lamotrigine 100 mg tablet generic lamictal, subvenite

Uses

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Seizure Disorders

Partial Seizures

Lamotrigine (given as immediate-release formulations) is used in combination with other anticonvulsant agents in the management of partial seizures, with or without secondary generalization, in adults and children 2 years of age or older. Lamotrigine (given as immediate-release formulations) also is used as monotherapy in patients converting from monotherapy with a hepatic enzyme-inducing anticonvulsant agent (e.g., phenytoin, carbamazepine, phenobarbital, primidone) or valproic acid in the management of partial seizures in patients 16 years of age or older. Extended-release lamotrigine is used in combination with other anticonvulsant agents in the management of partial seizures, with or without secondary generalization, in adults and children 13 years of age or older.

In 3 multicenter, double-blind, placebo-controlled clinical studies, adjunctive therapy with immediate-release lamotrigine was effective in reducing seizure frequency in adults with simple and/or complex partial seizures refractory to therapy with one or more conventional anticonvulsant drugs (e.g., phenytoin, carbamazepine, phenobarbital, valproic acid); the median reduction in seizure frequency was 20-36%. In a multicenter, double-blind, placebo-controlled clinical study in children 2-16 years of age with partial seizures, the median reduction in frequency of all partial seizures was 36 or 7% in patients receiving immediate-release lamotrigine or placebo, respectively, in addition to their current therapy (up to 2 conventional anticonvulsant drugs). In a multicenter, double-blind, placebo-controlled clinical study in adults and children 13 years of age or older with partial seizures and receiving 1 or 2 anticonvulsants, adjunctive treatment with extended-release lamotrigine substantially reduced the median weekly seizure frequency compared with placebo (by 47 versus 25%, respectively).

The effectiveness of lamotrigine monotherapy (given as immediate-release formulations) in adults with partial seizures who are converting from monotherapy with a hepatic enzyme-inducing anticonvulsant drug (e.g., phenytoin, carbamazepine, phenobarbital, primidone) was established in a controlled clinical study of patients who experienced at least 4 simple or complex partial seizures, with or without secondary generalization, during each of 2 consecutive 4-week baseline periods; during the baseline periods, patients were receiving either phenytoin or carbamazepine monotherapy. Patients were randomized either to lamotrigine (target dosage: 500 mg daily) or valproic acid (1000 mg daily) therapy, which was added to their baseline regimen over a 4-week period. Patients were then converted to either lamotrigine or valproic acid monotherapy over another 4-week period and monotherapy continued for another 12-week period. Study end points were either successful completion of the 12-week monotherapy period or meeting a study ''escape'' criterion, relative to baseline. Escape criteria were defined as doubling of the mean monthly seizure count; doubling of the highest consecutive 2-day seizure frequency; emergence of a new seizure type (defined as a seizure that did not occur during the 8-week baseline period) that was more severe than the other seizure types occurring during the study period; or clinically important prolongation of generalized tonic-clonic seizures. The proportion of lamotrigine- or valproic acid-treated patients meeting escape criteria was 42 or 69%, respectively; no differences in efficacy were detected based on age, race, or gender. It was noted that the patients in the valproic acid control arm were treated intentionally with a relatively low valproic acid dosage because the intent of the study was to establish the effectiveness of lamotrigine monotherapy, and that the study results cannot be interpreted to imply the superiority of lamotrigine therapy to adequate valproic acid therapy. In addition, the manufacturers state that the use of lamotrigine therapy for the management of partial seizures has not been established as initial monotherapy; for conversion from monotherapy from anticonvulsant drugs other than hepatic enzyme-inducing anticonvulsant drugs or valproate; or for simultaneous conversion to monotherapy from 2 or more concomitant anticonvulsant drugs.

Primary Generalized Tonic-Clonic Seizures

Lamotrigine (given as immediate-release formulations) is used in combination with other anticonvulsant agents in the management of primary generalized tonic-clonic seizures in adults and children 2 years of age and older. Efficacy of the drug as adjunctive therapy was established in a placebo-controlled trial in adult and pediatric patients at least 2 years of age who had experienced at least 3 primary generalized tonic-clonic seizures during an 8-week baseline phase. Patients were randomized to receive either placebo or immediate-release lamotrigine in a fixed-dose regimen (target dosages of 200-400 mg daily in adults and 3-12 mg/kg daily in children) for 19-24 weeks, which was added to their current anticonvulsant regimen of up to 2 anticonvulsant drugs. Patients receiving lamotrigine experienced a substantially greater median reduction in seizure frequency compared with baseline than did patients receiving placebo (66 and 34%, respectively).

Extended-release lamotrigine is used in combination with other anticonvulsants in the management of primary generalized tonic-clonic seizures in adults and adolescents 13 years of age and older. Efficacy of the extended-release formulation of the drug as adjunctive therapy was established in a multicenter, double-blind, placebo-controlled trial in adult and pediatric patients at least 13 years of age who had experienced at least 3 primary generalized tonic-clonic seizures during an 8-week baseline phase. Patients were randomized to receive either placebo or extended-release lamotrigine in a fixed-dose regimen (target dosages of 200-500 mg daily based on concomitant anticonvulsant therapy) for 19 weeks, which was added to their current anticonvulsant regimen of up to 2 anticonvulsant drugs. Patients receiving extended-release lamotrigine experienced a substantially greater median reduction in seizure frequency compared with baseline than did patients receiving placebo (75 and 32%, respectively).

Seizures Associated with Lennox-Gastaut Syndrome

Lamotrigine (given as immediate-release formulations) is used in combination with other anticonvulsant agents in the management of generalized seizures associated with Lennox-Gastaut syndrome in pediatric patients and adults. In a controlled clinical trial in patients with Lennox-Gastaut syndrome, adjunctive therapy with immediate-release lamotrigine resulted in a 32, 34, and 36% decrease in major motor seizures, drop attacks, and tonic-clonic seizures, respectively.

Bipolar Disorder

Lamotrigine (given as immediate-release formulations) is used in the maintenance therapy of bipolar 1 disorder to prevent or attenuate recurrences of bipolar episodes in adult patients who remain at high risk of relapse following treatment of an acute depressive or manic episode. The American Psychiatric Association (APA) currently recommends use of lamotrigine as an alternative to first-line maintenance therapies (e.g., lithium, valproic acid, or divalproex). The APA also states that both lamotrigine and lithium are effective in the maintenance treatment of bipolar 1 disorder; however, the results of two randomized, double-blind, placebo-controlled studies of 18 months' duration indicate that lamotrigine may be more effective in preventing depressive episodes while lithium may be more effective in preventing manic episodes.

Although efficacy of the drug in the acute treatment of mood episodes has yet to be fully established, lamotrigine is considered a first-line agent by the APA for the management of acute depressive episodes in patients with bipolar disorder. The APA also recommends the use of lamotrigine as an alternative to lithium, valproic acid, or divalproex in the management of patients with rapid cycling bipolar disorder, particularly in those with the bipolar 2 form of rapid cycling.

For further information on the management of bipolar disorder,

Dosage and Administration

Administration

Lamotrigine is administered orally as conventional tablets, chewable/dispersible tablets, extended-release tablets, or orally disintegrating tablets. Immediate-release formulations of the drug (e.g., conventional tablets, chewable/dispersible tablets, orally disintegrating tablets) are administered once or twice daily; the extended-release tablets (Lamictal XR) are administered once daily. Lamotrigine may be administered without regard to meals.

Lamotrigine conventional tablets should be swallowed whole.

Lamotrigine chewable/dispersible tablets may be swallowed whole, chewed (and consumed with a small amount of water or diluted fruit juice to aid swallowing), or dispersed in water or diluted fruit juice. To disperse the tablets, they should be added to a small volume (i.e., 5 mL or enough to cover the tablet) of liquid and allowed to disperse completely (over approximately 1 minute); the solution then should be swirled and consumed immediately. Administration of partial quantities of the dispersed tablets should not be attempted; calculated doses that do not correspond to available strengths of whole tablets should be rounded down to the nearest whole tablet.

Lamotrigine extended-release tablets should be swallowed whole and should not be chewed, crushed, or divided.

Lamotrigine orally disintegrating tablets should be placed on the tongue and moved around in the mouth, where the tablet disintegrates rapidly in saliva, and then subsequently can be swallowed with or without water.

Patients who are currently receiving or beginning therapy with lamotrigine and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.(See Suicidality Risk under Cautions: Precautions and Contraindications.)

Conversion from Immediate-release Lamotrigine to Extended-release Lamotrigine

Patients may be converted directly from immediate-release formulations to extended-release lamotrigine tablets (Lamictal XR). The initial dosage of extended-release lamotrigine should be the same as the total daily dosage of immediate-release lamotrigine. However, some patients receiving concomitant therapy with enzyme-inducing drugs may have lower plasma concentrations of lamotrigine on conversion and should be monitored. Following conversion to extended-release lamotrigine, all patients (particularly those receiving drugs that induce lamotrigine glucuronidation) should be closely monitored for seizure control. Depending on the therapeutic response following conversion, the total daily dosage of extended-release lamotrigine may require adjustment within the recommended dosing guidelines.

