Eprontia (topiramate)

Dosage of topiramate must be adjusted carefully and individualized according to patient response and tolerance and the condition being treated. The manufacturer states that titration of topiramate dosages too rapidly (e.g., over 3-6 weeks) to achieve target dosages and/or excessive target dosages may have contributed to an unnecessarily high incidence of adverse effects in clinical studies.

In patients with or without a history of seizures or epilepsy, anticonvulsant drugs, including topiramate, should be withdrawn gradually to minimize the risk of seizures or increased seizure frequency. In clinical studies for seizure disorders, daily dosages of topiramate were decreased in weekly intervals by 50-100 mg in adults and over a 2-8 week period in pediatric patients; transition to a new anticonvulsant regimen was permitted when clinically indicated. In clinical studies for migraine prophylaxis, daily dosages were decreased in weekly intervals by 25-50 mg. However, in situations where more rapid withdrawal of topiramate is clinically necessary, the manufacturers recommend appropriate monitoring.

Topiramate is administered orally; the drug is commercially available in various dosage forms for oral administration, including immediate-release tablets, sprinkle capsules, extended-release capsules, and an oral solution.

Store topiramate tablets at 15-30degreesC and topiramate sprinkle capsules at or below 25degreesC. Store Qudexy(R) XR extended-release capsules at 20-25degreesC (excursions permitted between 15-30degreesC). Store Trokendi XR(R) extended-release capsules at 25degreesC (excursions permitted between 15-30degreesC). Store Eprontia(R) oral solution at 20-25degreesC (excursions permitted between 15-30degreesC). Protect topiramate tablets, sprinkle capsules, and extended-release capsules from moisture during storage; additionally, protect Trokendi XR(R) from light during storage.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Cyp3a4 Inducers/Zuranolone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of zuranolone.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in a loss of zuranolone efficacy.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid the concurrent use of zuranolone with CYP3A4 inducers.(1)

DISCUSSION: Coadministration of zuranolone with rifampin decreased the maximum concentration (Cmax) by 0.31-fold and area-under-curve (AUC) by 0.15-fold.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib. Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Carbonic Anhydrase Inhibitors/Zonisamide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Zonisamide is a carbonic anhydrase inhibitor and can induce renal bicarbonate loss, resulting in metabolic acidosis. It can also reduce urinary citrate excretion and increase urinary pH, posing a risk for nephrolithiasis. As well, carbonic anhydrase inhibitors can cause decreased sweating and elevated body temperature, predisposing patients to heat-related disorders. Concurrent use of zonisamide with other carbonic anhydrase inhibitors may result in an additive risk of all these effects.(1-2)

CLINICAL EFFECTS: The concurrent use of zonisamide with another carbonic anhydrase inhibitor may increase the risk of metabolic acidosis and kidney stone formation.(1) Concurrent use of zonisamide with other carbonic anhydrase inhibitors may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death.

PREDISPOSING FACTORS: Patients with conditions that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, and being on a ketogenic diet) may be at increased risk of experiencing adverse effects from concurrent carbonic anhydrase inhibitors.(1) Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1)

PATIENT MANAGEMENT: The UK and US manufacturers of zonisamide state that caution should be used in adults when zonisamide is prescribed with other carbonic anhydrase inhibitors.(1-2) Pediatric and adolescent patients must not take carbonic anhydrase inhibitors concurrently with zonisamide.(1) Check serum bicarbonate at baseline and periodically during treatment. Monitor for signs and symptoms of metabolic acidosis: hyperventilation, fatigue, anorexia, arrhythmias, stupor. Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of metabolic acidosis, dehydration, oligohidrosis, or elevated body temperature occur, a decreased dose or discontinuation of zonisamide should be considered.

DISCUSSION: Zonisamide is a carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors increase urinary bicarbonate excretion, reduce urinary citrate excretion and increase urinary pH. Concurrent use of zonisamide with other carbonic anhydrase inhibitors may increase the risk of metabolic acidosis and kidney stone formation and should therefore be avoided.(1) Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment and resulted in death.(1)

Cyp3a4 Inducers/Erlotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of erlotinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a CYP3A4 inducer may result in decreased levels and effectiveness of erlotinib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid the concurrent use of CYP3A4 inducers in patients receiving therapy with erlotinib. Consider the use of alternative agents with less enzyme induction potential.(1) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued.(1)

