Pradox

Pharmacotherapeutic Group: Anticonvulsant.
Pharmacology: Pharmacodynamics: Mechanism of Action: Anticonvulsant activity may be die to a combination of potential mechanisms: Blocks neuronal voltage-dependent sodium channels, enhances GABA (A) activity, antagonizes AMPA/kainate glutamate receptors, and weakly inhibit carbonic anhydrase.
Pharmacokinetics: Absorption: Good, rapid; unaffected by food.
Protein binding: 15% to 41% (inversely related to plasma concentrations).
Metabolism: Hepatic via P450 enzymes.
Bioavailability: ~80%.
Half-Life Elimination: Mean: Adults: Normal renal function: 21 hours; shorter in pediatric patients.
Elderly: ~24 hours.
Excretion: Urine (~70% to 80% as unchanged drug).
Dialyzable: Significantly hemodialyzed; dialysis clearance: 120 mL/minute (4-6 times higher than in adults with normal renal function); supplemental doses may be required.

Monotherapy or adjunctive therapy for partial onset seizures and primary generalized tonic-clonic seizures; adjunctive treatment of seizures associated with Lennox-Gastaut syndrome; prophylaxis of migraine headache.

Oral: 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 (In clinical trials, adult doses were withdrawn by decreasing in weekly intervals of 50-100 mg/day gradually over 2-8 weeks for seizure treatment, and by decreasing in weekly intervals by 25-50 mg/day for migraine prophylaxis.)
Epilepsy, monotherapy: Children ≥10 years and Adults: Partial onset seizure and primary generalized tonic-clonic seizure: Initial: 25 mg twice daily; may increase weekly by 50 mg/day up to 100 mg twice daily (week 4 dose); thereafter, may further increase weekly by 100 mg/day up to the recommended maximum of 200 mg twice daily.
Canadian labeling: Children ≥6 years and Adults: 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/day up to recommended maximum of 200 mg twice daily.
Epilepsy, adjunctive therapy: Children 2-16 years: Partial onset seizure or seizure associated with Lennox­-Gastaut syndrome: Initial: 25 mg (1-3 mg/kg/day) once daily (in evening); may increase every 1-2 weeks in increments of 1-3 mg/kg/day up to the recom­mended maximum of 5-9 mg/kg/day in 2 divided doses.
Primary generalized tonic-clonic seizure: Use initial dose listed in the previous text for partial onset seizures, but use slower initial titration rate; titrate to the recommended maintenance dose of 6 mg/kg/day by the end of 8 weeks.
Canadian labeling: Initial: 25 mg (1-3 mg/kg/day) once daily (in evening); may increase every 1-2 weeks in increments of 1-3 mg/kg/day up to the recommended maximum of 5-9 mg/kg/day in two divided doses.
Adolescents ≥17 years and Adults: Partial onset seizures: Initial: 25 mg once or twice daily for 1 week; may increase weekly by 25-50 mg/day until response; usual maintenance dose: 100-200 mg twice daily. Doses >1600 mg/day have not been studied.
Primary generalized tonic-clonic seizures: Use initial dose as listed in the previous text for partial onset seizures, but use slower   initial titration rate; titrate upwards to rec­ommended dose by the end of a weeks; usual main­tenance dose: 200 mg twice daily. Doses >1600 mg/day have not been studied.
Canadian labeling: Initial: 25 mg once or twice daily; may increase weekly by 50 mg/day up to the recom­mended dose of 100-200 mg twice daily (maximum recommended dose: 800 mg/day; doses >400 mg/day have shown no additional benefit.
Migraine prophylaxis: Adults: Initial: 25 mg once daily (in evening); may increase weekly by 25 mg/day, up to the recommended dose of 100 mg/day given in 2 divided doses. Doses >100 mg/day have shown no additional benefit.
Cluster headache prophylaxis (unlabeled use): Adults: Initial: 25 mg/day, titrated at weekly intervals in 25 mg increments, up to 200 mg/day.
Neuropathic pain (unlabeled use): Adults: Initial: 25 mg/day, titrated at weekly intervals in 25-50 mg incre­ments to target dose of 400 mg daily in 2 divided doses.
Dosing adjustment in renal impairment: Cl_cr <70 mL/minute/1.73 m²: Administer 50% dose and titrate more slowly.
Hemodialysis: Supplemental dose may be needed during hemodialysis.
Dosing adjustment in hepatic impairment: Clearance may be reduced; however the manufacturer's labeling provides no specific dosing recommendations.
Administration: Oral: May be administered without regard to meals.

There are no contraindications listed in the manufacturers' 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).

