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Special Alerts
Antiepileptics: Increased Risk of Suicidal Behavior or Ideation - February, 2008
The U.S. Food and Drug Administration (FDA) is informing healthcare professionals of an increased risk of suicidality (suicidal behavior or ideation) observed from analysis of clinical studies using various antiepileptic medications compared to placebo. The analysis was performed on 199 placebo-controlled studies involving 43,892 patients (27,863 treated patients versus 16,029 placebo patients) aged ?5 years receiving one of the following 11 drugs: carbamazepine (Carbatrol®, Equetro™, Tegretol®, Tegretol® XR), felbamate (Felbatol®), gabapentin (Neurontin®), lamotrigine (Lamictal®), levetiracetam (Keppra®), oxcarbazepine (Trileptal®), pregabalin (Lyrica®), tiagabine (Gabitril®), topiramate (Topamax®), valproate (Depakote®, Depakote® ER, Depakene®, Depacon®), and zonisamide (Zonegran®). Studies examined medication efficacy in a variety of disorders, including epilepsy, psychiatric disorders (eg, depression, bipolar disorder), and other conditions (eg, migraine, neuropathic pain). According to the FDA, the results revealed a statistically significant increased risk of suicidality in 0.43% treated patients compared to 0.22% placebo patients, or an estimated 2.1 per 1000 (95% CI: 0.7, 4.2) more patients in the treated groups relative to placebo. This increased risk was reported anywhere from 1 week of therapy through 24 weeks. However, most trials were ?24 weeks duration and the risk of suicide extending beyond 24 weeks is currently unknown. The relative risk of suicidal behavior or ideation in the treated patients was higher for patients with epilepsy (RR=3.6) compared to patients treated for psychiatric (RR=1.6) or other conditions (RR=2.3). Overall, the incidence of suicidal behavior or ideation occurred consistently across all demographic subgroups and with each of the drugs studied. Of note, four patients receiving an antiepileptic committed suicide relative to none in the placebo groups.
Forthcoming product labeling changes are likely to extend to all antiepileptic drugs and not limited to the drugs used in the studies, pending discussions scheduled for the upcoming advisory committee meeting. Healthcare professionals and family members/caregivers are encouraged to monitor patients receiving any antiepileptic medication for signs/symptoms of suicidality (eg, anxiety, depression, behavior changes). Patients should not stop taking their antiepileptic therapy unless advised by a healthcare professional.
Additional information can be found at http://www.fda.gov/medwatch/safety/2008/safety08.htm#Antiepileptic
Medication Safety Issues
Sound-alike/look-alike issues:
Topamax® may be confused with Tegretol®, Tegretol®-XR, Toprol-XL®
Pronunciation
(toe PYRE a mate)
U.S. Brand Names
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
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
Use: Unlabeled/Investigational
Infantile spasms, neuropathic pain, cluster headache
Pregnancy Risk Factor
C
Pregnancy Considerations
Topiramate was found to be teratogenic in animal studies; however, there is limited information in pregnant women; use only if benefit to the mother outweighs the risk to the fetus. Based on limited data, topiramate was found to cross the placenta. Postmarketing experience includes reports of hypospadias following in vitro exposure to topiramate.
Lactation
Enters breast milk/not recommended
Breast-Feeding Considerations
Based on limited data, topiramate was found in breast milk; low concentrations were detected in nursing infants.
Contraindications
Hypersensitivity to topiramate or any component of the formulation
Warnings/Precautions
Concerns related to adverse effects:
• CNS effects: Cognitive dysfunction, psychiatric disturbances (mood disorders), and sedation (somnolence or fatigue) may occur with use; incidence may be related to rapid titration and higher doses. May also cause paresthesia, dizziness, and ataxia.
• Glaucoma: 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 or ocular pain.
• Hyperthermia: 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 drugs with anticholinergic activity.
• Metabolic acidosis (hyperchloremic, nonanion gap): May decrease serum bicarbonate concentrations, due to inhibition of carbonic anhydrase and increased renal bicarbonate loss. Decreases in serum bicarbonate are relatively common (7% to 67%) 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). Treatment-emergent metabolic acidosis is less common; however, risk may be increased in patients with a predisposing condition (renal, respiratory and/or hepatic impairment), ketogenic diet, 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, osteomalacia, and reduced growth rates 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.
• Renal calculus: Topiramate exhibits carbonic anhydrase properties and the risk of kidney stones is about 2-4 times that of the untreated population. Kidney stones have been reported in children and adults. The risk of stones may be reduced by increasing fluid intake.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment may be required.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be required.
Concurrent drug therapy issues:
• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.