DISCUSSION: Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(1) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(1) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(2) In a study, concurrent use of sorafenib (400 mg twice daily) and erlotinib (150 mg daily) decreased the concentration minimum (Cmin), concentration maximum (Cmax), and AUC of erlotinib.(3) In an animal study, concurrent use of dexamethasone and erlotinib decreased the AUC of erlotinib by 0.6-fold.(4) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(5,6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6) Weak inducers of CYP3A4 include: amprenavir, armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginkgo, ginseng, glycyrrhizin, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(5,6)

Selected Anticonvulsants/Ulipristal

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Eslicarbazepine, mephenytoin, oxcarbazepine, rufinamide, and topiramate may induce the metabolism of ulipristal by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use or use of eslicarbazepine, mephenytoin, oxcarbazepine, rufinamide, or topiramate within the previous 2-3 weeks may result in decreased levels and effectiveness of ulipristal.(1,2) In addition, topiramate has been associated with an increased risk of birth defects, including cleft palate.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US and UK manufacturers of ulipristal states that concurrent use with CYP3A4 inducers such as eslicarbazepine, mephenytoin, oxcarbazepine, rufinamide, or topiramate is not recommended. Decreased effectiveness of ulipristal may occur even 2-3 weeks after discontinuation of these agents.(1,2)

DISCUSSION: CYP3A4 inducers may decrease levels and effectiveness of ulipristal. Enzyme induction may take 2-3 weeks to wear off. Plasma levels of ulipristal may be reduced even if the CYP3A4 inducer was discontinued in the previous 2-3 weeks.(1) Concurrent administration of ulipristal 30 mg and rifampin 600 mg, another CYP3A4 inducer, for 9 days decreased the maximum concentration (Cmax) and area-under-the-curve (AUC) by 90% and 93%, respectively. The Cmax and AUC of monodemethyl-ulipristal decreased by 84% and 90%, respectively.(2)

Selected Anticonvulsants; Barbiturates/Contraceptives

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Barbiturates, hydantoins, and primidone may increase the metabolism of the contraceptives via CYP3A4 induction.

CLINICAL EFFECTS: May observe reduced contraceptive effects such as breakthrough bleeding, spotting, or pregnancy. Effects may be seen several days after discontinuation of the anticonvulsant or barbiturate. In addition, topiramate has been associated with an increased risk of birth defects, including cleft palate.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: To avoid pregnancy, additional or alternative means of non-hormonal contraception should be utilized. Depo medroxyprogesterone may be an alternative, since its effectiveness is not decreased by anticonvulsants. Patients receiving perampanel at doses of 12 mg/day should use alternative contraception methods, such as an intra-uterine device or condom. Patients receiving topiramate may observe decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg per day. Patients taking topiramate and estrogen containing or progestin-only contraceptives should be asked to report any change in their bleeding patterns.(20) Patients taking the combination of phentermine/topiramate for weight loss should be counseled that break-through bleeding may occur but is not expected to increase the risk of pregnancy. Instruct patients to report changes in bleeding patterns to their physician and to continue to take their hormonal contraceptive. Patients should not rely on hormonal contraceptives (other than implants or IUD) alone, but may use them in combination with a barrier contraceptive. It is necessary to use effective contraception with phentermine/topiramate, because the topiramate content of the product can cause birth defects. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.

DISCUSSION: Decreased effectiveness of oral contraceptives, characterized by breakthrough bleeding and amenorrhea have been documented. Through August, 2010, Australia's Therapeutic Goods Association had received 32 reports of contraceptive failure leading to pregnancy as a result of a suspected interaction between etonogestrel implants and carbamazepine. In a randomized, open-label study in healthy women, concurrent topiramate (50 mg daily to 200 mg daily) and Ortho Novum 1/35 (ethinyl estradiol and norethindrone) resulted in no changes in levels of ethinyl estradiol or norethindrone. However, in another study, concurrent topiramate at doses of 200 mg daily, 400 mg daily, and 800 mg daily with valproic acid decreased the area-under-curve (AUC) of ethinyl estradiol by 18%, 21%, and 30%, respectively. There were no changes in norethindrone levels. The US manufacturer of topiramate states that the possibility of decreased contraceptive effectiveness should be considered. At doses of 12 mg/day, perampanel decreased the maximum concentration (Cmax) and AUC of levonorgestrel by 40% each. The Cmax of ethinyl estradiol was decreased by 18%. There were no effects on ethinyl estradiol AUC. Doses of perampanel of 4 mg/day and 8 mg/day had no effect on contraceptive levels. The combination of phentermine/topiramate (15 mg/92 mg for 15 days) increased the Cmax and AUC of norethindrone by 22% and 16%, respectively. The Cmax and AUC of ethinyl estradiol decreased 8% and 16%, respectively. Because contraceptive efficacy is primarily determined by the progestin component, no effect on contraceptive efficacy is expected, although breakthrough bleeding may occur. The effectiveness of depo medroxyprogesterone is not decreased by anticonvulsants or barbiturates.

