fatigue and somnolence were also common at higher doses (20% of patients)
  • Side effects increase with higher doses


Drug Interactions
  • Oxcarbazepine is a CYP2C19 inhibitor and CYP3A inducer
  • CYP3A4 strong inducers - strong CYP3A4 inducers have been shown to decrease MHD (active oxcarbazepine metabolite) levels. When taken concurrently, monitor MHD levels.
  • UDP-glucuronosyltransferase (UGT) inducers - UGT inducers have been shown to decrease MHD (active oxcarbazepine metabolite) levels. When taken concurrently, monitor MHD levels.
  • 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

Contraindications / Precautions
  • 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

Phenobarbital

Dosage form
Tablet
  • 15 mg
  • 16.2 mg
  • 30 mg
  • 32.4 mg
  • 60 mg
  • 64.8 mg
  • 97.2 mg
  • 100 mg

Dosing
Epilepsy
  • 50 - 100 mg two to three times a day
Sedative
  • 30 - 120 mg a day given in 2 or 3 divided doses

Generic / Price - YES/$
Lab monitoring
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]
Other labs
  • It may be beneficial to monitor liver function tests periodically

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

Other
  • Phenobarbital is a C-IV controlled substance

Mechanism of action
  • Binds to GABA receptors
  • Causes membrane hyperpolarization
  • Inhibits action potentials (nerve-firing)

FDA-approved indications
  • Treatment of seizures
  • Sedative

Side effects
NOTE: The incidence of side effects with phenobarbital is not well-defined

  • Drowsiness
  • Sedation
  • Nausea
  • Paradoxical excitement

Drug Interactions
  • 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

Contraindications / Precautions
  • 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

Phenytoin | Dilantin® | Phenytek®

Dosage form
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

Dosing - 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

Generic / Price
  • Phenytoin (generic) - $ (90 capsules)
  • Dilantin® (brand) - $$$ (90 capsules)
  • Phenytek® (brand) - $$$$ (90 capsules)

Lab monitoring
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
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
Phenytoin, Total
  • Therapeutic level: 10 - 20 mcg/ml [5]
Phenytoin, Free
  • Therapeutic level: 1 - 2 mcg/ml [5]
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)

Pharmacokinetics
  • Average half-life at steady state: 22 hours (range 7 - 42 hours) [1]
  • Time to steady state: 7 - 10 days [1]

Other
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 indications
  • Epilepsy - generalized tonic-clonic and psychomotor (temporal lobe) seizures
  • Prevention of seizures with neurosurgery

Side effects
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

Drug Interactions
  • 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.
  • Delavirdine (Rescriptor®) - DO NOT COMBINE
  • 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.

Contraindications / Precautions
  • 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.
  • Hypothyroidism - phenytoin may increase the metabolism of thyroid hormone leading to decreased levels of free T3 and free T4.
  • Decreased blood cells - phenytoin has been associated with decreased blood cells. These reactions are rare.
  • Cardiac events - cases of cardiac arrest and bradycardia have been reported in patients receiving phenytoin at both therapeutic and toxic levels. Most patients had underlying cardiac disease.
  • 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

Pregabalin | Lyrica® | Lyrica® CR

Dosage form
Lyrica® capsule
  • 25 mg
  • 50 mg
  • 75 mg
  • 100 mg
  • 150 mg
  • 200 mg
  • 225 mg
  • 300 mg
Lyrica® solution
  • 20 mg/ml
  • Comes in 16 oz (473 ml) bottle
Lyrica® CR tablet
  • 82.5 mg
  • 165 mg
  • 330 mg

Dosing - Lyrica®
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
Dosing in kidney disease
  • See Lyrica® PI for specific recommendations in kidney disease

