Summary Of Exposure |
A) USES: Topiramate is a sulfamate-substituted monosaccharide used as an anticonvulsant and for the prophylactic treatment of migraines.
B) PHARMACOLOGY: The exact mechanism remains unknown. It may be able to block voltage-dependent sodium channels, augment the activity of the neurotransmitter gamma-aminobutyrate as some subtypes of GABA-A receptor, antagonize the AMPA/kainate subtype of the glutamate receptor, and inhibit the carbonic anhydrase enzyme, particularly isozymes II and IV.
C) TOXICOLOGY: Inhibits carbonic anhydrase, causing renal tubular acidosis and a non-anion gap metabolic acidosis.
D) EPIDEMIOLOGY: Data limited. In most cases, acute exposure produced only minimal to moderate effects. Fatalities have occurred, but were the result of polydrug exposure.
E) WITH THERAPEUTIC USE
1) ADVERSE EVENTS: COMMON: The most common dose-dependent events associated with topiramate therapy include: paresthesia, fatigue, nausea, anorexia, dizziness, weight decrease, diarrhea, difficulty with memory and concentration and somnolence. Other events that occur less frequently but are likely dose-dependent include: anxiety, depression, hypoesthesia, mood problems, dry mouth, confusion, involuntary muscle contractions, abnormal vision, and renal calculus.
2) Hyperchloremic metabolic acidosis has been associated with therapeutic use. Cases have developed in both adults (at doses as low as 50 mg/kg) and children (some as young as 5 months old at doses above 5 mg/kg/day).
F) WITH POISONING/EXPOSURE
1) OVERDOSE: Clinical effects in overdose are expected to be similar for both immediate-release and extended-release formulations.
2) MILD TO MODERATE TOXICITY: Data limited. Drowsiness, lethargy, seizures, dizziness, agitation, confusion, nausea, vomiting, ataxia, tremor, hypotension, depression, speech disturbances, impaired mentation, abnormal coordination, blurred vision and diplopia have occurred in overdose but the events were not reportedly severe in most cases.
3) SEVERE TOXICITY: Rarely, severe metabolic acidosis and coma have been reported after overdose.
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Vital Signs |
3.3.3) TEMPERATURE
A) WITH THERAPEUTIC USE 1) HYPERTHERMIA along with oligohidrosis have been reported infrequently with therapeutic use of topiramate. Most cases have occurred in children (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2014).
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Heent |
3.4.3) EYES
A) WITH THERAPEUTIC USE 1) Abnormal vision and diplopia occurred in up to 13% and 10%, respectively (versus approximately 2% and 5% in placebo, respectively) of patients taking topiramate at dosages of 200 to 1,000 mg/day (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2014).
2) Acute myopia and angle closure glaucoma has been reported in 23 patients taking topiramate (22 adults, 1 child) according to August 2001 postmarketing surveillance data. Symptoms typically develop during the first month of therapy and include acute onset of decreased visual acuity and/or eye pain. Physical exam may reveal myopia, redness, elevated intraocular pressure, shallow anterior chamber, and mydriasis (Personal Communication, 2001).
B) WITH POISONING/EXPOSURE 1) NYSTAGMUS: Mild lateral nystagmus was reported in a 5-year-old child following ingestion of an unknown amount of topiramate (Traub et al, 2003)
3.4.4) EARS
A) WITH THERAPEUTIC USE 1) Tinnitus was reported infrequently with topiramate therapy (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2014).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) HYPERTENSIVE DISORDER 1) WITH THERAPEUTIC USE a) There have been infrequent reports of hypertension following therapeutic use (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2014).
B) HYPOTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) Hypotension, postural hypotension and angina pectoris have been reported infrequently in both adults and children with epilepsy that have been treated with topiramate (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2014).
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 49-year-old man, with a history of bipolar affective disorder who had stopped taking his medications for months, was found minimally responsive in his home with 4 empty blister packs of 60 tablets of topiramate 100 mg (total dose: 24 g or 350 mg/kg). Upon arrival, the patient had mild tachycardia (120 beats/min) and hypotension (100 mmHg systolic) and CNS depression. Clinical findings included metabolic acidosis, CNS depression (Glasgow Coma Score 12) and 3 witnessed generalized tonic-clonic seizures over several hours. Following supportive care, the patient recovered completely over 2 days (Garcia-Gil et al, 2009).
