Topiramate

Pharmacologic Category

Anticonvulsant, Miscellaneous

Dosing: Adult

Note: The dosing recommendations in this monograph are expressed as the total daily dose (ie, per 24 hours) unless stated otherwise. The total daily oral dose is given in 1 to 2 divided doses per day depending on the type of preparation. Available preparations include: Oral immediate release (IR) (dosed twice daily) and extended release (ER) (dosed once daily).

Binge-eating disorder (alternative agent) (off-label use):

Oral: Initial: 25 mg once daily; increase dose gradually in progressively larger increments of 25 to 100 mg at intervals ≥1 week based on response and tolerability up to 400 mg/day (McElroy 2007).

Headache, cluster (prevention) (alternative agent; adjunctive therapy) (off-label use):

Note: Some experts often use in combination with verapamil (May 2019).

Oral: Initial: 25 to 50 mg once daily; increase dose gradually in 25 to 50 mg increments at intervals ≥1 week based on response and tolerability, up to a recommended dose of 100 mg/day; a further increase up to 200 mg/day may be necessary in some patients for optimal response (EFNS [May 2006]; Pascual 2007).

Headache, short-lasting unilateral neuralgiform attacks (prevention) (alternative agent) (off-label use): Based on limited data:

Oral: Initial: 15 to 25 mg once daily; may increase dose based on response and tolerability in 25 mg increments every 2 weeks up to 100 mg/day in 2 divided doses, and thereafter in 50 mg increments every few weeks up to 400 mg/day (Cohen 2007; Matharu 2019).

Migraine (prevention):

Oral: Initial: 25 mg once daily; increase dose in 25 to 50 mg increments at intervals ≥1 week based on response and tolerability up to 100 mg/day. Some patients may require up to 200 mg/day for optimal response; however, adverse effects may increase (Linde 2013).

Seizures:

Note: FDA-approved as monotherapy and adjunctive therapy for focal (partial) onset seizures and primary generalized tonic-clonic seizures, or as adjunctive therapy for Lennox-Gastaut syndrome; may be used off label for other seizure types.

Monotherapy: Oral: Initial: 50 mg/day; increase dose in 50 mg increments at weekly intervals based on response and tolerability up to 200 mg/day; thereafter, may further increase in 100 mg increments at weekly intervals up to 400 mg/day.

Adjunctive therapy: Oral: Initial: 25 to 50 mg/day; increase in 25 to 50 mg increments at weekly intervals based on response and tolerability up to 400 mg/day.

Tremor, essential (alternative agent for patients who fail preferred therapies) (off-label use):

Oral: Initial: 25 mg once or twice daily; increase dose gradually in increments of 25 to 50 mg at intervals ≥1 week based on response and tolerability up to 400 mg/day (AAN [Zesiewicz 2011]; Connor 2008; Ondo 2006).

Weight gain, antipsychotic-induced (alternative agent; adjunct to behavioral and antipsychotic modifications) (off-label use):

Oral: Initial: 50 mg/day; increase in 25 to 50 mg increments at weekly intervals based on response and tolerability up to a recommended dose of 200 mg/day (Jarskog 2019; Ko 2005; WFSBP [Hasan 2013]).

Dosing conversion:

Between IR and ER formulations: Convert using same total daily dose but adjust frequency as indicated for the IR (2 times daily) and ER (once daily) products.

Between ER formulations: Bioequivalence has not been demonstrated between Trokendi XR and Qudexy XR.

Discontinuation of therapy: In patients receiving topiramate long-term, unless safety concerns require a more rapid withdrawal, topiramate should be withdrawn gradually over a few weeks to several months to minimize the potential of seizures or other withdrawal symptoms (Schachter 2019). In clinical trials, adult doses were decreased by 50 to 100 mg each week over 2 to 8 weeks for seizure treatment, and by 25 to 50 mg each week for migraine prophylaxis.

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Most older adults have creatinine clearances <70 mL/minute/1.73 m2; obtain a serum creatinine and calculate creatinine clearance prior to initiation of therapy. An initial dose of 25 mg/day may be recommended, followed by incremental increases of 25 mg at weekly intervals until an effective dose is reached; refer to adult dosing for titration schedule.

Dosing: Renal Impairment: Adult

CrCl ≥70 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling.

CrCl <70 mL/minute/1.73 m2: Reduce dose to 50% of normal dose and titrate more slowly.

Hemodialysis: 50 to 100 mg twice daily; administer a supplemental dose (50 to 100 mg) post-dialysis (Israni 2006). Topiramate is cleared by hemodialysis.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; however, topiramate clearance may be reduced in hepatic impairment. Use with caution.

Dosing: Pediatric

Note: Do not abruptly discontinue therapy; taper dosage gradually to prevent rebound effects.

Infantile spasms; monotherapy or adjunctive: Limited data available, efficacy results variable (Weber 2015). Not typically used as first-line therapy, but may be considered in refractory cases (AAN [Go 2012]; Nelson 2015).

Infants, Children, and Adolescents: Oral: Immediate release: Initial dose: 0.5 to 1 mg/kg/day in divided doses twice daily; may titrate based on clinical response and tolerance in 0.5 to 1 mg/kg/day increments at 5- to 7-day intervals; reported range: 2 to 40 mg/kg/day (Korinthenberg 2007; Zou 2008).

Dosing based on an open-label trial of 544 patients diagnosed with infantile spasms (349 infants; 243 patients on monotherapy); initial topiramate dose was 0.5 to 1 mg/kg/day; doses were titrated as appropriate; reported final dose range: 3.57 to 20 mg/kg/day. After 20 weeks of therapy, 460 patients (84.5%) had a >50% reduction in seizures and seizure freedom was attained in 122 (50.2%) as monotherapy and in 117 (38.9%) as add-on therapy (Zou 2008). A higher median initial dose of 1.6 mg/kg/day was reported in another trial of 100 patients (median age: 11.9 months; range: 3.6 to 45.1 months; 36 patients on monotherapy); patients were titrated to an effective final dose; reported final dose range: 2 to 40 mg/kg/day; results showed reduction in infantile spasms from a median of 40 episodes/week to a median of 15 episodes/week and 47 patients had a >50% reduction in all seizures. No difference in efficacy was observed for final dose stratifications of low dose (n=31; 2 to 8 mg/kg/day), medium dose (n=39; 9 to 17 mg/kg/day), or high dose (n=24; 18 to 40 mg/kg/day) (Korinthenberg 2007). However, other trials have reported a poor response to topiramate; in a single-center trial evaluating 31 infants and young children, 9.7% (3/31) achieved remission with topiramate (responder maximum dose range: 25 to 28 mg/kg/day), and all experienced subsequent electroclinical relapse (Weber 2015).

Migraine; prevention:

Note: Pediatric migraine efficacy trials have been observed to have a high placebo response; a meta-analysis has shown that 30% to 61% of subjects receiving placebo report decreased number of migraine attacks or decrease in headache days. Specific to topiramate therapy, trials have shown a reduction in number of headache days and migraine attacks compared to placebo; there is insufficient evidence in pediatric subjects receiving topiramate to demonstrate a 50% reduction in headache frequency, headache day, and migraine disability compared to placebo (AAN/AHS [Oskoui 2019]).

Children 6 to <12 years; weight: ≥20 kg: Limited data available: Oral: Immediate release: Initial: 15 mg once daily for 1 week; then increase to 15 mg twice daily for 1 week; then increase to 25 mg twice daily for 7 days; continue to gradually titrate to effect up to target dose of 2 to 3 mg/kg/day divided twice daily; maximum daily dose: 200 mg/day has been reported; however, in older pediatric patients, a targeted daily dose of 100 mg/day is recommended (AAN/AHS [Oskoui 2019]; Winner 2005). Dosing based on a double-randomized, placebo-controlled trial of 90 pediatric patients <12 years (treatment arm: n=59; mean age: 11.3 years as part of a larger trial with a total of 108 pediatric patients receiving topiramate compared to 49 receiving placebo) which showed a mean reduction in migraine days/month with topiramate and significantly more topiramate patients experienced ≥75% reduction in mean monthly migraine days compared to placebo (32% vs 14%) for overall study population; mean maintenance dose: 2 mg/kg/day; treatment duration of maintenance dose: 12 weeks (Winner 2005).

Children ≥12 years and Adolescents:

Immediate release: Oral: Initial: 25 mg/day once daily at night for 1 week; increase at weekly intervals in 25 mg/day increments as tolerated and indicated to recommended dose of 50 mg twice daily; in a double-blind, placebo-controlled, dose-finding trial of 103 pediatric patients ≥12 years (mean age: 14.2 years), the daily dose of 100 mg/day was shown to significantly decrease frequency of migraine attacks compared to a lower dose of 50 mg/day (Lewis 2009).

Extended release: Qudexy XR, Trokendi: Oral: Initial: 25 mg/day once daily at night for 1 week; increase at weekly intervals in 25 mg/day increments as tolerated and indicated to recommended dose of 100 mg/day; during titration, some patients may require longer intervals prior to dose escalation.

Seizure disorder, adjunctive therapy for partial onset seizures, primary generalized tonic-clonic seizures, or Lennox Gastaut syndrome:

Children and Adolescents 2 to 16 years:

Immediate release: Children and Adolescents 2 to 16 years: Oral: Initial: 1 to 3 mg/kg/day (maximum dose: 25 mg/dose) administered nightly for 1 week; increase at 1- to 2-week intervals in increments of 1 to 3 mg/kg/day in 2 divided doses; titrate dose to response; usual maintenance: 5 to 9 mg/kg/day in 2 divided doses; maximum daily dose: 400 mg/day.