• Valproate: Hyperammonemia with or without encephalopathy may occur 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.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children <2 years of age for adjunctive treatment of seizures and <10 years of age for monotherapy treatment of seizures. Safety and efficacy have not been established in children for migraine prophylaxis.
Other warnings/precautions:
• Withdrawal: Anticonvulsants should not be discontinued 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).
Adverse Reactions
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: Dizziness (4% to 32%), ataxia (6% to 16%), somnolence (15% to 29%), psychomotor slowing (3% to 21%), nervousness (9% to 19%), memory difficulties (2% to 14%), speech problems (2% to 13%), fatigue (9% to 30%), difficulty concentrating (5% to 14%), depression (9% to 13%), confusion (4% to 14%)
Endocrine & metabolic: Serum bicarbonate decreased (dose-related: 7% to 67%; marked reductions [to <17 mEq/L] 1% to 11%)
Gastrointestinal: Nausea (6% to 12%; migraine trial: 14%), weight loss (8% to 13%), anorexia (4% to 24%)
Neuromuscular & skeletal: Paresthesia (1% to 19%; migraine trial: 35% to 51%)
Ocular: Nystagmus (10% to 11%), abnormal vision (<1% to 13%)
Respiratory: Upper respiratory infection (migraine trial: 12% to 13%)
Miscellaneous: Injury (6% to 14%)
1% to 10%:
Cardiovascular: Chest pain (2% to 4%), edema (1% to 2%), bradycardia (1%), pallor (up to 1%), hypertension (1% to 2%)
Central nervous system: Abnormal coordination (4%), hypoesthesia (1% to 2%; migraine trial: 8%), convulsions (1%), depersonalization (1% to 2%), apathy (1% to 3%), cognitive problems (3%), emotional lability (3%), agitation (3%), aggressive reactions (2% to 9%), tremor (3% to 9%), stupor (1% to 2%), mood problems (4% to 9%), anxiety (2% to 10%), insomnia (4% to 8%), fever (migraine trial: 1% to 2%), vertigo (1% to 2%), neurosis (1%)
Dermatologic: Pruritus (migraine trial: 2% to 4%), skin disorder (1% to 3%), alopecia (2%), dermatitis (up to 2%), hypertrichosis (up to 2%), rash erythematous (up to 2%), eczema (up to 1%), seborrhea (up to 1%), skin discoloration (up to 1%)
Endocrine & metabolic: Hot flashes (1% to 2%); metabolic acidosis (hyperchloremia, nonanion gap), dehydration, breast pain (up to 4%), menstrual irregularities (1% to 2%), hypoglycemia (1%), libido decreased (<1% to 2%)
Gastrointestinal: Dyspepsia (2% to 7%), abdominal pain (5% to 7%), constipation (3% to 5%), xerostomia (2% to 4%), fecal incontinence (1%), gingivitis (1%), diarrhea (2%; migraine trial: 11%), vomiting (1% to 3%), gastroenteritis (1% to 3%), GI disorder (1%), dysgeusia (2% to 4%; migraine trial: 12% to 15%), appetite increased (1%), dysphagia (1%), flatulence (1%), GERD (1%), glossitis (1%), gum hyperplasia (1%), weight gain (1%)
Genitourinary: Impotence, dysuria/incontinence (<1% to 4%), prostatic disorder (2%), UTI (2% to 3%), premature ejaculation (migraine trial: 3%), cystitis (2%)
Hematologic: Leukopenia (1% to 2%), purpura (8%), hematoma (1%), prothrombin time increased (1%), thrombocytopenia (1%)
Neuromuscular & skeletal: Myalgia (2%), weakness (3% to 6%), back pain (1% to 5%), leg pain (2% to 4%), rigors (1%), hypertonia, arthralgia (1% to 7%), gait abnormal (2% to 8%), involuntary muscle contractions (2%; migraine trial: 4%), skeletal pain (1%), hyperkinesia (up to 5%), hyporeflexia (up to 2%)
Ocular: Conjunctivitis (1%), diplopia (2% to 10%), myopia (up to 1%)
Otic: Hearing decreased (1% to 2%), tinnitus (1% to 2%), otitis media (migraine trial: 1% to 2%)
Renal: Nephrolithiasis, renal calculus (1% to 2%), hematuria (<1% to 2%)
Respiratory: Pharyngitis (3% to 6%), sinusitis (4% to 6%; migraine trial: 8% to 10%), epistaxis (1% to 4%), rhinitis (4% to 7%), dyspnea (1% to 2%), pneumonia (5%), cough (migraine trial: 2% to 3%), bronchitis (migraine trial: 3%)
Miscellaneous: Flu-like syndrome (3% to 7%), allergy (2% to 3%), body odor (up to 1%), viral infection (migraine trial: 3% to 4%), infection (<1% to 2%), diaphoresis (?1%), thirst (2%)