C) CONDUCTION DISORDER OF THE HEART 1) WITH POISONING/EXPOSURE a) CASE SERIES: In a series of 567 patients with topiramate overdose reported to a poison center, 1 patient developed a conduction disturbance (Lofton & Klein-Schwartz, 2005).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) DYSPNEA 1) WITH THERAPEUTIC USE a) Dyspnea, bronchitis and rhinitis have been reported infrequently with therapeutic use (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2014).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) DIZZINESS 1) WITH THERAPEUTIC USE a) Dizziness was a common dose-related central nervous system event reported with therapeutic use (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2014).
B) PARESTHESIA 1) WITH THERAPEUTIC USE a) Paresthesia and tremor were commonly reported dose-related adverse events associated with topiramate therapy (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2014).
2) WITH POISONING/EXPOSURE a) CASE SERIES: In a series of 567 patients with topiramate overdose reported to a poison center, 10 (1.8%) developed tremor (Lofton & Klein-Schwartz, 2005).
C) CENTRAL NERVOUS SYSTEM DEFICIT 1) WITH THERAPEUTIC USE a) Other adverse central nervous system disorders that can occur relatively frequently include: difficulty with memory and concentration, insomnia, psychomotor slowing and miscellaneous cognitive problems (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2014).
b) CASE REPORT: A 30-year-old woman developed decreased cognition, dulled thinking, blunted mental reactions, blurred vision, paresthesias, and moderate sleepiness after rapidly escalating her topiramate dose to 450 mg/day over 2 weeks in an attempt to lose weight (Colom et al, 2001).
c) CASE REPORT: A 17-year-old girl developed somnolence, mild metabolic acidosis, and reversible neurologic and speech abnormalities (i.e., motor agitation, incoherence, confusion, disorientation, and significant speech impairments including echolalia) after intentionally ingesting eight 100-mg topiramate tablets. Following supportive care, she was discharged home without further complications (Chung & Reed, 2004).
2) WITH POISONING/EXPOSURE a) In a series of 567 patients with topiramate overdose reported to a poison center, 88 (15.5%) developed drowsiness/lethargy, 28 (4.9%) developed dizziness/vertigo, 28 (4.9%) developed agitation, 22 (3.9%) became confused, and one patient developed coma (Lofton & Klein-Schwartz, 2005).
b) CASE REPORT: A 33-month-old girl developed confusion, visual hallucinations, slurred speech, and severe ataxia after ingesting an unknown amount of topiramate (100-mg tablets). Topiramate levels were 9.4 mcg/mL and 4.2 mcg/mL, 3 days and 4 days postingestion, respectively. She regained normal gait on the fourth day and her slurred speech improved on the sixth day after ingestion (Lin & Lawrence, 2006).
D) DELIRIUM 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 13-year-old healthy boy with no history of epilepsy, intentionally ingested 400 mg of topiramate and within 3 hours became acutely agitated and confused. Haldol was given for agitation when admitted to the ED. Other symptoms included incoherent speech, visual hallucinations, memory deficits, decreased attention, dyscalculia, and cognitive slowing. Signs and symptoms improved over 36 hours and he was discharged to home with no long-term sequelae (Brar et al, 2005).
b) CASE REPORT: A 16-year-old girl with a history of epilepsy intentionally ingested 218.2 mg/kg and developed agitation, confusion, and mydriasis. Metabolic acidosis also occurred and lasted for 7 days despite supportive care. The patient was discharged on day 8 without sequelae (Wisniewski et al, 2009).
E) DROWSY 1) WITH THERAPEUTIC USE a) Somnolence is a common adverse event associated with therapy and appears to be dose-related (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2014).
2) WITH POISONING/EXPOSURE a) CASE SERIES: In a series of 7 intentional topiramate exposures (acute and acute-on-chronic) in adults, somnolence (n=4) was the most frequent symptom observed. Other clinical effects included vertigo, agitation, and mydriasis. The doses ranged from 10.7 to 218 mg/kg of body weight (mean 62.4 mg/kg). Each patient recovered without sequelae and were discharged after 4 to 8 days of hospitalization (Wisniewski et al, 2009).
