SEIZURE MEDICATIONS









Carbamazepine | Tegretol® | Tegretol XR® | Carbatrol® | Equetro® | Epitol® | Teril®

Dosage forms

Tablet (Tegretol®, Epitol®)
  • 100 mg
  • 200 mg
  • 300 mg
  • 400 mg
Tablet, chewable (Tegretol®, Epitol®)
  • 100 mg
Tablet, extended-release (Tegretol XR®)
  • 100 mg
  • 200 mg
  • 400 mg
Capsule, extended-release (Carbatrol®)
  • 100 mg
  • 200 mg
  • 300 mg
Capsule, extended-release (Equetro®)
  • 100 mg
  • 200 mg
  • 300 mg
Suspension (Tegretol®, Teril®)
  • 100 mg/5ml
  • Comes in 450 ml bottle

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® (180 chewable tablets) - YES/$
  • Tegretol XR® (60 tablets) - YES/$
  • Carbatrol® (60 capsules) - YES/$
  • Suspension (450 ml) - 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 interactions. See Tegretol PI for more.
  • Delavirdine (Rescriptor®) - DO NOT COMBINE
  • Direct-acting oral anticoagulants - direct-acting oral anticoagulants (e.g. rivaroxaban, apixaban, dabigatran, and edoxaban) are P-glycoprotein substrates. Carbamazepine is a P-glycoprotein inducer and it may decrease exposure to these medications. Concomitant use is not recommended.
  • 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 is a CYP enzyme inducer and this may enhance the metabolism of vitamin D and increase the risk of osteoporosis. Consider checking vitamin D, calcium, and phosphate levels during prolonged therapy. BMD testing may be appropriate in some patients.
  • Serious skin reactions - SJS, DRESS, and TEN have been reported
  • HLA-B*1502 allele - carriers of the 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 the 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.
  • Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
  • Low sodium (hyponatremia) - carbamazepine may cause SIADH
  • Glaucoma - carbamazepine may cause pupil dilation
  • Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
  • Liver disease - consider reducing dose; no specific recommendation given
  • Kidney disease - effect unknown; no recommendation given

Cenobamate (Xcopri™)

Dosage forms

Tablet (Xcopri™)
  • 50 mg
  • 100 mg
  • 150 mg
  • 200 mg
Titration packs (3 different packs)
  • 12.5 mg X 14 / 25 mg X 14
  • 50 mg X 14 / 100 mg X 14
  • 150 mg X 14 / 200 mg X 14
Maintenance packs
  • 250 mg/day (28 days worth)
  • 350 mg/day (28 days worth)

Dosing

Partial seizures in adults
  • Starting
    • Week 1 and 2: 12.5 mg once daily
    • Week 3 and 4: 25 mg once daily
    • Week 5 and 6: 50 mg once daily
    • Week 7 and 8: 100 mg once daily
    • Week 9 and 10: 150 mg once daily
    • Week 11 and on: 200 mg once daily
  • Max: 400 mg once daily
  • For doses above 200 mg/day, increase dose in increments of 50 mg/day every 2 weeks
  • May take without regard to food
  • Do not crush, cut, or chew tablets

Efficacy


Other

  • Cenobamate is a DEA Schedule V (CV) controlled substance

Generic / Price

- NO/$$$$

Lab monitoring

  • The value of routine monitoring has not been established

Pharmacokinetics

  • Half-life: 50 - 60 hours
  • Time to steady state: 2 weeks

Mechanism of action

  • The precise mechanism by which cenobamate exerts its therapeutic effects in patients with partial-onset seizures is unknown. Cenobamate has been demonstrated to reduce repetitive neuronal firing by inhibiting voltage-gated sodium currents. It is also a positive allosteric modulator of the γ-aminobutyric acid (GABAA) ion channel

FDA-approved indications

  • Partial-onset seizures in adults (monotherapy and adjunctive therapy)

Side effects

  • NOTE: Only side effects that occurred at an incidence ≥ 5% are listed

Side effect Xcopri 200 mg
(N=223)
Xcopri 400 mg
(N=111)
Placebo
(N=216)
Somnolence 22% 37% 11%
Dizziness 22% 33% 15%
Fatigue 14% 24% 7%
Headache 12% 10% 9%
Diplopia 7% 15% 2%
Nausea 6% 9% 3%
Balance Disorder 5% 9% 1%
Gait Disturbance 3% 8% 1%
Constipation 4% 8% 0%
Dysarthria 1% 7% 0%
Nystagmus 7% 6% 0%
Ataxia 3% 6% 2%
Vertigo 1% 6% 1%
Diarrhea 3% 5% 0%
Vomiting 4% 5% 0%
Nasopharyngitis 4% 5% 3%
Decreased Appetite 1% 5% 1%
Back Pain 2% 5% 3%
Urinary Tract Infection 5% 0% 2%


Drug interactions

  • Lamotrigine - cenobamate may decrease lamotrigine exposure. Increase lamotrigine doses as needed when taken with cenobamate.
  • Carbamazepine - cenobamate may decrease carbamazepine exposure. Increase carbamazepine doses as needed when taken with cenobamate.
  • Phenytoin - cenobamate may increase phenytoin exposure. Because of a potential 2-fold increase in phenytoin levels, gradually decrease phenytoin dosage by up to 50% as cenobamate is being titrated.
  • Phenobarbital - cenobamate may increase phenobarbital exposure. Consider reducing the phenobarbital dose when combining with cenobamate.
  • Clobazam - cenobamate may increase clobazam exposure. Consider reducing the clobazam dose when combining with cenobamate.
  • CYP2B6 substrates - cenobamate is a CYP2B6 inducer. Doses of CYP2B6 substrates may need to be increased when combining.
  • CYP3A4 substrates - cenobamate is a CYP3A4 inducer. Doses of CYP3A4 substrates may need to be increased when combining.
  • CYP2C19 substrates - cenobamate is a CYP2C19 inhibitor. Doses of CYP2C19 substrates may need to be decreased when combining.
  • Oral contraceptives - cenobamate may reduce the efficacy of oral contraceptives. Women should use additional or alternative non-hormonal birth control while taking cenobamate.
  • Drugs that shorten the QT interval - cenobamate can shorten the QT interval. Use caution when combining with other drugs that shorten the QT interval. Patients with symptoms of QT shortening (e.g. prolonged palpitations or fainting) should report them to their physician immediately.
  • CNS depressants including alcohol - CNS depressants including alcohol may potentiate the sedating effects of cenobamate