Topiramate/Carbonic Anhydrase Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Topiramate is a weak carbonic anhydrase inhibitor and can induce renal bicarbonate loss, resulting in metabolic acidosis. It can also reduce urinary citrate excretion and increase urinary pH, posing a risk for nephrolithiasis. As well, carbonic anhydrase inhibitors can cause decreased sweating and elevated body temperature, predisposing patients to heat-related disorders.(1)

CLINICAL EFFECTS: The concurrent use of topiramate with another carbonic anhydrase inhibitor may increase the risk of metabolic acidosis and kidney stone formation.(1) Concurrent use of topiramate with other carbonic anhydrase inhibitors may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death.

PREDISPOSING FACTORS: Patients with conditions that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, and being on a ketogenic diet) may be at increased risk of experiencing adverse effects from concurrent carbonic anhydrase inhibitors.(1) Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1)

PATIENT MANAGEMENT: The US manufacturer of topiramate states that the concurrent use of topiramate with other carbonic anhydrase inhibitors should be avoided. Patients receiving concurrent therapy should be monitored for the appearance of or worsening of metabolic acidosis, nephrolithiasis, and hyperthermia.(1) Check serum bicarbonate at baseline and periodically during treatment. Monitor for signs and symptoms of metabolic acidosis: hyperventilation, fatigue, anorexia, arrhythmias, stupor. Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of metabolic acidosis, dehydration, oligohidrosis, or elevated body temperature occur, a decreased dose or discontinuation of zonisamide should be considered.

DISCUSSION: Topiramate is a weak carbonic anhydrase inhibitor. Carbonic anhydrase inhibitors increase urinary bicarbonate excretion, reduce urinary citrate excretion and increase urinary pH. Concurrent use of topiramate with other carbonic anhydrase inhibitors may increase the risk of metabolic acidosis and kidney stone formation and should therefore be avoided.(1) Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Carbonic Anhydrase Inhibitors/Metformin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Carbonic anhydrase inhibitors increase bicarbonate excretion which may cause metabolic acidosis.(1) High systemic concentrations of metformin may result in lactic acidosis.(2,3) Topiramate, a mild carbonic anhydrase inhibitor, may also increase systemic exposure to metformin.(1)

CLINICAL EFFECTS: Carbonic anhydrase inhibitors may increase the risk for metformin associated lactic acidosis.(1-3) Untreated lactic acidosis may be fatal. Symptoms of lactic acidosis include malaise, myalgias, respiratory distress, low blood pH, increased anion gap and elevated blood lactate.(2) Carbonic anhydrase inhibitors linked to this monograph are acetazolamide, dichlorphenamide, methazolamide, sulthiame, topiramate, and zonisamide.

PREDISPOSING FACTORS: Risk factors for metformin associated lactic acidosis include renal impairment,sepsis, dehydration, excessive alcohol intake, acute or chronic metabolic acidosis, hepatic insufficiency, acute heart failure, metformin plasma levels > 5 micrograms/mL, and conditions which may lead to tissue hypoxia. Geriatric patients may also be at higher risk due to slower metformin clearance and increased half-life in this population. The risk for metabolic acidosis is higher with increased doses of either agent.

PATIENT MANAGEMENT: For patients receiving concurrent therapy, monitor renal function and assure that patient does not have risk factors for metformin associated lactic acidosis. Discontinue metformin when risk factors are present. If both drugs are given, monitor renal function and for signs and symptoms of metformin toxicity (lactic acidosis) such as malaise, myalgias, respiratory distress, increasing somnolence, and respiratory distress. Laboratory results which may signal lactic acidosis include: low pH, an increased anion gap, and increased lactate to pyruvate ratio. Manufacturer recommendations: the manufacturer of metformin recommends caution with concomitant use of carbonic anhydrase inhibitors due to an increased risk for metformin associated lactic acidosis.(2) The manufacturer of topiramate notes that topiramate can frequently cause metabolic acidosis and that metformin should not be used in patients with metabolic acidosis.(1)

DISCUSSION: A literature search for lactic acidosis due solely to the combination of metformin and carbonic anhydrase inhibitors or topiramate did not reveal any case reports of symptomatic metabolic acidosis due to this combination. Never-the-less, since carbonic anhydrase inhibitors act by inhibiting the reabsorption of bicarbonate in the renal tubule, some lowering of systemic bicarbonate and pH is common and supports the plausibility of this interaction. In addition, a pharmacokinetic interaction has been described with topiramate. A study in healthy volunteers evaluated the effect of topiramate 100 mg every 12 hours on the kinetics of metformin 500 mg every 12 hours. Mean metformin exposure (area-under-curve or AUC) was increased 25%.(1)