F) COMA 1) WITH POISONING/EXPOSURE a) A 37-year-old woman with a history of bipolar disorder was treated with topiramate and diazepam and was found unconscious by her husband. She was in her normal state of health about 12 hours earlier. At the time of admission, she had clonic movements consistent with seizure activity which stopped with lorazepam. The patient remained unresponsive following naloxone administration and was intubated to protect her airway. Metabolic acidosis (pH 7.26, PCO2 41 mmHg, bicarbonate 21 mEq/L with an anion gap of 16) was present. A toxicology screen for salicylate, acetaminophen and ethanol were negative. A serum topiramate level was 356.6 mcg/mL (reference range, 5 to 20 mcg/mL) obtained at least 12 hours after ingestion. The patient gradually awoke over 12 hours and was successfully extubated on hospital day 2; she was intubated for a total of 18 hours. Once extubated, her speech remained slurred for the next day with mild somnolence. Topiramate levels were measured several times throughout her hospitalization as follows: 173.6 mcg/mL on day 2 , and 61.2 and 44 mcg/mL, respectively, on day 3 approximately 6 hours apart. Once she was fully awake she could not remember how much topiramate she had taken or when; she was transferred to inpatient psychiatric care on day 3 with ongoing elevated topiramate levels and persistent acidosis (Lynch et al, 2010).
G) SEIZURE 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 21-year-old man with a history of epilepsy was found confused and had a confirmed nonconvulsive status epilepticus after ingesting an estimated 8000 mg (80 g; ingested 40 200 mg tablets) of topiramate after an argument with his girlfriend. The patient was treated with lorazepam which terminated his seizure; however, when he awoke he had inappropriate verbal responses. His topiramate concentration was 144.6 mcg/mL on the day of admission. A toxicologic drug screen was negative. His topiramate was discontinued and he was treated with clobazam (10 mg twice daily) from day 2 to 8 with no further reports of seizures. Decontamination or hemodialysis were not performed as more than 24 hours had passed since ingestion. His cognitive issues gradually resolved with no permanent sequelae (Brandt et al, 2010).
b) CASE REPORT: A 49-year-old man, with a history of bipolar affective disorder who had stopped taking his medications for months, was found minimally responsive in his home with 4 empty blister packs of 60 tablets of topiramate 100 mg (total dose: 24 g or 350 mg/kg). Upon arrival, the patient had mild tachycardia, hypotension and CNS depression. Clinical findings included metabolic acidosis, CNS depression (Glasgow Coma Score 12) and 3 witnessed generalized tonic-clonic seizures over several hours. The patient returned to baseline mental status between each seizure. A urine toxicology screen was negative along with a normal head CT. Following supportive care, the patient recovered completely over 2 days (Garcia-Gil et al, 2009).
c) CASE REPORT: A 38-year-old man, not previously treated with topiramate, intentionally ingested 31.3 mg/kg and developed three generalized tonic-clonic seizures, deep coma, bradykinesia, bradyphasia, and vertigo. The patient recovered with supportive care (Wisniewski et al, 2009).
H) HEMIPARESIS 1) WITH THERAPEUTIC USE a) CASE REPORT: Two patients developed transient hemiparesis during topiramate therapy with resolution of weakness when topiramate was discontinued. Both patients has significant underlying neurologic pathology (CP with right sided weakness and complex partial seizures in one patient, and previous herpes simplex encephalitis, extensive left temporal infarction and secondary generalized seizures in the other) (Stephen et al, 1999).
I) NEUROPATHY 1) WITH POISONING/EXPOSURE a) CASE REPORT: Neurological changes, including numbness and repetitive mouthing movements, occurred in a 5-year-old child following ingestion of an unknown amount of topiramate. The patient recovered uneventfully with supportive care (Traub et al, 2003).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) NAUSEA 1) WITH THERAPEUTIC USE a) Nausea (14% versus 8% placebo), abdominal pain (7% versus 3% placebo) and constipation (3.2% versus 1% placebo) occurred during topiramate clinical studies in patients at 1000 mg/day (Prod Info TOPAMAX(R) oral tablets, oral capsules, 2006).