<1% (Limited to important or life-threatening): Anemia, angina, apraxia, AV block, bone marrow depression, deep vein thrombosis, dehydration, delirium, diabetes mellitus, dyskinesia, electrolyte imbalance, encephalopathy (with valproate therapy), eosinophilia, euphoria, granulocytopenia, hypokalemia, hypotension, liver enzymes increased, lymphadenopathy, lymphopenia, manic reaction, neuropathy, pancytopenia, paranoid reaction, photosensitivity, psychosis, pulmonary embolism, suicidal behavior, syncope, tongue edema
Postmarketing and/or case reports: Accommodation abnormality, erythema multiforme, eye pain, hepatic failure, hepatitis, hyperammonemia (with valproate therapy), hyperthermia (severe), migraine aggravated, oligohydrosis, pancreatitis, pemphigus, rash, renal tubular acidosis, Stevens-Johnson syndrome, syndrome of acute myopia/secondary angle-closure glaucoma, toxic epidermal necrolysis
Metabolism/Transport Effects
Inhibits CYP2C19 (weak); Induces CYP3A4 (weak)
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
CarBAMazepine: May decrease the serum concentration of Topiramate. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Maraviroc: CYP3A4 Inducers may decrease the serum concentration of Maraviroc. Risk D: Consider therapy modification
Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated in persons with a history of convulsions. If anticonvulsant is being used for another indication monitor response to treatment closely, as concurrent mefloquine may decrease response to treatment. Risk D: Consider therapy modification
Oral Contraceptive (Estrogens): Topiramate may decrease the serum concentration of Oral Contraceptive (Estrogens). Contraceptive failure is possible. Risk D: Consider therapy modification
Phenytoin: Topiramate may decrease the metabolism of Phenytoin. Phenytoin may increase the metabolism of Topiramate. Risk C: Monitor therapy
Valproic Acid: Topiramate may enhance the hepatotoxic effect of Valproic Acid. Risk C: Monitor therapy
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).
Storage
Store at room temperature of 15°C to 30°C (59°F to 86°F). Protect from moisture.
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
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; clearance is 50% higher in pediatric patients; Elderly: ~24 hours
Time to peak, serum: ~1-4 hours
Excretion: Urine (~70% to 80% as unchanged drug)
Dialyzable: ~30%
Dosage
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.
Epilepsy, adjunctive therapy:
Children 2-16 years:
Partial onset seizure or seizure associated with Lennox-Gastaut syndrome: Initial dose titration should begin at 25 mg (or less, based on a range of 1-3 mg/kg/day) nightly for the first week; dosage may be increased in increments of 1-3 mg/kg/day (administered in 2 divided doses) at 1- or 2-week intervals to a total daily dose of 5-9 mg/kg/day
Primary generalized tonic-clonic seizure: Use initial dose listed above, but use slower initial titration rate; titrate to recommended maintenance dose by the end of 8 weeks
Adolescents ?17 years and Adults:
Partial onset seizures: Initial: 25-50 mg/day (given in 2 divided doses) for 1 week; increase at weekly intervals 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 above for partial onset seizures, but use slower initial titration rate; titrate upwards to recommended dose by the end of 8 weeks; usual maintenance dose: 200 mg twice daily. Doses >1600 mg/day have not been studied.
Adults:
Migraine prophylaxis: Initial: 25 mg/day (in the evening), titrated at weekly intervals in 25 mg increments, up to the recommended total daily dose of 100 mg/day given in 2 divided doses
Cluster headache (unlabeled use): Initial: 25 mg/day, titrated at weekly intervals in 25 mg increments, up to 200 mg/day
Neuropathic pain (unlabeled use): Initial: 25 mg/day, titrated at weekly intervals in 25-50 mg increments to target dose of 400 mg daily in 2 divided doses. Reported dosage range studied: 25-800 mg/day
Dosing adjustment in renal impairment: Clcr <70 mL/minute: Administer 50% dose and titrate more slowly
Hemodialysis: Supplemental dose may be needed during hemodialysis
Dosing adjustment in hepatic impairment: Clearance may be reduced
Administration: Oral
May be administered without regard to meals
Capsule sprinkles: May be swallowed whole or opened to sprinkle the contents on soft food (drug/food mixture should not be chewed).
Tablet: Because of bitter taste, tablets should not be broken.