Moderate And Weak Cyp3a4 Inducers/Tacrolimus

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may accelerate the metabolism of tacrolimus.(1)

CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of tacrolimus.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and adjusting tacrolimus dose if needed. Monitor clinical response closely.(1)

DISCUSSION: A 13-year-old cystic fibrosis patient with a history of liver transplant on stable doses of tacrolimus underwent 2 separate courses of nafcillin therapy (a moderate CYP3A4 inducer). During the 1st course of nafcillin, his tacrolimus levels started to fall 3 days after starting nafcillin, became undetectable at day 8, and recovered to therapeutic levels without a change in tacrolimus dose 5 days after discontinuation of nafcillin. During the 2nd course of nafcillin, tacrolimus level became undetectable 4 days after starting nafcillin and recovered 3 days after stopping nafcillin.(2) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, modafinil, nafcillin, repotrectinib, telotristat, and tovorafenib.(3,4) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, nevirapine, oritavancin, omaveloxolone, oxcarbazepine, pioglitazone, relugolix, rufinamide, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vinblastine, and zanubrutinib.(3,4)

Moderate And Weak Cyp3a4 Inducers/Ubrogepant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may induce the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of ubrogepant.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with moderate or weak CYP3A4 inducers. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the dose of ubrogepant should be 100 mg.(1)

DISCUSSION: Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, dexamethasone, dicloxacillin, echinacea, elafibranor, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, relugolix, repotrectinib, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Selected Moderate-Weak Cyp3a4 Inducers/Exemestane

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of exemestane.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in decreased levels and effectiveness of exemestane.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The US manufacturer of exemestane recommends that patients receiving concurrent therapy with a strong CYP3A4 inducer receive 50 mg of exemestane daily after a meal.(1) It may be prudent to consider a dosage increase for patients receiving weaker CYP3A4 inducers.

DISCUSSION: In a study in 10 healthy postmenopausal subjects, pretreatment with rifampin (a strong CYP3A4 inducer, 600 mg daily for 14 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of exemestane (25 mg) by 54% and 41%, respectively.(1) Strong inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 80% or more and include: carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort.(1-3) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, gingko, ginseng, glycyrrhizin, lorlatinib, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Sodium Channel Blocker; Potassium Channel Blocker/Lacosamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (sodium channel blockers and potassium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers and potassium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1)

DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) A case report of a 49 year old male with refractory complex partial and generalized seizures described the development of ventricular tachycardia four months after addition of lacosamide 400 mg/day to the existing regimen of carbamazepine, lamotrigine, clonazepam, and valproate. The patient's ECG showed first-degree AV block, posterior left fascicular block, and severe widening of the QRS complex, all of which resolved upon discontinuation of lacosamide.(2)

Topiramate/Anticholinergics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Topiramate can cause decreased sweating and elevated body temperature. Agents with anticholinergic activity can predispose patients to heat-related disorders.(1-2)

CLINICAL EFFECTS: Concurrent use of topiramate with agents with anticholinergic activity may increase the incidence of oligohidrosis and hyperthermia, especially in pediatric or adolescent patients.(1-2) Overheating and dehydration can lead to brain damage and death.

PREDISPOSING FACTORS: Pediatric and adolescent patients and patients with dehydration may be more likely to experience heat-related disorders.(1)

PATIENT MANAGEMENT: The manufacturer of topiramate states that caution should be used when topiramate is prescribed with other medicinal products that predispose to heat-related disorders, such as agents with anticholinergic activity (e.g. clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin) concurrently with zonisamide.(1) Monitor for signs and symptoms of heat stroke: skin feels very hot with little or no sweating, confusion, muscle cramps, rapid heartbeat, or rapid breathing. Monitor for signs and symptoms of dehydration: dry mouth, urinating less than usual, dark-colored urine, dry skin, feeling tired, dizziness, or irritability. If signs or symptoms of dehydration, oligohidrosis, or elevated body temperature occur, discontinuation of zonisamide should be considered.

DISCUSSION: Case reports of decreased sweating and elevated temperature have been reported, especially in pediatric patients. Some cases resulted in heat stroke that required hospital treatment.(1) A 64-year old woman developed non-exertional hyperthemia while taking multiple psychiatric medications with topiramate.(2)

Topiramate/Hydrochlorothiazide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Hydrochlorothiazide may increase levels of topiramate. Also, both agents may decrease potassium levels.(1,2)

CLINICAL EFFECTS: Concurrent use of hydrochlorothiazide may result in elevated levels of topiramate and hypokalemia.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor serum potassium and topiramate in patients receiving concurrent therapy. The dosage of topiramate may need to be adjusted, an alternative diuretic or potassium supplement may be needed.