Dispensing and Administration Precautions

Dispensing errors have occurred because of the similarity in spelling between Lamictal (the trade name for lamotrigine) and Lamisil (terbinafine hydrochloride), lamivudine, labetalol hydrochloride, Lomotil (the fixed combination of atropine sulfate and diphenoxylate hydrochloride), and Ludiomil (the former trade name for maprotiline hydrochloride; no longer commercially available under this trade name in the US). Medication errors also may occur between the different formulations of lamotrigine (Lamictal, Lamictal XR, generic lamotrigine tablets). Therefore, extra care should be exercised in ensuring the accuracy of both oral and written prescriptions for lamotrigine and these other drugs. The manufacturers recommend that clinicians consider including the intended use of the particular drug on the prescription, in addition to alerting patients to carefully check that they are receiving the correct drug as well as the correct formulation of the drug each time they fill their prescription and to promptly bring any question or concern to the attention of the dispensing pharmacist. The manufacturer of Lamictal also recommends that pharmacists assess various measures of avoiding dispensing errors and implement them as appropriate (e.g., by computerized filling and handling of prescriptions, patient counseling).(See Possible Prescribing and Dispensing Errors under Cautions: Precautions and Contraindications.)

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Because of the possibility of increasing seizure frequency, anticonvulsant drugs, including lamotrigine, should not be discontinued abruptly, particularly in patients with preexisting seizure disorders. Discontinuance of lamotrigine therapy should be done gradually over at least 2 weeks, in a step-wise fashion (e.g., achieving a 50% reduction in the daily dosage of lamotrigine each week). However, concerns for patient safety with continued use of lamotrigine may require more rapid withdrawal of the drug.

The dosage regimen of lamotrigine used in combination with other anticonvulsant drugs depends on whether valproic acid, hepatic enzyme-inducing anticonvulsant drugs, other anticonvulsants, or a combination of these is administered concomitantly. Addition to lamotrigine therapy of an anticonvulsant drug that induces hepatic microsomal enzymes (e.g., carbamazepine, phenobarbital, phenytoin, primidone) may be expected to increase the clearance (i.e., reduce plasma concentrations) of lamotrigine; conversely, discontinuance of such a concomitantly administered anticonvulsant drug may result in decreased clearance (i.e., increased plasma concentrations) of lamotrigine. Addition of valproate sodium to lamotrigine therapy also decreases the clearance (i.e., increases plasma concentrations) of lamotrigine. Therefore, clinicians should be aware that addition of hepatic enzyme-inducing anticonvulsant drugs or valproic acid to, or their discontinuance from, an anticonvulsant regimen including lamotrigine may require modification of the dosage of lamotrigine and/or the other anticonvulsant agent(s). Exceeding the recommended initial dosage and subsequent dosage escalations of lamotrigine may increase the risk of developing a rash and is not recommended.

Estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine. The manufacturers state that no dosage adjustment to the recommended dosage escalation guidelines for lamotrigine should be necessary based solely on concomitant use of estrogen-containing oral contraceptives. Dosage escalation should follow the recommended guidelines for initiating adjunctive lamotrigine therapy based on the concomitant anticonvulsant(s) or other concomitant medications.In women currently receiving estrogen-containing oral contraceptives and not receiving carbamazepine, phenobarbital, phenytoin, primidone, or other drugs that induce lamotrigine glucuronidation (e.g., rifampin), the maintenance dosage of lamotrigine will in most cases need to be increased as much as twofold over the recommended target maintenance dosage in order to maintain a consistent plasma lamotrigine concentration.In women starting estrogen-containing oral contraceptives, receiving a stable lamotrigine dosage, and not receiving carbamazepine, phenobarbital, phenytoin, primidone, or other drugs that induce lamotrigine glucuronidation (e.g., rifampin), the maintenance dosage of lamotrigine will in most cases need to be increased as much as twofold in order to maintain a consistent plasma lamotrigine level. The dosage increases should begin at the same time that the oral contraceptive is added and continue, based on clinical response, no more rapidly than by 50-100 mg daily every week. Dosage increases should not exceed the recommended rate unless plasma lamotrigine concentrations or clinical response supports larger increases. Gradual transient increases in plasma lamotrigine concentrations may occur during the week of inactive hormonal preparation (i.e., the ''pill-free'' week); these increases will be greater if dosage increases are made during the days before or during the week of the inactive hormonal preparation. Such increased lamotrigine levels could potentially result in additional adverse effects (such as dizziness, ataxia, and diplopia). If such adverse effects consistently occur during the ''pill-free'' week, dosage adjustments to the overall maintenance dosage may be necessary; however, dosage adjustments limited to the ''pill-free'' week are not recommended. In women starting estrogen-containing oral contraceptives and receiving lamotrigine in addition to carbamazepine, phenobarbital, phenytoin, primidone, or other drugs that induce lamotrigine glucuronidation (e.g., rifampin), no adjustment to the lamotrigine dosage should be necessary.

When discontinuing estrogen-containing oral contraceptives in women not concurrently receiving carbamazepine, phenobarbital, phenytoin, primidone, or other drugs that induce lamotrigine glucuronidation (e.g., rifampin), the maintenance dosage of lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent plasma lamotrigine concentration. The decrease in lamotrigine dosage should not exceed 25% of the total daily dosage per week over a 2-week period unless clinical response or plasma lamotrigine concentrations indicate otherwise. In women receiving lamotrigine in addition to carbamazepine, phenobarbital, phenytoin, primidone, or other drugs that induce lamotrigine glucuronidation (e.g., rifampin), adjustment of the maintenance dosage of lamotrigine should not be necessary upon discontinuance of estrogen-containing oral contraceptives. The effects of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine have not been systematically evaluated. Ethinyl estradiol, but not progestins, reportedly increased lamotrigine clearance up to twofold, and progestin-only formulations did not affect lamotrigine plasma concentrations. Therefore, adjustment of lamotrigine dosage in patients receiving progestins alone is unlikely to be necessary.

Seizure Disorders

Adjunctive Therapy

For adjunctive therapy in the management of partial seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome in adults and children older than 12 years of age who are receiving hepatic enzyme-inducing anticonvulsant drugs without concomitant valproic acid therapy, the usual initial dosage of lamotrigine given as immediate-release formulations (e.g., conventional tablets, chewable/dispersible tablets, orally disintegrating tablets) is 50 mg daily for 2 weeks, then 100 mg daily in 2 divided doses for 2 weeks. The daily dosage may then be increased by 100 mg every 1-2 weeks until an effective maintenance dosage of 300-500 mg daily given in 2 divided doses is reached.

If extended-release tablets of lamotrigine (Lamictal XR) are used for the management of partial seizures or primary generalized tonic-clonic seizures in adults and children 13 years of age or older who are receiving hepatic enzyme-inducing anticonvulsant drugs without concomitant valproic acid therapy, the usual initial dosage of lamotrigine is 50 mg once daily for 2 weeks, then 100 mg once daily for 2 weeks. The daily dosage may then be increased by 100 mg every week for the next 3 weeks (weeks 5 through 7), with subsequent increases made as necessary until an effective maintenance dosage of 400-600 mg once daily is reached. Dosage increases from week 8 and onward should not exceed 100 mg daily at weekly intervals.

For adjunctive therapy in the management of partial seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome in adults and children older than 12 years of age who are receiving an anticonvulsant regimen containing valproic acid, the usual initial dosage of lamotrigine given as immediate-release formulations (e.g., conventional tablets, chewable/dispersible tablets, orally disintegrating tablets) is 25 mg every other day for 2 weeks, followed by 25 mg once daily for 2 weeks. The initial dosage of lamotrigine in patients also receiving valproic acid should not exceed 25 mg every other day because of an increased incidence of rash with concomitant lamotrigine and valproic acid therapy. After the initial 4 weeks of therapy, the daily dosage of lamotrigine may be increased by 25-50 mg every 1-2 weeks until an effective maintenance dosage of 100-400 mg daily given in 1 or 2 divided doses is reached. The usual maintenance dosage of lamotrigine when added to valproic acid alone in adults and children older than 12 years of age is 100-200 mg daily given in 1 or 2 divided doses. The usual maintenance dosage of lamotrigine when added to valproic acid and other drugs that induce glucuronidation in adults and children older than 12 years of age is 100-400 mg daily given in 1 or 2 divided doses.

If extended-release tablets of lamotrigine (Lamictal XR) are used for adjunctive therapy in the management of partial seizures or primary generalized tonic-clonic seizures in adults and children 13 years of age or older who are receiving an anticonvulsant regimen containing valproic acid, the usual initial dosage of lamotrigine is 25 mg every other day for 2 weeks, followed by 25 mg once daily for 2 weeks. The daily dosage may then be increased to 50 mg once daily at week 5, 100 mg once daily at week 6, and 150 mg once daily at week 7. The usual maintenance dosage of lamotrigine when added to valproic acid alone in adults and children 13 years of age or older is 200-250 mg once daily. Dosage increases from week 8 and onward should not exceed 100 mg daily at weekly intervals.

For adjunctive therapy in the management of partial seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome in adults and children older than 12 years of age who are receiving an anticonvulsant regimen that does not include carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid, the usual initial dosage of lamotrigine given as immediate-release formulations (e.g., conventional tablets, chewable/dispersible tablets, orally disintegrating tablets) is 25 mg once daily for 2 weeks, followed by 50 mg daily for 2 weeks. After the initial 4 weeks of therapy, the daily dosage of lamotrigine may be increased by 50 mg every 1-2 weeks until an effective maintenance dosage of 225-375 mg daily given in 2 divided doses is reached.

If extended-release tablets of lamotrigine (Lamictal XR) are used for adjunctive therapy in the management of partial seizures or primary generalized tonic-clonic seizures in adults and children 13 years of age or older who are receiving an anticonvulsant regimen that does not include carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid, the usual initial dosage of lamotrigine is 25 mg once daily for 2 weeks, then 50 mg once daily for 2 weeks. The daily dosage may then be increased by 50 mg every week for the next 3 weeks (weeks 5 through 7), with subsequent increases made as necessary until an effective maintenance dosage of 300-400 mg once daily is reached. Dosage increases from week 8 and onward should not exceed 100 mg daily at weekly intervals.