Antiepileptics are associated with an increased risk of suicidal behavior/thoughts with use (regardless of indication); patients should be monitored for signs/symptoms of depression, suicidal tendencies, and other unusual behavior changes during therapy and instructed to inform their healthcare provider immediately if symptoms occur. Use with caution in patients with hepatic, respiratory or renal impairment. Topiramate may decrease serum bicarbonate concentrations (up to 67% of patients); treatment-emergent metabolic acidosis is less common. Risk may be increased in patients with a predis­posing condition (organ dysfunction, ketogenic diet, or concurrent treatment with, other drugs which may cause acidosis). Metabolic acidosis may occur at dosages as low as 50 mg/day. Monitor serum bicarbonate as well as potential complications of chronic acidosis (nephrolithiasis, osteomalacia, and reduced growth rates in children). Kid­ney stones have been reported in both children and adults; the risk of kidney stones is about 2-4 times that of the untreated population; the risk of this event may be reduced by increasing fluid intake.
Cognitive dysfunction, psychiatric disturbances (mood dis­orders), and sedation (somnolence or fatigue) may occur with topiramate 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). Topiramate may also cause paresthesia, dizziness, and ataxia. Topiramate has been associated with acute myopia and secondary angle­ closure glaucoma in adults and children, typically within 1 month of initiation; discontinue in patients vvith acute onset of decreased visual acuity or ocular pain. Hyperammone­mia with or without encephalopathy may occur with or without concomitant valproate administration; valproic acid dose-dependency was observed in limited pediatric stud­ies; use with caution in patients with inborn errors of metabolism or decreased hepatic mitochondrial activity. Topiramate may be associated (rarely) with severe 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 receiving other carbonic anhydrase inhibitors and drugs with anticholinergic activity. Concur­rent use of topiramate and hydrochlorothiazide may increase the risk for hypokalemia; monitor potassium closely.
Avoid abrupt withdrawal of topiramate therapy, it should be withdrawn/tapered slowly to minimize the potential of increased seizure frequency. Doses were also gradually withdrawn in migraine prophylaxis studies. Effects with other sedative drugs or ethanol may be potentiated. Safety and efficacy have not been established in children <2 years of age for adjunctive treatment of·seizure and <10 years of age for monotherapy treatment of seizures. In pediatric patients, weight loss may occur most often early in therapy; in clinical trials of at least 1 year, the majority of patients with weight loss had a resumption of weight gain within the study period. Safety and efficacy have not been established in children for migraine prophylaxis.

Pregnancy: Pregnancy Risk Factor: C.
Topiramate was found to be teratogenic in animal studies. Based on limited data, top­iramate was found to cross the placenta. 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.
Lactation: Pradox enters the breast milk and should be used in caution in lactating women.