DISCUSSION: In a study in 23 healthy subjects, concurrent hydrochlorothiazide (25 mg daily) increased the maximum concentration (Cmax) and area-under-curve (AUC) of topiramate (96 mg BID) by 27% and 29%, respectively. During concurrent therapy, 61% of patients had a serum potassium level less than 3.5 mEq/L, compared with 27% with topiramate alone and 25% with hydrochlorothiazide alone. During concurrent therapy, the mean decrease in serum potassium levels was -0.60 mEq/L, compared with -0.25 mEq/L with topiramate alone and -0.12 mEq/L with hydrochlorothiazide alone.(1)

Topiramate/Valproic Acid Derivatives

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown, but a pharmacokinetic interaction does not occur.(1-4) Topiramate may contribute to increased ammonia levels by inhibiting carbonic anhydrase and cerebral glutamine.(5) Concurrent use may exacerbate or unmask existing metabolism defects.(1-4)

CLINICAL EFFECTS: Concurrent use of valproic acid or its derivatives and topiramate may increase the risk of hyperammonemia with or without encephalopathy. Hyperammonemic encephalopathy may present as changes in state of consciousness and/or cognitive function with lethargy and vomiting.(1-4) Concurrent use has also resulted in hypothermia.(1)

PREDISPOSING FACTORS: The risk of hyperammonemia with or without encephalopathy may be increased in patients with inborn metabolism errors or decreased hepatic mitochondrial activity.(1-4)

PATIENT MANAGEMENT: In patients receiving concurrent valproic acid derivatives and topiramate, monitor for unexplained lethargy, vomiting, and/ or changes in mental status. If these symptoms develop, check the patient's ammonia level.(1-4) The valproic acid derivative and/or topiramate may need to be discontinued if hyperammonemia develops.(1-3)

DISCUSSION: There have been several reports of hyperammonemia with and without encephalopathy in patients receiving concurrent valproic acid derivatives and topiramate.(1-12) In many of these reports, the patients tolerated the valproic acid derivative alone, but developed hyperammonemia with or without encephalopathy following the addition of topiramate.(1-9) Two clinical trials showed no clinically significant pharmacokinetic interaction between valproic acid and topiramate.(12,13)

Weak Cyp3a4 Inducers/Atogepant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Weak CYP3A4 inducers may increase the metabolism of atogepant by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of weak CYP3A4 inducers with atogepant may result in decreased levels and clinical effectiveness of atogepant.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of atogepant recommends that patients on concomitant weak CYP3A4 inducers receive atogepant 30 mg or 60 mg once daily for prevention of episodic migraines and receive atogepant 60 mg once daily for prevention of chronic migraines.(1) Patients receiving concurrent therapy with CYP3A4 inducers and atogepant should be observed for decreased clinical effectiveness.

DISCUSSION: In a study of healthy subjects, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of atogepant by 60% and 30%, respectively. Topiramate, a weak CYP3A4 inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1) Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(1,2)

*There are no known contraindications to the use of immediate-release topiramate and Qudexy(R) XR extended-release topiramate capsules. Trokendi XR(R) extended-release topiramate capsules are contraindicated in patients with recent alcohol use (i.e., within 6 hours prior to or 6 hours after topiramate use).

There are no contraindication contraindications for this drug.

• Acute cognitive impairment
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Concentration difficulty
• Depression
• Fever
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Memory impairment
• Metabolic acidosis
• Ocular hypertension
• Pregnancy
• Reduced visual acuity
• Suicidal ideation

• Arginase deficiency
• Argininosuccinate lyase deficiency
• Carbamoyl phosphate synthetase deficiency
• Citrullinemia
• Diarrhea
• Disease of liver
• Hyperammonemia associated with n-acetylglutamate synthase deficiency
• Kidney stone
• Ornithine carbamoyltransferase deficiency

The most common adverse effects reported in adults and pediatric patients receiving topiramate for epilepsy (>=10% incidence and occurring more frequently with the drug than placebo) include paresthesia, anorexia, weight loss, speech disorders or other related speech problems, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, abnormal vision, and fever.

The most common adverse effects reported in adults and pediatric patients receiving topiramate for migraine prophylaxis (5% or greater incidence and occurring more frequently with the drug than with placebo) include paresthesia, anorexia, weight loss, difficulty with memory, taste perversion, diarrhea, hypoesthesia, nausea, abdominal pain, and upper respiratory tract infection.