Dosing - Lyrica® CR
Diabetic neuropathy
  • Dosing: Begin with 165 mg once daily and increase to 330 mg once daily within 1 week based on response/tolerability
  • Max: 330 mg once daily
  • Take after evening meal
Postherpetic neuralgia
  • Starting: Begin with 165 mg once daily and increase to 330 mg once daily within 1 week based on response/tolerability
  • Maintenance: 165 - 660 mg once daily
  • Max: 660 mg once daily
  • Patients who do not achieve pain control on 330 mg may increase to 660 mg once daily after 2 - 4 weeks
  • Take after evening meal
Dosing in kidney disease
  • CrCL ≥ 60 ml/min: no dose adjustment necessary
  • CrCL 30 - 60 ml/min: use half the recommended dose
  • CrCL < 30 ml/min: DO NOT USE
Converting between Lyrica and Lyrica CR

Lyrica total daily dose Lyrica CR dose
75 mg 82.5 mg
150 mg 165 mg
225 mg 247.5 mg
300 mg 330 mg
450 mg 495 mg
600 mg 660 mg

Efficacy
Generic / Price - NO/$$$$ (all forms)
Lab monitoring
  • 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
Lyrica
  • Half-life: 6 hours
  • Time to steady state: 1 - 2 days [2]
Lyrica CR
  • Half-life: 6 hours
  • Time to steady state: 2 - 3 days

Other
Lyrica
  • May take without regard to food
  • Pregabalin is a Schedule-V controlled substance
  • When discontinuing, taper gradually over a minimum of 1 week
Lyrica CR
  • Do not crush, cut, or chew tablet
  • Take following a meal. Food increases absorption.
  • When discontinuing, taper gradually over a minimum of 1 week

Mechanism of action
  • Mechanism not completely understood
  • Binds to alpha₂-delta site on voltage-gated calcium channels
  • Inhibits action potentials (nerve-firing)

FDA-approved indications
Lyrica
  • Epilepsy - as adjunctive therapy in partial seizures
  • Postherpetic neuralgia
  • Diabetic peripheral neuropathy
  • Fibromyalgia
  • Neuropathic pain associated with spinal cord injury
Lyrica CR
  • Postherpetic neuralgia
  • Diabetic peripheral neuropathy

Side effects

Side effect Pregabalin Placebo
Dizziness 30% 8%
Somnolence 23% 8%
Weight gain 9% 2%
Blurred vision 7% 2%
Peripheral edema 6% 2%
Dry mouth 5% 1%
Weakness 5% 2%


Drug Interactions
  • Pregabalin does not undergo significant liver metabolism
  • Glitazones (Actos® and Avandia®) - Pregabalin may potentiate the fluid retention that is seen with glitazones

Contraindications / Precautions
  • Angioedema (swelling of the mouth, face, and tongue) - pregabalin has been associated with rare cases of angioedema during both initial and chronic treatment. Use caution in patients with a history of angioedema.
  • Hypersensitivity reactions - hypersensitivity reactions including skin redness, blisters, hives, rash, dyspnea, and wheezing have been reported
  • Peripheral edema - pregabalin may cause peripheral edema. Concomitant glitazones (Actos, Avandia) may increase the risk.
  • Weight gain - pregabalin may cause weight gain. Concomitant glitazones (Actos, Avandia) may increase the risk.
  • Heart failure - pregabalin may worsen fluid retention in some patients
  • Pregnancy - the effects of pregabalin on the developing fetus are unknown. An observational study found a significant link between pregabalin and birth defects (see pregnancy studies for more).
  • 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 - abrupt discontinuation may increase risk of seizure frequency and some patients report insomnia, nausea, headache, anxiety, and diarrhea. Taper Lyrica and Lyrica CR gradually over a minimum of 1 week when discontinuing.
  • Liver disease - pregabalin does not undergo significant liver metabolism; no dose adjustment necessary
  • Kidney disease
    • Lyrica
    • Lyrica CR
      • CrCL ≥ 60 ml/min: no dose adjustment necessary
      • CrCL 30 - 60 ml/min: use half the recommended dose
      • CrCL < 30 ml/min: DO NOT USE

Topiramate | Topamax® | Qsymia®

Dosage form
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® capsule
  • Phentermine(mg):Topiramate(mg)
    • 3.75 : 23
    • 7.5 : 46
    • 11.25 : 69
    • 15 : 92