Contraindications / Precautions

  • Pregnancy and nursing - risk is unknown
  • Familial Short QT syndrome - DO NOT COMBINE. Cenobamate has been shown to shorten the QT interval.
  • DRESS syndrome - rare cases of DRESS have been reported in patients taking cenobamate. DRESS may present with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present, and systemic symptoms (e.g., fever, lymphadenopathy) may present before a rash is present. Cenobamate should be titrated slowly and any symptoms consistent with DRESS should be evaluated immediately.
  • QT shortening - in studies, a significant percentage of patients taking cenobamate had QT shortening of > 20 msec (31% at 200 mg and 66% at 500 mg). Familial Short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. These events are believed to occur primarily when the corrected QT interval falls below 300 msec. Symptoms of QT shortening may include prolonged palpitations and/or fainting. Do not use cenobamate in patients with Familial Short QT syndrome, and use caution when combining with other QT shortening drugs.
  • Elevated liver enzymes - in one study, ALT elevations > 3 X ULN occurred in up to 2.7% of cenobamate-treated patients and no placebo-treated patients
  • Elevated potassium - in one study, potassium elevations of > 5 meq/L occurred in 17% of cenobamate-treated patients (200 mg) compared to 7% of placebo-treated patients
  • Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
  • Adverse neurological effects - in trials, a significant number of patients taking cenobamate experienced adverse neurological effects including somnolence, fatigue, gait disturbances, cognitive impairment, and visual changes. Patients should be advised that cenobamate may impair their ability to engage in hazardous activities such as driving.
  • Abrupt discontinuation - abrupt discontinuation of cenobamate can increase the risk of seizures. Gradual withdrawal is recommended.
  • Liver disease
    • Child-Pugh A/B: use caution. Dose should not exceed 200 mg once daily.
    • Child-Pugh C: not recommended
  • Kidney disease - use caution and consider dose reductions. Do not use in end-stage renal disease or dialysis.

Eslicarbazepine (Aptiom®)

Dosage forms

Tablet (Aptiom®)
  • 200 mg
  • 400 mg
  • 600 mg
  • 800 mg

Dosing

Partial seizures (adults)
  • Starting: 400 mg once daily
  • Maintenance: 800 - 1600 mg once daily
  • Maximum: 1600 mg once daily
  • Increase dose in increments of 400 - 600 mg at weekly intervals
  • Treatment may be initiated at 800 mg once daily if need for seizure control outweighs risk for side effects
  • May take without regard to food
  • Tablet may be crushed
Partial seizures (4 - 17 years old)
  • May take without regard to food
  • Tablet may be crushed

  • Increase dose at weekly intervals
Body Weight Range Initial and Maximum Titration Increment Dosage (mg/day) Maintenance Dosage (mg/day)
11 - 21 kg 200 400 to 600
22 - 31 kg 300 500 to 800
32 - 38 kg 300 600 to 900
>38 kg 400 800 to 1200

Efficacy


Generic / Price

- NO/$$$$

Lab monitoring

Levels
  • Eslicarbazepine levels are available at some labs
  • There is no established therapeutic range
  • Trough plasma levels following doses of 400 - 2400 mg/day, averaged 2 - 28 mcg/mL
  • Maximum plasma concentrations following 2400 mg/day dosages averaged 55 mcg/mL [2]
Liver enzymes
  • Eslicarbazepine has been associated with rare cases of hepatotoxicity
  • Baseline liver function tests are recommended

Pharmacokinetics

  • Half-life: 13 - 20 hours
  • Time to steady state: 4 - 5 days

Mechanism of action

  • The precise mechanism(s) by which eslicarbazepine exerts anticonvulsant activity is unknown but is thought to involve inhibition of voltage-gated sodium channels

FDA-approved indications

  • Partial-onset seizures in adults and children ≥ 4 years old (monotherapy and adjunctive therapy)

Side effects

  • NOTE: Only side effects that occurred at an incidence ≥ 5% are listed

Side effect Placebo
(N=426)
Aptiom 800 mg
(N=415)
Aptiom 1200 mg
(N=410)
Dizziness 9% 20% 28%
Somnolence 8% 11% 18%
Nausea 5% 10% 16%
Headache 9% 13% 15%
Diplopia 2% 9% 11%
Vomiting 3% 6% 10%
Fatigue 4% 4% 7%
Blurred vision 1% 6% 5%
Ataxia 2% 4% 6%
Vertigo < 1% 2% 6%


Drug interactions

  • Oxcarbazepine - DO NOT TAKE eslicarbazepine with oxcarbazepine. Eslicarbazepine is partially metabolized to oxcarbazepine.
  • Carbamazepine - carbamazepine may reduce exposure to eslicarbazepine. When taken together, higher doses of eslicarbazepine may be needed.
  • Phenytoin - phenytoin may reduce exposure to eslicarbazepine. When taken together, higher doses of eslicarbazepine may be needed.
  • Phenobarbital - phenobarbital may reduce exposure to eslicarbazepine. When taken together, higher doses of eslicarbazepine may be needed.
  • Primidone - primidone may reduce exposure to eslicarbazepine. When taken together, higher doses of eslicarbazepine may be needed.
  • CYP2C19 substrates - eslicarbazepine is a CYP2C19 moderate inhibitor. Doses of CYP2C19 substrates may need to be decreased when combining.
  • CYP3A4 substrates - eslicarbazepine is a CYP3A4 inducer. Doses of CYP3A4 substrates may need to be increased when combining.
  • Oral contraceptives - eslicarbazepine lowers levels of ethinyl estradiol and levonorgestrel which can reduce the efficacy of oral contraceptives. Women should use additional or alternative non-hormonal birth control while taking cenobamate.