In controlled clinical trials evaluating topiramate for alcohol dependence+, paresthesia, taste perversion, fatigue, anorexia, insomnia, concentration and attention difficulties, memory impairment, nervousness, somnolence, diarrhea, dizziness, and pruritus were reported more frequently in patients receiving topiramate than in patients receiving placebo.

Less Frequent

• Infection
• Kidney stone
• Leukopenia

Rare or Very Rare

• Anaphylaxis
• Anemia
• Angioedema
• Asthma
• Bullous dermatitis
• Choroidal effusion
• Decreased sweating
• DRESS syndrome
• Drug-induced psychosis
• Encephalopathy
• Eosinophilia
• Erythema multiforme
• Hallucinations
• Hepatic failure
• Hepatitis
• Hyperammonemia
• Hyperthermia
• Hypokalemia
• Hypotension
• Hypothermia
• Maculopathy
• Metabolic acidosis
• Myopia
• Nephrocalcinosis
• Ocular hypertension
• Osteomalacia
• Osteopenia
• Osteoporosis
• Pancreatitis
• Pemphigus
• Pneumonia
• Retinal pigment epithelial detachment
• Scotomata
• Secondary angle-closure glaucoma
• Stevens-johnson syndrome
• Suicidal
• Suicidal ideation
• Tongue swelling
• Toxic epidermal necrolysis

More Frequent

• Acute abdominal pain
• Acute cognitive impairment
• Anorexia
• Behavioral disorders
• Bradykinesia
• Concentration difficulty
• Diplopia
• Dizziness
• Drowsy
• Dysarthria
• Dysmenorrhea
• Fatigue
• Fever
• Flushing
• General weakness
• Hypoesthesia
• Insomnia
• Irregular menstrual periods
• Mastalgia
• Memory impairment
• Nausea
• Nervousness
• Nystagmus
• Paresthesia
• Weight loss

Less Frequent

• Aggressive behavior
• Agitation
• Alopecia
• Altered mental status
• Arthralgia
• Ataxia
• Back pain
• Bronchitis
• Chest pain
• Constipation
• Cough
• Depression
• Diarrhea
• Dysgeusia
• Dyspepsia
• Ecchymosis
• Edema
• Epistaxis
• Gastroenteritis
• Gingivitis
• Hemorrhage
• Hypertonia
• Involuntary muscle movement
• Leg pain
• Libido changes
• Mood changes
• Pharyngitis
• Premature ejaculation
• Purpura
• Rhinitis
• Sinusitis
• Symptoms of anxiety
• Tinnitus
• Tremor
• Upper respiratory infection
• Urinary tract infection
• Viral infection
• Vomiting
• Xerostomia

Rare or Very Rare

• Abnormal vaginal bleeding
• Accidental fall
• Acne vulgaris
• Chills
• Conjunctivitis
• Cystitis
• Dyspnea
• Dysuria
• Erectile dysfunction
• Flu-like symptoms
• Gastroesophageal reflux disease
• Gingival bleeding
• Headache disorder
• Hematuria
• Hypercalcinuria
• Hyperhidrosis
• Increased urinary frequency
• Lip swelling
• Myalgia
• Ocular pain
• Ocular redness
• Orthostatic hypotension
• Periorbital edema
• Polydipsia
• Pruritus of skin
• Skin rash
• Syncope
• Urinary incontinence
• Urticaria
• Vertigo
• Visual changes
• Visual field defect
• Vulvovaginal candidiasis

No enhanced messaging available.

Safety and efficacy of topiramate for the management of seizure disorders have not been established in children younger than 2 years of age. In a randomized, double-blind, placebo-controlled study in infants 1-24 months of age, topiramate in fixed dosages of 5, 15, and 25 mg/kg daily was not shown to be more effective than placebo in controlling seizures after 20 days of treatment. Results of this study in addition to a long-term open-label study in infants and toddlers suggest that very young children may experience adverse effects not previously observed in older pediatric patients and adults or that occur with greater frequency or severity than in these older age groups. Such adverse effects included growth/length retardation, changes in certain laboratory parameters (e.g., increased serum creatinine concentrations, increased BUN, increased protein concentrations, decreased potassium concentrations, increased eosinophil count, increased alkaline phosphatase concentrations), and impairment of adaptive behavior. Although other preparations of topiramate may be used in children as young as 2 years of age for the management of seizure disorders, use of Trokendi XR(R) extended-release capsules is recommended only in children 6 years of age or older because this capsule formulation must be swallowed whole and cannot be sprinkled on food, crushed, or chewed.