Extended release:

Qudexy XR: Children and Adolescents 2 to 16 years: Oral: Initial: 25 mg once daily (approximately 1 to 3 mg/kg/day) administered nightly for 1 week; increase at 1- to 2-week intervals in increments of 1 to 3 mg/kg/day rounded to the nearest appropriate capsule size administered once daily; titrate dose to response; usual maintenance range: 5 to 9 mg/kg/dose once daily; maximum daily dose: 400 mg/day.

Trokendi XR: Children and Adolescents 6 to 16 years, able to swallow capsule whole: Oral: Initial: 25 mg once daily (approximately 1 to 3 mg/kg/day) administered nightly for 1 week; increase at 1- to 2-week intervals in increments of 1 to 3 mg/kg/day rounded to the nearest appropriate capsule size administered once daily; titrate dose to response; usual maintenance: 5 to 9 mg/kg/dose once daily; maximum daily dose: 400 mg/day.

Adolescents ≥17 years:

Immediate release: Oral: Initial: 25 to 50 mg/day administered daily for 1 week; increase at weekly intervals by 25 to 50 mg/day; administer in 2 divided doses; titrate dose to response. Usual maintenance dose dependent on seizure type; for partial onset seizures or Lennox-Gastaut syndrome: 100 to 200 mg twice daily; usual maintenance dose for primary generalized tonic-clonic seizures 200 mg twice daily; maximum daily dose: 400 mg/day; Note: Doses above 400 mg/day have not been shown to increase efficacy in dose-response studies in adults with partial onset seizures.

Extended release: Quedexy XR, Trokendi XR: Oral: Initial: 25 to 50 mg once daily for 1 week; increase at weekly intervals by 25 to 50 mg/day once daily; titrate dose to response; longer intervals between dosage adjustment may be used; usual maintenance dose for partial onset seizures or Lennox Gastaut syndrome: 200 to 400 mg once daily; usual maintenance dose for primary generalized tonic-clonic seizures: 400 mg once daily; maximum daily dose: 400 mg/day; higher doses have not been studied.

Seizure disorder, monotherapy for partial onset seizures or primary generalized tonic-clonic seizures:

Immediate release:

Children 2 to <10 years: Oral: Initial: 25 mg once daily (in evening); may increase if tolerated to 25 mg twice daily in week 2; thereafter, may increase by 25 to 50 mg/day at weekly intervals over 5 to 7 weeks up to the lower end of the target daily maintenance dosing range (ie, to the minimum recommended maintenance dose); if additional seizure control is needed and therapy is tolerated, may further increase by 25 to 50 mg/day at weekly intervals up to the upper end of the target daily maintenance dosing range (ie, to the maximum recommended maintenance dose):

Target daily fixed maintenance dosing range:

≤11 kg: 150 to 250 mg/day in 2 divided doses.

12 to 22 kg: 200 to 300 mg/day in 2 divided doses.

23 to 31 kg: 200 to 350 mg/day in 2 divided doses.

32 to 38 kg: 250 to 350 mg/day in 2 divided doses.

>38 kg: 250 to 400 mg/day in 2 divided doses.

Children ≥10 years and Adolescents: Oral: Initial: 25 mg twice daily; increase at weekly intervals by 50 mg/day increments up to a dose of 100 mg twice daily (week 4 dose); thereafter, may further increase at weekly intervals by 100 mg/day increments up to the recommended maximum dose of 200 mg twice daily.

Extended release:

Qudexy XR:

Children 2 to 9 years: Oral: Initial: 25 mg once daily (in evening); may increase if tolerated to 50 mg once daily in week 2; thereafter, may increase by 25 to 50 mg/day at weekly intervals over 5 to 7 weeks up to the lower end of the target daily maintenance dosing range (ie, to the minimum recommended maintenance dose); if additional seizure control is needed and therapy is tolerated, may further increase by 25 to 50 mg/day at weekly intervals up to the upper end of the target daily maintenance dosing range (ie, to the maximum recommended maintenance dose); see the following table.

Children ≥10 years and Adolescents: Oral: Initial: 50 mg once daily for 1 week; increase at weekly intervals by 50 mg/day increments up to a dose of 200 mg once daily (week 4 dose); thereafter, may increase at weekly intervals by 100 mg/day increments up to the recommended dose of 400 mg once daily.

Trokendi XR:

Children 6 to 9 years able to swallow capsule whole: Oral: Initial: 25 mg once daily (in evening); may increase if tolerated to 50 mg once daily in week 2; thereafter, may increase by 25 to 50 mg/day at weekly intervals over 5 to 7 weeks up to the lower end of the target daily maintenance dosing range (ie, to the minimum recommended maintenance dose); if additional seizure control is needed and therapy is tolerated, may further increase by 25 to 50 mg/day at weekly intervals up to the upper end of the target daily maintenance dosing range (ie, to the maximum recommended maintenance dose); see the following table.

Children ≥10 years and Adolescents: Oral: Initial: 50 mg once daily for 1 week; increase at weekly intervals by 50 mg/day increments up to a dose of 200 mg once daily (week 4 dose); thereafter, may increase at weekly intervals by 100 mg/day increments up to the recommended dose of 400 mg once daily.

Dosing: Renal Impairment: Pediatric

Oral:

Infants, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; however, the following guidelines have been used by some clinicians (Aronoff 2007): Immediate release:

GFR >50 mL/minute/1.73 m2: No dosage adjustment necessary

GFR 10 to 50 mL/minute/1.73 m2: Administer 50% of dose

GFR <10 mL/minute/1.73 m2: Administer 25% of dose

Hemodialysis/peritoneal dialysis (PD): Administer 25% of dose; supplemental dose after hemodialysis needed

Continuous renal replacement therapy (CRRT): Administer 50% of dose

Dosing: Hepatic Impairment: Pediatric

Children and Adolescents: There are no dosage adjustments provided in the manufacturer's labeling; however, clearance may be reduced. Carefully adjust dose as plasma concentrations may be increased if normal dosing is used.

Calculations

• Creatinine Clearance by Cockcroft-Gault
• Creatinine Clearance by Cockcroft-Gault (SI units)
• Creatinine Clearance by Cockcroft-Gault with IBW
• Creatinine Clearance by Cockcroft-Gault with IBW (SI units)

Use: Labeled Indications

Migraine (prevention): Prophylaxis of migraine headache in patients ≥12 years of age

Seizures: Monotherapy or adjunctive therapy in patients ≥2 years of age (immediate release and Qudexy XR) or ≥6 years of age (Trokendi XR) with focal (partial) onset or primary generalized tonic-clonic seizures; adjunctive therapy in patients ≥2 years of age (immediate release and Qudexy XR) or ≥6 years of age (Trokendi XR only) with seizures associated with Lennox-Gastaut syndrome

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Antipsychotic-induced weight gainLevel of Evidence [B, G]

Data from multiple meta-analyses with varying degrees of heterogeneity support the use of topiramate in promoting modest weight loss and preventing weight gain associated with second-generation antipsychotics in patients with schizophrenia (evidence is more limited in patients with bipolar disorder) Ref.

Based on the Canadian Network for Mood and Anxiety Treatments (CANMAT) recommendations for the management of patients with mood disorders and comorbid metabolic disorders, topiramate is recommended as a second-line option after nonpharmacologic strategies for managing weight gain in patients with bipolar and major depressive disorders, and is recognized as often being used as a secondary prevention strategy for antipsychotic-related weight gain Ref. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects suggest topiramate as an alternative option based on some evidence that it may improve metabolic parameters and antipsychotic-induced weight gain, especially when given in combination with olanzapine; however, caution is advised based on cases of agitation and aggressive behavior associated with topiramate therapy. Access Full Off-Label Monograph

Binge eating disorderLevel of Evidence [B, G]

Data from 3 randomized, double-blind, placebo-controlled trials support the use of topiramate in the treatment of binge eating disorder for reduction of binge episode frequency and body weight Ref.

Based on the American Psychiatric Association guidelines for the treatment of patients with eating disorders, topiramate is an effective alternative agent for binge reduction and weight loss; however, adverse effects may be problematic for some patients. Similarly, based on the WFSBP guidelines for the pharmacological treatment of eating disorders, topiramate is effective and recommended for the management of binge eating disorder, with a moderate risk-benefit ratio. Access Full Off-Label Monograph

Headache, cluster (prevention)Level of Evidence [C]

Data from a limited number of preliminary clinical trials suggest that topiramate may be beneficial in the prevention of cluster headache Ref.

Based on the European Federation of Neurological Societies (EFNS) guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias, topiramate is probably effective for the prevention of cluster headache and may be considered as an alternative treatment option.

Headache, short-lasting unilateral neuralgiform attacks (prevention)Level of Evidence [C]

Data from a limited number of patients studied suggest that topiramate may be beneficial for the prevention of short-lasting unilateral neuralgiform headache attacks Ref.

Tremor, essentialLevel of Evidence [B, G]

Data from a randomized, double-blind, placebo-controlled study and a pooled analysis of 3 double-blind, placebo-controlled, crossover studies support the use of topiramate in the treatment of essential tremor; however, many patients experienced treatment-limiting adverse effects, including paresthesia, nausea, concentration/attention difficulty, and somnolence Ref.