Contraindications / Precautions

  • Pregnancy and nursing - risk is unknown
  • Oxcarbazepine allergy/hypersensitivity reactions - DO NOT USE. Eslicarbazepine is partially metabolized to oxcarbazepine.
  • Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
  • Serious dermatologic reactions - serious dermatologic reactions including Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving eslicarbazepine
  • DRESS syndrome - rare cases of DRESS have been reported in patients taking eslicarbazepine. DRESS may present with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present, and systemic symptoms (e.g., fever, lymphadenopathy) may present before a rash is present.
  • Anaphylaxis and angioedema - rare cases of anaphylaxis and angioedema have been reported in patients receiving eslicarbazepine
  • Hyponatremia - in trials, eslicarbazepine-treated patients had a higher incidence of sodium levels < 125 mEq/L than placebo-treated patients (1% with 800 mg, 1.5% with 1200 mg, 0% with placebo). In addition, 5.1% of eslicarbazepine-treated patients experienced a decrease in sodium levels of > 10 mEq/L compared to 0.7% of placebo-treated patients. Sodium decreases were dose-related and typically occurred within the first 8 weeks of therapy. Concurrent hypochloremia was also present. Measurement of sodium levels should be considered during therapy and if signs of hyponatremia develop (e.g., nausea/vomiting, malaise, headache, lethargy, confusion, irritability, muscle weakness/spasms, obtundation, or increase in seizure frequency or severity). Sodium levels typically normalized within a few days of stopping eslicarbazepine.
  • Adverse neurological effects - in trials, a significant number of patients taking eslicarbazepine experienced adverse neurological effects including somnolence, fatigue, gait disturbances, cognitive impairment, and visual changes. Patients should be advised that eslicarbazepine may impair their ability to engage in hazardous activities such as driving.
  • Abrupt discontinuation - abrupt discontinuation of eslicarbazepine can increase the risk of seizures. Gradual withdrawal is recommended.
  • Hepatic toxicity - cases of hepatotoxicity have been reported with eslicarbazepine. Elevations in ALT/AST and bilirubin without evidence of obstruction are a predictor of severe liver injury. Baseline liver function tests are recommended.
  • Abnormal thyroid tests - dose-dependent decreases in serum T3 and T4 (free and total) have been observed in patients taking eslicarbazepine. These changes were not associated with increases in TSH levels.
  • Hematologic adverse reactions - rare cases of pancytopenia, agranulocytosis, and leukopenia have been reported in the postmarketing setting
  • Liver disease
    • Child-Pugh A/B: no dose adjustment necessary
    • Child-Pugh C: has not been studied. Not recommended.
  • Kidney disease
    • CrCl ≥ 50 ml/min: no dose adjustment necessary
    • CrCl < 50 ml/min: decrease dose by 50%. Clearance is decreased.

Gabapentin | Neurontin® | Horizant® | Gralise®

Dosage forms

Tablet (Neurontin®)
  • 100 mg
  • 300 mg
  • 400 mg
  • 600 mg
  • 800 mg
Capsule (Neurontin®)
  • 100 mg
  • 300 mg
  • 400 mg
Solution (Neurontin®)
  • 250 mg/5 ml
  • Comes in 470 ml bottle
  • Store in refrigerator
Tablet (Horizant®)
  • 300 mg
  • 600 mg
Tablet (Gralise®)
  • 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/$ (solution and pills)
  • 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.
  • Solution should be refrigerated
  • 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 - antacids containing aluminum hydroxide and/or magnesium hydroxide may decrease gabapentin absorption when taken concomitantly. Take gabapentin at least 2 hours after antacids.
  • Naproxen - naproxen may increase gabapentin levels
  • Opiate medications - respiratory depression and sedation, sometimes resulting in death, have been reported following coadministration of gabapentin with opioids. Use caution when prescribing together.
  • Hydrocodone - gabapentin may decrease hydrocodone levels, and hydrocodone may increase gabapentin levels
  • Morphine - morphine may increase gabapentin levels. Monitor for signs of increased sedation when prescribing together.
  • Cimetidine - cimetidine may increase gabapentin levels

Lab interactions

  • Urine dipsticks - false-positive urine protein findings have been reported in patients receiving gabapentin when the Ames N-Multistix SG® dipstick is used. More specific measures such as the sulfosalicylic acid precipitation method should be used instead.

Contraindications / Precautions

  • Anaphylaxis and angioedema - have occurred in patients taking gabapentin. May occur at any time during therapy.
  • Respiratory depression - cases of serious and sometimes fatal respiratory depression have been reported when gabapentin was taken with other CNS depressants, including opioids, and in patients with underlying respiratory disorders. Use caution when prescribing in these situations.
  • Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
  • Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
  • 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 forms

Tablet (Lamictal®)
  • 25 mg
  • 100 mg
  • 150 mg
  • 200 mg
Tablet, extended-release (Lamictal XR®)
  • 25 mg
  • 50 mg
  • 100 mg
  • 200 mg
  • 250 mg
  • 300 mg
Tablet, chewable (Lamictal CD®)
  • 2 mg
  • 5 mg
  • 25 mg
Tablet, orally disintegrating (Lamictal ODT®)
  • 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

Efficacy



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
  • Atazanavir/ritonavir - may decrease lamotrigine levels by 32%
  • Lopinavir/ritonavir - may decrease lamotrigine levels by 50%
  • OCT2 substrates - lamotrigine is an inhibitor of OCT2. Exposure to OCT2 substrates may be increased when given with lamotrigine.
  • Olanzapine - olanzapine may reduce lamotrigine levels
  • Rifampin - rifampin may decrease lamotrigine levels by 40%
  • Sodium channel blockers - in vitro studies have shown that lamotrigine has sodium channel blocking activity at relevant concentrations. Concomitant use with other sodium channel blocking drugs (e.g. quinidine, procainamide, lidocaine, mexiletine, phenytoin, flecainide, propafenone, carbamazepine) may increase the risk of arrhythmias.
  • 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.