Safety and efficacy of topiramate for migraine prophylaxis have not been established in pediatric patients younger than 12 years of age. In a controlled study in pediatric patients 6-16 years of age, topiramate 2-3 mg/kg daily was not more effective than placebo for preventing migraine headaches.

As in adults, cognitive/neuropsychiatric effects are commonly reported in pediatric patients receiving topiramate, although the incidence appears to be lower than that observed in adults. Such effects include psychomotor slowing, difficulty with concentration or attention, speech disorders, and language problems. The most common adverse CNS effects reported in pediatric patients receiving topiramate as initial monotherapy for seizure disorders include dizziness, headache, anorexia, and somnolence. The most common adverse CNS effects reported in pediatric patients receiving the drug as adjunctive therapy for seizure disorders include somnolence and fatigue. In migraine prophylaxis studies in pediatric patients 12-17 years of age, difficulty with concentration/attention was the most commonly reported adverse CNS effect. Adverse cognitive effects observed in pediatric migraine studies were dose dependent and occurred with greater frequency in younger (6-11 years of age) compared with older (12-17 years of age) children. Topiramate may cause psychomotor slowing and decreased verbal fluency based on results of a standard neuropsychological test that was administered to adolescents 12-17 years of age.

Hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate concentrations to below the normal reference range in the absence of chronic respiratory alkalosis) has been reported in pediatric patients receiving topiramate. In pediatric studies evaluating topiramate as adjunctive therapy for refractory partial-onset seizures or Lennox-Gastaut syndrome, the incidence of decreased serum bicarbonate concentrations was as high as 67 or 10% for patients receiving topiramate (approximately 6 mg/kg daily) or placebo, respectively. Markedly abnormally low serum bicarbonate concentrations (defined as concentrations of less than 17 mEq/L and a decrease from pretreatment values exceeding 5 mEq/L) were observed in up to 11% of patients receiving topiramate in these studies compared with no more than 2% of those receiving placebo. Similar reductions in serum bicarbonate were reported in an open-label, active-controlled study of pediatric patients treated with topiramate monotherapy for partial-onset seizures. Markedly low serum bicarbonate concentrations and persistent metabolic acidosis were reported in 35 and 76% of patients treated with topiramate, respectively. Chronic, untreated metabolic acidosis may have potentially serious sequelae, including development of osteomalacia (rickets), reduction of growth rates, and a decrease in maximal height achieved in pediatric patients. Although the effects of topiramate on growth and bone-related sequelae have not been systematically evaluated in long-term, placebo-controlled trials, results of an open-label study demonstrated that pediatric patients 1-24 months old who received topiramate for up to 1 year had reduced length, weight, and head circumference compared with age- and sex-matched normative data; reductions in length and weight were correlated with the degree of acidosis. Because of the potential risk of metabolic acidosis, the manufacturers state that serum bicarbonate concentrations should be measured at baseline and periodically during topiramate therapy.

Reductions in bone mineral density and growth have been reported in a 1-year active-controlled study of pediatric patients receiving monotherapy with topiramate for treatment of partial-onset seizures. In an open-label, active-controlled study of pediatric patients aged 4-15 years with partial-onset seizures, statistically significant reductions in weight and bone mineral density in the lumbar spine and total body less head were reported among patients treated with topiramate monotherapy compared to those treated with levetiracetam monotherapy.

Oligohidrosis (decreased sweating) and hyperthermia have been reported in clinical trials and during postmarketing surveillance of topiramate. Because oligohidrosis and hyperthermia typically occurred in children and may have potentially serious sequelae, the manufacturers state that patients, particularly pediatric patients, receiving topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather.

Clearance of topiramate is higher in pediatric patients than in adults, and also higher in younger versus older pediatric patients, presumably because of age-related changes in the rate of drug metabolism. Pediatric patients (2 to younger than 16 years of age) receiving adjunctive therapy with topiramate exhibited higher oral topiramate clearance than those receiving topiramate monotherapy; the observed difference was presumably due to concomitant use of enzyme-inducing anticonvulsant agents.