2) WITH POISONING/EXPOSURE a) CASE SERIES: In a series of 567 patients with topiramate overdose reported to a poison center, 15 (2.6%) developed nausea and 14 (2.5%) vomited (Lofton & Klein-Schwartz, 2005).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) LIVER ENZYMES ABNORMAL 1) WITH THERAPEUTIC USE a) Non-dose related increases in SGPT and SGOT have occurred infrequently in epileptic patients (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2014).
b) CASE REPORT: A 39-year-old woman maintained on carbamazepine for 2 years with evidence of liver disease began taking topiramate with the dose increased gradually to 300 mg/day over 4 months. A few days after the last dose increase she developed CNS depression and was admitted to the hospital one week later with hypoglycemia, elevated liver enzymes, and metabolic acidosis. This progressed to fulminant liver failure with encephalopathy, renal failure, and coagulopathy. She received a liver allograft 4 days after admission. The explanted liver showed massive centrilobular necrosis. Viral hepatitis, autoimmune liver diseases, metabolic diseases, and vascular diseases were excluded (Bjoro et al, 1998).
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Acid-Base |
3.11.2) CLINICAL EFFECTS
A) METABOLIC ACIDOSIS 1) WITH THERAPEUTIC USE a) SUMMARY: Hyperchloremic, non-anion gap, metabolic acidosis (i.e., a decrease in serum bicarbonate in the absence of chronic respiratory alkalosis) has been associated with topiramate therapy. This effect is due to renal bicarbonate loss secondary to the inhibitory effects of topiramate on carbonic anhydrase. Cases have developed in both adults (at doses as low as 50 mg/day) and children (some as young as 5 months old at doses above 5 mg/kg/day) (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2014).
b) CASE REPORT: Hyperchloremic metabolic acidosis was reported in a 20-year-old man with a seizure disorder who was taking phenytoin, valproic acid, and topiramate. The patient presented with acute mental status changes consisting of disorientation, somnolence, headache, and intermittent combativeness. Lab analysis showed an elevated chloride level (120 mEq/L) and a decreased bicarbonate level (12 mEq/L). A CT scan of the patient's head showed findings consistent with cerebral edema. The patient's mental status and acidosis gradually improved following tapering of the topiramate dosage and administration of sodium bicarbonate infusion (Stowe et al, 2000).
c) CASE REPORT: Severe hyperchloremic metabolic acidosis was also reported in a 34-year-old woman with a history of a seizure disorder, AIDS and mentally disabled who was receiving topiramate, ritonavir, lamivudine, nevirapine, ethambutol, rifabutin, fluconazole, clonazepam and levetiracetam. Upon presentation, the patient was alert with a complaint of shortness of breath. An initial ABG (pH 7.14, PCO2 9, PO2 144, anion gap 11 and serum lactate 1.2 mmol/L) revealed a non-anion gap metabolic acidosis. As symptoms progressed, the patient received intubation and mechanical ventilation for increasing respiratory fatigue. Aggressive fluid replacement, sodium bicarbonate and potassium supplementation gradually improved acidemia and the patient was successfully extubated on day 3 with a pH of 7.40. All laboratory parameters returned to normal. The patient fully recovered by day 4; topiramate remained discontinued (Shiber, 2009).
2) WITH POISONING/EXPOSURE a) Metabolic acidosis has been described in a number of case reports, most patients improved within several days of exposure with supportive care (Lynch et al, 2010; Garcia-Gil et al, 2009; Fakhoury et al, 2002; Wisniewski et al, 2009; Chung & Reed, 2004).
b) CASE REPORTS: Non-anion-gap metabolic acidosis was reported in two patients after intentionally ingesting topiramate in total doses of 20 and 40 grams. The acidosis persisted in both patients for several days postingestion until spontaneously resolving (Fakhoury et al, 2002).
c) CASE REPORT: A 16-year-old girl with a history of epilepsy intentionally ingested 218.2 mg/kg and developed agitation, confusion, and mydriasis. Metabolic acidosis (pH 7.33; HCO3 15.3 mEq/L; pCO2 -29; Base excess -8.9) also occurred and lasted for 7 days despite supportive therapy. The patient was discharged on day 8 without sequelae (Wisniewski et al, 2009).