Contraindications / Precautions

  • 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).
  • Serious skin reactions - serious skin reactions including SJS, DRESS, and TEN have been reported in patients taking lamotrigine. In studies, serious skin reactions were seen in up to 0.3% of adults and up to 0.8% of children. The risk may be higher with concomitant valproic acid, higher starting doses, and rapid titration.
  • Multiorgan hypersensitivity reactions and organ failure - multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred with lamotrigine. DRESS typically presents with fever, rash, eosinophilia, and/or lymphadenopathy in association with other organ involvement (e.g. hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis). Constitutional symptoms (e.g. fever, lymphadenopathy) may present before a rash is present. Patients taking lamotrigine should be aware that a rash or other nonspecific symptoms (e.g. fever) may herald the start of a serious reaction, and they should seek prompt medical attention.
  • Cardiac rhythm and conduction abnormalities - in vitro studies have shown that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations. Based on this activity, lamotrigine could slow ventricular conduction (widened QRS) and induce arrhythmias in patients with structural heart disease or myocardial ischemia. Lamotrigine should be avoided or used with caution in patients with structural or functional heart disease including heart failure, valvular heart disease, congenital heart disease, conduction system disease, ventricular arrhythmias, cardiac channelopathies (e.g., Brugada syndrome), clinically important ischemic heart disease, or multiple risk factors for ischemic heart disease.
  • Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
  • Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
  • 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 forms

Tablet (Keppra®)
  • 250 mg
  • 500 mg
  • 750 mg
  • 1000 mg
Extended-release tablet (Keppra XR®)
  • 500 mg
  • 750 mg
Tablet for oral suspension (Spritam®)
  • 250 mg
  • 500 mg
  • 750 mg
  • 1000 mg
Solution (Keppra®)
  • 100 mg/ml

Dosing - Keppra® | Spritam®

NOTE: the dosing presented here is general dosing in adults. See the Keppra PI [sec 2] for specific recommendations based on seizure type and age
Seizure disorders (adults and children weighing > 40 kg)
  • Initial: 500 mg twice a day
  • Max: 1500 mg twice a day
  • Increase dose by 1000 mg/day at 2 week intervals to the recommended daily dose of 3000 mg
  • May take without regard to food
Dosing in kidney disease
  • CrCl 50 - 80 ml/min: 500 - 1000 mg twice daily
  • CrCl 30 - 49 ml/min: 250 - 750 mg twice daily
  • CrCl < 30 ml/min: 250 - 500 mg twice daily

Dosing - Keppra XR®

Partial-onset seizures (adults and adolescents ≥ 12 years old weighing > 50 kg)
  • Initial: 1000 mg once daily
  • Max: 3000 mg once daily
  • Increase dose by 1000 mg/day at 2 week intervals to the recommended daily dose of 3000 mg
  • May take without regard to food
Dosing in kidney disease
  • CrCl 50 - 80 ml/min: 1000 - 2000 mg once daily
  • CrCl 30 - 49 ml/min: 500 - 1500 mg once daily
  • CrCl < 30 ml/min: 500 - 1000 mg once daily

Efficacy


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®
  • Do not crush, cut, or chew tablet
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®
  • Treatment of partial-onset seizures in patients 1 month of age and older
  • 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®
  • Treatment of partial-onset seizures in patients 12 years of age and older

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

  • Pregnancy - prolonged experience with levetiracetam in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy registries and reflects experience over two decades. An observational study detailed below found no significant link between prenatal levetiracetam exposure and cognition in children (see pregnancy studies for more). Physiological changes during pregnancy may lower levetiracetam levels, particularly in the third trimester. Dose adjustments may be necessary to maintain clinical response.
  • Hypersensitivity reactions - levetiracetam may cause hypersensitivity reactions including angioedema and anaphylaxis. Reactions may occur with the first dose or at any time during treatment.
  • Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
  • Behavioral changes - in trials, 13% of adults and 38% of pediatric patients reported behavioral 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.
  • Psychosis - in trials, psychotic symptoms were reported in 1% of adults and 2% of pediatric patients taking levetiracetam
  • Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
  • 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

Lacosamide (Vimpat®)

Dosage forms

Tablet (Vimpat®)
  • 50 mg
  • 100 mg
  • 150 mg
  • 200 mg
Solution (Vimpat®)
  • 10 mg/ml mg
  • Comes in 200 and 465 ml bottle

Dosing

NOTE: the dosing presented here is general dosing in adults. See the Vimpat PI [sec 2] for pediatric dosing recommendations
Partial onset seizures (adults ≥ 17 years)
  • Monotherapy
    • Initial: 100 mg twice daily
    • Maintenance: 150 - 200 mg twice daily
    • Max: 200 mg twice daily
    • Increase by 50 mg twice daily (100 mg per day) every week
    • May take without regard to food
  • Adjunctive therapy
    • Initial: 50 mg twice daily
    • Maintenance: 100 - 200 mg twice daily
    • Max: 200 mg twice daily
    • Increase by 50 mg twice daily (100 mg per day) every week
    • May take without regard to food

Generic / Price

  • Vimpat® (60 tablets) - NO/$$$$
  • Vimpat™ solution (200 ml) - NO/$$$$

Lab monitoring

  • The value of routine monitoring has not been established
  • Checking levels may be appropriate to monitor compliance, in patients with renal or hepatic disease, and when drug interactions can affect levels.
  • Trough levels should be taken
  • Lacosamide levels of 1 - 10 mcg/ml are generally considered therapeutic
  • Levels > 20 mcg/ml may be toxic [7]

Pharmacokinetics

  • Half-life: 15 - 23 hours
  • Time to steady state: 3 days

Other

  • Tablets should be swallowed whole. Do not divide tablets.
  • Lacosamide is a C-V controlled substance

Mechanism of action

  • The precise mechanism by which lacosamide exerts its antiepileptic effects in humans remains to be fully elucidated. In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.

