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Topiramate

Pronunciation

Pronunciation

(toe PYRE a mate)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule ER 24 Hour Sprinkle, Oral:

Qudexy XR: 25 mg (30 ea, 500 ea); 50 mg (30 ea, 500 ea); 100 mg (30 ea, 500 ea); 150 mg (30 ea, 500 ea); 200 mg (30 ea, 500 ea)

Generic: 25 mg (30 ea, 500 ea); 50 mg (30 ea, 500 ea); 100 mg (30 ea, 500 ea); 150 mg (30 ea, 500 ea); 200 mg (30 ea, 500 ea)

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

Topiragen: 25 mg [DSC], 50 mg [DSC], 100 mg [DSC], 200 mg [DSC]

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

Brand Names: U.S.

  • Qudexy XR
  • Topamax
  • Topamax Sprinkle
  • Topiragen [DSC]
  • Trokendi XR

Pharmacologic Category

  • Anticonvulsant, Miscellaneous

Pharmacology

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.

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

Metabolism

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)

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 (Fillipi 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 (Fillipi 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

Time to Peak

Immediate release:

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

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

Half-Life Elimination

Immediate release:

Not receiving concomitant enzyme inducers or valproic acid:

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

Protein Binding

15% to 41% (inversely related to plasma concentrations)

Special Populations: 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).

Special Populations: Hepatic Function Impairment

Cl may be decreased.

Special Populations: Elderly

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).

Use: Labeled Indications

Epilepsy:

Monotherapy: As initial monotherapy in patients ≥2 years (immediate release and Qudexy XR) or ≥10 years (Trokendi XR) with partial-onset or primary generalized tonic-clonic seizures

Adjunctive therapy: As adjunctive therapy in patients ≥2 years (immediate release and Qudexy XR only) or ≥6 years (Trokendi XR only) with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome

Migraine (immediate release only): Prophylaxis of migraine headache in adults and adolescents ≥12 years.

Use: Unlabeled

Infantile spasms, neuropathic pain; prophylaxis of cluster headache

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

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

Canadian labeling (not in U.S. 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)

Dosing: Adult

Note: Do not abruptly discontinue therapy; taper dosage gradually to prevent rebound effects. (In clinical trials, adult doses were withdrawn by decreasing in weekly intervals of 50 to 100 mg daily gradually over 2 to 8 weeks for seizure treatment, and by decreasing in weekly intervals by 25 to 50 mg daily for migraine prophylaxis.) Bioequivalence has not been demonstrated between Trokendi XR and Qudexy XR.

Epilepsy, monotherapy: Partial-onset seizure and primary generalized tonic-clonic seizure: Oral:

Immediate release: Initial: 25 mg twice daily; may increase weekly by 50 mg daily up to 100 mg twice daily (week 4 dose); thereafter, may further increase weekly by 100 mg daily up to the recommended dose of 200 mg twice daily.

Extended release: Initial: 50 mg daily for 1 week; may increase weekly by 50 mg daily up to 200 mg once daily (week 4 dose); thereafter, may further increase weekly by 100 mg daily up to the recommended dose of 400 mg once daily.

Canadian labeling: Oral: Immediate release: Initial: 25 mg once daily (in evening); may increase to 25 mg twice daily in weeks 2 or 3 and up to 50 mg twice daily by weeks 3 or 4; may further increase weekly in increments of 50 mg daily up to recommended maximum of 200 mg twice daily.

Epilepsy, adjunctive therapy: Partial-onset seizure, primary generalized tonic-clonic seizure, or Lennox-Gastaut syndrome: Oral: Note: Doses >1600 mg have not been studied.

Immediate release: Initial: 25 mg once or twice daily for 1 week; may increase weekly by 25 to 50 mg daily until response; usual maintenance dose: 100 to 200 mg twice daily (partial-onset seizures) or 200 mg twice daily (primary generalized tonic-clonic seizures). Doses >400 mg have not shown additional benefit for treatment of partial-onset seizures.