d) CASE REPORT: A 29-year-old woman intentionally ingested 3 grams of topiramate, along with bupropion (4.5 grams), enalapril (200 mg), fluoxetine (600 mg), and glimepiride (20 mg), and presented with hypertension and tachycardia, which quickly resolved following decontamination with activated charcoal and sorbitol. However, approximately 12 hours postingestion, the patient developed non-anion gap metabolic acidosis associated with decreased consciousness. Three days later, the patient gradually recovered with supportive care (Kemmerer et al, 2002).
e) CASE REPORT: A 17-year-old girl developed somnolence, mild metabolic acidosis (pH 7.38, PCO2 32.4 mm Hg, PO2 108 mm Hg, and HCO3 19.5 mEq/L, with a base excess of -4.1 mEq/L, serum bicarbonate 18 mEq/L, anion gap 13, and chloride 105 mEq/L), and reversible neurologic and speech abnormalities after intentionally ingesting eight 100-mg topiramate tablets. Following supportive care, she was discharged home without further complications (Chung & Reed, 2004).
f) CASE SERIES: In a series of 567 patients with topiramate overdose reported to a poison center, 1 patient developed metabolic acidosis (Lofton & Klein-Schwartz, 2005).
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Reproductive |
3.20.1) SUMMARY
A) Topiramate is classified as FDA pregnancy category D and the topiramate and phentermine combination is classified as FDA pregnancy category X. Monotherapy increases the risk for cleft lip and/or cleft palate (oral clefts) in babies born to women who use the medication during the first trimester of pregnancy. Hypospadia was observed in 4 of 203 pregnancies exposed to topiramate during at least the first trimester in one prospective study. Abortions, premature births, low birth weights, and a reduction in live births have also been observed in prospective studies of topiramate use during the first trimester. In experimental animals, topiramate has demonstrated teratogenicity, embryotoxicity, fetotoxicity, and maternal toxicity. In limited human lactation data, 5 nursing infants had plasma topiramate levels equal to 10% to 20% of the maternal plasma levels; however, the effects of topiramate use on nursing infants are not known.
3.20.2) TERATOGENICITY
A) CONGENITAL ANOMALIES 1) A systematic review of six studies including a total of 3420 patients and 1,204,981 controls reported that first-trimester topiramate exposure is associated with a 6-fold increased risk of oral cleft. The findings recommend that women of reproductive age who may be prescribed topiramate should be informed of the teratogenic risk and urged to use effective contraception (Alsaad et al, 2015).
2) In a multicenter retrospective cohort study, a moderate increased risk of oral cleft was reported with topiramate use during the first trimester of pregnancy. The birth prevalence of oral cleft was 0.36% (7/1945) in the topiramate cohort compared with 0.14% (20/13,512) and 0.7% (9/13,614) in the formerly exposed and similar medical profile cohorts, respectively. Further analyses adjusting for confounding using different techniques resulted in similar results. Its suggested that if the relation is causal, there would be an additional 1 to 2 cases of oral cleft among 1000 infants exposed to topiramate during the first trimester (Mines et al, 2014).
3) A search of reported postmarketing events with topiramate monotherapy found that in 589 pregnancies, 73% resulted in live births, 16.5% resulted in spontaneous abortions, 7.5% were electively terminated, and 3.1% involved late fetal deaths (ie, stillborns). Three-hundred and seventy fetal or neonatal malformations were reported in 183 infants with maternal topiramate therapy use, including 72 major fetal or neonatal anomalies reported in 54 infants, most often reported as cleft lip or palate (Castilla-Puentes et al, 2014).
4) In an analysis of data collected by the Australian Pregnancy Register from 1999 through 2010 (n=1317), the incidence of fetal malformations that occurred with prenatal exposure to antiepileptic (AED) drug therapy during the first trimester was similar among women who used new AEDs (lamotrigine, levetiracetam, or topiramate), women with epilepsy untreated with AEDs, and women who used traditional AEDs (carbamazepine, clonazepam, or phenytoin), with the exception of valproic acid. The incidence of fetal malformations was 12/231 (5.2%), 0/22 (0%), and 1/31 (3.2%) among patients treated with lamotrigine, levetiracetam, and topiramate monotherapy, respectively, compared with 19/301 (6.3%), 0/24 (0%), 1/35 (2.9%), and 35/215 (16.3%) among patients treated with carbamazepine, clonazepam, phenytoin, or valproate monotherapy, respectively. Fetal malformations were reported in 6/139 (5.2%) of patients who were not treated with AEDs for at least the first trimester (Vajda et al, 2012).