FDA-approved indications

  • Partial-onset seizures - in patients 4 years of age and older
  • Primary generalized tonic-clonic seizures - as adjunctive therapy in patients 4 years of age and older

Side effects

NOTE: Only side effects that occurred at an incidence ≥ 5% are listed

Side effect Lacosamide 200 mg/day
(N=270)
Lacosamide 400 mg/day
(N=471)
Placebo
(N=364)
Dizziness 16% 30% 8%
Headache 11% 14% 9%
Nausea 7% 11% 4%
Diplopia 6% 10% 2%
Vomiting 6% 9% 3%
Blurred vision 2% 9% 3%
Somnolence 5% 8% 5%
Ataxia 4% 7% 2%
Fatigue 7% 7% 6%
Tremor 4% 6% 4%
Nystagmus 2% 5% 4%
Diarrhea 3% 5% 3%
Vertigo 5% 3% 1%


Drug interactions

  • CYP3A4 strong inhibitors - in patients with renal or hepatic impairment, strong CYP3A4 inhibitors may increase exposure to lacosamide. Dose reductions may be necessary. Manufacturer makes no specific recommendation.
  • CYP2C9 strong inhibitors - in patients with renal or hepatic impairment, strong CYP2C9 inhibitors may increase exposure to lacosamide. Dose reductions may be necessary. Manufacturer makes no specific recommendation.
  • Medications that affect cardiac conduction - cases of bradycardia, AV block, and ventricular tachyarrhythmia, which have rarely resulted in asystole, cardiac arrest, and death have been reported in patients taking lacosamide. Use caution when giving with other medications that affect cardiac conduction (beta blockers, calcium channel blockers, sodium channel blockers, and potassium channel blockers) including those that prolong the PR interval (e.g. sodium channel blocking antiseizure meds). Obtaining an ECG before and after therapy titration is recommended in susceptible patients.

Contraindications / Precautions

  • Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
  • Dizziness and ataxia - lacosamide can cause a significant amount of dizziness (up to 30% with 400 mg/day) and ataxia. Symptoms were typically worse during the titration phase. Use caution if performing complex tasks such as driving.
  • PR interval prolongation - dose-dependent prolongation of the PR interval has been observed with lacosamide. In trials, asymptomatic first-degree atrioventricular (AV) block was observed in 0.4% (4/944) of lacosamide-treated patients and 0% of placebo-treated patients. In the postmarketing setting, there have been reports of bradycardia, AV block, and ventricular tachyarrhythmia, which have rarely resulted in asystole, cardiac arrest, and death. Most cases occurred in patients with underlying proarrhythmic conditions, or in those taking concomitant medications that affect cardiac conduction or prolong the PR interval. Use caution in patients with conduction abnormalities (e.g. marked first-degree AV block, second-degree or higher AV block and sick sinus syndrome without pacemaker), severe cardiac disease (such as myocardial ischemia or heart failure, or structural heart disease), and cardiac sodium channelopathies (e.g. Brugada Syndrome). It is recommended that an ECG be performed before therapy and after titration in at-risk patients.
  • Atrial fibrillation and flutter - atrial fibrillation and atrial flutter have been reported in the postmarketing setting in adults treated with lacosamide. In an exploratory trial for diabetic neuropathy, 0.5% of lacosamide-treated patients developed A fib/flutter compared to 0% of placebo-treated patients.
  • Syncope - in partial seizure trials, no syncopal events were reported in lacosamide-treated patients. In an exploratory trial for diabetic neuropathy, 1.2% of lacosamide-treated patients reported syncope or loss of consciousness compared to 0% of placebo-treated patients. The cause of syncope was unknown in most cases, however, several were associated with either changes in orthostatic blood pressure, atrial flutter/fibrillation (and associated tachycardia), or bradycardia. Most cases occurred at doses > 400 mg/day.
  • Withdrawal of antiepileptic drugs - seizure risk may increase when withdrawing antiepileptic drugs. Discontinue lacosamide gradually over a minimum of 1 week to minimize the risk of rebound seizures.
  • Serious skin reactions - serious skin reactions including DRESS syndrome have been reported in patients taking antiepileptic drugs. DRESS may present with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present, and systemic symptoms (e.g., fever, lymphadenopathy) may present before a rash is present.
  • Phenylketonuria - lacosamide oral solution contains aspartame, a source of phenylalanine. A 200 mg dose of lacosamide oral solution (equivalent to 20 mL) contains 0.32 mg of phenylalanine.
  • Pregnancy - there are no adequate data on the developmental risks associated with the use of lacosamide in pregnant women
  • Liver disease
    • Child-Pugh A/B: reduce maximum dose by 25%
    • Child-Pugh C: has not been studied. Not recommended.
  • Kidney disease
    • CrCl ≥ 30 ml/min: no dose adjustment necessary
    • CrCl < 30 ml/min: reduce maximum dose by 25%

Oxcarbazepine | Trileptal® | Oxtellar XR®

Dosage forms

Tablet (Trileptal®)
  • 150 mg
  • 300 mg
  • 600 mg
Tablet, extended-release (Oxtellar XR®)
  • 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 an 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 - 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.
  • Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
  • Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
  • 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 forms

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 is a CYP enzyme inducer and this may enhance the metabolism of vitamin D and increase the risk of osteoporosis. Consider checking vitamin D, calcium, and phosphate levels during prolonged therapy. BMD testing may be appropriate in some patients.
  • Serious skin reactions - SJS, DRESS, and TEN have been reported
  • Abuse and addiction - phenobarbital has abuse and addiction potential
  • Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
  • Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
  • 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 forms

Capsule
  • 30 mg
  • 100 mg
  • 200 mg
  • 300 mg
Tablet, chewable
  • 50 mg
Capsule (Dilantin®)
  • 30 mg
  • 100 mg
Capsule (Phenytek®)
  • 200 mg
  • 300 mg
Suspension
  • 125 mg/5 ml
  • Comes in 237 ml (8 oz) bottle