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, osteomalacia, and reduced growth rates in children); ammonia level in patients with unexplained lethargy, vomiting, or mental status changes; intraocular pressure, symptoms of secondary angle closure glaucoma
Patient Education
Take exactly as directed; do not increase dose or frequency or discontinue without consulting prescriber. While using this medication, do not use alcohol and other prescription or OTC medications (especially pain medications, sedatives, antihistamines, or hypnotics) without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake; possibly to prevent the development of kidney stones and dehydration. You may be at risk for decreased sweating and increased body temperature, especially in hot weather. You may experience drowsiness, dizziness, disturbed concentration, memory changes, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); or mouth sores, nausea, vomiting, or loss of appetite (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). Wear identification of epileptic status and medications. Report behavioral or CNS changes, suicidal ideation, or depression; skin rash; muscle cramping, numbness in extremities, weakness, tremors, changes in gait; chest pain, irregular heartbeat, or palpitations; hearing loss; cough or respiratory difficulty; or worsening of seizure activity or loss of seizure control. Seek immediate medical evaluation if you experience sudden vision changes, periorbital pain, flank pain, or blood in urine. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant or intend to become pregnant. Breast-feeding is not recommended.
Geriatric Considerations
This drug may not be a drug of choice in the elderly until all other therapies for seizures have been exhausted. Follow the recommended titration schedule and adjust time intervals to meet patient's needs. Since most elderly will have a Clcr <70 mL/minute, it is important to either measure or estimate by calculation the Clcr prior to initiating therapy.
Additional Information
May be associated with weight loss in some patients
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Gingivitis, dysphagia, glossitis, gum hyperplasia, and xerostomia (normal salivary flow resumes upon discontinuation).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Comment
Large double-blind studies have failed to differentiate this drug from placebo when used for bipolar disorder.
Nursing: Physical Assessment/Monitoring
Assess effectiveness and interactions of other medications patient may be taking. Monitor therapeutic effectiveness (seizure activity, force, type, duration), laboratory values, and adverse reactions at beginning of therapy and periodically with long-term use. Taper dosage slowly when discontinuing. May cause weight loss; monitor weight periodically. Assess knowledge/teach patient appropriate use, seizure safety precautions, interventions to reduce side effects, and adverse symptoms to report..
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, sprinkle:
Topamax®: 15 mg, 25 mg
Tablet:
Topamax®: 25 mg, 50 mg, 100 mg, 200 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Topamax)
25 mg (60): $148.51
50 mg (60): $278.81
100 mg (60): $395.39
200 mg (60): $457.08
References
Bar-Oz B, Nulman I, Koren G, et al, “Anticonvulsants and Breast Feeding: A Critical Review,” Paediatr Drugs, 2000, 2(2):113-26.
Carroll DG, Kline KM, and Malnar KF, "Role of Topiramate for the Treatment of Painful Diabetic Peripheral Neuropathy," Pharmacotherapy, 2004, 24(9):1186-93.
Chong MS and Libretto SE, " The Rationale and Use of Topiramate for Treating Neuropathic Pain," Clin J Pain, 2003, 19(1):59-68.
Dib JG, "Focus on Topiramate in Neuropathic Pain," Curr Med Res Opin, 2004, 20(12):1857-61.
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.
Glauser TA, “Preliminary Observations on Topiramate in Pediatric Epilepsies,” Epilepsia, 1997, 38(Suppl 1):37-41.
Glauser TA, “Topiramate Use in Pediatric Patients,” Can J Neurol Sci, 1998, 25(3):S8-12.
Glauser TA, Clark PO, and Strawsburg R, “A Pilot Study of Topiramate in the Treatment of Infantile Spasms,” Epilepsia, 1998, 39(12):1324-8.
Hershey AD, Powers SW, Vockell AL, et al, “Effectiveness of Topiramate in the Prevention of Childhood Headaches,” Headache, 42(8):810-18.
Krymchantowski AV, Bigal ME, and Moreira PR, “New and Emerging Prophylactic Agents for Migraine,” CNS Drugs, 2002, 16(9):611-34.
Mathew NT, Kailasam J, and Meadors L, “Prophylaxis of Migraine, Transformed Migraine, and Cluster Headache With Topiramate,” Headache, 2002, 42(8):796-803.
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.
Silberstein SD and Goadsby PJ, “Migraine: Preventataive Treatment,” Cephalalgia, 2002, 22(7):491-512.
Sachdeo RC, “Topiramate. Clinical Profile in Epilepsy,” Clin Pharmacokinet, 1998, 34(5):335-46.
Story JR, Calder CS, Hart DE, et al, “Topiramate in Migraine Prevention: A Double-Blind, Placebo-Controlled Study,” Headache, 2001, 41(10):968-75.
Young WB, Hopkins MM, Shechter AL, et al, “Topiramate: A Case Series Study in Migraine Prophylaxis,” Cephalalgia, 2002, 22(8):659-63.
International Brand Names
Lexi-Comp.com
Last full review/revision September 2008
Content last modified September 2008
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