5) Topiramate monotherapy increases the risk for cleft lip and/or cleft palate (oral clefts) in babies born to women who use the medication during the first trimester of pregnancy. Data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry indicate the prevalence of oral clefts was 1.4% for infants whose mothers used topiramate compared with 0.38% to 0.55% for infants who were exposed to other antiepileptic drugs (AEDs) or 0.07% for infants of mothers without epilepsy. The relative risk of oral clefts was 21.3 for infants exposed to topiramate when compared to infants who were not exposed to AEDs in utero (95% confidence interval, 7.9 to 57.1). Similar data have been reported from the United Kingdom Epilepsy and Pregnancy Register, with oral clefts occurring in 3.2% of infants exposed to topiramate compared with 0.2% of infants from the background population, a 16-fold increase in risk with topiramate exposure (US Food and Drug Administration, 2011).
6) In a prospective, observational study of 203 pregnancies in which the mothers had received topiramate as monotherapy (n=70) or as part of an antiepileptic drug (AED) polytherapy regimen (n=133) during the first trimester, major congenital malformations (MCMs) were reported in 16 topiramate exposures. An MCM was defined as an anomaly of a vital embryonic structure present at birth or during the first 6 weeks of life requiring significant treatment. Abnormalities were observed in 31 of the 178 live births (17.4%; 95% confidence interval (CI), 12.5% to 23.7%). Of the 16 MCMs, 3 occurred with monotherapy (4.8%; 95% CI, 1.7% to 13.3%) and 13 with polytherapy (19.8%; CI, 13.6% to 28%). Four of the MCMs were oral cleft palate (2.2%; 95% CI, 5.6% to 14.1%), 3 were cleft lip plus cleft palate, and 4 were hypospadia (5.1%; 95% CI, 0.2% to 10.1%), 2 of which were classified as major, among 78 live male births. High MCM rates were associated with valproate either as duotherapy with topiramate (n=12; 36.4%; 95% CI, 15.2% to 64.6%) or as part of a 3 or more AED regimen (n=23; 23.8%, 10.6% to 45.1%). Mean topiramate daily doses were not significantly different between those with or without MCMs for monotherapy or polytherapy exposure (p=0.123 and p=0.539, respectively) (Hunt et al, 2008).
7) In a 10-year, prospective study of pregnancies in which mothers called a teratogen information service following topiramate exposure during the first trimester or longer (n=52) compared to a control group with no exposure to nonteratogenic agents (n=212), frequency of major anomalies was not significant between the groups. Two of 4 anomalies in the topiramate group were non-genetic (pulmonary artery stenosis with maternal topiramate exposure and fatal multiple brain cysts with neonatal seizures with maternal exposure to topiramate, valproic acid, and clonazepam) (Ornoy et al, 2008).
8) In a preclinical trial involving eight exposed pregnancies, 5 fetuses were electively aborted and 3 normal infants resulted. In one case, reported only in abstract, an infant with multiple minor anomalies was born to a mother treated with topiramate monotherapy 700 mg twice daily throughout gestation. The infant girl was delivered by elective cesarean section at 40 weeks' gestation. At birth, anomalies noted included prenatal onset growth deficiency, generalized hirsutism, a third fontanelle, short nose with anteverted nares, blunt distal phalanges, and generalized blunting of the nails with 5th nail hypoplasia. This collection of defects is consistent with anomalies found in infants exposed to a number of different anticonvulsants prenatally (Hoyme et al, 1998).