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)
  • Suspension (generic) - $ (237 ml)

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.
Suspension and tablet
  • Phenytoin suspension and tablets contain the free acid form of phenytoin where the capsules contain the sodium salt of phenytoin
  • There is approximately an 8% increase in drug content with the free acid form over that of the sodium salt
  • Dosage adjustments may be necessary when switching between the capsules and suspension/tablet
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 primarily metabolized by CYP2C9 and to a lesser extent by CYP2C19. It is also a CYP3A4 strong inducer and a CYP1A2 moderate inducer. This, combined with the fact that it has a narrow therapeutic index and is highly protein bound, gives it the potential for a large number of drug interactions. See the Dilantin PI for a comprehensive review.
  • 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 is a CYP enzyme inducer and this may enhance the metabolism of vitamin D and increase the risk of osteoporosis. Consider checking vitamin D, calcium, and phosphate levels during prolonged therapy. BMD testing may be appropriate in some patients.
  • 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 - serious skin reactions including TEN, SJS, acute generalized exanthematous pustulosis (AGEP), and DRESS have been reported in patients taking phenytoin. Reactions can occur at any time during therapy, but they usually occur within the first 28 days. Discontinue phenytoin if a rash occurs, unless it is clearly not drug-related.
  • CYP2C9 alleles - studies have found that Asian carriers of the CYP2C9*3 allele have a higher risk of serious skin reactions when taking phenytoin. CYP2C9 alleles that are associated with decreased CYP2C9 activity (*1/*3, *2/*2, *3/*3) may also cause higher phenytoin levels when compared to normal metabolizers (*1/*1). Use caution when prescribing phenytoin to these patients. [PMID 25096692].
  • HLA-B*1502 allele - carriers of the HLA-B*1502 allele have a higher risk of SJS and TEN when taking carbamazepine. There is some evidence that Asian carriers of this allele may also be at greater risk for serious skin reactions when taking phenytoin. Phenytoin should not be used as an alternative to carbamazepine in patients who are positive for HLA-B*1502. 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.
  • Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
  • Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
  • 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 forms

Capsule (Lyrica®)
  • 25 mg
  • 50 mg
  • 75 mg
  • 100 mg
  • 150 mg
  • 200 mg
  • 225 mg
  • 300 mg
Tablet, extended-release (Lyrica® CR)
  • 82.5 mg
  • 165 mg
  • 330 mg
Solution (Lyrica®)
  • 20 mg/ml
  • Comes in 16 oz (473 ml) bottle

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

  • Lyrica capsule (60 capsules) - YES/$
  • Lyrica solution (473 ml) - YES/$$
  • Lyrica CR (30 tablets) - NO/$$$$

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).
  • Respiratory depression - cases of serious and sometimes fatal respiratory depression have been reported when pregabalin was taken with other CNS depressants, including opioids, and in patients with underlying respiratory disorders. Use caution when prescribing in these situations.
  • Driving and operating machinery - pregabalin may cause dizziness and somnolence which can impair a person's ability to drive and operate machinery
  • 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
  • Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
  • 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® | Trokendi XR® | Qudexy® XR

Dosage forms

Capsule (Topamax®)
  • 15 mg
  • 25 mg
Tablet (Topamax®)
  • 25 mg
  • 50 mg
  • 100 mg
  • 200 mg
Capsule, extended-release (Trokendi XR®)
  • 25 mg
  • 50 mg
  • 100 mg
  • 200 mg
Capsule, extended-release (Qudexy® XR)
  • 25 mg
  • 50 mg
  • 100 mg
  • 150 mg
  • 200 mg
Capsule (Qsymia®)
  • Phentermine - Topiramate
    • 3.75 mg - 23 mg
    • 7.5 mg - 46 mg
    • 11.25 mg - 69 mg
    • 15 mg - 92 mg

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

Topamax® (≥ 12 years old)
  • 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® (≥ 12 years old)
  • 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

Efficacy


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 is a carbonic anhydrase inhibitor and it may increase the risk of metabolic acidosis, hyperammonemia, and kidney stones when given with other carbonic anhydrase inhibitors (e.g. zonisamide, acetazolamide, and dichlorphenamide)

Contraindications / Precautions

  • Pregnancy - DO NOT USE. May increase risk of cleft lip and/or cleft palate (oral clefts) and being small for gestational age.
  • Acute myopia and secondary angle closure glaucoma - topiramate has been associated with a syndrome of acute myopia with secondary angle closure glaucoma. Onset typically occurs within the first month of therapy, and cases have been reported in adults and children. Patients who complain of decreased visual acuity and/or ocular pain should be evaluated immediately. The primary treatment is discontinuation of topiramate as rapidly as possible.
  • Visual field defects - visual field defects independent of elevated intraocular pressure have been reported in patients treated with topiramate. In trials, most defects resolved after discontinuation of topiramate. Consider discontinuing topiramate if vision problems occur at any time during therapy.
  • 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. The risk may be higher when topiramate is taken with valproic acid or zonisamide. 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)
  • Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
  • Serious skin reactions - serious skin reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving topiramate. Topiramate should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. Inform patients about the signs of serious skin reactions.
  • Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
  • 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 forms

NOTE: Each form of valproic acid delivers an equivalent amount of valproate ion, the active ingredient
Capsule (Depakene®)
  • 250 mg
Tablet (Depakote®)
  • 125 mg
  • 250 mg
  • 500 mg
Sprinkle capsule (Depakote®)
  • 125 mg
Tablet, extended-release (Depakote ER®)
  • 250 mg
  • 500 mg
Injection (Depacon®)
  • 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

Efficacy


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 to subtherapeutic levels. Monitor levels closely when combining.
  • 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

Lab interactions

  • Urine ketones - valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test
  • Thyroid function tests - there have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown.