Extended release: Initial: 25 to 50 mg once daily for 1 week; may increase weekly by 25 to 50 mg daily until response; usual maintenance dose: 200 to 400 mg once daily (partial-onset seizures, Lennox-Gastaut syndrome) or 400 mg once daily (primary generalized tonic-clonic seizures). Doses >400 mg daily have not shown additional benefit for treatment of partial-onset seizures.

Canadian labeling: Oral: Immediate release: Initial: 25 mg once or twice daily; may increase weekly by 50 mg daily up to the recommended dose of 100 to 200 mg twice daily (maximum recommended dose: 800 mg daily; doses >400 mg daily have shown no additional benefit).

Migraine prophylaxis: Oral: Immediate release: Initial: 25 mg once daily (in evening); may increase weekly by 25 mg daily up to the recommended dose of 100 mg daily given in 2 divided doses. Increased intervals between dose adjustments may be considered. Doses >100 mg daily have shown no additional benefit.

Cluster headache prophylaxis (off-label use): Oral: Initial: 25 mg daily, titrated at weekly intervals in 25 mg increments, up to 200 mg daily (Pascual 2007)

Essential tremor (off-label use): Oral: Initial: 25 mg once daily; increase dose at weekly intervals based on response and tolerability in 25 mg increments up to 100 mg/day and then in 50 mg increments up to 400 mg/day (Ondo 2006). Alternatively, once 200 mg/day is achieved, doses may be increased weekly in 100 mg increments up to 400 mg/day (Connor 2008). For dosages ≥50 mg/day administer in 2 divided doses (Ondo 2006). Average doses in clinical trials were 292 mg/day (median: 375 mg/day) (Ondo 2006) and 215 mg/day (range: 25 to 400 mg/day) (Connor 2008)

Status epilepticus, refractory (off-label use): Oral, NG: Initial: 200 to 400 mg; maintenance: 300 to 1600 mg in 2 to 4 divided doses (NCS [Brophy 2012]). Additional data is necessary to further define the role of topiramate in this condition.

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: Pediatric

Note: Do not abruptly discontinue therapy; taper dosage gradually to prevent rebound effects. Bioequivalence has not been demonstrated between Trokendi XR and Qudexy XR.

Epilepsy, monotherapy: Partial-onset seizure and primary generalized tonic-clonic seizure:

Children 2 to <10 years: Oral:

Immediate release:

Initial: 25 mg once daily (in evening); may increase to 25 mg twice daily in week 2; thereafter, may increase by 25 to 50 mg daily at weekly intervals over 5 to 7 weeks up to the following minimum recommended maintenance dose:

≤11 kg: 150 mg daily in 2 divided doses

12 to 22 kg: 200 mg daily in 2 divided doses

23 to 31 kg: 200 mg daily in 2 divided doses

32 to 38 kg: 250 mg daily in 2 divided doses

≥39 kg: 250 mg daily in 2 divided doses

Maximum maintenance dose: If additional seizure control is needed and therapy is tolerated, may further increase by 25 to 50 mg daily at weekly intervals up to the following maximum recommended maintenance dose:

≤11 kg: 250 mg daily in 2 divided doses

12 to 22 kg: 300 mg daily in 2 divided doses

23 to 31 kg: 350 mg daily in 2 divided doses

32 to 38 kg: 350 mg daily in 2 divided doses

≥39 kg: 400 mg daily in 2 divided doses

Extended release (Qudexy XR only):

Initial: 25 mg once daily (in the evening); if tolerated, may increase to 50 mg once daily in week 2; thereafter, may increase by 25 to 50 mg daily at weekly intervals over 5 to 7 weeks up to the following minimum recommended maintenance dose:

≤11 kg: 150 mg once daily

12 to 31 kg: 200 mg once daily

≥32 kg: 250 mg once daily

Maximum maintenance dose: If additional seizure control is needed and therapy is tolerated, may further increase by 25 to 50 mg daily at weekly intervals up to the following maximum recommended maintenance dose:

≤11 kg: 250 mg once daily

12 to 22 kg: 300 mg once daily

23 to 38 kg: 350 mg once daily

>38 kg: 400 mg once daily

Children ≥10 years and Adolescents: Refer to adult dosing.