Dosing - 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

Dosing - 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

Dosing - 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

Generic / Price
  • Topamax® (60 tablets) - YES/$
  • Trokendi XR® (30 capsules) - NO/$$$$
  • Qudexy® XR (30 capsules) - YES/$$$$
  • Qsymia® - NO/$$$$

Lab monitoring
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]
Other labs
  • 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)

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
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 indications
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

Side effects

Side effect Topiramate 100 mg/day Placebo
Paresthesia (typically tingling of the extremities) 51% 6%
Fatigue 15% 11%
Decreased appetite 15% 6%
Nausea 13% 8%
Diarrhea 11% 4%
Change in taste 8% 1%
Diarrhea 11% 4%
Weight loss 9% 1%
Reduced touch sensation 7% 2%
Memory problems 7% 2%
Somnolence 7% 5%
Concentration problems 6% 2%


Drug Interactions
  • 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. Combination may increase risk of hypokalemia.
  • Metformin - topiramate may cause metabolic acidosis in which case metformin would be contraindicated
  • Pioglitazone (Actos®) - topiramate may decrease pioglitazone levels. The clinical relevance of this effect is unknown.
  • 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.

Contraindications / Precautions
  • 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 - topiramate may cause non-anion gap metabolic acidosis due to renal bicarbonate loss caused by topiramate's inhibition of carbonic anhydrase. Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended.
  • Hyperammonemia and encephalopathy - topiramate may raise ammonia levels and cause encephalopathy. Risk is higher when taken with valproic acid. The incidence of hyperammonemia in patients 12 - 17 years of age in migraine trials was 26% (topiramate 100 mg/day), 14% (topiramate 50 mg/day), and 9% (placebo).
  • Kidney stones - may increase risk of kidney stones because of decreased urinary citrate excretion. During adjunctive epilepsy trials, the risk for kidney stones in topiramate-treated adults was 1.5% which is about 2 to 4 times greater than expected in a similar, untreated population.
  • Increase in serum creatinine - topiramate may cause an increase in serum creatinine levels. Peak increases typically occur 4 - 8 weeks after initiating therapy. In Qsymia trials, serum creatinine increases ≥ 0.3 mg/dl occurred in 8.4% of Qsymia-treated patients (15/92 mg dose) compared to 2% of placebo-treated patients. Increases in creatinine ≥ 50% over baseline occurred in 2.8% of Qsymia-treated patients (15/92 mg dose) and 0.6% of placebo-treated patients.
  • 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. Topiramate may also raise ammonia levels. Use caution.
  • Kidney disease
    • CrCl < 70 ml/min: use one-half the usual adult dose

Valproic acid (Depakene®) | Divalproex sodium (Depakote®) (Depakote ER®) | Valproate sodium (Depacon®)

Dosage form
NOTE: Each form of valproic acid 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

Dosing
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

Generic / Price
  • Depakote® (60 tablets) - YES/$
  • Depakote ER® (60 tablets) - YES/$
  • Depakene® (120 capsules) - YES/$

Lab monitoring
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]
Other labs
  • 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

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

Other
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 indications
  • Epilepsy - monotherapy and adjunctive therapy in complex partial seizures, and simple and complex absence seizures
  • Bipolar mania
  • Prevention of migraine headache

Side effects

Side effect Valproic acid Placebo
Nausea 31% 10%
Fatigue / Weak 20% 9%
Somnolence 17% 5%
Upset stomach 13% 9%
Dizziness 12% 6%
Diarrhea 12% 7%
Vomiting 11% 1%
Tremor 9% 0%
Abdominal pain 9% 4%
Weight gain 8% 2%
Hair loss 7% 1%


Drug Interactions
  • 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

Contraindications / Precautions
  • Mitochondrial DNA disorders (POLG, Alpers-Huttenlocher Syndrome) - DO NOT USE
  • Urea cycle disorders - DO NOT USE
  • Pregnancy - DO NOT USE. See pregnancy studies for more.
  • 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.