Based on the American Academy of Neurology practice parameter for the treatment of essential tremor, topiramate is probably effective and may be considered as an alternative agent for the treatment of limb tremor associated with essential tremor. Access Full Off-Label Monograph

Level of Evidence Definitions

Level of Evidence Scale

Use: Unsupported: Adult

Neuropathic pain

Data from a meta-analysis of 3 parallel-group, double-blind, placebo-controlled trials in diabetic neuropathy and a double-blind, randomized, cross-over study in lumbar radiculopathy demonstrated negative results indicating that topiramate is no more effective than placebo in the treatment of neuropathic pain. In addition, withdrawals due to adverse events were significantly higher in patients receiving topiramate than placebo (Wiffen 2013).

American Academy of Neurology evidence-based guidelines for the treatment of painful diabetic neuropathy (PDN) describe topiramate as an agent with insufficient evidence to support or refute use in the treatment of PDN (AAN [Bril 2011]). However, a consensus statement from the International Association for the Study of Pain suggests that topiramate may be considered in patients who have not responded to first- or second-line medications (Dworkin 2007).

Clinical Practice Guidelines

Cluster Headache:

European Federation of Neurological Societies (EFNS), “EFNS Guidelines on the Treatment of Cluster Headache and Other Trigeminal-Autonomic Cephalalgias,” 2006

Eating Disorders:

American Psychiatric Association (APA), “Guideline Watch (August 2012): Practice Guideline for the Treatment of Patients With Eating Disorders, Third Edition,” 2012

American Psychiatric Association (APA), “Practice Guideline for the Treatment of Patients With Eating Disorders, Third Edition,” 2006

World Federation of Societies of Biological Psychiatry (WFSBP), “WFSBP Guidelines for the Pharmacological Treatment of Eating Disorders,” 2011

Essential Tremor:

American Academy of Neurology, “Practice Parameter: Therapies for Essential Tremor,” June 2005

American Academy of Neurology, “Evidence-based Guideline Update: Treatment of Essential Tremor,” 2011

Metabolic Disorders:

Canadian Network for Mood and Anxiety Treatments (CANMAT), “Recommendations for the Management of Patients with Mood Disorders and Comorbid Metabolic Disorders,” February 2012

World Federation of Societies of Biological Psychiatry (WFSBP), “WFSBP Guidelines for Biological Treatment of Schizophrenia, Part 2: Update 2012 on the Long-term Treatment of Schizophrenia and Management of Antipsychotic-induced Side Effects,” 2013

Migraine Prophylaxis:

Neurology, "Evidence-Based Guideline Update: Pharmacologic Treatment for Episodic Migraine Prevention in Adults,” April 2012

Personality Disorders:

World Federation of Societies of Biological Psychiatry (WFSBP), “WFSBP guidelines for biological treatment of personality disorders,” 2007.

Seizure Disorders:

American Academy of Neurology and American Epilepsy Society, “Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy,” 2018

American Academy of Neurology and American Epilepsy Society, “Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy, “ 2018

Administration: Oral

Administer without regard to meals. Administer the IR formulation in divided doses. It is not recommended to crush, break, or chew IR tablets due to bitter taste. Swallow ER and sprinkle capsules whole. Sprinkle capsules and Qudexy XR capsules may also be opened to sprinkle the entire contents on a small amount (~1 teaspoon) of soft food; swallow immediately and do not chew. Do not store drug/food mixture for future use. Do not sprinkle Trokendi XR capsules on food, chew, or crush. Avoid alcohol use with Trokendi XR within 6 hours prior to and 6 hours after administration.

Bariatric surgery: Capsule, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR tablet and sprinkle capsule formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, if swallowing is an issue after surgery, Qudexy XR formulation may be sprinkled on a small amount of soft food.

Administration: Pediatric

Oral: May be administered without regard to food.

Immediate release:

Tablets: Broken tablets have a bitter taste; tablets may be crushed, mixed with water, and administered immediately.

Sprinkle capsules: Swallow sprinkle capsules whole or open and sprinkle contents on small amount of soft food (eg, 1 teaspoonful of applesauce, oatmeal, ice cream, pudding, custard, or yogurt); swallow sprinkle/food mixture immediately; do not chew; do not store for later use; drink fluids after dose to make sure mixture is completely swallowed.

Extended release:

Qudexy XR: May be swallowed whole or may be opened and sprinkled on a small amount (~1 teaspoon) of soft food; swallow immediately and do not chew.

Trokendi XR: Swallow capsules whole; do not sprinkle capsules on food, chew, or crush. Avoid alcohol use with within 6 hours prior to and 6 hours after administration.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 3]).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.

NIOSH recommends single gloving for administration of intact tablets or capsules. If manipulating tablets/capsules (eg, to prepare an oral suspension), NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye/face protection as well as ventilated engineering controls are recommended. NIOSH recommends double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection for administration of an oral liquid/feeding tube administration (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).

Storage/Stability

Extended release capsules: Store at 15°C to 30°C (59°F to 86°F). Protect from moisture. Protect from light.

Sprinkle capsules: Store at or below 25°C (77°F). Protect from moisture.

Tablets: Store at 15°C to 30°C (59°F to 86°F). Protect from moisture.

Extemporaneously Prepared

20 mg/mL Oral Suspension (ASHP Standard Concentration) (ASHP 2017)

A 20 mg/mL oral suspension may be made with topiramate tablets or powder, Ora-Plus and Ora-Sweet. Measure out 2,000 mg of topiramate (equivalent tablets or powder). If using tablets, crush in a mortar and reduce to a fine powder. Add 10 mL of Ora-Plus and mix to a uniform paste; mix while adding an additional 40 mL of Ora-Plus in incremental proportions. Add a small amount of Ora-Sweet and mix. Transfer to a calibrated, amber bottle; rinse mortar with Ora-Sweet and add sufficient quantity to make 100 mL. Label "shake well." Stable for 90 days refrigerated or at room temperature (Allen 2017).

Allen LV Jr. Contemporary compounding: topiramate 20 mg/mL oral suspension. U.S. Pharmacist. 2017;42(5):46-47.

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat seizures.

• It is used to prevent migraine headaches.

• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Nausea

• Weight loss

• Change in taste

• Diarrhea

• Anxiety

• Fatigue

• Loss of strength and energy

• Common cold symptoms

• Joint pain

• Headache

• Dry mouth

• Flushing

• Hair loss

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection

• Acidosis like confusion, fast breathing, fast heartbeat, abnormal heartbeat, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or loss of strength and energy.

• Depression like thoughts of suicide, anxiety, emotional instability, or confusion.

• High ammonia levels like abnormal heartbeat, abnormal breathing, confusion, pale skin, slow heartbeat, seizures, sweating, vomiting, or twitching.

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding.

• Kidney stone like back pain, abdominal pain, or blood in the urine.

• Confusion

• Difficulty focusing

• Change in balance

• Severe dizziness

• Passing out

• Inability to eat

• Unable to pass urine

• Seizures

• Burning or numbness feeling

• Bone pain

• Chest pain

• Trouble with memory

• Muscle pain

• Muscle weakness

• Difficulty speaking

• Trouble sleeping

• Tremors

• Abnormal gait

• Involuntary eye movements

• Agitation

• Irritability

• Panic attacks

• Mood changes

• Blurred vision

• Eye redness

• Vision changes

• Eye pain

• Eye irritation

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

Administration issues

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Qudexy XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/205122s010lbl.pdf#page=60

Topamax: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020505s060,020844s051lbl.pdf#page=51

Trokendi XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/201635s011s017lbl.pdf#page=58

Contraindications

Extended release: Recent alcohol use (ie, within 6 hours prior to and 6 hours after administration) (Trokendi XR only); patients with metabolic acidosis who are taking concomitant metformin (Qudexy XR only).

Immediate release: There are no contraindications listed in the manufacturer's labeling.

Canadian labeling: Hypersensitivity to topiramate or any component of the formulation or container; pregnancy and women in childbearing years not using effective contraception (migraine prophylaxis only).

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: Cognitive dysfunction (confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems), psychiatric disturbances (depression or mood disorders), and sedation (somnolence or fatigue) may occur with use; incidence may be related to rapid titration and higher doses; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). May also cause paresthesia, dizziness, and ataxia.

• Hyperammonemia/encephalopathy: Hyperammonemia with or without encephalopathy may occur with monotherapy or in combination with valproic acid and has been documented in patients who have tolerated each drug alone; incidence may be dose-related. Risk may be increased in patients with inborn errors of metabolism or decreased hepatic mitochondrial activity. May be asymptomatic; monitor for lethargy, vomiting, or unexplained changes in mental status.

• Metabolic acidosis: May be associated with hyperchloremic nonanion gap metabolic acidosis due to inhibition of carbonic anhydrase and increased renal bicarbonate loss. Decreases in serum bicarbonate are relatively common (up to 67% of epilepsy patients and 77% of migraine patients) but usually mild-to-moderate (average decrease of 4 mEq/L at dose of 400 mg/day in adults and 6 mg/kg/day in children). However, risk may be increased in patients with a predisposing condition (renal, respiratory and/or hepatic impairment), diarrhea, ketogenic diet, status epilepticus, or concurrent treatment with other drugs which may cause acidosis. Metabolic acidosis may occur at dosages as low as 50 mg/day. Serum bicarbonate should be monitored, as well as potential complications of chronic acidosis (nephrolithiasis, nephrocalcinosis, osteomalacia/osteoporosis, and reduced growth rates and/or reduced weight in children). Dose reduction or discontinuation (by tapering dose) should be considered in patients with persistent or severe metabolic acidosis. If treatment is continued, alkali supplementation should be considered.