Canadian labeling: Children ≥6 years: Refer to adult dosing.

Epilepsy, adjunctive therapy: Partial-onset seizure, primary generalized tonic-clonic seizure, or Lennox-Gastaut syndrome:

Children 2 to <6 years: Oral:

Immediate release: Initial: 25 mg (1 to 3 mg/kg/day) once daily (in evening) for 1 week; may increase every 1 to 2 weeks in increments of 1 to 3 mg/kg/day up to the recommended dose of 5 to 9 mg/kg/day in 2 divided doses.

Extended release (Qudexy XR only): Initial: 25 mg (1 to 3 mg/kg/day) once daily (in evening) for 1 week; may increase every 1 to 2 weeks in increments of 1 to 3 mg/kg/day up to the recommended dose of 5 to 9 mg/kg once daily.

Children ≥6 years and Adolescents <17 years: Oral:

Immediate release: Initial: 25 mg (1 to 3 mg/kg/day) once daily (in evening) for 1 week; may increase every 1 to 2 weeks in increments of 1 to 3 mg/kg/day up to the recommended dose of 5 to 9 mg/kg/day in 2 divided doses.

Extended release (Qudexy XR and Trokendi XR): Initial: 25 mg (1 to 3 mg/kg/day) once daily (in evening) for 1 week; may increase every 1 to 2 weeks in increments of 1 to 3 mg/kg/day up to the recommended dose of 5 to 9 mg/kg once daily.

Adolescents ≥17 years: Refer to adult dosing.

Migraine prophylaxis: Adolescents ≥12 years: Oral: Immediate release: Refer to adult dosing.

Dosing: Renal Impairment

CrCl <70 mL/minute/1.73 m2: Administer 50% dose and titrate more slowly.

Hemodialysis: Supplemental dose may be needed during hemodialysis

Dosing: Hepatic Impairment

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

Extemporaneously Prepared

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

A 6 mg/mL topiramate oral suspension may be made with tablets and one of two different vehicles (a 1:1 mixture of Ora-Sweet and Ora-Plus, or a mixture of Simple Syrup, NF and methylcellulose 1% with parabens). Crush six 100 mg tablets in a mortar and reduce to a fine powder. Add a small amount of methylcellulose gel and mix to a uniform paste (Note: Use a small amount of methylcellulose gel when using the 1:1 Ora-Sweet and Ora-Plus mixture as the vehicle; use 10 mL methylcellulose 1% with parabens when using Simple Syrup, NF as the vehicle); mix while adding the chosen vehicle in incremental proportions to almost 100 mL; transfer to a graduated cylinder; rinse mortar with vehicle, and add quantity of vehicle sufficient to make 100 mL. Store in plastic prescription bottles; label "shake well" and "refrigerate". Stable for 90 days refrigerated (preferred) or at room temperature.

Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Administration

Administer without regard to meals. Administer the immediate release formulation in divided doses. It is not recommended to crush, break, or chew immediate release tablets due to bitter taste. Swallow extended release (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 capsules within 6 hours prior to and 6 hours after administration.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Storage

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.