Topiramate can cause fetal harm when administered to pregnant patients. Exposure to the drug in utero has been associated with an increased risk of oral clefts (cleft lip and/or palate) and for neonates being SGA (i.e., birth weight less than 10th percentile). Data from pregnancy registries, including the North American Antiepileptic Drug (NAAED) pregnancy registry, indicate that infants exposed to topiramate in utero have a higher prevalence of oral cleft birth defects than those with no such exposure. The prevalence of oral clefts among infants in the NAAED registry who were exposed to topiramate in utero was 1.1% compared with a prevalence of 0.36% in infants exposed to a reference anticonvulsant and a prevalence of 0.12% in infants born to women without epilepsy and without exposure to anticonvulsant agents. For comparison, the estimated background rate of oral clefts in the US as estimated by the US Centers for Disease Control and Prevention (CDC) is 0.17%. Based on NAAED data, the relative risk of developing an oral cleft defect in topiramate-exposed pregnancies was 9.6 compared with the risk in a background population of untreated women. The United Kingdom Epilepsy and Pregnancy Registry reported a similarly increased prevalence of oral clefts of 3.2% among infants exposed in utero to topiramate monotherapy; the reported rate was 16 times higher than the background rate in the United Kingdom, which is approximately 0.2%.

Data from the NAAED registry indicate that 19.7% of infants who were exposed to topiramate in utero were SGA compared with 7.9% of infants exposed to a reference anticonvulsant and 5.4% of infants born to women without epilepsy and without exposure to anticonvulsant agents. In another population-based birth registry, 25% of topiramate-exposed infants were SGA compared with 9% of infants who were not exposed to anticonvulsants. The prevalence of this adverse effect is higher in infants born to women who received higher dosages of topiramate during pregnancy or who continued to receive topiramate through the third trimester. SGA has been observed at all dosages of topiramate and appears to be dose dependent; however, the long-term consequences of these findings are not known.

Topiramate has demonstrated selective developmental toxicity, including teratogenicity and embryotoxicity, in multiple species of animals (rats, rabbits, mice). Structural malformations, including craniofacial defects, and reduced fetal weights have occurred in the offspring of pregnant animals exposed to topiramate at clinically relevant dosages in the absence of maternal toxicity. However, there also was some evidence of maternal toxicity (e.g., decreased maternal body weight gain, increased mortality).

Topiramate therapy can cause metabolic acidosis. The effect of topiramate-induced metabolic acidosis has not been specifically studied during pregnancy; however, metabolic acidosis from other causes during pregnancy can result in decreased fetal growth, decreased fetal oxygenation, and fetal death, and also may affect the ability of the fetus to tolerate labor. Therefore, pregnant women receiving topiramate should be monitored and treated for metabolic acidosis in the same manner as nonpregnant patients. In addition, neonates born to women treated with topiramate should be monitored for metabolic acidosis because of possible drug transfer to the fetus and possible occurrence of transient metabolic acidosis following birth.

The benefits and risks of topiramate therapy should be carefully considered when use of the drug in females of reproductive potential is contemplated, particularly for conditions not usually associated with permanent injury or death. All females of reproductive potential should be informed of the potential risks to the fetus from exposure to topiramate. Alternative options should be considered in patients who are planning a pregnancy. If a decision is made to use topiramate in a female of reproductive potential who is not planning a pregnancy, clinicians should recommend use of effective contraception. The potential for decreased efficacy of estrogen-containing oral contraceptives should be considered.

Women who become pregnant while receiving topiramate should be encouraged to enroll in the NAAED pregnancy registry; patients can enroll by calling 888-233-2334. Information on the registry also can be found on the website https://www.aedpregnancyregistry.org.

Limited data indicate that topiramate distributes into human milk at concentrations similar to those in maternal plasma. The effects of topiramate on milk production are not known. Diarrhea and somnolence have been reported in breast-fed infants whose mothers were receiving topiramate treatment. The known benefits of breast-feeding should be considered along with the clinical importance of the drug to the mother and any potential adverse effects on the breast-fed infant from topiramate or the underlying maternal condition.

The manufacturers make no specific dosage recommendations for geriatric patients.

While clinical studies evaluating topiramate did not include sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults, approximately 3% of patients receiving the drug in clinical trials were older than 60 years of age. Although no age-related differences in efficacy or safety were evident in these patients, pharmacokinetic data from one controlled clinical study revealed a decreased clearance of topiramate in geriatric patients with reduced renal function (i.e., creatinine clearance reduced by 20% compared with that in younger adults). Following administration of a single 100-mg dose of topiramate in these patients, plasma clearance and renal clearance of topiramate were reduced by 21 and 19%, respectively; half-life was prolonged by 13%; and peak plasma concentrations and area under the plasma concentration-time curve (AUC) were increased by 23 or 25%, respectively, compared with younger adults. Therefore, the manufacturers state that it may be useful to monitor renal function in geriatric patients; dosage adjustment may be necessary in geriatric patients with impaired renal function (i.e., creatinine clearance less than 70 mL/minute per 1.73 m2).