  • Reference [6]
Prevalence of HLA-B*1502 allele
Population Prevalence
Filipino and Malaysian > 15%
Han Chinese 2 - 12%
Thai 8%
Indian 6%
Korean 2%
European, Japanese, Hispanic, African < 1%



Pregnancy exposure studies

Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child, Cochrane Review (2016) [PubMed abstract]
  • Design: Meta-analysis of cohort studies and randomized controlled trials (N=31 studies)
  • Exposure: Antiepileptic drug (AED) during gestation
  • Primary outcome: Major congenital malformation
  • Findings: Exposure in the womb to certain AEDs carried an increased risk of malformation in the fetus and may be associated with specific patterns of malformation. Based on current evidence, levetiracetam and lamotrigine exposure carried the lowest risk of overall malformation; however, data pertaining to specific malformations are lacking. Physicians should discuss both the risks and treatment efficacy with the patient prior to commencing treatment.

Pregnancy outcome following maternal exposure to pregabalin may call for concern - Neurology (2016) [PubMed abstract]
  • Design: Prospective cohort study (N=820 pregnancies)
  • Exposure: Pregabalin during pregnancy
  • Primary outcome: Major birth defect rate
  • Findings: This study demonstrated a signal for increased risk of major birth defects after first trimester exposure to pregabalin. However, several limitations such as the small sample size, differences across groups in maternal conditions, and concomitant medication exposure exclude definitive conclusions, so these results call for confirmation through independent studies.

Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies - Neurology (2016) [PubMed abstract]
  • Design: Case-control registry study (N=6.3 million births)
  • Exposure: Lamotrigine during pregnancy
  • Primary outcome: Orofacial cleft (OC), clubfoot, and other congenital anomalies
  • Findings: The risk of OC was not significantly raised and we estimate the excess risk of OC to be less than 1 in every 550 exposed babies. We have not found strong independent evidence of a risk of clubfoot subsequent to our original signal. Our study cannot assess the general malformation risk among lamotrigine-exposed pregnancies.

Cognition in school-age children exposed to levetiracetam, topiramate, or sodium valproate - Neurology (2016) [PMID 27581218]
  • Design: Cross-sectional observational study (N=171)
  • Exposure: Prenatal exposure to levetiracetam, topiramate, or valproate
  • Primary outcome: Cognitive abilities at age 5 - 9 years
  • Findings: In the adjusted analyses, prenatal exposure to levetiracetam and topiramate were not found to be associated with reductions in child cognitive abilities, and adverse outcomes were not associated with increasing dose. Increasing dose of valproate, however, was associated with poorer full-scale IQ, verbal abilities, nonverbal abilities, and expressive language ability.

Gabapentin vs Epidural Steroid Injections for Sciatica, BMJ (2015) [PubMed abstract]
  • The study enrolled 145 patients at military treatment facilities with radicular leg pain (sciatica) from either a herniated disc or spinal stenosis
Main inclusion criteria
  • Leg pain score of ≥ 4 (0 - 10 scale) over the preceding week or 3/10 if the leg pain was as bad as or worse than back pain
  • Symptoms for > 6 weeks and < 4 years
  • MRI findings of herniated disc or spinal stenosis consistent with physical findings
Main exclusion criteria
  • Previous failed therapy with gabapentin or pregabalin
  • Epidural steroid injection within last 3 years
  • Neurogenic claudication
  • Previous lumbar surgery
  • Active litigation
  • Psychiatric illness
Baseline characteristics
  • Average age 42 years
  • Herniated disc ∼ 87.5%
  • Spinal stenosis ∼ 12.5%
  • Duration of symptoms: < 3 months ∼ 18% | > 3 months ∼ 82%
  • Treatment with opioids - 16%
Randomized treatment groups
  • Group 1 (73 patients) - Epidural steroid injection (60 mg methylprednisolone + 1 mL of 0.25% bupivacaine) + placebo pills
  • Group 2 (72 patients) - Sham injection + gabapentin (target dose 1800 - 3600 mg/day)
  • Injection approach: transforaminal ∼ 84% | interlaminar ∼ 16%
  • Gabapentin was dosed 3 times a day and titrated over 15 - 24 days
  • Tramadol and NSAIDs could be prescribed on an “as needed” basis as rescue medications (or opioids could be increased by up to 20% for those taking opioids), but no other co-interventions were permitted
  • Patients with a negative outcome at one month left the study and were not included in the 3 month follow-up
Primary outcome: Average change from baseline on a leg pain score (scale 0 - 10 with 0 indicating no pain and 10 worst pain) at one and three months. Score reflects the average pain experienced during the week before follow-up.
Results