Drug 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. Avoid combination

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

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

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

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

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

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

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 patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

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

CarBAMazepine: May decrease the serum concentration of Topiramate. Consider therapy modification

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. Avoid combination

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

Contraceptives (Estrogens): Topiramate may decrease the serum concentration of Contraceptives (Estrogens). 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. Consider therapy modification

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

Dimethindene: May enhance the CNS depressant effect of CNS Depressants. 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. Monitor therapy

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

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

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

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

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

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

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

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

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

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

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

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

MetFORMIN: Topiramate may enhance the adverse/toxic effect of MetFORMIN. 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. 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. Consider therapy modification

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

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

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

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

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

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

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. 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. Consider therapy modification

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

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

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

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

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

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

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

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

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. 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. Consider therapy modification

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

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

Valproate Products: Topiramate may enhance the adverse/toxic effect of Valproate Products. 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. Consider therapy modification

Adverse Reactions

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

Epilepsy, monotherapy:

>10%:

Central nervous system: Paresthesia (adolescents ≥16 years and adults: 21% to 40%; children and adolescents 6 to <16 years: 2% to 16%), drowsiness (adolescents ≥16 years and adults: 9% to 15%), fatigue (14%), dizziness (adolescents ≥16 years and adults: 13% to 14%), memory impairment (adolescents ≥16 years and adults: 5% to 11%; children and adolescents 6 to <16 years: 1% to 3%), mood disorder (1% to 11%)

Endocrine & metabolic: Decreased serum bicarbonate (children ≥6 years, adolescents, and adults: 9% to 25%), weight loss (6% to 21%)

Gastrointestinal: Anorexia (4% to 14%), diarrhea (5% to 11%)

Respiratory: Upper respiratory tract infection (children and adolescents 6 to <16 years: 16% to 18%)

Miscellaneous: Fever (children and adolescents 6 to <16 years: ≤12%)

1% to 10%:

Cardiovascular: Flushing (children and adolescents 6 to <16 years: ≤5%), chest pain (adolescents ≥16 years and adults: 1% to 2%)

Central nervous system: Lack of concentration (7% to 10%), depression (≤9%), insomnia (adolescents ≥16 years and adults: 8% to 9%), cognitive dysfunction (≤7%), anxiety (adolescents ≥16 years and adults: 4% to 6%), hypoesthesia (adolescents ≥16 years and adults: 4% to 5%), nervousness (children and adolescents 10 to 16 years: 4% to 5%), psychomotor retardation (adolescents ≥16 years and adults: 3% to 5%), ataxia (adolescents ≥16 years and adults: 3% to 4%), confusion (≤4%), behavioral problems (children and adolescents 6 to <16 years: ≤3%), hypertonia (adolescents ≥16 years and adults: ≤3%), vertigo (children and adolescents 6 to <16 years: ≤3%)

Dermatologic: Alopecia (1% to 5%), pruritus (adolescents ≥16 years and adults: 1% to 4%), skin rash (1% to 4%), acne vulgaris (adolescents ≥16 years and adults: 2% to 3%)

Endocrine & metabolic: Increased gamma-glutamyl transferase (adolescents ≥16 years and adults: 1% to 3%), intermenstrual bleeding (children and adolescents 6 to <16 years: ≤3%)

Gastrointestinal: Dysgeusia (adolescents ≥16 years and adults: 3% to 5%), constipation (adolescents ≥16 years and adults: 1% to 4%), gastritis (adolescents ≥16 years and adults: ≤3%), xerostomia (adolescents ≥16 years and adults: 1% to 3%), gastroesophageal reflux disease (adolescents ≥16 years and adults: 1% to 2%)

Genitourinary: Decreased libido (adolescents ≥16 years and adults: ≤3%), urinary frequency (≤3%), vaginal hemorrhage (adolescents ≥16 years and adults: ≤3%), cystitis (adolescents ≥16 years and adults: 1% to 3%), urinary incontinence (children and adolescents 6 to <16 years: 1% to 3%), dysuria (adolescents ≥16 years and adults: ≤2%), urinary tract infection (adolescents ≥16 years and adults: 1% to 2%)

Hematologic & oncologic: Anemia (1% to 3%)

Infection: Viral infection (3% to 9%), infection (2% to 8%)

Neuromuscular & skeletal: Weakness (≤6%), muscle spasm (children and adolescents 6 to <16 years: ≤3%), leg pain (adolescents ≥16 years and adults: 2% to 3%)

Renal: Nephrolithiasis (adolescents ≥16 years and adults: ≤3%)

Respiratory: Rhinitis (2% to 7%), bronchitis (1% to 7%), sinusitis (children and adolescents 6 to <16 years: 1% to 5%), epistaxis (children and adolescents 6 to <16 years: ≤4%), dyspnea (adolescents ≥16 years and adults: 1% to 2%)

Migraine prophylaxis:

Frequency not always defined.