• Oligohidrosis/hyperthermia: May be associated with oligohidrosis and hyperthermia, most frequently in children; use caution and monitor closely during strenuous exercise, during exposure to high environmental temperature, or in patients receiving other carbonic anhydrase inhibitors and drugs with anticholinergic activity.

• Ophthalmic effects: Has been associated with acute myopia and secondary angle-closure glaucoma in adults and children, typically within 1 month of initiation; discontinue in patients with acute onset of decreased visual acuity and/or ocular pain.

• Renal calculus: Topiramate exhibits weak carbonic anhydrase inhibitory properties and may increase the risk of kidney stones about 2 to 4 times that of the untreated population. Kidney stones have been reported in children and adults (incidence higher in males). Consider avoiding use in patients on a ketogenic diet. The risk of kidney stones may be reduced by increasing fluid intake.

• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.

• Visual field defects: Has been reported independent of increased intraocular pressure; generally reversible upon discontinuation. Consider discontinuation if visual problems occur at any time during treatment.

Disease-related concerns:

• Depression: Use with caution in patients with depression or suicidal tendencies.

• Eating disorders: The exacerbation and development of eating disorders, including anorexia nervosa and bulimia, has been reported in case reports of adolescents receiving topiramate for migraines or chronic headaches and an adult receiving topiramate for epilepsy. Prior to initiation of topiramate screen for a history of eating disorder symptoms, eating disorder risk factors (eg, history of dieting behavior), cognitive symptoms of eating disorders (eg, weight or shape concerns, fear of gaining weight, drive for thinness), and any recent changes in social functioning including increased withdrawal or isolation. Inquire whether the patient has unrealistic or unhealthy weight goals. Evaluate exercise habits (eg, look for over-exercising or compulsive exercising above that of similarly athletic peers) and dietary intake; assess rigid patterns or avoidance of specific categories of foods and preoccupation with maintaining a “healthy diet” or experimentation with fad diets. In adolescents assess developmental weight history with growth curves. Monitor eating behaviors and weight closely in patients receiving topiramate who have eating disorder symptoms or risk factors (Lebow 2015; Rosenow 2002).

• Hepatic impairment: Use caution with hepatic impairment; clearance may be reduced. Dosage adjustment may be required.

• Renal impairment: Use caution with renal impairment; clearance may be reduced. Dosage adjustment may be required.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution; dosage adjustment may be necessary. Weight loss, cognitive impairment, sedation, and gait/balance disturbances may be more pronounced in the older adult cohort (Sommer 2010).

Other warnings/precautions:

• Withdrawal: Do not discontinue abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. Doses were also gradually withdrawn in migraine prophylaxis studies (decreased in weekly intervals by 25-50 mg/day).

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Despite evidence of benefit as monotherapy in the older adult population, this drug may not be a drug of choice in the elderly until all other therapies for seizures have been exhausted. This is due to a cadre of adverse effects which can be pronounced in the older adult patient. Weight loss, gait/balance impairments, tremor, sedation, and cognitive impairment can be especially troublesome in the older adult (Blaszczyk 2015; Groselj 2005; Sommer 2010). Because of the cognitive impairment issues which can manifest with topiramate (eg, word recall, short-term memory impairment), this medication should be identified as potentially at issue when a patient is being worked up for dementia.

Since most elderly will have a CrCl <70 mL/minute, it is important to either measure or estimate by calculation the CrCl prior to initiating therapy.

Warnings: Additional Pediatric Considerations

In pediatric clinical trials for adjunctive treatment of seizures, persistent decreases in serum bicarbonate occurred in 67% of patients receiving topiramate (versus 10% of those receiving placebo). Markedly low serum bicarbonate values were reported in 11% of pediatric patients receiving topiramate (versus 0% of those receiving placebo). In pediatric monotherapy trials, persistent decreases in serum bicarbonate occurred in 9% of patients receiving 50 mg/day and 25% of patients receiving 400 mg/day. Markedly low serum bicarbonate values were reported in 1% to 6% of pediatric patients receiving topiramate monotherapy. The risk of topiramate-induced metabolic acidosis may be increased in patients with predisposing conditions (eg, diarrhea, status epilepticus, hepatic impairment, renal dysfunction, severe respiratory disorders, ketogenic diet, surgery) or concurrent treatment with other drugs that may cause acidosis. Metabolic acidosis may be more common and more severe in infants and children <2 years of age with up to 45% of patients receiving 25 mg/kg/day developing metabolic acidosis in clinical trials. Monitor for potential complications of chronic acidosis including nephrolithiasis, nephrocalcinosis, osteomalacia/osteoporosis, and reduction in growth rates (including weight). Reductions in Z scores (from baseline) for length, weight, and head circumference were observed in infants and toddlers who received long-term topiramate (for up to 1 year) for intractable partial epilepsy; reductions in Z scores for length and weight correlated to the severity of metabolic acidosis. Serum bicarbonate should be monitored at baseline and periodically during topiramate therapy. The most common adverse effects of topiramate observed in children include the following: Anorexia, cognitive problems, dizziness, fatigue, fever, flushing, headache, mood problems, paresthesia, somnolence, and weight loss; neuropsychiatric and cognitive adverse effects were reported with a lower incidence in children than adults. Pediatric patients <24 months of age may be at increased risk for topiramate-associated hyperammonemia, especially when used concurrently with valproic acid; monitor closely for lethargy, vomiting, or unexplained changes in mental status.

Risk of nephrolithiasis (kidney stones) is higher in children; reported incidence in adults: 1.5%; in pediatric patients <24 months with long-term use (up to 1 year): 7% (kidney or bladder stones); one retrospective study evaluating long-term use (1 year) in children with epilepsy (n=96; mean age: 6.9 ± 3.8 years) reported an incidence of 5.2% (Mahmoud 2011); risk may be increased with ketogenic diet or concomitant drugs that produce metabolic acidosis; avoid use while on topiramate therapy; maintain adequate hydration during therapy; monitor for signs or symptoms of kidney or bladder or kidney stone development.

Extended release dosage forms (Qudexy XR and Trokendi XR) are not bioequivalent and should not be interchanged. Qudexy XR capsules may be opened and contents sprinkled on a small amount (~1 teaspoon) of soft food. Do not open and sprinkle Trokendi XR capsules on food, nor chew or crush; doing so may disrupt the triphasic release properties.

Reproductive Considerations

Effective contraception should be used in females of reproductive potential who are not planning a pregnancy; consider use of alternative medications in women who wish to become pregnant.

Pregnancy Considerations

Based on limited data (n=5), topiramate was found to cross the placenta and could be detected in neonatal serum (Ohman 2002).

Topiramate may cause fetal harm if administered to a pregnant woman. An increased risk of oral clefts (cleft lip and/or palate) and for being small for gestational age (SGA) has been observed following in utero exposure. Data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry reported that the prevalence of oral clefts was 1.1% for infants exposed to topiramate during the first trimester of pregnancy, versus 0.36% for infants exposed to a reference antiepileptic drug, and 0.12% for infants with no exposure born to mothers without epilepsy; the relative risk of oral clefts in infants exposed to topiramate was calculated to be 9.6 (95% CI: 4 to 23). Data from the NAAED Pregnancy Registry reported that the prevalence of small for gestational age newborns was 19.7% for newborns exposed to topiramate in utero, versus 7.9% for newborns exposed to a reference antiepileptic drug, and 5.4% for newborns with no exposure born to mothers without epilepsy. Although not evaluated during pregnancy, metabolic acidosis may be induced by topiramate. Metabolic acidosis during pregnancy may result in adverse effects and fetal death. Pregnant women and their newborns should be monitored for metabolic acidosis. In general, maternal polytherapy with antiepileptic drugs may increase the risk of congenital malformations; monotherapy with the lowest effective dose is recommended. Newborns of women taking antiepileptic medications may be at an increased risk of a 1 minute Apgar score <7 (Harden 2009).

Maternal serum concentrations may decrease during the second and third trimesters of pregnancy; therefore, therapeutic drug monitoring should be considered during pregnancy and postpartum in patients who require therapy (Ohman 2009; Westin 2009).

Data collection to monitor pregnancy and infant outcomes following exposure to topiramate is ongoing. Patients may enroll themselves into the NAAED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.

Breast-Feeding Considerations

Topiramate is present in breast milk.

The relative infant dose (RID) of topiramate is ~3% to 23% when calculated using a range of breast milk concentrations obtained from three lactating women and compared to a weight-adjusted maternal dose of 150 to 200 mg/day (Ohman 2002).

In general, breastfeeding is considered acceptable when the RID of a medication is <10%; when the RID is >25% breastfeeding should generally be avoided (Anderson 2016; Ito 2000).

