LAMORIG

Lamotrigine, USP an AED of the phenyltriazine class, is chemically unrelated to existing AEDs.

Lamotrigine’s chemical name is 3,5-diamino-6-(2,3-dichlorophenyl).

• as -triazine, its molecular formula is C 9 H 7 N 5 Cl 2, and its molecular weight is 256.09.

Lamotrigine, USP is a white to pale cream-colored powder and has a pK a of 5.7.

Lamotrigine, USP is slightly soluble in 0.1 N hydrochloric acid, in acetone, in methanol and in water.

The structural formula is

Lamotrigine orally disintegrating tablets are supplied for oral administration.

The tablets contain 25 mg (white), 50 mg (white), 100 mg (peach), 200 mg (white) of lamotrigine, USP and the following inactive ingredients: For lamotrigine orally disintegrating tablets 25 mg, 50 mg and 200 mg: Colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, starch (maize), microcrystalline cellulose, pregelatinized starch, peppermint flavor, sodium stearyl fumarate and sucralose.

For lamotrigine orally disintegrating tablets 100 mg: Colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, starch (maize), microcrystalline cellulose, pregelatinized starch, peppermint flavor, sodium stearyl fumarate, sucralose and idacol red oxide of iron.

Lamotrigine orally disintegrating tablets are formulated using in-house technologies designed to mask the bitter taste of lamotrigine and achieve a rapid dissolution profile. lamotrigine.

Adults and adolescents aged 13 years and older.

• Treatment as monotherapy or in combination with partial and generalized epilepsy, including tonic-clonic seizures.

• Crisis associated with Lennox-Gastaut syndrome.

Lamotrigine is given in combination with other therapy but may be first-line antiepileptic (AE) in Lennox-Gastaut syndrome.

Children and adolescents aged 2-12 years.

• Treatment in combination with partial and generalized epilepsy, including tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome.

• Treatment as monotherapy of typical absences Bipolar disorders Adults aged 18 years and older.

• Prevention of depressive episodes in patients with bipolar I disorder and predominance of depressive episodes.

LAB is not indicated for the acute treatment of manic or depressive episodes.

The risk of a serious rash is a serious rash in children.

The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown.

In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity.

Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state.

The relevance of these models to human epilepsy, however, is not known.

One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels.

In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).

Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor-Mediated

Activity Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP).

The IC for lamotrigine effects on

NMDA-induced currents (in the presence of 3 µM of glycine) in cultured hippocampal neurons exceeded 100 µM. The mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder have not been established. 12.2 Pharmacodynamics Folate Metabolism In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate.

Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins.

When oral daily doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal folate concentrations were reduced.

Significantly reduced concentrations of folate are associated with teratogenesis.

Folate concentrations were also reduced in male rats given repeated oral doses of lamotrigine.

Reduced concentrations were partially returned to normal when supplemented with folinic acid.

Cardiac Electrophysiology Effect of Lamotrigine

In vitro studies show that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations.

It inhibits human cardiac sodium channels with rapid onset and offset kinetics and strong voltage dependence, consistent with other Class IB antiarrhythmic agents.

At therapeutic doses, lamotrigine did not slow ventricular conduction (widen QRS) in healthy individuals in a thorough QT study; however, in patients with clinically important structural or functional heart disease (i.e., patients with heart failure, valvular heart disease, congenital heart disease, conduction system disease, ventricular arrhythmias, cardiac channelopathies [e.g., Brugada syndrome], clinically important ischemic heart disease, or multiple risk factors for coronary artery disease), lamotrigine could slow ventricular conduction (widen QRS) and induce proarrhythmia, which can lead to sudden death.

Elevated heart rates could also increase the risk of ventricular conduction slowing with lamotrigine.

In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite.

This metabolite causes dose-dependent prolongation of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block.

The in vitro electrophysiological effects of this metabolite have not been studied.

Similar cardiovascular effects from this metabolite are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose) have been found in human urine.

However, it is conceivable that plasma concentrations of this metabolite could be increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease, patients taking concomitant medications that inhibit glucuronidation).

Lamotrigine accumulated in the kidney of the male rat, causing chronic progressive nephrosis, necrosis, and mineralization.

These findings are attributed to α-2 microglobulin, a species.