Contraindications / Precautions

  • Mitochondrial DNA disorders (POLG, Alpers-Huttenlocher Syndrome) - DO NOT USE. Risk of hepatotoxicity is increased in these patients. Signs of mitochondrial DNA disorders include unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura.
  • Urea cycle disorders (UCD) - DO NOT USE. Cases of sometimes fatal hyperammonemic encephalopathy have been reported in patients with urea cycle disorders. Urea cycle disorders are rare, but should be considered in patients with with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, history of elevated plasma ammonia or glutamine, cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, protein avoidance, family history of UCD or a family history of unexplained infant deaths (particularly males).
  • Pregnancy - DO NOT USE. Valproic acid can cause major congenital malformations, particularly neural tube defects. See pregnancy studies for more.
  • Hepatotoxicity - cases of hepatotoxicity including liver failure have occurred in patients receiving valproate and its derivatives, especially in the first 6 months of treatment. Children under the age of 2 who are on multiple anticonvulsants, have congenital metabolic disorders, have severe seizure disorders accompanied by mental retardation, and/or have organic brain diseases are at greatest risk. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months.
  • Low platelets - valproic acid may cause a decrease in platelets. In trials of patients with epilepsy who were receiving around 50 mg/kg/day, 27% of patients had at least one platelet count ≤ 75,000 K/µL. After treatment discontinuation, counts returned to normal. The risk appears to be highest at higher blood levels (≥ 110 mcg/ml in females and ≥ 135 mcg/ml in males).
  • Myelodysplasia - cases of myelodysplasia have been reported
  • Hyperammonemia and encephalopathy - valproic acid may raise ammonia levels and cause encephalopathy. The risk is higher when taken with topiramate. Most ammonia elevations are asymptomatic. Consider checking an ammonia level in patients with unexplained lethargy, vomiting, changes in mental status, and/or hypothermia.
  • Hypothermia - hypothermia (temp < 35°C or 95°F) has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. The risk may be greater when taken with topiramate.
  • Serious skin reactions - serious skin reactions including SJS, DRESS, and TEN have been reported. Symptoms may present as fever, rash, lymphadenopathy, and/or facial swelling in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis.
  • Virus stimulation - in vitro studies have suggested that valproic acid may stimulate the replication of HIV and CMV virus. The clinical significance of this is unknown.
  • Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
  • Medication residue in stool - there have been rare reports of medication residue in the stool. Patients with shortened bowels (e.g. colostomy) or diarrhea may be at greater risk. If residue is seen, valproate levels should be monitored closely.
  • Abrupt discontinuation - seizure medications should be withdrawn gradually when possible because abrupt discontinuation may increase the risk of seizure frequency and status epilepticus
  • Pancreatitis - rare cases of pancreatitis have been reported with valproic acid use. Cases have occurred shortly after starting therapy and after years of use. In trials, 2 cases of pancreatitis without alternative etiology were seen in 1,044 patient-years of use.
  • Elderly patients - in trials, elderly patients were at greater risk for somnolence. Starting doses should be lower and dose titrations should be slower in elderly patients.
  • Brain atrophy - rare cases have been reported
  • Liver disease - DO NOT USE. Valproic acid elimination is greatly reduced in significant liver disease.
  • Kidney disease - protein-binding may be decreased. Measure free levels.

Zonisamide (Zonegran®)

Dosage forms

Capsule (Zonegran®)
  • 25 mg
  • 50 mg
  • 100 mg

Dosing

Partial seizures (adults and children > 16 years)
  • Starting: 100 mg once daily
  • Maintenance: 100 - 600 mg/day
  • Max: 600 mg/day
  • May be given once or twice daily
  • Increase dose in increments of 100 mg/day at intervals of no less than 2 weeks
  • Doses > 400 mg/day have not been shown to increase response
  • Zonisamide has a long half-life and it takes 2 weeks to achieve steady state
  • May take without regard to food
  • Swallow capsules whole

Efficacy


Generic / Price

- YES/$ (120 capsules)

Lab monitoring

Levels
  • Trough levels in the range of 10 - 40 mcg/ml are generally considered therapeutic
  • It takes 2 weeks to achieve steady state after dose adjustments [1,4,7]

Pharmacokinetics

  • Half-life (plasma): 63 hours
  • Half-life (red blood cells): 105 hours
  • Time to steady state: 14 days

Mechanism of action

  • The precise mechanism(s) by which zonisamide exerts its antiseizure effect is unknown
  • Zonisamide may work through action at sodium and calcium channels. In vitro pharmacological studies suggest that zonisamide blocks sodium channels and reduces voltage-dependent, transient inward currents (T-type Ca2+ currents), consequently stabilizing neuronal membranes and suppressing neuronal hypersynchronization.

FDA-approved indications

  • Zonisamide is indicated as adjunctive therapy in the treatment of partial seizures in adults (> 16 years) with epilepsy

Side effects

  • NOTE: Side effects presented below are from trials where zonisamide was added to other seizure medications. Only side effects that occurred at an incidence ≥ 4% are listed.

Side effect Zonisamide
(N=269)
Placebo
(N=230)
Somnolence 17% 7%
Anorexia 13% 6%
Dizziness 13% 7%
Headache 10% 8%
Nausea 9% 6%
Agitation/Irritability 9% 4%
Fatigue 8% 6%
Tiredness 7% 5%
Abdominal Pain 6% 3%
Ataxia 6% 1%
Confusion 6% 3%
Difficulty Concentrating 6% 2%
Difficulty with Memory 6% 2%
Depression 6% 3%
Insomnia 6% 3%
Diplopia 6% 3%
Diarrhea 5% 2%
Speech Abnormalities 5% 2%
Flu Syndrome 4% 3%
Nystagmus 4% 2%
Paresthesia 4% 1%
Mental Slowing 4% 2%