The RID of topiramate was calculated using a range of milk concentrations of 1.6 to 14.6 micromolar, providing an estimated daily infant dose via breast milk of ~0.1 to 0.7 mg/kg/day. These milk concentrations were obtained following maternal administration of oral topiramate 150 to 200 mg/day in three women 2 weeks' to 3 months' postpartum; concomitant medications included carbamazepine or valproic acid, both of which may have had an impact on maternal serum concentrations. Topiramate was detected in the plasma of the breastfed infants at ~10% to 20% of the maternal plasma concentration (Ohman 2002).

Diarrhea and somnolence have been reported in breastfed infants. In 1 infant, resolution of diarrhea occurred 2 days after breastfeeding was stopped (Westergren 2014).

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Briggs' Drugs in Pregnancy & Lactation

• Topiramate

Adverse Reactions

Adverse events are reported for adult and pediatric patients for various indications and regimens. A wide range of dosages were studied. Incidence of adverse events was frequently lower in the pediatric population studied.

>10%:

Central nervous system: Paresthesia (adolescents and adults: 19% to 51%; children and adolescents: 3% to 12%), fatigue (8% to 15%), drowsiness (adolescents and adults: 6% to 15%), dizziness (adolescents and adults: 6% to 14%), memory impairment (1% to 11%)

Endocrine & metabolic: Decreased serum bicarbonate (adolescents and adults: 14% to 77%; children and adolescents: 9% to 25%; >5 mEq/L to <17 mEq/L: 1% to 11%), hyperammonemia (adolescents: 14% to 26%; ≥50% above ULN [adolescents]: 9%), weight loss (4% to 17%)

Gastrointestinal: Abdominal pain (adolescents and adults: 6% to 15%), anorexia (adolescents and adults: 4% to 15%), dysgeusia (adolescents and adults: 3% to 15%), nausea (adolescents and adults: 8% to 13%), diarrhea (2% to 11%)

Respiratory: Upper respiratory tract infection (13% to 26%)

Miscellaneous: Fever (1% to 12%)

1% to 10%:

Cardiovascular: Flushing (children and adolescents: ≤5%), chest pain (adults: 1% to 2%)

Central nervous system: Disturbance in attention (≤10%), lack of concentration (≤10%), depression (adults: 7% to 9%; children and adolescents: ≤3%), insomnia (adolescents and adults: 6% to 9%), mood disorder (1% to 8%), hypoesthesia (adolescents and adults 4% to 7%), anxiety (adolescents and adults: 4% to 6%), cognitive dysfunction (1% to 6%), psychomotor impairment (adolescents and adults: 2% to 5%), headache (children and adolescents: 4%), nervousness (adolescents and adults: 4%), ataxia (adolescents and adults: 1% to 4%), behavioral problems (children and adolescents: ≤3%), confusion (≤3%), hypertonia (adults: ≤3%), vertigo (children and adolescents: ≤3%), agitation (adolescents and adults: 2%), exacerbation of depression (adolescents and adults: 2%), speech disturbance (adolescents and adults: 1%)

Dermatologic: Alopecia (1% to 4%), pruritus (adolescents and adults: 1% to 4%), skin rash (1% to 4%), acne vulgaris (adults: 2% to 3%)

Endocrine & metabolic: Menstrual disease (adolescents and adults: 3%), intermenstrual bleeding (children and adolescents: ≤3%), increased gamma-glutamyl transferase (adults: 1% to 3%), increased thirst (adolescents and adults: 2%)

Gastrointestinal: Dyspepsia (adolescents and adults: 4% to 5%), constipation (adolescents and adults: 1% to 4%), gastroenteritis (adolescents and adults: 3%), gastritis (adults: ≤3%), xerostomia (adolescents and adults: 1% to 3%), gastroesophageal reflux disease (adults: 1% to 2%), ageusia (adolescents and adults: 1%)

Genitourinary: Urinary tract infection (adolescents and adults: 1% to 4%), premature ejaculation (adolescents and adults: 3%), decreased libido (adults: ≤3%), urinary frequency (≤3%), vaginal hemorrhage (adults: ≤3%), cystitis (adults: 1% to 3%), urinary incontinence (children and adolescents: 1% to 3%), dysuria (adults: ≤2%)

Hematologic & oncologic: Hemorrhage (4% to 5%), anemia (children and adolescents: 1% to 3%), neoplasm (adolescents and adults: 2%)

Hypersensitivity: Hypersensitivity reaction (adolescents and adults: 2% to 4%)

Infection: Viral infection (3% to 8%), infection (2% to 8%)

Neuromuscular & skeletal: Arthralgia (adolescents and adults: 3% to 7%), asthenia (≤6%), muscle spasm (≤3%), lower extremity pain (adolescents and adults: 2% to 3%)

Ophthalmic: Conjunctivitis (adolescents and adults: 2% to 7%), blurred vision (adolescents and adults: 4%), visual disturbance (adolescents and adults: 1% to 2%)

Otic: Otitis media (adolescents and adults: 1% to 2%)

Renal: Nephrolithiasis (adolescents and adults: ≤3%)

Respiratory: Sinusitis (1% to 10%), cough (adolescents and adults: 2% to 7%), rhinitis (2% to 7%), pharyngitis (adolescents and adults: 5% to 6%), bronchitis (1% to 5%), epistaxis (children and adolescents: ≤4%), dyspnea (adolescents and adults: 1% to 3%)

Miscellaneous: Accidental injury (adolescents and adults: 9%), language problems (adolescents and adults: 6% to 7%)

Frequency not defined:

Cardiovascular: Hypotension, orthostatic hypotension, syncope

Central nervous system: Suicidal ideation, suicidal tendencies

Endocrine & metabolic: Hyperchloremia, increased serum total protein, increased uric acid

Gastrointestinal: Gingival hemorrhage, hematuria

Hematologic & oncologic: Abnormal serum phosphorus level (decreased), decreased neutrophils, decreased white blood cell count, eosinophilia, quantitative disorders of platelets (increased)

Hepatic: Increased serum alkaline phosphatase

Neuromuscular & skeletal: Myalgia

Ophthalmic: Myopia, scotoma, visual field defect

Renal: Increased blood urea nitrogen, increased serum creatinine

<1%, postmarketing, and/or case reports: Acute myopia with secondary angle-closure glaucoma, bullous rash, calcium nephrolithiasis, erythema multiforme, hepatic failure, hepatitis, hyperammonemic encephalopathy, hyperchloremic metabolic acidosis (nonanion gap), hyperthermia, hypohidrosis, maculopathy, major hemorrhage (children), pancreatitis, pemphigus, Stevens-Johnson syndrome, toxic epidermal necrolysis

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Amphetamine Allergy

Metabolism/Transport Effects

None known.

Drug Interactions Open Interactions

Alcohol (Ethyl): May enhance the CNS depressant effect of Topiramate. Alcohol (Ethyl) may increase the serum concentration of Topiramate. This applies specifically to use with the extended-release topiramate capsules (Trokendi XR). Also, topiramate concentrations may be subtherapeutic in the later portion of the dosage interval. Management: Concurrent use of alcohol within 6 hours of ingestion of extended-release topiramate (Trokendi XR) is contraindicated. Any use of alcohol with topiramate should be avoided when possible and should only be undertaken with extreme caution. Risk X: Avoid combination

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Alpha-/Beta-Agonists (Indirect-Acting): Carbonic Anhydrase Inhibitors may increase the serum concentration of Alpha-/Beta-Agonists (Indirect-Acting). Risk C: Monitor therapy

Amantadine: Carbonic Anhydrase Inhibitors may increase the serum concentration of Amantadine. Risk C: Monitor therapy

Amitriptyline: Topiramate may enhance the CNS depressant effect of Amitriptyline. Topiramate may increase serum concentrations of the active metabolite(s) of Amitriptyline. Topiramate may increase the serum concentration of Amitriptyline. Risk C: Monitor therapy

Amphetamines: Carbonic Anhydrase Inhibitors may decrease the excretion of Amphetamines. Risk C: Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of Topiramate. Risk C: Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

CarBAMazepine: May decrease the serum concentration of Topiramate. Risk C: Monitor therapy

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of other Carbonic Anhydrase Inhibitors. The development of acid-base disorders with concurrent use of ophthalmic and oral carbonic anhydrase inhibitors has been reported. Management: Avoid concurrent use of different carbonic anhydrase inhibitors if possible. Monitor patients closely for the occurrence of kidney stones and with regards to severity of metabolic acidosis. Risk X: Avoid combination

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk D: Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Estrogen Derivatives (Contraceptive): Topiramate may decrease the serum concentration of Estrogen Derivatives (Contraceptive). Contraceptive failure is possible. Management: Risk appears greatest for higher topiramate doses (200 mg/day or greater). Some have recommended using at least 50 mcg/day of ethinyl estradiol, but the effectiveness of this is unclear. Consider a nonhormonal form of contraception. Risk D: Consider therapy modification

Flecainide: Carbonic Anhydrase Inhibitors may increase the serum concentration of Flecainide. Risk C: Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Risk D: Consider therapy modification

Fosphenytoin: May decrease the serum concentration of Topiramate. Topiramate may increase the serum concentration of Fosphenytoin. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Lacosamide: Antiepileptic Agents (Sodium Channel Blockers) may enhance the adverse/toxic effect of Lacosamide. Specifically the risk for bradycardia, ventricular tachyarrhythmias, or a prolonged PR interval may be increased. Risk C: Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lithium: Topiramate may increase the serum concentration of Lithium. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Risk C: Monitor therapy