Although maintenance dosages of immediate-release lamotrigine as high as 700 mg daily have been used in anticonvulsant drug regimens that included hepatic enzyme-inducing anticonvulsants but not valproic acid or as high as 200 mg daily in drug regimens that included valproic acid alone, dosages exceeding 300-500 mg daily (in regimens not containing valproic acid) or exceeding 200 mg daily (in regimens containing valproic acid alone) have not been evaluated in controlled studies.

For adjunctive therapy in the management of partial seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome in patients 2-12 years of age who are receiving hepatic enzyme-inducing anticonvulsant drugs without concomitant valproic acid therapy, the usual initial dosage of lamotrigine given as immediate-release formulations (e.g., conventional tablets, chewable/dispersible tablets, orally disintegrating tablets) is 0.6 mg/kg daily (rounded down to the nearest whole tablet) in 2 divided doses for 2 weeks. During the subsequent 2 weeks of therapy, the usual dosage is 1.2 mg/kg daily (rounded down to the nearest whole tablet) in 2 divided doses. Subsequent daily dosages should be increased every 1-2 weeks by 1.2 mg/kg (rounded down to the nearest whole tablet) until an effective daily maintenance dosage of 5-15 mg/kg (maximum of 400 mg/day in 2 divided doses) is reached. In patients weighing less than 30 kg, increases in maintenance dosages of up to 50% may be required based on the response and tolerance of the patient.

For adjunctive therapy in the management of partial seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome in patients 2-12 years of age who are receiving an anticonvulsant regimen containing valproic acid, the usual initial dosage of lamotrigine given as immediate-release formulations (e.g., conventional tablets, chewable/dispersible tablets, orally disintegrating tablets) is 0.15 mg/kg daily (rounded down to the nearest whole tablet) in 1 or 2 divided doses for 2 weeks. During the subsequent 2 weeks of therapy, the usual dosage is 0.3 mg/kg daily (rounded down to the nearest whole tablet) in 1 or 2 divided doses. Subsequent daily dosages should be increased every 1-2 weeks by 0.3 mg/kg (rounded down to the nearest whole tablet) until an effective daily maintenance dosage of 1-5 mg/kg (maximum of 200 mg/day in 1 or 2 divided doses) is reached. Usual maintenance dosages range from 1-3 mg/kg daily in patients receiving lamotrigine and valproic acid alone. In patients weighing less than 30 kg, increases in maintenance dosages of up to 50% may be required based on the response and tolerance of the patient.

For adjunctive therapy in the management of partial seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut syndrome in patients 2-12 years of age who are receiving an anticonvulsant regimen that does not include carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid, the usual initial dosage of lamotrigine given as immediate-release formulations (e.g., conventional tablets, chewable/dispersible tablets, orally disintegrating tablets) is 0.3 mg/kg daily (rounded down to the nearest whole tablet) in 1 or 2 divided doses for 2 weeks. During the subsequent 2 weeks of therapy, the usual dosage is 0.6 mg/kg daily (rounded down to the nearest whole tablet) in 2 divided doses. Subsequent daily dosages should be increased every 1-2 weeks by 0.6 mg/kg (rounded down to the nearest whole tablet) until an effective daily maintenance dosage of 4.5-7.5 mg/kg (maximum of 300 mg/day in 2 divided doses) is reached. In patients weighing less than 30 kg, increases in maintenance dosages of up to 50% may be required based on the response and tolerance of the patient.

Monotherapy for Partial Seizures

For subsequent monotherapy in the management of partial seizures in patients converted from monotherapy with a hepatic enzyme-inducing anticonvulsant drug, the recommended maintenance dosage of lamotrigine given as immediate-release formulations (e.g., conventional tablets, chewable/dispersible tablets, orally disintegrating tablets) in adults and children 16 years of age or older is 500 mg daily given in 2 divided doses. The transition regimen for converting patients from monotherapy with a hepatic enzyme-inducing anticonvulsant drug to lamotrigine monotherapy is a 2-step process; the goal of the transition regimen is to ensure adequate seizure control while minimizing the possibility of developing a serious rash associated with the rapid titration of lamotrigine.

In the first step of the process, immediate-release lamotrigine therapy is added to the current drug regimen (which should be maintained at a fixed dosage) at a dosage of 50 mg once daily for 2 weeks, followed by 100 mg daily in 2 divided doses for 2 weeks; the daily dosage is then increased by 100 mg every 1-2 weeks until the maintenance dosage of 500 mg daily (in 2 divided doses) is reached. Once the maintenance lamotrigine dosage is reached, the concomitant hepatic enzyme-inducing anticonvulsant drug can then be withdrawn gradually over a period of 4 weeks; based on experience from the controlled clinical trial, the concomitant drug was withdrawn by 20% decrements each week over a 4-week period.

Bipolar Disorder

For monotherapy in the maintenance treatment of bipolar disorder, the recommended initial adult dosage of lamotrigine given as immediate-release formulations (e.g., conventional tablets, chewable/dispersible tablets, orally disintegrating tablets) is 25 mg once daily for 2 weeks, followed by 50 mg once daily for 2 weeks. After the initial 4 weeks of therapy, the daily dosage of lamotrigine may be doubled at weekly intervals until an effective maintenance dosage of 200 mg daily is reached. Because 400-mg daily dosages were shown to be no more effective than 200-mg daily dosages in clinical studies of immediate-release lamotrigine monotherapy, the manufacturers recommend that daily dosages not exceed 200 mg daily.

For adjunctive therapy in the maintenance treatment of bipolar disorder in patients who are receiving carbamazepine or other hepatic enzyme-inducing drugs without concomitant valproic acid therapy, the usual initial adult dosage of immediate-release lamotrigine is 50 mg once daily for 2 weeks, followed by 100 mg daily in 2 divided doses for 2 weeks; the daily dosage is then increased in 100-mg increments at weekly intervals until the maintenance dosage of 400 mg daily (in 2 divided doses) is reached.

For adjunctive therapy in the maintenance treatment of bipolar disorder in adults who are receiving valproic acid, the usual initial dosage of immediate-release lamotrigine is 25 mg every other day for 2 weeks, followed by 25 mg once daily for 2 weeks. After the initial 4 weeks of therapy, the daily dosage of lamotrigine may be doubled at weekly intervals until an effective maintenance dosage of 100 mg daily is reached. To minimize the risk of potentially serious rash in patients receiving lamotrigine in conjunction with valproic acid, the recommended initial dosages and subsequent dose escalations of lamotrigine should not be exceeded.

Addition of hepatic enzyme-inducing drugs (e.g., carbamazepine) or hepatic enzyme-inhibiting drugs (e.g., valproic acid) to a regimen including immediate-release lamotrigine may require modification of the dosage of lamotrigine and/or the hepatic enzyme-inducing or -inhibiting drug. In pivotal clinical studies, dosages of lamotrigine were halved immediately following the addition of valproic acid to treat an acute mood episode and maintained at that dosage as long as valproic acid was administered concomitantly with lamotrigine. Following addition of carbamazepine or other hepatic enzyme-inducing drugs to treat an acute mood episode, dosages of lamotrigine were gradually doubled (e.g., over a period of at least 3 weeks) and maintained at that dosage as long as these drugs were administered concomitantly with lamotrigine. Following the addition of other psychotropic agents with no known clinical pharmacokinetic interactions with lamotrigine, patients were maintained at current maintenance dosages of lamotrigine.

Discontinuance of hepatic enzyme-inducing drugs (e.g., carbamazepine) or hepatic enzyme-inhibiting drugs (e.g., valproic acid) from a regimen including immediate-release lamotrigine may require modification of the dosage of lamotrigine. For patients discontinuing carbamazepine or other enzyme-inducing agents following resolution of the acute mood episode and achievement of a maintenance lamotrigine dosage, lamotrigine dosage should remain constant for the first week and then should be decreased in 100-mg daily increments at weekly intervals until an effective maintenance dosage of 200 mg daily is reached. For patients discontinuing valproic acid following resolution of the acute mood episode and achievement of a maintenance lamotrigine dosage, lamotrigine dosage should be increased in 50-mg daily increments at weekly intervals until an effective maintenance dosage of 200 mg daily is reached.

The optimum duration of lamotrigine therapy for the management of bipolar disorder has not been established, and the usefulness of the drug during prolonged therapy (i.e., longer than 18 months) should be reevaluated periodically.

Dosage in Renal and Hepatic Impairment

Because clinical experience with lamotrigine is limited in patients with concomitant illness, the drug should be used with caution in patients with conditions (e.g., renal, hepatic, cardiac impairment) that may affect metabolism and elimination of the drug.

The manufacturers state that lamotrigine should be used with caution in patients with severe renal impairment because there is insufficient information from controlled clinical studies to establish the safety and efficacy of therapy with the drug in such patients. The initial dosage of lamotrigine in patients with renal impairment should be based on the patient's existing anticonvulsant drug regimen (see Dosage and Administration: Dosage). The manufacturers state that a reduced maintenance dosage of lamotrigine may be effective in patients with substantial renal impairment; however, the manufacturers currently make no specific recommendations for dosage adjustment in such patients.

The manufacturers state that experience with lamotrigine therapy in patients with hepatic impairment is limited. Based on a clinical pharmacology study of the drug in a small number of patients with moderate to severe hepatic dysfunction, the manufacturers make the general recommendation that initial, escalation, and maintenance dosages of lamotrigine therapy should be decreased by approximately 25% in patients with moderate (e.g., Child-Pugh class B) or severe (e.g., Child-Pugh class C) hepatic impairment without ascites and by 50% in patients with severe hepatic impairment with ascites. Escalation and maintenance dosages should be adjusted according to clinical response. Dosage adjustment is not necessary in patients with mild (e.g., Child-Pugh class A) hepatic impairment.

Cautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Lamotrigine generally is well tolerated. However, there have been rare reports of serious dermatologic reactions (including some fatalities) in adults and children receiving lamotrigine. Nervous system and dermatologic effects are among the most frequently reported adverse effects of lamotrigine and among those most frequently requiring discontinuance of the drug. The most frequently occurring adverse effects associated with lamotrigine as adjunctive therapy in adults in controlled clinical trials include dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Discontinuance of lamotrigine because of adverse effects was required in about 11% of adult patients receiving immediate-release lamotrigine as adjunctive therapy in uncontrolled and controlled clinical trials; the adverse effects most frequently associated with discontinuance of lamotrigine in these trials were rash (3% of patients), dizziness (2.8% of patients), and headache (2.5% of patients). In children receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials, the most commonly reported adverse effects were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia. Approximately 11.5% of pediatric patients receiving immediate-release lamotrigine as adjunctive therapy in clinical trials discontinued the drug because of an adverse effect; the adverse effects most frequently associated with discontinuance of lamotrigine therapy in these patients were rash (4.4% of patients), reaction aggravated (1.7% of patients), and ataxia (0.6% of patients).

The most common adverse effects associated with extended-release lamotrigine given as adjunctive anticonvulsant therapy in adults and adolescents 13 years of age or older in 2 controlled clinical trials included dizziness, tremor/intention tremor, nausea, vomiting, diarrhea, diplopia, asthenia and fatigue, and somnolence. Discontinuance of lamotrigine because of adverse effects was required in 5% of patients receiving extended-release lamotrigine as adjunctive therapy in these trials; the adverse effects most frequently associated with discontinuance of therapy were dizziness (3% of patients), rash (1% of patients), headache (1% of patients), nausea (1% of patients), and nystagmus (1% of patients).

The most common adverse effects associated with immediate-release lamotrigine as monotherapy in adults in the controlled clinical trial were vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and dysmenorrhea; during the conversion period (i.e., when lamotrigine was initially added on to an existing monotherapy regimen consisting of a hepatic enzyme-inducing anticonvulsant drug), the most commonly reported adverse effects were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia, nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis. The adverse effects most commonly associated with discontinuance of the drug in this trial were rash (4.5% of patients), headache (3.1% of patients), and asthenia (2.4% of patients).

The adverse effect profiles in males and females in clinical trials of immediate-release lamotrigine were similar and were independent of age; the rates of discontinuance of lamotrigine for individual adverse effects also were similar for males and females. In general, females receiving adjunctive therapy with immediate-release lamotrigine or placebo in controlled trials were more likely to report adverse effects than were males; however, dizziness was the only adverse effect reported with at least 10% greater frequency (i.e., 16.5% greater frequency) in females than in males (without a corresponding difference by gender with placebo) in controlled trials.

Because clinical trials of lamotrigine therapy involved specific patient populations and use of the drug as adjunctive therapy or monotherapy following conversion from therapy with another single hepatic enzyme-inducing anticonvulsant drug, it is difficult to determine whether a causal relationship exists for many reported adverse effects, to compare adverse effect frequencies with those in other clinical reports, and/or to extrapolate the adverse effects experience from controlled clinical trials to usual clinical practice.

Nervous System Effects

Nervous system effects were among the most frequent adverse effects reported in patients receiving lamotrigine as adjunctive therapy in controlled clinical trials. Dizziness, headache, and ataxia were the most frequent adverse nervous system effects, occurring in 38, 29, and 22% of adults, respectively, in controlled trials of immediate-release lamotrigine adjunctive therapy. The frequency of dizziness and ataxia and the rate of discontinuance of lamotrigine because of these adverse effects were dose related in clinical trials; in a dose-response study, dizziness occurred in 54, 31, or 27% of patients receiving lamotrigine 500 mg/day, lamotrigine 300 mg/day, or placebo, respectively, while ataxia occurred in 28, 10, or 10% of those receiving these respective regimens. Limited data also suggest an increased incidence of adverse nervous system effects in patients receiving carbamazepine concomitantly with lamotrigine.(See Drug Interactions under Cautions: Precautions and Contraindications.)

Somnolence or insomnia occurred in 14 or 6%, respectively, of adults receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. Incoordination or tremor was reported in 6 or 4%, respectively, of lamotrigine-treated adults; limited evidence suggests that incoordination and tremor may be dose related, and tremor may occur more frequently with concomitant administration of valproic acid and lamotrigine. Depression occurred in 4%, anxiety in 4%, irritability in 3%, speech disorder in 3%, and concentration disturbance in 2% of adults receiving lamotrigine as adjunctive therapy in controlled clinical trials. Seizure or seizure exacerbation has been reported in 3 or 2% of adults, respectively, receiving lamotrigine as adjunctive therapy in controlled trials; an increase in seizure frequency also has been reported with lamotrigine therapy. Treatment-emergent seizures diagnosed unequivocally as status epilepticus were reported in 7 of 2343 adults receiving adjunctive therapy with immediate-release lamotrigine in clinical trials; however, the manufacturers state that valid estimates of the incidence of treatment-emergent status epilepticus are difficult to obtain because of variations in the definitions used by different investigators to identify such cases.

Coordination abnormality, dizziness, anxiety, and insomnia occurred in 7, 7, 5, and 5%, respectively, of adults receiving immediate-release lamotrigine as monotherapy in a controlled trial; amnesia, ataxia, asthenia, depression, hypesthesia, libido increase, decreased or increased reflexes, nystagmus, and irritability each occurred in 2% of such patients. Paresthesia or asthenia occurred in more than 1% of adults receiving lamotrigine as adjunctive therapy in controlled clinical trials but with equal or greater frequency in those receiving placebo.

Somnolence occurred in 17%, dizziness in 14%, ataxia in 11%, tremor in 10%, and asthenia in 8% of children receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. Emotional lability, gait abnormality, thinking abnormality, seizures, nervousness, and vertigo each occurred in 2-4% of children receiving lamotrigine as adjunctive therapy in controlled clinical trials.

Amnesia, confusion, hostility, decreased memory, nervousness, nystagmus, thinking abnormality, or vertigo was reported in at least 1% of patients receiving immediate-release lamotrigine in uncontrolled and controlled clinical trials. Abnormal dreams, abnormal gait, agitation, akathisia, apathy, aphasia, CNS depression, depersonalization, dysarthria, dyskinesia, dysphoria, emotional lability, euphoria, faintness, grand mal seizures, hallucinations, hyperkinesia, hypertonia, hypesthesia, increased libido, mind racing, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, migraine, sleep disorder, or stupor occurred in at least 0.1% but in less than 1% of such patients. Cerebellar syndrome, choreoathetosis, CNS stimulation, delirium, delusions, dystonia, hypoesthesia, hypotonia, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypomania, decreased libido, manic-depressive reaction, movement disorder, neuralgia, neurosis, or paralysis occurred in less than 0.1% of patients.

Suicidal ideation has been reported in 2-5% of adult patients receiving immediate-release lamotrigine monotherapy for partial seizures in a controlled clinical trial and in less than 1% of pediatric and adult patients receiving the drug in uncontrolled and controlled clinical trials; suicide and/or suicide attempt has been reported rarely. The US Food and Drug Administration (FDA) has analyzed suicidality reports from placebo-controlled studies involving 11 anticonvulsants, including lamotrigine, and found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).(See Suicidality Risk under Cautions: Precautions and Contraindications.)

Lamotrigine therapy increases the risk of developing aseptic meningitis. FDA states that a total of 40 cases of aseptic meningitis have been identified in pediatric and adult lamotrigine-treated patients from December 1994 through November 2009. Symptoms in these cases included headache, fever, nausea, vomiting, nuchal rigidity, skin rash, photophobia, chills, altered consciousness, and/or somnolence and occurred 1-42 days (mean of 16 days) after beginning therapy with the drug. There was one death reported; however, the death was not thought to be caused by aseptic meningitis. Hospitalization was required in 35 of the patients. In most of the cases, symptoms resolved following discontinuance of lamotrigine. In 15 cases, however, symptoms rapidly returned (within 0.5-24 hours; mean: 5 hours) following reinitiation of lamotrigine. In these rechallenge cases, symptoms were frequently more severe following reexposure to the drug. Data on CSF findings were available in 25 cases; CSF analyses were characterized by mild to moderate pleocytosis, normal glucose concentrations, and mild to moderate increases in protein. CSF white blood cell differentials showed a predominance of neutrophils in the majority of cases; however, a predominance of lymphocytes was reported in approximately one-third of the cases. Some of the lamotrigine-treated patients who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases. In addition, some of the patients had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that some of the reported cases of lamotrigine-associated meningitis were part of a hypersensitivity or generalized drug reaction.(See Aseptic Meningitis under Cautions: Precautions and Contraindications.)

Exacerbation of parkinsonian manifestations in patients with preexisting parkinsonian syndrome and the occurrence of tics have been reported during postmarketing experience with lamotrigine and/or in worldwide uncontrolled clinical trials; however, the data are insufficient to provide an estimate of the incidence of such effects or to establish a causal relationship to lamotrigine.