Duration: 3 months
Outcome Steroid injection Gabapentin Comparisons
Average baseline leg pain score 5.4 5.4 N/A
Primary outcome (decrease at one month) 2.2 1.7 diff 0.4, 95%CI [−0.3 to 1.2], p=0.25
Primary outcome (decrease at three months) 2.0 1.6 diff 0.3, 95%CI [−0.5 to 1.2], p=0.43
  • At one month, 23 patients in Group 1 had a negative outcome and left the study compared to 39 patients in Group 2
  • Within one year of enrollment, 13% of patients in Group 1 proceeded to surgery compared to 15% in Group 2 (p=0.73)
  • There was no significant difference in adverse events

Findings: Although epidural steroid injection might provide greater benefit than gabapentin for some outcome measures, the differences are modest and are transient for most people
StraightHealthcare analysis:
  • This study found no difference between epidural steroid injections and gabapentin for radicular nerve pain. The one-month outcomes are valid, but the three-month outcomes cannot be considered valid because nonresponders were excluded from the study after one month.
  • Epidural steroid injections have failed to show a clear benefit in well-done studies
  • It's unclear from this study what the true benefit of either intervention was since there was no placebo-control group
  • In conclusion, gabapentin appears to offer the same short-term benefit as epidural steroid injections, whatever that benefit may be

Pregabalin studies

Pregabalin vs Placebo for Acute and Chronic Sciatica, NEJM (2017) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=209 | length = 8 weeks) in patients with sciatica for at least 1 week and less than 1 year
  • Treatment: Pregabalin 150 - 600 mg/day vs Placebo
  • Primary outcome: Leg-pain intensity score on a 10-point scale (with 0 indicating no pain and 10 the worst possible pain) at week 8
  • Results:
    • Average baseline leg-pain intensity score: Pregabalin - 6.3, Placebo - 6.1
    • Primary outcome (score at week 8): Pregabalin - 3.7, Placebo - 3.1 (p=0.19)
  • Findings: Treatment with pregabalin did not significantly reduce the intensity of leg pain associated with sciatica and did not significantly improve other outcomes, as compared with placebo, over the course of 8 weeks. The incidence of adverse events was significantly higher in the pregabalin group than in the placebo group.

Pregabalin vs Diphenhydramine (active control) for Neurogenic Claudication, Neurology (2015) [PubMed abstract]
  • Design: Randomized, placebo-controlled, crossover trial (N=29 | length = 30 days) in patients with spinal stenosis and neurogenic claudication
  • Treatment: Pregabalin 150 mg twice daily vs Diphenhydramine 12.5 mg twice daily, each for 13 days in a crossover design with 7 day washout period in between
  • Primary outcome: Time to first moderate pain symptom (Numeric Rating Scale score ≥ 4) during a 15-minute treadmill test. Test was performed at baseline and Day 10 of each period.
  • Results:
    • No significant difference was found between pregabalin and active placebo in the distribution of time to first moderate pain (difference in median Tfirst = −1.08 [95% CI −2.25 to 0.08], p = 0.61)
  • Findings: Pregabalin was not more effective than active placebo in reducing painful symptoms or functional limitations in patients with neurogenic claudication associated with lumbar spinal stenosis.



Pricing legend
  • $ = 0 - $50
  • $$ = $51 - $100
  • $$$ = $101 - $150
  • $$$$ = > $151
  • Pricing based on one month of therapy at standard dosing in an adult
  • Pricing based on information from GoodRX.com®
  • Pricing may vary by region and availability