Loop Diuretics: May enhance the hypokalemic effect of Topiramate. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification

Memantine: Carbonic Anhydrase Inhibitors may increase the serum concentration of Memantine. Risk C: Monitor therapy

MetFORMIN: Topiramate may enhance the adverse/toxic effect of MetFORMIN. Risk C: Monitor therapy

Methenamine: Carbonic Anhydrase Inhibitors may diminish the therapeutic effect of Methenamine. Management: Consider avoiding this combination. Monitor for decreased therapeutic effects of methenamine if used concomitant with a carbonic anhydrase inhibitor. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Mianserin: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Orlistat: May decrease the serum concentration of Anticonvulsants. Risk C: Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Risk D: Consider therapy modification

Phenytoin: Topiramate may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Topiramate. Risk C: Monitor therapy

Pioglitazone: Topiramate may decrease the serum concentration of Pioglitazone. Risk C: Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Primidone: Carbonic Anhydrase Inhibitors may enhance the adverse/toxic effect of Primidone. Specifically, osteomalacia and rickets. Carbonic Anhydrase Inhibitors may decrease the serum concentration of Primidone. Risk C: Monitor therapy

Progestins (Contraceptive): Topiramate may decrease the serum concentration of Progestins (Contraceptive). Management: Caution patients that this combination may be associated with reduced contraceptive effectiveness. Consider adding an additional (non-hormonal) contraceptive method. Risk D: Consider therapy modification

QuiNIDine: Carbonic Anhydrase Inhibitors may decrease the excretion of QuiNIDine. Risk C: Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Salicylates: May enhance the adverse/toxic effect of Carbonic Anhydrase Inhibitors. Salicylate toxicity might be enhanced by this same combination. Management: Avoid these combinations when possible.Dichlorphenamide use with high-dose aspirin as contraindicated. If another combination is used, monitor patients closely for adverse effects. Tachypnea, anorexia, lethargy, and coma have been reported. Risk D: Consider therapy modification

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Risk D: Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Thiazide and Thiazide-Like Diuretics: May enhance the hypokalemic effect of Topiramate. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Topiramate. Management: Monitor for increased topiramate levels/adverse effects (e.g., hypokalemia) with initiation/dose increase of a thiazide diuretic. Closely monitor serum potassium concentrations with concomitant therapy. Topiramate dose reductions may be necessary. Risk D: Consider therapy modification

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ulipristal: Topiramate may decrease the serum concentration of Ulipristal. Risk X: Avoid combination

Valproate Products: Topiramate may enhance the adverse/toxic effect of Valproate Products. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Food Interactions

Ketogenic diet may increase the possibility of acidosis and/or kidney stones. Management: Monitor for symptoms of acidosis or kidney stones.

Monitoring Parameters

Seizure frequency, hydration status; electrolytes (recommended monitoring includes serum bicarbonate at baseline and periodically during treatment), serum creatinine; monitor for symptoms of acute acidosis and complications of long-term acidosis (nephrolithiasis, nephrocalcinosis, osteomalacia/osteoporosis, and reduced growth rates and/or weight in children); ammonia level in patients with unexplained lethargy, vomiting, or mental status changes; intraocular pressure, symptoms of secondary angle closure glaucoma; suicidality (eg, suicidal thoughts, depression, behavioral changes); weight and eating behaviors in patients with eating disorder symptoms or risk factors; sedation

Advanced Practitioners Physical Assessment/Monitoring

Obtain electrolytes (including sodium bicarbonate at baseline and periodically), serum creatinine, and ammonia levels (if altered mental status occurs). Dosage adjustment may be needed in renal impairment. Monitor therapeutic effectiveness (seizure activity, type, duration) at beginning of therapy and throughout. Monitor weight periodically. Monitor for visual changes/disturbances. Assess for signs and symptoms of acidosis. Assess eating and weight behaviors in patients with eating disorder symptoms or risk factors. Teach patient seizure safety precautions.

Nursing Physical Assessment/Monitoring

Check ordered labs and report abnormalities. Monitor therapeutic response (seizure activity, force, type, duration) at beginning of therapy and throughout. Use and teach seizure/safety precautions. Monitor weight periodically. Monitor for visual changes/disturbances. Educate patient to monitor for weight loss or changes in appetite and to report.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule ER 24 Hour Sprinkle, Oral:

Qudexy XR: 25 mg, 50 mg, 100 mg, 150 mg, 200 mg

Generic: 25 mg, 50 mg, 100 mg, 150 mg, 200 mg

Capsule Extended Release 24 Hour, Oral:

Trokendi XR: 25 mg [contains brilliant blue fcf (fd&c blue #1), sodium benzoate]

Trokendi XR: 50 mg, 100 mg, 200 mg [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #6 (sunset yellow), sodium benzoate]

Capsule Sprinkle, Oral:

Topamax Sprinkle: 15 mg, 25 mg

Generic: 15 mg, 25 mg

Tablet, Oral:

Topamax: 25 mg, 50 mg, 100 mg, 200 mg

Generic: 25 mg, 50 mg, 100 mg, 200 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule Sprinkle, Oral:

Topamax Sprinkle: 15 mg, 25 mg

Tablet, Oral:

Topamax: 25 mg, 100 mg, 200 mg [contains polysorbate 80]

Generic: 25 mg, 50 mg, 100 mg, 200 mg

Anatomic Therapeutic Chemical (ATC) Classification

• N03AX11

Generic Available (US)

May be product dependent

Pricing: US

Capsule ER 24 Hour Sprinkle (Qudexy XR Oral)

25 mg (per each): $10.15

50 mg (per each): $13.22

100 mg (per each): $26.19

150 mg (per each): $32.21

200 mg (per each): $35.83

Capsule ER 24 Hour Sprinkle (Topiramate ER Oral)

25 mg (per each): $9.37

50 mg (per each): $12.21

100 mg (per each): $24.18

150 mg (per each): $29.75

200 mg (per each): $33.08

Capsule ER 24 Hour Therapy Pack (Trokendi XR Oral)

25 mg (per each): $12.39

50 mg (per each): $16.14

100 mg (per each): $31.97

200 mg (per each): $43.74

Capsule, sprinkles (Topamax Sprinkle Oral)

15 mg (per each): $7.01

25 mg (per each): $8.47

Capsule, sprinkles (Topiramate Oral)

15 mg (per each): $2.42

25 mg (per each): $2.92

Tablets (Topamax Oral)

25 mg (per each): $7.41

50 mg (per each): $14.79

100 mg (per each): $20.20

200 mg (per each): $23.65

Tablets (Topiramate Oral)

25 mg (per each): $2.22 - $2.55

50 mg (per each): $4.42 - $5.10

100 mg (per each): $6.04 - $6.96

200 mg (per each): $7.07 - $8.15

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Anticonvulsant activity may be due to a combination of potential mechanisms: Blocks neuronal voltage-dependent sodium channels, enhances GABA(A) activity, antagonizes AMPA/kainate glutamate receptors, and weakly inhibits carbonic anhydrase.

Pharmacodynamics/Kinetics

Note: Immediate release preparations are bioequivalent (sprinkle capsule and tablet); extended release capsules (Trokendi XR) administered once daily is bioequivalent to twice daily administration of immediate release formulations.

Absorption: Good, rapid; immediate release formulation is unaffected by food. A single Trokendi XR dose with a high-fat meal increased the Cmax by 37% and shortened the Tmax to approximately 8 hours; this effect is significantly reduced following repeat administrations. A single Qudexy XR dose with a high-fat meal delayed the Tmax by 4 hours.

Distribution: Vd: 0.6 to 0.8 L/kg

Protein binding: 15% to 41% (inversely related to plasma concentrations)

Metabolism: Not extensively metabolized. Minor amounts metabolized in liver via hydroxylation, hydrolysis, and glucuronidation; there is evidence of renal tubular reabsorption; percentage of dose metabolized in liver and clearance are increased in patients receiving enzyme inducers (eg, carbamazepine, phenytoin)

Bioavailability: ~80% (immediate release)

Half-life elimination:

Immediate release:

Not receiving concomitant enzyme inducers or valproic acid:

Neonates (full-term) with hypothermia: ~43 hours (Filippi 2009)

Infants and Children 9 months to <4 years: 10.4 hours (range: 8.5 to 15.3 hours) (Mikaeloff 2004)

Children 4 to 7 years: Mean range: 7.7 to 8 hours (Rosenfeld 1999)

Children 8 to 11 years: Mean range: 11.3 to 11.7 hours (Rosenfeld 1999)

Children and Adolescents 12 to 17 years: Mean range: 12.3 to 12.8 hours (Rosenfeld 1999)

Receiving concomitant enzyme inducers (eg, carbamazepine, phenytoin, phenobarbital):

Neonates (full-term) with hypothermia: 26.5 hours (Filippi 2009)

Infants and Children 9 months to <4 years: 6.5 hours (range: 3.75 to 10.2 hours) (Mikaeloff 2004)

Children and Adolescents 4 to 17 years: 7.5 hours (Rosenfeld 1999)

Receiving valproic acid: Infants and Children 9 months to 4 years: 9.2 hours (range: 7.23 to 12 hours) (Mikaeloff 2004)

Adults: 19 to 23 hours (mean: 21 hours)