GI Effects

GI effects were among the most frequent adverse effects reported in adults receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. Nausea was the most frequent adverse GI effect, occurring in 19% of adults in controlled clinical trials; vomiting was reported in 9% of patients in these trials. The frequency of nausea and vomiting appears to be dose related; in a dose-response study, nausea occurred in 25, 18, or 11% of patients receiving lamotrigine 500 mg daily, lamotrigine 300 mg daily, or placebo, respectively, while vomiting occurred in 18, 11, or 4% of those receiving these respective regimens. Diarrhea occurred in 6%, dyspepsia in 5%, abdominal pain in 5%, constipation in 4%, tooth disorder in 3%, and anorexia in 2% of adults receiving lamotrigine as adjunctive therapy in controlled clinical trials. Flatulence was reported in more than 1% of adults receiving lamotrigine as adjunctive therapy in controlled clinical trials but occurred with equal or greater frequency in patients receiving placebo. Vomiting, dyspepsia, and nausea occurred in 9, 7, and 7%, respectively, of adults receiving lamotrigine as monotherapy in a controlled trial; anorexia, dry mouth, rectal hemorrhage, and peptic ulcer each occurred in 2% of such patients.

Vomiting occurred in 20%, diarrhea in 11%, abdominal pain in 10%, and nausea in 10% of children receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. Constipation, dyspepsia, and tooth disorder each occurred in 2-4% of children receiving lamotrigine as adjunctive therapy in controlled clinical trials.

Halitosis, dry mouth, dysphagia, gingivitis, glossitis, gum hyperplasia, increased appetite, increased salivation, mouth ulceration, stomatitis, taste perversion, thirst, or tooth disorder occurred in at least 0.1% but in less than 1% of patients receiving immediate-release lamotrigine in uncontrolled and controlled clinical trials. Eructation, gastritis, GI hemorrhage, gum hemorrhage, hematemesis, hemorrhagic colitis, melena, gastric ulcer, taste loss, or tongue edema was reported in less than 0.1% of patients.

Esophagitis and pancreatitis have been reported during postmarketing experience with lamotrigine and/or in worldwide uncontrolled clinical trials; however, data are insufficient to provide an estimate of the incidence of such effects or to establish a causal relationship to lamotrigine.

Dermatologic and Sensitivity Reactions

Serious dermatologic reactions (including some fatalities) have been reported in adults and children receiving lamotrigine therapy. Rash occurred in 10% of adults and 14% of children receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. The incidence of severe rash associated with lamotrigine also appears to be higher in pediatric patients than in adults; severe rash, including Stevens-Johnson syndrome, has been reported in approximately 0.8% of children younger than 16 years of age and in 0.3% of adults receiving immediate-release lamotrigine as adjunctive therapy in epilepsy clinical trials. In clinical trials of bipolar disorder and other mood disorders, the incidence of serious rash was 0.08% in adults receiving immediate-release lamotrigine as initial monotherapy and 0.13% in adults receiving the drug as adjunctive therapy. The risk of serious rashes associated with extended-release lamotrigine therapy is not expected to differ from that with the immediate-release formulations of the drug; however, the relatively limited treatment experience makes it difficult to characterize the incidence and risk of such rashes with the extended-release formulation.

There is evidence that most cases of rash associated with lamotrigine therapy are associated with transiently high plasma concentrations of the drug occurring during the initial weeks of therapy or with high plasma concentrations occurring during concomitant valproic acid therapy. Cases of life-threatening rashes associated with lamotrigine almost always have occurred within 2-8 weeks of treatment initiation; however, severe rashes rarely have presented following prolonged treatment (e.g., 6 months). Lamotrigine-associated rashes do not appear to have distinguishing features. Because it is not possible to distinguish benign rashes from those that may become severe and/or life-threatening, lamotrigine generally should be discontinued at the first sign of rash (unless the rash is known not to be drug related). However, a rash may become life-threatening or permanently disabling or disfiguring despite discontinuance of the drug. Discontinuance of immediate-release lamotrigine because of rash was required in 3% of adults receiving the drug as adjunctive therapy and 4.5% of adults receiving the drug as monotherapy in controlled clinical trials; 4.4% of pediatric patients receiving immediate-release lamotrigine in controlled clinical trials discontinued the drug because of the development of rash. The potential for development of a rash at the beginning of lamotrigine therapy may be decreased by employing low initial dosages and by gradual escalation of dosage to avoid initially high plasma concentrations of the drug.

Rash, including serious and potentially life-threatening rash, appears to be more likely to occur in patients receiving concomitant valproic acid. Valproic acid can decrease clearance and increase plasma concentrations of lamotrigine more than twofold; exceeding the recommended reduced initial dosage of lamotrigine or the subsequent recommended schedule for escalation of lamotrigine dosage (see Dosage and Administration: Dosage and see Drug Interactions under Cautions: Precautions and Contraindications), particularly in patients receiving valproic acid, may increase the incidence of rash, including serious rash, in lamotrigine-treated patients. In clinical trials, 1% of adults and 1.2% of children receiving a drug regimen including immediate-release lamotrigine concomitantly with valproic acid experienced a rash requiring hospitalization, while 0.16% of adults and 0.6% of children receiving a drug regimen of lamotrigine without valproic acid were hospitalized because of rash.

Rashes severe enough to cause hospitalization, including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, angioedema, and a hypersensitivity syndrome (usually consisting of fever, rash, facial swelling, and hematologic, hepatic, and/or lymphatic involvement), occurred in 0.3% of adults receiving immediate-release lamotrigine in premarketing controlled and uncontrolled clinical trials and in about 0.8% of pediatric patients receiving the drug in clinical trials; death associated with rash has been reported rarely in postmarketing use of lamotrigine. Erythema multiforme has been reported in patients receiving lamotrigine in premarketing controlled and uncontrolled clinical trials in the US, while lupus-like syndrome and vasculitis have been reported during postmarketing experience with the drug and/or in worldwide uncontrolled clinical trials.

Pruritus occurred in 3% of adults receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. Contact dermatitis, dry skin, peripheral edema, and sweating each occurred in 2% of adults receiving lamotrigine as monotherapy in a controlled trial. Eczema, facial edema, photosensitivity, and pruritus each were reported in 2% of children receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. Acne, alopecia, facial edema, dry skin, erythema, hirsutism, maculopapular rash, peripheral edema, skin discoloration, Stevens-Johnson syndrome, sweating, urticaria, or vesiculobullous rash occurred in at least 0.1% but in less than 1% of patients receiving lamotrigine in uncontrolled and controlled clinical trials. Angioedema, erythema multiforme, fungal dermatitis, herpes zoster, leukoderma, petechial rash, pustular rash, seborrhea, or photosensitivity occurred in less than 0.1% of patients.

Hypersensitivity reactions, which can be fatal or life-threatening, have been reported in patients treated with lamotrigine. In some cases, manifestations of these reactions have included multiorgan dysfunction (including hepatic abnormalities and disseminated intravascular coagulation) (see Cautions: Hepatic Effects). Early signs of a possible hypersensitivity reaction, such as fever and lymphadenopathy, should prompt immediate evaluation of the patient; a rash may or may not be present. Unless another cause for the signs or symptoms is found, lamotrigine should be discontinued.

Cardiovascular Effects

Hemorrhage was reported in 2% of pediatric patients receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. Chest pain occurred in more than 1% of adults receiving lamotrigine as adjunctive therapy in controlled clinical trials but occurred with equal or greater frequency in patients receiving placebo. Chest pain also occurred in 5% of adults receiving lamotrigine as monotherapy in a controlled clinical trial. Flushing, hot flushes, palpitations, postural hypotension, syncope, tachycardia, or vasodilation occurred in at least 0.1% but in less than 1% of patients receiving lamotrigine in uncontrolled and controlled clinical trials. Cerebrovascular accident, cerebral sinus thrombosis, deep thrombophlebitis, myocardial infarction, atrial fibrillation, angina pectoris, hemorrhage, or hypertension occurred in less than 0.1% of patients receiving lamotrigine in uncontrolled and controlled clinical trials.

Respiratory Effects

Rhinitis occurred in 14%, pharyngitis in 10%, increased cough in 8%, and flu-like syndrome in 7% of adults receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. Respiratory disorder was reported in more than 1% of adults receiving lamotrigine as adjunctive therapy in controlled clinical trials but occurred with equal or greater frequency in patients receiving placebo. Rhinitis occurred in 7% of adults receiving lamotrigine as monotherapy in a controlled trial; epistaxis, bronchitis, and dyspnea each occurred in 2% of such patients. Pharyngitis, bronchitis, and increased cough occurred in 14, 7, and 7%, respectively, of children receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. Sinusitis and bronchospasm each were reported in 2% of children in these trials. Dyspnea, epistaxis, or hyperventilation occurred in at least 0.1% but in less than 1% of patients in uncontrolled and controlled clinical trials, and bronchospasm, hiccups, or sinusitis occurred in less than 0.1% of patients. Apnea has been reported during postmarketing experience with lamotrigine and/or in worldwide uncontrolled clinical trials; however, data are insufficient to provide an estimate of the incidence of this adverse effect or to establish a causal relationship to lamotrigine.

Ocular and Otic Effects

Ocular effects were among the most frequent adverse effects reported in patients receiving lamotrigine as adjunctive therapy in controlled clinical trials. Diplopia was the most frequent adverse ocular effect reported in adults receiving immediate-release lamotrigine as adjunctive therapy in controlled trials, occurring in 28% of such patients, and blurred vision occurred in 16% of patients. The frequency of diplopia and blurred vision appears to be dose related; in a dose-response study, diplopia occurred in 49, 24, or 8% of patients receiving lamotrigine 500 mg daily, lamotrigine 300 mg daily, or placebo, respectively, while blurred vision occurred in 25, 11, or 10% of patients receiving these respective regimens. Limited data also indicate an increased incidence of some adverse effects, including diplopia and blurred vision, in patients receiving carbamazepine concomitantly with lamotrigine.(See Drug Interactions under Cautions: Precautions and Contraindications.)