Central nervous system: Paresthesia (adults: 35% to 51%; children and adolescents ≥12 years: 19% to 20%; dose related), fatigue (8% to 15%; dose related), insomnia (6% to 9%), drowsiness (6% to 8%; dose related), memory impairment (adults 7%; dose related), hypoesthesia (adults 6% to 7%; dose related), dizziness (children and adolescents ≥12 years: 6%), lack of concentration (adults: 3% to 6%; children and adolescents ≥12 years: ≤2%), mood disorder (adults: 3% to 6%; dose related), anxiety (adults: 4% to 5%; dose related), headache (children and adolescents ≥12 years: 4%; adults: >1%), nervousness (4%), confusion (adults: 3%; dose related), psychomotor retardation (≤3%), agitation (adults: 2%), cognitive dysfunction (adults: 2%), exacerbation of depression (adults: 2%), ataxia (adults: 1% to 2%), pain (children and adolescents ≥12 years: >1%), sensory disturbance (adults: >1%), vertigo (adults: >1%), speech disturbance (adults: 1%; dose related)

Dermatologic: Pruritus (4%), alopecia (adults: >1%), skin rash (>1%)

Endocrine & metabolic: Decreased serum bicarbonate (23% to 39%), hyperammonemia (children and adolescents ≥12 years: 14% to 26%), weight loss (4% to 9%; dose related), menstrual disease (adults: 3%), increased thirst (adults: 2%), intermenstrual bleeding (adults: >1%), hyperchloremia, increased serum total protein, increased uric acid

Gastrointestinal: Anorexia (9% to 15%; dose related), abdominal pain (6% to 15%), dysgeusia (6% to 15%), nausea (8% to 13%), dyspepsia (adults: 4% to 5%), gastroenteritis (3%), xerostomia (adults: 3%; dose related), diarrhea (children and adolescents ≥12 years: 2%), constipation (adults: >1%), gastroesophageal reflux disease (adults: >1%), vomiting (children and adolescents ≥12 years: >1%), ageusia (adults: 1%)

Genitourinary: Urinary tract infection (4%), premature ejaculation (adults: ≤3%), genital candidiasis (adults: >1%), urinary incontinence (children and adolescents ≥12 years: >1%)

Hematologic & oncologic: Neoplasm (adults: 2%), abnormal phosphorus levels (decreased), thrombocythemia

Hypersensitivity: Hypersensitivity reaction (≤4%)

Infection: Viral infection (4% to 8%), infection (>1%)

Neuromuscular & skeletal: Arthralgia (adults: 3% to 7%), leg pain (children and adolescents ≥12 years: 2%), muscle spasm (adults: 2%; dose related), weakness (adults: 2%), back pain (children and adolescents ≥12 years: >1%), myalgia (>1%), tremor (adults: >1%)

Ophthalmic: Conjunctivitis (children and adolescents ≥12 years: 7%; adults: 2%), blurred vision (adults: 4%), visual disturbance (1% to 2%; dose related), accommodation disturbance (adults: >1%), eye pain (>1%)

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

Renal: Nephrolithiasis (adults: ≤1%; dose related), increased blood urea nitrogen, increased serum creatinine

Respiratory: Upper respiratory tract infection (children and adolescents ≥12 years: 23% to 26%; adults: 13% to 14%), sinusitis (4% to 10%), rhinitis (children and adolescents ≥12 years: 6% to 7%; adults: 2%), cough (2% to 7%), pharyngitis (5% to 6%), bronchitis (adults: 3%; children and adolescents ≥12 years: >1%), dyspnea (adults: 3%), epistaxis (2%), asthma (>1%), flu-like symptoms (children and adolescents ≥12 years: >1%), pneumonia (adults: >1%)