Adverse events are reported for placebo-controlled trials of adjunctive therapy in adult and pediatric patients. Unless otherwise noted, the percen­tages refer to incidence in epilepsy trials.
Note: A wide range of dosages were studied; incidence of adverse events was frequently lower in the pediatric population studied.
>10%: Central nervous system: Somnolence (15% to 29%), dizziness (4% to 25%; dose dependent), fatigue (9% to 16%; dose-dependent), nervousness (9% to 18%), ataxia (6% to 16%), psychomotor slowing (3% to 13%; dose dependent), speech problems (2% to 13%), mem­ory difficulties (2% to 12%), behavior problems (children 11%), confusion (4% to 11%).
Endocrine and metabolic: Serum bicarbonate decreased (dose related: 7% to 67%; marked reductions [to <17 mEq/L] 1% to 11%).
Gastrointestinal: Anorexia (4% to 24%; dose dependent), nausea (6% to 10%; migraine trial: 9% to 14%).
Neuromuscular and skeletal: Paresthesia (1% to 11%; migraine trial: 35% to 51%).
Ocular: Abnormal vision (2% to 13%).
Respiratory: Upper respiratory infection (migraine trial: 12% to 14%).
Miscellaneous: Injury (14%).
1% to 10%: Cardiovascular: Chest pain (2% to 4%), edema (2%), hypertension (1% to 2%), bradycardia (1%), pallor (1%), syncope (1%).
Central nervous system: Difficulty concentrating (5% to 10%), aggressive reactions (2% to 9%), depression (5% to 9%; dose dependent, insomnia (4% to 8%), mood problems (≤6%), abnormal coordination (4%), agitation (3%), cognitive problems (3%), emotional lability (3%), anxiety (2% to 3%; dose dependent), hypoesthesia (2%; migraine trial: 6% to 8%), stupor (2%), vertigo (2%), fever (migraine trial: 1% to 2%), apathy (1%), hallucination (1%), neurosis (1%), psychosis (1%), seiz­ure (1%), suicide attempt (1%).
Dermatologic: Pruritus (migraine trial: 2% to 4%), skin disorder (2% to 3%); alopecia (2%), dermatitis (2%), hypertrichosis (2%), rash erythematous (1% to 2%), eczema (1%), seborrhea (1%), skin discoloration (1%).
Endocrine and metabolic: Breast pain (4%), hot flashes (1% to 2%), libido decreased (<1% to 2%), menstrual irregularities (1% to 2%), hypoglycemia (1%), acidosis (hyperchloremia, nonanion gap), metabolic.
Gastrointestinal: Weight loss (4% to 9%), dyspepsia  (2% to 7%), abdominal pain (5% to 6%), salivation increased (6%), constipation (4% to 5%), gastroenteritis (2% to 3%), vomiting (migraine trial: 1% to 3%), diarrhea (2%; migraine trial: 9% to 11%), dysgeusia (2%; migraine trial: 8% to 15%), xerostomia (2%), loss of taste (migraine trial: <2%), appetite increased, (1%), dyspha­gia, (1%), fecal incontinence (1%), flatulence (1%), GERD (1%), gingivitis (1%), glossitis (1%), gum hyperplasia (1%), weight gain (1%).
Genitourinary: Incontinence (2% to 4%), UTI (2%), premature ejaculation (migraine trial: ≤3%), cystitis (2%), leukorrhea (2%), impotence (1%), nocturia (1%).
Hematologic: Purpura (8%), leukopenia (2%), anemia (1%), hematoma (1%), prothrombin time increased (1%), thrombocytopenia (1%).
Neuromuscular and skeletal: Tremor (3% to 9%), gait abnormal (3% to 8%), arthraglia (migraine trial: 1% to 7%), weakness (6%), hyperkinesia (5%), back pain (1% to 5%), involuntary muscle contractions (2%; migraine trial: 2% to 4%), leg cramps (2%), leg pain (2%), myaglia (2%), hyporeflexia (2%), rigors (1%), skeletal pain (1%).
Ocular: Diplopia (1% to 10%), nystagmus (10%), conjunctivitis (1%), lacrimation abnormal (1%), myopia (1%).
Otic: Hearing decreased (2%), tinnitus (2%), otitis media (migraine trial: 1% to 2%).
Renal: Hematuria (2%), renal calculus (migraine trial ≤2%).
Respiratory: Rhinitis (4% to 7%), pharyngitis (6%), sinus­itis (5%; migraine trial: 6% to 10%), pneumonia (5%), epistaxis (2%·to 4%), cough (migraine trial: 2% to 4%), bronchitis (migraine trial: 3%), dyspnea (migraine trial: 1% to 3%).
Miscellaneous: Viral infection (2% to 7%: migraine trial: 3% to 4%), flu-like syndrome (3%), allergy (2%), infection (2%), thirst (2%), body odor (1%), diaphoresis (1%), moniliasis (1%).
<1% (Limited to important or life-threatening): Angina, apraxia, AV block, bone marrow depression, deep vein thrombosis, dehydration, delirium, delusion, diabetes mellitus, dyskinesia, eosinophilia, erythema multiforme, euphoria, granulocytopenia, hepatic failure, hepatitis, hyperammonemia/encephalopathy (with or without val­proate therapy), hyperthermia (severe), hypokalernia, hypotension, lymphadenopathy, lymphopenia, maculop­athy, manic reaction, neuropathy, oligohydrosis, pancreatitis, pancytopenia, paranoid reaction, pemphigus, photosensitivity, pulmonary embolism, renal tubular acidosis, Stevens-Johnson syndrome, suicidal behavior, suicide, suicidal ideation, syndrome of acute myopia/secondary angle-closure  glaucoma, tongue edema, toxic epidermal necrolysis.

Metabolism/Transport Effects Inhibits: CYP2C19 (weak); Induces CYP3A4 (weak).
Avoid Concomitant Use: There are no known interac­tions where it is recommended to avoid concomitant use.
Increased Effect/Toxicity: Topiramate may increase the levels/effects of: Alcohol (Ethyl); cns depressants; divalproex; lithium; methotri­meprazine; phenytoin; valproic Acid.
The levels/effects of Topiramate may be increased by: Droperidol; methotrimeprazine; thiazide diuretics.
Decreased Effect: Topiramate may decrease the levels/effects of: Contra­ceptives (estrogens); contraceptives (progestins); sax­agliptin.
The levels/effects of Topiramate may be decreased by: Carbamazepine; ketorolac; ketorolac (systemic); meflo­quine; phenytoin.
Ethanol/Nutrition/Herb Interactions: Ethanol: Avoid ethanol (may increase CNS depression).
Food: Ketogenic diet may increase the possibility of acido­sis and/or kidney stones.
Herb/Nutraceutical: Avoid evening primrose (seizure threshold decreased).

Store at room temperature of 15°C to 30°C (59°F to 86°F). Protect from moisture.

Anticonvulsants / Antimigraine Preparations

N03AX11 - topiramate ; Belongs to the class of other antiepileptics.

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