Vision abnormality occurred in 3% of adults receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials and in 2% of adults receiving immediate-release lamotrigine as monotherapy in a controlled trial. Diplopia, blurred vision, or vision abnormality occurred in 5, 4, or 2%, respectively, of children receiving lamotrigine as adjunctive therapy in controlled clinical trials. Abnormality of accommodation, conjunctivitis, oscillopsia, or photophobia occurred in at least 0.1% but in less than 1% of patients in uncontrolled and controlled clinical trials, and dry eyes, lacrimation disorder, strabismus, ptosis, or uveitis occurred in less than 0.1% of patients.

Ear disorder was reported in 2% of children receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. Otic pain or tinnitus occurred in at least 0.1% but in less than 1% of patients in uncontrolled and controlled clinical trials. Deafness was reported in less than 0.1% of patients in uncontrolled and controlled clinical trials.

Musculoskeletal Effects

Neck pain and arthralgia each occurred in 2% of adults receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. Back pain or myalgia occurred in more than 1% of patients receiving lamotrigine as adjunctive therapy in controlled trials but with equal or greater frequency in patients receiving placebo. Joint disorder, myasthenia, muscle spasm, or twitching occurred in at least 0.1% but in less than 1% of patients in uncontrolled and controlled trials, and arthritis, bursitis, leg cramps, tendinous contracture, or pathological fracture occurred in less than 0.1% of patients. Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions during postmarketing experience with lamotrigine and/or in worldwide uncontrolled trials; however, data are insufficient to provide an estimate of the incidence of this adverse effect or to establish a causal relationship to lamotrigine.

Genitourinary Effects

Dysmenorrhea occurred in 7%, vaginitis in 4%, and amenorrhea in 2% of women receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. Dysmenorrhea occurred in 5% of women receiving lamotrigine as monotherapy in a controlled trial. Menstrual disorder or urinary tract infection occurred in more than 1% of adults receiving adjunctive lamotrigine therapy in controlled trials but with equal or greater frequency in patients receiving placebo. Urinary tract infection occurred in 3% of children receiving lamotrigine as adjunctive therapy in controlled clinical trials; penis disorder was reported in 2% of male pediatric patients receiving lamotrigine in these trials.

Lactation (in females), vaginal candidiasis, hematuria, polyuria, urinary frequency, urinary incontinence, or urinary retention occurred in at least 0.1% but in less than 1% of patients receiving immediate-release lamotrigine therapy in uncontrolled and controlled clinical trials. Abnormal ejaculation, impotence, epididymitis, cystitis, urine abnormality, dysuria, kidney pain, kidney failure, acute kidney failure, or menorrhagia occurred in less than 0.1% of patients in uncontrolled and controlled clinical trials.

Endocrine and Metabolic Effects

Goiter or hyperthyroidism occurred in less than 0.1% of patients receiving immediate-release lamotrigine in uncontrolled and controlled clinical trials. Weight decrease occurred in 5% of adults receiving lamotrigine as monotherapy in a controlled trial. Weight loss or weight gain occurred in at least 0.1% but in less than 1% of patients in uncontrolled and controlled clinical trials. Edema occurred in 2% of children receiving lamotrigine as adjunctive therapy in controlled clinical trials. Edema or hyperglycemia occurred in less than 0.1% of patients in uncontrolled and controlled clinical trials.

Hepatic Effects

Fatalities associated with multiorgan failure and various degrees of hepatic failure have been reported rarely during premarketing trials of immediate-release lamotrigine as adjunctive therapy. A young woman receiving concomitant valproic acid and carbamazepine developed a possible hypersensitivity syndrome consisting of headache, fever, and a maculopapular rash 3 weeks following addition of lamotrigine to therapy; fulminant hepatic failure and hepatic coma developed within 3 days, and despite subsequent clinical improvement, the patient died of a massive pulmonary embolus 2 months later. Multiorgan (including renal and/or hepatic) failure and disseminated intravascular coagulation associated with frequent generalized seizures or status epilepticus have been reported in several patients receiving immediate-release lamotrigine; it has been suggested that this syndrome may have resulted from rhabdomyolysis caused by uncontrolled generalized seizures. The majority of these cases of hepatic and/or multiorgan failure occurred in association with other serious medical events (e.g., status epilepticus, overwhelming sepsis), making it difficult to identify the initiating cause. However, disseminated intravascular coagulation, rhabdomyolysis, renal failure, maculopapular rash, ataxia, and increased liver enzymes (e.g., AST [SGOT]) in the absence of generalized seizures also have been reported rarely with lamotrigine as adjunctive therapy. Abnormal liver function test results occurred in at least 0.1% but in less than 1% of patients receiving immediate-release lamotrigine in uncontrolled and controlled clinical trials, and hepatitis, increased alkaline phosphatase, or bilirubinemia occurred in less than 0.1% of patients.

Hematologic Effects

Blood dyscrasias that may or may not be associated with hypersensitivity reactions, including neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and rarely, aplastic anemia and pure red cell aplasia (PRCA), have been reported with lamotrigine. Lymphadenopathy occurred in 2% of children receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. Anemia, ecchymosis, petechiae, leukocytosis, leukopenia, or lymphadenopathy occurred in at least 0.1% but in less than 1% of patients receiving immediate-release lamotrigine in uncontrolled and controlled clinical trials. Eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, lymphocytosis, macrocytic anemia, or thrombocytopenia occurred in less than 0.1% of patients receiving immediate-release lamotrigine in uncontrolled and controlled clinical trials.

Disseminated intravascular coagulation has been reported rarely in conjunction with multiorgan (e.g., renal and/or hepatic) failure in patients receiving lamotrigine as adjunctive therapy.(See Cautions: Hepatic Effects.) Agranulocytosis, aplastic anemia, hemolytic anemia, neutropenia, pancytopenia, red cell aplasia, and progressive immunosuppression have been reported during postmarketing experience with lamotrigine and/or in worldwide uncontrolled clinical trials; however, data are insufficient to provide an estimate of the incidence of such effects or to establish a causal relationship to lamotrigine.

Other Adverse Effects

Flu syndrome or fever occurred in 7 or 6%, respectively, of adults receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. Pain and infection each occurred in 5% and fever in 2% of adults receiving lamotrigine as monotherapy in a controlled trial. Infection occurred in 20%, fever in 15%, accidental injury in 14%, flu syndrome in 7%, and pain in 5% of children receiving immediate-release lamotrigine as adjunctive therapy in controlled clinical trials. Pain occurred in at least 1% of patients receiving immediate-release lamotrigine in uncontrolled and controlled clinical trials. Accidental injury, infection, chills, and malaise occurred in at least 0.1% but in less than 1% of patients receiving immediate-release lamotrigine in uncontrolled and controlled clinical trials. Breast pain, breast abscess, breast neoplasm, enlarged abdomen, increase in serum creatinine concentration, parosmia, or alcohol intolerance occurred in less than 0.1% of patients.

Precautions and Contraindications

Risk Evaluation and Mitigation Strategy

A Risk Evaluation and Mitigation Strategy (REMS) has been required and approved by the US Food and Drug Administration (FDA) for lamotrigine. The goal of this REMS program is to inform patients about the serious risks associated with use of the drug, including an increased risk of suicidal thoughts and behavior.(See Cautions.) The REMS program consists of a medication guide to be dispensed with every lamotrigine prescription.

Withdrawal Seizures

Because of the possibility of increased seizure frequency, anticonvulsant drugs, including lamotrigine, should not be discontinued suddenly, particularly in patients with preexisting seizure disorders. Unless safety concerns dictate a more rapid withdrawal of the drug, discontinuance of lamotrigine should be done gradually over a period of at least 2 weeks.(See Dosage and Administration: Dosage.) Seizure exacerbation and/or status epilepticus have been reported in patients receiving lamotrigine as adjunctive therapy in the management of seizure disorders, although the incidence of these adverse effects has been difficult to determine conclusively.(See Cautions: Nervous System Effects.) The use and dosage of all anticonvulsant drugs in a regimen including lamotrigine should be reevaluated if there is a change in seizure control or appearance or worsening of adverse effects, and patients should be instructed to report immediately any worsening of seizure control.

Suicidality Risk

FDA has informed healthcare professionals about an increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants compared with placebo. FDA's analysis included 199 randomized, placebo-controlled studies of 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) involving over 43,000 patients 5 years of age or older; the studies evaluated the effectiveness of the anticonvulsants in epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain). The analysis revealed that patients receiving these anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%); this increased suicidality risk was observed as early as one week after beginning therapy and continued through 24 weeks. The results were generally consistent among the 11 drugs studied. In addition, patients who were treated for epilepsy, psychiatric disorders, and other conditions were all found to be at increased risk for suicidality when compared with placebo; there did not appear to be a specific demographic subgroup of patients to which the increased risk could be attributed. However, the relative risk for suicidality was found to be higher in patients with epilepsy compared with patients who were given one of the drugs for psychiatric or other conditions.