B) ORAL CLEFT 1) There is an increased risk for cleft lip and/or cleft palate (oral clefts) in babies born to women who used topiramate during the first trimester of pregnancy. Data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry demonstrated that the relative risk of oral clefts was 9.6 for infants exposed to topiramate in utero (95% confidence interval (CI), 3.6 to 25.7). Retrospective epidemiology studies (Wolters Kluwer, FORTRESS, and Slone/CDC) showed a 1.47- (95% CI, 0.36 to 6.06), 2.22- (95% CI, 0.78 to 6.36), and 5.36-fold (95% CI, 1.49 to 20.07) respective increased risk of oral clefts for infants exposed to topiramate monotherapy in utero. The FORTRESS study further found a 1.5-fold (95% CI, -1.1 to 4.1) excess risk of oral clefts per 1,000 infants if exposed to topiramate during the first trimester. The Wolters Kluwer, FORTRESS, and Slone/CDC studies also showed a 1.12- (95% CI, 0.81 to 1.55), 1.21- (95% CI, 0.99 to 1.47), and 1.01-fold (95% CI, 0.37 to 3.22) increased risk for major congenital malformations in infants exposed to topiramate in utero (Prod Info QSYMIA(R) oral extended-release capsules, 2014).
C) ANIMAL STUDIES 1) TOPIRAMATE a) Topiramate has demonstrated teratogenicity in experimental animal studies (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2009).
b) MICE: The incidence of craniofacial defects increased as the dose of topiramate was increased during the period of organogenesis. The lowest dose utilized (20 mg/kg) was 0.2 times the recommended human dose on a milligram/square meter basis (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2009).
c) RATS: The incidence of limb malformations increased as the dose of topiramate was increased during the period of organogenesis. Teratogenicity was observed at doses of 400 mg/kg (equivalent to 10 times the recommended human dose on a mg/m(2) basis) and greater (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2009).
d) RABBITS: Oral administration of 120 mg/kg topiramate and greater increased the incidence of teratogenic events (6 times the recommended human dose on a mg/m(2) basis) (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2009).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) MONOTHERAPY: Topiramate is classified as FDA pregnancy category D. The North American Drug Pregnancy Registry has been established to evaluate safety outcomes of pregnant women who are receiving antiepileptic therapy. Patients or their healthcare providers are encouraged to enroll. To enroll, contact the registry at 1-888-233-2334. To find out more about the North American Drug Pregnancy Registry, go to http://www.massgeneral.org/aed/ (US Food and Drug Administration, 2011; Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2009).
2) COMBINATION THERAPY: The combination of topiramate and phentermine is classified as FDA pregnancy category X (Prod Info QSYMIA(TM) extended-release oral capsules, 2012).
B) ABORTION 1) In a 10-year, prospective study of pregnancies in which mothers called a teratogen information service following topiramate exposure during the first trimester or longer (n=52) compared to a control group with no exposure to nonteratogenic agents (n=212), spontaneous abortions occurred at a higher frequency in the topiramate group compared to the control group (11.3% vs 2.8%; p=0.017). However, the odds ratio for miscarriage adjusted for gestational age at call, maternal age, previous miscarriages, and smoking was 3.07 (95% confidence interval, 0.796 to 11.832). A regression analysis, performed to determine the cause of increased miscarriages, revealed that gestational age at contact was a significant predictor, but not treatment (Ornoy et al, 2008).
C) REDUCTION IN LIVE BIRTHS 1) In a 10-year, prospective study of pregnancies in which mothers called a teratogen information service following topiramate exposure during the first trimester or longer (n=52) compared to a control group with no exposure to nonteratogenic agents (n=212), there was a significant difference in number of deliveries. Among pregnancies in the topiramate group, 41 (77.4%) resulted in live birth deliveries compared to 196 (92.5%) in the control group (p=0.001) (Ornoy et al, 2008).
2) In a prospective, observational study of 203 pregnancies in which the mothers had received topiramate as monotherapy (n=70) or as part of an antiepileptic drug (AED) polytherapy regimen (n=133) during the first trimester, 25 outcomes did not result in live births. Spontaneous abortions (6 monotherapy, 12 polytherapy), induced abortions (2 monotherapy, 3 polytherapy), and stillbirths (2 polytherapy) were reported (Hunt et al, 2008).
D) BIRTH WEIGHT DECREASED 1) In a 10-year, prospective study of pregnancies in which mothers called a teratogen information service following topiramate exposure during the first trimester or longer (n=52) compared to a control group with no exposure to nonteratogenic agents (n=212), there were significant differences in median birth weight and birth weight of term infants without multiple gestations. Median birth weight was 2932 g for the topiramate group compared to 3300 g for the control group (p=0.024). The birth weight of term infants without multiple gestations was also lower in the topiramate group (3084 g vs 3356 g; p=0.001) (Ornoy et al, 2008).