Miscellaneous: Accidental injury (9%), language problems (adults: 6% to 7%), fever (children and adolescents ≥12 years: 4% to 6%)

<1%, postmarketing, and/or case reports (any indication): Abnormal electroencephalogram, acute myopia with secondary angle-closure glaucoma, albuminuria, alcohol intolerance, angina pectoris, apraxia, atrioventricular block, bone marrow depression, brain disease, bullous rash, cerebellar syndrome, chloasma, deep vein thrombosis, dehydration, delirium, delusions, diabetes mellitus, erythema multiforme, hepatic failure, hepatitis, hyperchloremic metabolic acidosis (nonanion gap), hyperesthesia, hyperglycemia, hyperlipidemia, hypernatremia, hyperthermia, hypocalcemia, hypocholesterolemia, hypohidrosis, hyponatremia, hypotension, hypothermia (with valproic acid, with or without hyperammonemia). impotence, iritis, lymphadenopathy, lymphocytopenia, lymphocytosis, maculopathy, manic reaction, melena, neuropathy, ostealgia, pancreatitis, pancytopenia, pemphigus, phlebitis, photophobia, polycythemia, psychosis, pulmonary embolism, renal pain, scotoma, skin photosensitivity, Stevens-Johnson syndrome, stomatitis, strabismus, suicidal ideation, suicidal tendencies, tongue edema, tongue paralysis, toxic epidermal necrolysis, upper motor neuron lesion, urinary retention, urticaria, vasodilatation, vasospasm, visual field defect, xerophthalmia

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: Cognitive dysfunction (confusion, psychomotor slowing, difficultly with concentration/attention, difficultly 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. Risk may be increased in patients with inborn errors of metabolism or decreased hepatic mitochondrial activity. 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 oligohydrosis 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 2-4 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:

• 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, weigh 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.

• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.

Special populations:

• Elderly: Use with caution; dosage adjustment may be necessary.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

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).

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

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. 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) has been observed following first trimester exposure. Data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry reported that the prevalence of oral clefts was 1.2% for infants exposed to topiramate during the first trimester of pregnancy, versus 0.39% to 0.46% for infants exposed to other antiepileptic drugs and 0.12% with no exposure. Although not evaluated during pregnancy, metabolic acidosis may be induced by topiramate. In general, metabolic acidosis during pregnancy may result in adverse effects and fetal death. Pregnant women and their newborns should be monitored for metabolic acidosis. Maternal serum concentrations may decrease during the second and third trimesters of pregnancy therefore therapeutic drug monitoring should be considered in pregnant women who require therapy (Ohman 2009; Westin 2009).

Use for migraine prophylaxis is contraindicated per the Canadian labeling in pregnant women or women of childbearing potential who are not using effective contraception.

Patients exposed to topiramate during pregnancy are encouraged to enroll themselves into the AED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, change in taste, lack of appetite, diarrhea, fatigue, loss of strength and energy, headache, dry mouth, or hair loss. Have patient report immediately to prescriber signs of infection, signs of acidosis (confusion, fast breathing, tachycardia, arrhythmia, severe abdominal pain, nausea, vomiting, fatigue, shortness of breath, or feeling very tired or weak), signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of bleeding (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 bleeding that is very bad or that will not stop), signs of a kidney stone (back pain, abdominal pain, or blood in the urine), confusion, difficulty focusing, change in balance, severe dizziness, passing out, inability to eat, difficult urination, seizures, lack of sweat, burning or numbness feeling, excessive weight loss, bone pain, angina, memory impairment, muscle pain, muscle weakness, tinnitus, difficulty speaking, tremors, abnormal gait, involuntary eye movements, agitation, irritability, panic attacks, mood changes, blurred vision, vision changes, eye pain, or eye irritation (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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