Based on the current analysis of the available data, FDA recommends that all patients who are currently receiving or beginning therapy with any anticonvulsant for any indication be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior. Symptoms such as anxiety, agitation, hostility, mania, and hypomania may be precursors to emerging suicidality. Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality so that they are aware and able to notify their clinician of any unusual behavioral changes. Patients, family members, and caregivers also should be advised not to make any changes to the anticonvulsant regimen without first consulting with the responsible clinician. They should pay close attention to any day-to-day changes in mood, behavior, and actions; since changes can happen very quickly, it is important to be alert to any sudden differences. In addition, patients, family members, and caregivers should be aware of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions). If these or any new and worrisome behaviors occur, the responsible clinician should be contacted immediately. FDA also recommends that clinicians who prescribe lamotrigine or any other anticonvulsant balance the risk for suicidality with the risk of untreated illness. Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with an increased risk of morbidity and mortality and an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician must consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Sudden Death in Epilepsy

During the premarketing development of lamotrigine, 20 sudden and unexplained deaths were reported among a cohort of 4700 patients with epilepsy receiving adjunctive therapy with immediate-release lamotrigine (5747 patient-years of exposure). Although the rate of these deaths exceeds that expected to occur in a healthy (nonepileptic) population matched for age and gender, this rate was similar to that occurring in a similar population of epileptic patients receiving a chemically unrelated anticonvulsant agent. This evidence suggests, but does not prove, that the incidence of sudden, unexplained death observed with lamotrigine adjunctive therapy may be reflective of the population itself rather than the effects of lamotrigine.

Serious Skin Rash

Some evidence suggests that use of lamotrigine concomitantly with valproic acid increases the risk of serious rash. The incidence of rash also appears to increase with the magnitude of the initial dosage of lamotrigine and the subsequent rate of dosage escalation; exceeding the recommended dosage of lamotrigine at initiation of therapy appears to increase the risk of rash requiring withdrawal of therapy.(See Dosage and Administration: Dosage.) A benign initial appearance of a rash in a patient receiving lamotrigine therapy cannot predict an entirely benign outcome. Patients receiving lamotrigine, especially in conjunction with valproic acid, should be cautioned that rash, in some cases potentially life-threatening, may occur, and that any occurrence of rash should immediately be reported by the patient to their clinician.

Drug Interactions

The concomitant use of valproic acid and/or hepatic enzyme-inducing anticonvulsant drugs (e.g., phenobarbital, primidone, carbamazepine, phenytoin) can increase or decrease the metabolism and elimination of lamotrigine, requiring dosage adjustments to maintain efficacy and/or avoid toxicity.(See Dosage and Administration: Dosage.) Addition of valproic acid to lamotrigine therapy reduces lamotrigine clearance and increases steady-state plasma lamotrigine concentrations by slightly more than 50% whether or not hepatic enzyme-inducing anticonvulsant drugs are given concomitantly. Conversely, steady-state plasma concentrations of lamotrigine are decreased by about 40% when phenobarbital, primidone, or carbamazepine is added to lamotrigine therapy and by about 45-54% when phenytoin is added to lamotrigine therapy; the magnitude of the effect with phenytoin is dependent on the total daily dosage of phenytoin (from 100-400 mg daily). Discontinuance of an enzyme-inducing anticonvulsant drug can be expected to increase, and discontinuance of valproic acid can be expected to decrease, the elimination half-life and plasma concentrations of lamotrigine. Although the manufacturers state that a therapeutic plasma concentration range has not been established for lamotrigine and that dosage should be based on therapeutic response, the change in plasma lamotrigine concentrations resulting from addition or discontinuance of enzyme-inducing anticonvulsant drugs or valproic acid should be considered when these drugs are added to or withdrawn from an existing anticonvulsant drug regimen that includes lamotrigine.

Addition of lamotrigine to existing therapy with phenytoin or carbamazepine generally does not appreciably alter the steady-state plasma concentrations of these concomitantly administered drugs. Addition of lamotrigine to carbamazepine therapy reportedly has resulted in increased plasma concentrations of a pharmacologically active metabolite of carbamazepine (carbamazepine-10,11-epoxide) and an increased incidence of some adverse effects (e.g., dizziness, headache, diplopia, blurred vision, ataxia, nausea, nystagmus). However, elevations in carbamazepine-10,11-epoxide plasma concentrations and/or increased toxicity have not been consistently observed with concomitant administration of lamotrigine and carbamazepine, and the mechanism of the interaction between these drugs remains unclear.

Addition of lamotrigine to valproic acid therapy in healthy individuals resulted in a 25% reduction in trough steady-state plasma concentrations of valproic acid over a 3-week period, followed by stabilization of these concentrations.

The effects of adding lamotrigine to an existing regimen including valproic acid, phenytoin, and/or carbamazepine may be expected to be similar to those associated with addition of each drug independently (i.e., valproic acid concentrations decrease, phenytoin and carbamazepine concentrations do not change).

Some estrogen-containing oral contraceptives have been shown to decrease plasma concentrations of lamotrigine. Therefore, dosage adjustment of lamotrigine will be necessary in most patients who begin or stop estrogen-containing oral contraceptives while receiving lamotrigine therapy. During the week of inactive hormonal preparation (i.e., ''pill-free'' week) of oral contraceptive therapy, plasma lamotrigine concentrations are expected to increase by as much as twofold by the end of the week. Adverse effects associated with elevated plasma lamotrigine concentrations (such as dizziness, ataxia, and diplopia) may occur.(See Dosage and Administration: Dosage.)

Lamotrigine is a weak inhibitor of dihydrofolate reductase. Although clinically important alterations in blood folate concentrations or hematologic parameters have not been documented in clinical studies of lamotrigine therapy of at least 5 years duration, the manufacturers state that clinicians should be aware of this effect when prescribing other drugs that inhibit folate metabolism.

Acute Multiorgan Failure

Multiorgan failure and various degrees of hepatic failure, in some cases fatal or irreversible, have been reported rarely with immediate-release lamotrigine therapy.(See Cautions: Hepatic Effects.) The possibility of such potentially fatal adverse effects should be considered in patients who exhibit signs and symptoms associated with multiorgan and/or hepatic impairment following initiation of lamotrigine as adjunctive therapy.

Aseptic Meningitis

Lamotrigine may cause aseptic meningitis.(See Cautions: Nervous System Effects.) Patients receiving the drug should be instructed to immediately contact their clinician if they experience headache, fever, chills, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, myalgia, drowsiness, and/or confusion. If meningitis is suspected, patients should be evaluated and treated, as indicated, for other possible causes of meningitis. Discontinuance of lamotrigine should be considered if no other clear cause of meningitis is identified.

Somnolence and Dizziness

Lamotrigine can produce drowsiness and dizziness, and patients should be cautioned that the drug may impair their ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).

Renal Impairment

Limited information indicates that the elimination half-life of immediate-release lamotrigine is prolonged in patients with severe chronic renal failure (mean creatinine clearance of 13 mL/minute) not receiving other anticonvulsant drugs. In a study of a limited number of patients and healthy individuals receiving a single 100-mg dose of immediate-release lamotrigine, the mean plasma half-life of the drug was 42.9 hours in patients with chronic renal failure, 57.4 hours between treatments in dialysis patients, and 26.2 hours in healthy individuals. The mean plasma half-life of lamotrigine was decreased to 13 hours during hemodialysis; an average of 20% (range: 5.6-35.1%) of the total body load of lamotrigine was eliminated during a 4-hour hemodialysis treatment. The manufacturers state that a reduced maintenance dosage of lamotrigine may be effective in patients with substantial renal impairment; however, the manufacturers currently make no specific recommendations for dosage adjustment in such patients.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Hepatic Impairment

The manufacturers state that experience with use of lamotrigine in patients with impaired liver function is limited. Following a single 100-mg dose of immediate-release lamotrigine, the mean half-life of the drug in patients with hepatic impairment that was mild (Child-Pugh class A), moderate (Child-Pugh class B), severe (Child-Pugh class C) without ascites, or severe with ascites was 46, 72, 67, or 100 hours, respectively, compared with 33 hours in healthy individuals. The manufacturers recommend reduction of initial, escalation, and maintenance dosages of lamotrigine in patients with moderate or severe hepatic impairment.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Concomitant Diseases

Because lamotrigine is transformed in the liver principally to glucuronide metabolites that are eliminated renally, the drug should be used with caution in patients with diseases or conditions (e.g., renal, hepatic, or cardiac impairment) that could affect metabolism and/or elimination of the drug. In dogs, lamotrigine is extensively metabolized to its 2-N-methyl metabolite, which has caused dose-dependent prolongations of the PR interval, widening of the QRS complex, and at high dosages, complete AV block. There have been no consistent effects of lamotrigine metabolites on cardiac conduction in humans. Trace amounts of the 2-N-methyl metabolite of lamotrigine have been found in urine, but not in plasma, with chronic dosing of lamotrigine in humans. However, the manufacturers state that it is possible that increased plasma concentrations of the 2-N-methyl metabolite could occur in patients with hepatic disease who have decreased ability to glucuronidate lamotrigine.

Binding to Melanin-Rich Tissues

Lamotrigine binds to melanin-containing ocular tissue in pigmented rats and cynomolgus monkeys, but evidence of this manifestation has not been reported in humans. Although ophthalmologic testing was conducted in one controlled clinical trial of lamotrigine therapy, the manufacturers state that it was inadequate to detect subtle effects or injury resulting from long-term administration of lamotrigine and that the ability of available tests to detect potentially adverse effects associated with the binding of lamotrigine to melanin is unknown. The manufacturers further state that while no specific recommendations for periodic ophthalmologic monitoring of patients receiving long-term lamotrigine therapy can be provided, prolonged administration of the drug could potentially result in its accumulation and possible toxic effects in melanin-rich tissues, including those of the eye, and that clinicians should be aware of possible adverse ophthalmologic effects occurring as a result of binding of the drug to melanin.