Adults with renal impairment: 59 ± 11 hours

Extended release: Qudexy XR: ~56 hours; Trokendi XR: ~31 hours

Time to peak, serum:

Immediate release:

Neonates (full-term) with hypothermia: 3.8 hours (Filippi 2009)

Infants and Children 9 months to <4 years: 3.7 hours (range: 1.5 to 10.2 hours) (Mikaeloff 2004)

Children 4 to 17 years: Mean range: 1 to 2.8 hours (Rosenfeld 1999)

Adults: 2 hours; range: 1.4 to 4.3 hours

Extended release: Qudexy XR: ~20 hours; Trokendi XR: ~24 hours

Excretion: Urine (~70% as unchanged drug); may undergo renal tubular reabsorption

Clearance:

Not receiving concomitant enzyme inducers or valproic acid:

Neonates (full-term) with hypothermia: 13.4 mL/kg/hour (Filippi 2009)

Infants and Children 9 months to <4 years: 46.5 mL/kg/hour (range: 30.5 to 70.9 mL/kg/hour) (Mikaeloff 2004)

Children 4 to 17 years: 27.6 mL/kg/hour (Rosenfeld 1999)

Receiving concomitant enzyme inducers:

Neonates (full-term) with hypothermia: 17.9 mL/kg/hour (Filippi 2009)

Infants and Children 9 months to <4 years: 85.4 mL/kg/hour (range: 46.2 to 135 mL/kg/hour) (Mikaeloff 2004)

Children and Adolescents 4 to 17 years: 60.6 mL/kg/hour (Rosenfeld 1999)

Receiving valproic acid: Infants and Children 9 months to <4 years: 49.6 mL/kg/hour (range: 26.6 to 60.2 mL/kg/h) (Mikaeloff 2004)

Adults: 20 to 30 mL/minute

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Clearance is reduced 42% in moderately impaired (creatinine clearance [CrCl] 30 to 69 mL/minute/1.73 m2) and 54% in severely impaired (CrCl <30 mL/minute/1.73 m2) patients. Significantly hemodialyzed; dialysis clearance is 120 mL/minute (4-6 times higher than in adults with normal renal function).

Hepatic function impairment: Clearance is reduced by a mean of 26% in patients with moderate to severe hepatic impairment.

Geriatric: Half-life elimination is longer. Plasma and renal clearance were reduced 21% and 19%, respectively. Reduced clearance resulted in slightly higher Cmax (23% for immediate release; 30% for Trokendi XR) and AUC (25% for immediate release; 44% for Trokendi XR). Topiramate clearance is decreased only to the extent that renal function is reduced. Tmax for Trokendi XR is shorter (16 hours).

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Frequent occurrence of distorted sense of taste (dysgeusia); occurrence of loss of taste (ageusia), xerostomia (normal salivary flow resumes upon discontinuance); gingival hemorrhage has been reported.

Effects on Bleeding

No information available to require special precautions

Related Information

• Adverse Effects of Anticonvulsants
• Beers Criteria 2019: Potentially Inappropriate Medication Use in Older Adults ≥65 Years of Age
• Oral Medications That Should Not Be Crushed or Altered
• Safe Handling of Hazardous Drugs

Pharmacotherapy Pearls

May be associated with weight loss in some patients

FDA Approval Date

December 24, 1996

References

<800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 40-NF 35). Rockville, MD: United States Pharmacopeia Convention; 2017:83-102.

Aigner M, Treasure J, Kaye W, Kasper S; WFSBP Task Force on Eating Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of eating disorders. World J Biol Psychiatry. 2011;12(6):400-443. doi: 10.3109/15622975.2011.602720.[PubMed 21961502]

Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42-52.[PubMed 27060684]

Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007.

ASHP. Standardize 4 Safety Initiative Compounded Oral Liquid Version 1.01. July 2017. https://www.ashp.org/-/media/assets/pharmacy-practice/s4s/docs/s4s-ashp-oral-compound-liquids.ashx?la=en&hash=4C2E4F370B665C028981B61F6210335AD5D0D1D6.

Brandes JL, Saper JR, Diamond M, et al, “Topiramate for Migraine Prevention: A Randomized Controlled Trial,” JAMA, 2004, 291(8):965-73.[PubMed 14982912]

Bril V, England J, Franklin GM, et al; American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation [published correction appears in Neurology. 2011;77(6):603]. Neurology. 2011;76(20):1758-1765.[PubMed 21482920]

Brophy GM, Bell R, Claassen J, et al, "Guidelines For the Evaluation and Management of Status Epilepticus," Neurocrit Care, 2012, 17(1):3-23.[PubMed 22528274]

Claudino AM, de Oliveira IR, Appolinario JC, et al. Double-blind, randomized, placebo-controlled trial of topiramate plus cognitive-behavior therapy in binge-eating disorder. J Clin Psychiatry. 2007;68(9):1324-1332.[PubMed 17915969]

Cohen AS. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. Cephalalgia. 2007;27(7):824-832.[PubMed 17598764]

Connor GS, Edwards K, Tarsy D. Topiramate in essential tremor: findings from double-blind, placebo-controlled, crossover trials. Clinical Neuropharmacol. 2008;31(2):97-103.[PubMed 18382182]

Correll CU, Maayan L, Kane J, Hert MD, Cohen D. Efficacy for psychopathology and body weight and safety of topiramate-antipsychotic cotreatment in patients with schizophrenia spectrum disorders: results from a meta-analysis of randomized controlled trials. J Clin Psychiatry. 2016;77(6):e746-e756. doi: 10.4088/JCP.15r10373.[PubMed 27337425]

Das C, Mendez G, Jagasia S, Labbate LA. Second-generation antipsychotic use in schizophrenia and associated weight gain: a critical review and meta-analysis of behavioral and pharmacologic treatments. Ann Clin Psychiatry. 2012;24(3):225-239.[PubMed 22860242]

Doose DR, Walker SA, Gisclon LG, et al, “Single-Dose Pharmacokinetics and Effect of Food on the Bioavailability of Topiramate, a Novel Antiepileptic Drug,” J Clin Pharmacol, 1996, 36(10):884-91.[PubMed 8930774 ]

Dworkin RH, O'Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132(3):237-251.[PubMed 17920770]

Fiedorowicz JG, Miller DD, Bishop JR, Calarge CA, Ellingrod VL, Haynes WG. Systematic review and meta-analysis of pharmacological interventions for weight gain from antipsychotics and mood stabilizers. Curr Psychiatry Rev. 2012;8(1):25-36.[PubMed 22712004]

Filippi L, la Marca G, Fiorini P, et al, "Topiramate Concentrations in Neonates Treated With Prolonged Whole Body Hypothermia for Hypoxic Ischemic Encephalopathy," Epilepsia, 2009, 50(11):2355-61.[PubMed 19744111]

Filippi L, Poggi C, la Marca G, et al, "Oral Topiramate in Neonates With Hypoxic Ischemic Encephalopathy Treated With Hypothermia: A Safety Study," J Pediatr, 2010, 157(3):361-6.[PubMed 20553846]

Glass HC, Poulin C, and Shevell MI, "Topiramate For the Treatment of Neonatal Seizures," Pediatr Neurol, 2011, 44(6):439-42.[PubMed 21555055]

Glauser TA, “Preliminary Observations on Topiramate in Pediatric Epilepsies,” Epilepsia, 1997, 38(Suppl 1):S37-41.[PubMed 9092958 ]

Glauser T, Ben-Menachem E, Bourgeois B, et al, "ILAE Treatment Guidelines: Evidence-Based Analysis of Antiepileptic Drug Efficacy and Effectiveness as Initial Monotherapy For Epileptic Seizures and Syndromes," Epilepsia, 2006, 47(7):1094-120.[PubMed 16886973]

Glauser TA, “Topiramate Use in Pediatric Patients,” Can J Neurol Sci, 1998b, 25(3):S8-12.[PubMed 9706734]

Go CY, Mackay MT, Weiss SK, et al, "Evidence-Based Guideline Update: Medical Treatment of Infantile Spasms. Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society," Neurology, 2012, 78(24):1974-80.[PubMed 22689735]

Harden CL, Meador KJ, Pennell PB, et al. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology. 2009;73(2):133-141.[PubMed 19398681]

Hasan A, Falkai P, Wobrock T, et al; WFSBP Task force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects. World J Biol Psychiatry. 2013;14(1):2-44. doi: 10.3109/15622975.2012.739708.[PubMed 23216388]

Hershey AD, Powers SW, Vockell AL, et al, “Effectiveness of Topiramate in the Prevention of Childhood Headaches,” Headache, 2002, 42(8):810-8.[PubMed 12390646 ]

Israni RK, Kasbekar N, Haynes K, Berns JS. Use of antiepileptic drugs in patients with kidney disease. Semin Dial. 2006;19(5):408-416.[PubMed 16970741]

Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000;343(2):118-126.[PubMed 10891521]

Jarskog LF, Yu R. Modifiable risk factors for cardiovascular disease in patients with severe mental illness. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed February 21, 2019.