Drug interactions

  • CNS depressants - CNS depressants including alcohol may increase the risk of sedation and other neuropsychiatric adverse events when given with zonisamide. Use caution.
  • Carbonic anhydrase inhibitors - zonisamide is a carbonic anhydrase inhibitor and it may increase the risk of metabolic acidosis, hyperammonemia, and kidney stones when given with other carbonic anhydrase inhibitors (e.g. topiramate, acetazolamide, and dichlorphenamide)
  • P-glycoprotein substrates - zonisamide is a weak P-glycoprotein inhibitor. It may increase exposure to P-glycoprotein substrates.
  • CYP3A4 inducers - zonisamide is a CYP3A4 substrate and exposure may be decreased when taken with CYP3A4 inducers. This effect is unlikely to be significant when zonisamide is added to existing therapy, but it may be necessary to adjust zonisamide if CYP3A4 inducers are withdrawn, added, or adjusted during therapy.
  • CYP3A4 inhibitors - zonisamide is a CYP3A4 substrate. In pharmacokinetic studies, strong CYP3A4 inhibitors had no significant effect on zonisamide levels so dose adjustments are not recommended.

Contraindications / Precautions

  • Pregnancy - DO NOT USE. Zonisamide may increase the risk of birth defects.
  • Sulfa allergy - zonisamide is a sulfonamide. Patients with a history of allergies to sulfa drugs may be at increased risk of having an allergic reaction to zonisamide.
  • Serious skin reactions - serious skin reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. Consider discontinuing zonisamide in patients who develop an otherwise unexplained rash. In trials, serious rash or rash that led to discontinuation occurred in up to 2% of patients. Rash typically occurred within the first 16 weeks of treatment.
  • Aplastic anemia and agranulocytosis - rare cases of aplastic anemia and agranulocytosis have been reported in patients receiving zonisamide
  • DRESS syndrome/Multi-Organ Hypersensitivity - rare cases of drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multi-organ hypersensitivity, have been reported in patients receiving zonisamide. DRESS may present with fever, rash, eosinophilia, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.
  • Decreased sweating and hyperthermia - in the postmarketing setting, decreased sweating and hyperthermia have been reported with an incidence of up to 12 cases per 10,000 patient-years of use. Children appear to be at greater risk. Use caution in patients who are exposed to warm weather and when taken with concomitant carbonic anhydrase inhibitors and anticholinergics.
  • Acute myopia and angle closure glaucoma - zonisamide has been associated with a syndrome of acute myopia and angle closure glaucoma. Cases have occurred in both children and adults, and onset typically occurs within the first month of therapy. Patients who complain of decreased visual acuity and/or ocular pain should be evaluated immediately.
  • Suicidal thoughts and behavior - in trials, antiseizure medications have been associated with a higher risk of suicidal thoughts and behaviors. A pooled analysis of 199 placebo-controlled trials that involved 11 different antiepileptic drugs found that the estimated incidence of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients. The increase in risk occurred as early as one week after starting treatment and persisted throughout treatment. The risk was consistent across the drugs analyzed and did not vary by indication (e.g. epilepsy, mood disorders) or age.
  • Non-anion gap metabolic acidosis - zonisamide is a carbonic anhydrase inhibitor and it may cause a non-anion gap, hyperchloremic, metabolic acidosis secondary to renal bicarbonate loss. Zonisamide-induced metabolic acidosis typically occurs early in treatment, but it can develop at any time and at doses as low as 25 mg/day. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet, or specific drugs) may be additive to the bicarbonate-lowering effects of zonisamide. Symptoms of metabolic acidosis include hyperventilation, fatigue, anorexia, and in severe cases, cardiac arrhythmias and stupor. Baseline and periodic measurement of bicarbonate levels is recommended.
  • Kidney stones - the chronic metabolic acidosis induced by zonisamide may increase the risk of kidney stones. Use caution in susceptible patients.
  • Osteomalacia and osteoporosis - the chronic metabolic acidosis induced by zonisamide may increase the risk of osteomalacia and osteoporosis. In trials, zonisamide was associated with reductions in serum phosphorus and increases in serum alkaline phosphatase, changes that may be related to metabolic acidosis and osteomalacia. The effects of zonisamide on growth rates in children and fracture risk in adults is unknown. Use caution in susceptible patients.
  • Serum bicarbonate loss - zonisamide inhibits carbonic anhydrase which leads to the loss of sodium bicarbonate. In adult trials, average serum bicarbonate levels decreased by 2 mEq/L at doses of 100 mg/day and by 4 mEq/L at doses of 300 mg/day. Serum bicarbonate levels persistently < 20 mEq/L were observed in 21% of subjects at doses of 25 mg - 100 mg/day and in 43% at doses of 300 mg/day.
  • Abrupt discontinuation - abrupt withdrawal of zonisamide may increase the risk of seizures. Zonisamide should be discontinued gradually.
  • Depression - zonisamide may increase the risk of depression. In trials, 2.2% of zonisamide-treated patients discontinued zonisamide or were hospitalized for depression compared to 0.4% of placebo-treated patients.
  • Hyperammonemia and encephalopathy - zonisamide can cause metabolic acidosis which can raise ammonia levels and cause encephalopathy. The risk may be higher when zonisamide is taken with valproic acid or topiramate. Measure serum ammonia concentration if signs or symptoms (e.g., unexplained change in mental status, vomiting, or lethargy) of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued. Hyperammonemia from zonisamide may resolve or decrease in severity with a decrease of the daily dose.
  • Increase in serum creatinine - in studies, serum creatinine increased an average of 8% in zonisamide-treated patients compared to none in placebo-treated patients. The increase appeared within the first 4 weeks of treatment, and it was persistent but not progressive. In short-term studies, the GFR returned to normal within 2 - 3 weeks of drug discontinuation. No data is available for long-term use.
  • Liver disease - zonisamide is metabolized by the liver. It has not been studied in liver impairment. Slower titration and more frequent monitoring should be used in liver disease. Manufacturer makes no specific dosage recommendation.
  • Kidney disease
    • CrCl < 50 ml/min: not recommended. Has not been studied.



  • 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.



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