Possible Prescribing and Dispensing Errors

Because of similarity in spelling between Lamictal (the trade name for lamotrigine) and labetalol, Lamisil (terbinafine hydrochloride), lamivudine, Lomotil (the fixed combination of atropine sulfate and diphenoxylate hydrochloride), and Ludiomil (no longer commercially available under this trade name in the US; maprotiline hydrochloride), dispensing errors have been reported to the manufacturer of Lamictal (GlaxoSmithKline). These medication errors may be associated with serious adverse events either due to lack of appropriate therapy for seizures (e.g., in patients not receiving the prescribed anticonvulsant, lamotrigine, which may lead to status epilepticus) or, alternatively, to the risk of developing adverse effects (e.g., serious rash) associated with the use of lamotrigine in patients for whom the drug was not prescribed and consequently was not properly titrated. Therefore, extra care should be exercised in ensuring the accuracy of both oral and written prescriptions for Lamictal and these other drugs. When appropriate, clinicians might consider including the intended use of the particular drug on the prescription in addition to alerting patients to carefully check the drug they receive and promptly bring any question or concern to the attention of the dispensing pharmacist. The manufacturer of Lamictal also recommends that pharmacists assess various measures of avoiding dispensing errors and implement them as appropriate (e.g., by computerized filling and handling of prescriptions, patient counseling). Medication errors also may occur between the different formulations of lamotrigine. Depictions of Lamictal conventional tablets, chewable/dispersible tablets, and orally disintegrating tablets, Lamictal XR extended-release tablets, and generic lamotrigine tablets may be found in the medication guide; patients are strongly advised to visually inspect their tablets to verify that they are lamotrigine as well as the correct formulation of the drug each time they fill their prescription.

Contraindications

Lamotrigine is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.

Pediatric Precautions

Safety and efficacy of immediate-release formulations of lamotrigine have not been established in pediatric patients younger than 2 years of age. Safety and efficacy of immediate-release lamotrigine in children 2-16 years of age have not been established for uses other than adjunctive therapy of partial seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome.

Safety and efficacy of extended-release lamotrigine tablets for adjunctive therapy of partial seizures and primary generalized tonic-clonic seizures have not been established in pediatric patients younger than 13 years of age.

Safety and efficacy of immediate-release lamotrigine for the management of bipolar disorder in patients younger than 18 years of age have not been established.

The incidence of severe rashes requiring hospitalization and discontinuance of immediate-release lamotrigine appears to be higher in pediatric patients compared with adults (about 0.8% versus 0.3%, respectively).(See Cautions: Dermatologic and Sensitivity Reactions.)

Analyses of population pharmacokinetic data for children 2-18 years of age demonstrated that lamotrigine clearance is influenced mainly by total body weight and concomitant anticonvulsant therapy. Oral clearance of lamotrigine is higher in children than adults when calculated on the basis of body weight; patients weighing less than 30 kg have a higher clearance on a weight-adjusted basis than patients weighing more than 30 kg and may require increases in maintenance dosage.(See Dosage and Administration: Dosage.)

Geriatric Precautions

The manufacturers state that clinical trials of lamotrigine in epilepsy and in bipolar disorder did not include sufficient numbers of patients older than 65 years of age to determine whether they respond differently than younger patients or exhibit a different safety profile than that of younger patients. Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant diseases and drug therapy in geriatric patients, the manufacturers recommend cautious dosage selection in patients in this age group, usually beginning at the lower end of the usual range.

Mutagenicity and Carcinogenicity

No evidence of mutagenicity was demonstrated by lamotrigine in vitro in the Ames Salmonella microbial mutagen test or the mammalian mouse lymphoma assay. Lamotrigine also did not increase the incidence of structural or numerical chromosomal abnormalities in the in vitro human lymphocyte assay and the in vivo rat bone marrow assay.

No evidence of carcinogenicity was demonstrated by lamotrigine in studies in mice receiving 30 mg/kg daily and in rats receiving 10-15 mg/kg daily for up to 2 years. Steady-state plasma lamotrigine concentrations produced by these dosages ranged from 1-4 mcg/mL in mice and from 1-10 mcg/mL in rats. In humans receiving the recommended lamotrigine dosage of 300-500 mg daily, plasma lamotrigine concentrations generally are in the range of 2-5 mcg/mL, although plasma concentrations up to 19 mcg/mL have been reported.

Pregnancy, Fertility, and Lactation

Pregnancy

The safety of lamotrigine when used during pregnancy in humans is unknown, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. Patients should be advised to notify their clinician if they become pregnant or intend to become pregnant. The manufacturer of Lamictal, in collaboration with the US Centers for Disease Control and Prevention (CDC), maintains a lamotrigine pregnancy registry to monitor fetal outcomes of pregnant women exposed to lamotrigine. Clinicians aware of patients who have received lamotrigine at any time during their pregnancy and who wish to register these cases before fetal outcome is known (e.g., through ultrasound, amniocentesis, birth) may obtain information by calling the Lamotrigine Pregnancy Registry at 800-336-2176. Patients can enroll themselves in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 888-233-2334; registry information also is available on the website at http://www.aedpregnancyregistry.org/.

Preliminary information from the NAAED Pregnancy Registry suggests a possible association between exposure to lamotrigine monotherapy during the first trimester of pregnancy and an increased incidence of cleft lip or cleft palate in infants. Of 564 pregnant women listed in the NAAED Pregnancy Registry who received lamotrigine monotherapy during the first trimester, 5 cases of oral clefts (2 cases of isolated cleft lips, 3 cases of isolated cleft palate) occurred, yielding a total prevalence of 8.9 cases per 1000 exposures compared with a prevalence of 0.5-2.16 reported among infants of nonepileptic women who were not receiving lamotrigine. However, other pregnancy registries of similar size have not replicated this observation, and the validity of this association cannot be established until additional data are collected in the NAAED Pregnancy Registry, in other pregnancy registries, or by additional research. The US Food and Drug Administration (FDA) states that the clinical importance of this preliminary report remains uncertain pending further data collection and more research is needed. FDA recommends that women who are pregnant should not begin or discontinue lamotrigine therapy without first talking to their clinician.

Although there are no adequate and controlled studies to date in humans, lamotrigine has been shown to produce maternal toxicity and secondary fetal toxicity (e.g., reduced fetal weight and/or delayed ossification) in mice and rats receiving oral dosages up to 1.2 or 0.5 times (on a mg/m basis), respectively, the maximum usual human maintenance dosage of 500 mg daily during the period of organogenesis. However, no evidence of teratogenicity was found in mice, rats, or rabbits receiving the drug orally in dosages up to 1.2, 0.5, or 1.1 times (on a mg/m basis), respectively, the maximum usual human daily maintenance dosage. Maternal toxicity and fetal death occurred in rats receiving lamotrigine orally during late gestation (days 15-20) in dosages of 0.1, 0.14, or 0.3 times (on a mg/m basis) the maximum usual human daily maintenance dosage; food consumption and weight gain were reduced in dams, and the gestation period was slightly prolonged. Stillborn pups were found in all three groups of rats receiving lamotrigine, with the greatest number of stillborn pups in the group receiving the highest dosage. Postnatal death of pups occurred between days 1 and 20 only in the group of rats receiving 0.14 or 0.3 times (on a mg/m basis) the maximum usual human daily maintenance dosage. Some of these deaths appeared to be drug related and not secondary to maternal toxicity. No evidence of teratogenicity was demonstrated in rats receiving lamotrigine in dosages 0.4 times (on a mg/m basis) the maximum usual human daily maintenance dosage prior to and during mating and throughout gestation and lactation. However, the incidence of intrauterine death without signs of teratogenicity was increased in rat dams receiving lamotrigine isethionate by rapid IV injection in a dosage 0.6 times (on a mg/m basis) the maximum usual human daily maintenance dosage. In a study designed to determine the effects of lamotrigine on postnatal development, pregnant rats received lamotrigine orally in dosages 0.1 and 0.5 times (on a mg/m basis) the recommended human daily dosage during the period of organogenesis. At day 21 postpartum, pups born to dams receiving the lower dosage (5 mg/kg daily) exhibited a longer latent period for open field exploration and a lower frequency of rearing. Pups born to dams receiving the higher dosage (25 mg/kg daily) demonstrated an increased time to completion of a swimming maze test performed 39-44 days postpartum. No evidence of adverse effects on development of pups was demonstrated by lamotrigine in a group of rats receiving the drug in dosages 0.4 times (on a mg/m basis) the maximum usual human daily maintenance dosage prior to and during mating, and throughout gestation and lactation.

Because lamotrigine is a dihydrofolate reductase inhibitor, it decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis in animals and humans. However, there are no adequate and well-controlled studies in pregnant women, and animal reproduction studies are not always predictive of human response. Decreased plasma folate concentrations in rats were partially returned to normal by administration of leucovorin. Clinicians should be aware of lamotrigine's dihydrofolate reductase inhibiting activity, especially when prescribing other drugs that inhibit folate metabolism.

The effect of lamotrigine on labor and delivery in humans is unknown.

Physiologic changes during pregnancy may affect plasma lamotrigine concentrations and/or therapeutic effect. Decreased lamotrigine concentrations during pregnancy and restoration of prepartum concentrations after delivery have been reported. Dosage adjustment of lamotrigine may be necessary to maintain clinical response.

Fertility

Reproduction studies revealed no adverse effects on fertility in rats receiving lamotrigine in oral dosages 0.4 times (on a mg/m basis) the maximum usual human daily maintenance dosage prior to and during mating, and throughout gestation and lactation. The effect of lamotrigine on human fertility is unknown.

Lactation

Lamotrigine is distributed into milk. Because of the potential for serious adverse reactions to lamotrigine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.