Korinthenberg R, Schreiner A. Topiramate in children with west syndrome: a retrospective multicenter evaluation of 100 patients. J Child Neurol. 2007;22(3):302-306.[PubMed 17621500]

Ko YH, Joe SH, Jung IK, Kim SH. Topiramate as an adjuvant treatment with atypical antipsychotics in schizophrenic patients experiencing weight gain. Clin Neuropharmacol. 2005;28(4):169-175.[PubMed 16062095]

Lebow J, Chuy JA, Cedermark K, Cook K, Sim LA. The development or exacerbation of eating disorder symptoms after topiramate initiation [published online April 6, 2015]. Pediatrics.[PubMed 25847809]

Lewis D, Winner P, Saper J, et al, "Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Topiramate For Migraine Prevention in Pediatric Subjects 12 to 17 Years of Age," Pediatrics, 2009, 123(3):924-34.[PubMed 19255022]

Linde M, Mulleners WM, Chronicle EP, McCrory DC. Topiramate for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev. 2013;(6):CD010610. doi: 10.1002/14651858.CD010610.[PubMed 23797676]

Mahmood S, Booker I, Huang J, Coleman CI. Effect of topiramate on weight gain in patients receiving atypical antipsychotic agents. J Clin Psychopharmacol. 2013;33(1):90-94.[PubMed 23277264]

Mahmoud AA, Rizk T, El-Bakri NK, et al, "Incidence of Kidney Stones With Topiramate Treatment in Pediatric Patients," Epilepsia, 2011, 52(10):1890-3.[PubMed 21883178]

Matharu MS, Cohen AS. Short-lasting unilateral neuralgiform headache attacks: Treatment. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 6, 2019.

May A, Leone M, Afra J, et al; EFNS Task Force. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol. 2006;13(10):1066-1077.[PubMed 16987158]

May A. Cluster headache: Treatment and prognosis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed February 1, 2019.

McElroy SL, Arnold LM, Shapira NA, et al. Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial [published correction appears in Am J Psychiatry. 2003;160(3):612]. Am J Psychiatry. 2003;160(2):255-261. doi:10.1176/appi.ajp.160.2.255.[PubMed 12562571]

McElroy SL, Hudson JI, Capece JA, Beyers K, Fisher AC, Rosenthal NR; Topiramate Binge Eating Disorder Research Group. Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry. 2007;61(9):1039-1048. doi:10.1016/j.biopsych.2006.08.008.[PubMed 17258690]

McIntyre RS, Alsuwaidan M, Goldstein BI, et al; Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force. The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force recommendations for the management of patients with mood disorders and comorbid metabolic disorders. Ann Clin Psych. 2012;24(1):69-81.[PubMed 22303523]

Mikaeloff Y, Rey E, Soufflet C, et al, "Topiramate Pharmacokinetics in Children With Epilepsy Aged From 6 Months to 4 Years," Epilepsia, 2004, 45(11):1448-52.[PubMed 15509246]

Mizuno Y, Suzuki T, Nakagawa A, et al. Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: a systematic review and meta-analysis. Schizophren Bull. 2014;40(6):1385-1403.[PubMed 24636967]

Nelson GR. Management of infantile spasms. Transl Pediatr. 2015;4(4):260-270.[PubMed 26835388]

Ohman I, Vitols S, Luef G, et al, “Topiramate Kinetics During Delivery, Lactation, and in the Neonate: Preliminary Observations,” Epilepsia, 2002, 43(10):1157-60.[PubMed 12366729]

Ohman I, Sabers A, de Flon P, et al, "Pharmacokinetics of Topiramate During Pregnancy," Epilepsy Res, 2009, 87(2-3):124-9.[PubMed 19740626]

Ondo WG, Jankovic J, Connor GS, et al; Topiramate Essential Tremor Study Investigators. Topiramate in essential tremor: a double-blind, placebo-controlled trial. Neurology. 2006;66(5):672-677.[PubMed 16436648]

Oskoui M, Pringsheim T, Billinghurst L, et al. Practice guideline update summary: Pharmacologic treatment for pediatric migraine prevention: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Headache Society [published correction appears in Neurology. 2020;94(1):50]. Neurology. 2019;93(11):500-509.[PubMed 31413170]

Pascual J, Láinez MJ, Dodick D, Hering-Hanit R. Antiepileptic drugs for the treatment of chronic and episodic cluster headache: a review. Headache. 2007;47(1):81-89.[PubMed 17355498]

Pellock JM, “Managing Pediatric Epilepsy Syndromes With New Antiepileptic Drugs,” Pediatrics, 1999, 104(5 Pt 1):1106-16.[PubMed 10545555 ]

Qudexy XR (topiramate) extended-release capsules [prescribing information]. Maple Grove, MN: Upsher-Smith Laboratories, LLC; February 2020.

Rosenfeld WE, Doose DR, Walker SA, et al, "A Study of Topiramate Pharmacokinetics and Tolerability in Children With Epilepsy," Pediatr Neurol, 1999, 20(5):339-44.[PubMed 10371378]

Rosenow F, Knake S, Hebebrand J. Topiramate and anorexia nervosa. Am J Psychiatry. 2002;159(12):2112-2113.[PubMed 12450969 ]

Sachdeo RC, “Topiramate. Clinical Profile in Epilepsy,” Clin Pharmacokinet, 1998, 34(5):335-46.[PubMed 9592618]

Schachter SC. Overview of the management of epilepsy in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed September 6, 2019.

Silverstein FS and Ferriero DM, "Off-Label Use of Antiepileptic Drugs For the Treatment of Neonatal Seizures," Pediatr Neurol, 2008, 39(2):77-9.[PubMed 18639748]

Sommer BR, Fenn HH. Review of topiramate for the treatment of epilepsy in elderly patients. Clin Interv Aging. 2010;5:89-99.[PubMed 20458347]

Topamax (topiramate) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals Inc; May 2019.

Topamax (topiramate) [product monograph]. Toronto, Ontario, Canada: Janssen Inc; March 2019.

Trokendi XR (topiramate) extended-release capsules [prescribing information]. Rockville, MD: Supernus Pharmaceuticals Inc; February 2019.

US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. http://www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-161.pdf. Updated September 2016. Accessed October 5, 2016.

Weber A, Cole JW, Mytinger JR. Infantile spasms respond poorly to topiramate. Pediatr Neurol. 2015;53(2):130-134.[PubMed 26068002]

Westergren T, Hjelmeland K, Kristoffersen B, Johannessen SI, Kalikstad B. Probable topiramate-induced diarrhea in a 2-month-old breast-fed child - a case report. Epilepsy Behav Case Rep. 2014;(2):22-23.[PubMed 25667861]

Westin AA, Nakken KO, Johannessen SI, et al, "Serum Concentration/dose Ratio of Topiramate During Pregnancy," Epilepsia, 2009, 50(3):480-5.[PubMed 19178558]

Wiffen PJ, Derry S, Lunn MP, Moore RA. Topiramate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2013;(8):CD008314. doi: 10.1002/14651858.CD008314.pub3.[PubMed 23996081]

Winner P, Pearlman EM, Linder SL, et al, "Topiramate For Migraine Prevention in Children: A Randomized, Double-Blind, Placebo-Controlled Trial," Headache, 2005, 45(10):1304-12.[PubMed 16324162]

Yager J, Devlin MJ, Halmi KA, et al; American Psychiatric Association. Practice guideline for the treatment of patients with eating disorders, 3rd edition. http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/eatingdisorders.pdf. Published June 2006.

Yager J, Devlin MJ, Halmi KA, et al; American Psychiatric Association. Guideline watch (August 2012): practice guideline for the treatment of patients with eating disorders, 3rd edition. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/eatingdisorders-watch.pdf. Published August 2012.

Zesiewicz TA, Elble RJ, Louis ED, et al. Evidence-based guideline update: treatment of essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2011;77(19):1752-1755. doi: 10.1212/WNL.0b013e318236f0fd.[PubMed 22013182]

Zou LP, Lin Q, Qin J, et al. Evaluation of open-label topiramate as primary or adjunctive therapy in infantile spasms. Clin Neuropharmacol. 2008;31(2):86-92.[PubMed 18382180]

Brand Names: International

Acomicil (ES); Conviban (EG); Epilramate (TW); Epimate (BH, EG, LK, PH, ZW); Epiramat (UA); Epitomax (FI, FR); Epitop (PH); Etopira (BD); Fagodol (ES); Gabatopa (KR); Ipramax (BH, LB); Moramax (TH); Piramed (BD); Pitomate (TH); Pradox (TH); Seziril (LK); Tamate (AU); Tiramate (NZ); Topagan (LB); Topamac (AR, CO, EC, IN, PE, PY, UY); Topamax (AE, AT, AU, BB, BE, BG, BH, BR, CH, CL, CN, CR, CY, CZ, DE, DO, EE, EG, ES, FI, GB, GT, HK, HN, HR, IE, IL, IQ, IR, IT, JM, JO, KR, KW, LB, LK, LT, LU, LV, LY, MT, MX, MY, NI, NL, NZ, OM, PA, PH, PK, PL, PT, QA, RO, RU, SA, SG, SI, SK, SV, SY, TH, TR, TW, VE, VN, YE, ZA); Topamax Sprinkle (AE, BB, CY, HK, KR, KW, NZ, SA); Topictal (EC, PY); Topilepsin (UA); Topimax (DK, IS, NO, SE); Topina (JP); Topinmate (TW); Topirol (PH); Topiromax (UA); Topiron (KR); Topirva (BD); Topitrim (IL); Topmate (BD, KR); Topnotch (EG); Topomac (GR); Topvex (PH); Toramat (LB); Toramate (TW)

Last Updated 5/5/20