2) In a prospective, observational study of 203 pregnancies in which the mothers had received topiramate as monotherapy (n=70) or as part of an antiepileptic drug (AED) polytherapy regimen (n=133) during the first trimester, there were 6 (9.8%) and 17 (15.3%) infants born at 37 weeks or less of those exposed to monotherapy and polytherapy, respectively (Hunt et al, 2008).
E) BIRTH PREMATURE 1) In a prospective, observational study of 203 pregnancies in which the mothers had received topiramate as monotherapy (n=70) or as part of an antiepileptic drug (AED) polytherapy regimen (n=133) during the first trimester, there were 8 (14.3%) and 20 (19.4%) infants that were small for gestational age of those exposed to monotherapy and polytherapy, respectively (Hunt et al, 2008).
F) ANIMAL STUDIES 1) Maternal and fetal toxicity were observed in experimental animal studies (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2009).
2) MICE: Maternal toxicity (decreased weight gain), reduced fetal body weights, and ossification were observed at topiramate doses greater than or equal to 500 mg/kg/day (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2009).
3) RATS: Maternal toxicity was observed after 400 mg/kg/day and above with reduced maternal weight gain at doses of 100 mg/kg/day topiramate and greater. The offspring of female rats treated with topiramate exhibited decreased viability and delayed physical development at 200 mg/kg/day and reductions in pre- and/or postweaning body weight gain at 2 mg/kg/day (0.05 times the recommended human dose on a milligram/square meter basis). Embryotoxicity (reduced fetal body weights, increased incidence of structural variations) was observed at doses as low as 20 mg/kg/day topiramate (0.5 times the recommended human dose) (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2008).
4) RABBITS: Maternal toxicity (decreased weight gain, clinical signs, and/or mortality) and embryo and fetal toxicity were observed at 35 mg/kg/day of topiramate, or greater (equivalent to 2 times the recommended human dose on a milligram/square meter basis) (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2008).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREAST MILK 1) MONOTHERAPY: In limited data of nursing infants (n=5), infant plasma topiramate levels were 10% to 20% of the maternal plasma levels; however, the effects of topiramate use in nursing infants are not known (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2009).
2) COMBINATION THERAPY: Topiramate and amphetamines (phentermine has pharmacologic activity and a chemical structure similar to amphetamines) are excreted in human milk (Prod Info QSYMIA(TM) extended-release oral capsules, 2012).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) RATS: No adverse effects on male or female fertility were observed in rats receiving up to 2.5 times the recommended human dose on a mg/m(2) of body surface area basis (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2009).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) At the time of this review, the manufacturer does not report any long term studies in humans. Mice have developed bladder tumors at topiramate doses of 300 mg/kg for 21 months.
3.21.3) HUMAN STUDIES
A) LACK OF INFORMATION 1) At the time of this review, the manufacturer does not report any long term studies in humans (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2009).
3.21.4) ANIMAL STUDIES
A) BLADDER TUMORS 1) MICE: A statistically significant increase of urinary bladder tumors were observed in preclinical studies at doses of 300 mg/kg topiramate (approximately 0.5 to 1 times a steady-state exposure as measured in a patient receiving a recommended dose of 400 mg). This type of tumor which was due to the increased occurrence of a smooth muscle tumor is considered histomorphologically unique to mice. The relevance to humans is unknown (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2009).
B) LACK OF EFFECT 1) RATS: No evidence of carcinogenicity was observed after 2 years at doses up to 120 mg/kg (approximately 3 times the recommended human dose on a mg/(2)m basis) (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2009).
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Genotoxicity |
A) Topiramate did not demonstrate genotoxic potential following a series of in vitro or in vivo assays, which included the Ames test, in vitro mouse lymphoma, unscheduled DNA synthesis in rat hepatocytes or cause chromosomal aberrations in human lymphocytes in vitro or rat bone marrow in vivo (Prod Info TOPAMAX(R) oral tablets, oral sprinkle capsules, 2009).
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