• and sex-specific protein that has not been detected in humans or other animal species.

Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin.

It has been found in the uveal tract up to 52 weeks after a single dose in rodents. 12.3 Pharmacokinetics The pharmacokinetics of lamotrigine have been studied in subjects with epilepsy, healthy young and elderly volunteers, and volunteers with chronic renal failure.

Lamotrigine pharmacokinetic parameters for adult and pediatric subjects and healthy normal volunteers are summarized in Tables and 16.

Table 14.

Mean Pharmacokinetic Parameters a in Healthy Volunteers and Adult Subjects with Epilepsy Adult Study Population Number of Subjects T max: Time of Maximum Plasma Concentration (h) t 1/2: Elimination Half-life (h) CL/F: Apparent Plasma Clearance (mL/min/kg) Healthy volunteers taking no other medications: Single-dose lamotrigine 179 2.2 (0.25 to 12) 32.8 (14 to 103) 0.44 (0.12 to 1.1) Multiple-dose lamotrigine 36 1.7 (0.5 to 4) 25.4 (11.6 to 61.6) 0.58 (0.24 to 1.15) Healthy volunteers taking valproate: Single-dose lamotrigine 6 1.8 (1 to 4) 48.3 (31.5 to 88.6) 0.3 (0.14 to 0.42) Multiple-dose lamotrigine 18 1.9 (0.5 to 3.5) 70.3 (41.9 to 113.5) 0.18 (0.12 to 0.33) Subjects with epilepsy taking valproate only: Single-dose lamotrigine 4 4.8 (1.8 to 8.4) 58.8 (30.5 to 88.8) 0.28 (0.16 to 0.4) Subjects with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone b plus valproate: Single-dose lamotrigine 25 3.8 (1 to 10) 27.2 (11.2 to 51.6) 0.53 (0.27 to 1.04) Subjects with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone: b Single-dose lamotrigine 24 2.3 (0.5 to 5) 14.4 (6.4 to 30.4) 1.1 (0.51 to 2.22) Multiple-dose lamotrigine 17 2 (0.75 to 5.93) 12.6 (7.5 to 23.1) 1.21 (0.66 to 1.82) a The majority of parameter means determined in each study had coefficients of variation between 20% and 40% for half-life and CL/F and between 30% and 70% for T max.

The overall mean values were calculated from individual study means that were weighted based on the number of volunteers/subjects in each study.

The numbers in parentheses below each parameter mean represent the range of individual volunteer/subject values across studies. b Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of lamotrigine.

Estrogen-containing oral contraceptives and other drugs, such as rifampin and protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir, that induce lamotrigine glucuronidation have also been shown to increase the apparent clearance of lamotrigine.

Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-pass metabolism (absolute bioavailability is 98%).

The bioavailability is not affected by food.

Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration.

The lamotrigine tablets for oral suspension were found to be equivalent, whether administered as dispersed in water, chewed and swallowed, or swallowed whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption.

In terms of rate and extent of absorption, lamotrigine orally disintegrating tablets, whether disintegrated in the mouth or swallowed whole with water, were equivalent to the lamotrigine compressed tablets swallowed with water.

In healthy volunteers not receiving any other medications and given single doses, the plasma concentrations of lamotrigine increased in direct proportion to the dose administered over the range of to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were maintained on other AEDs, there also was a linear relationship between dose and lamotrigine plasma concentrations at steady-state following doses of to 350 mg twice daily.

Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers.

Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations from to 10 mcg/mL (10 mcg/mL is to 6 times the trough plasma concentration observed in the controlled efficacy trials).

Because lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely.

The binding of lamotrigine to plasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate.

Lamotrigine did not displace other

AEDs (carbamazepine, phenytoin, phenobarbital) from protein-binding sites.

Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate.

After oral administration of 240 mg of 14 C-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces.

The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).

The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated.

Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t 1/2 and a 37% increase in CL/F at steady-state compared with values obtained in the same volunteers following a single dose.

Evidence gathered from other sources suggests that self-induction by lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation.

The elimination half-life and apparent clearance of lamotrigine following oral administration of lamotrigine to adult subjects with epilepsy and healthy volunteers is summarized in Table 14.

Half-life and apparent oral clearance vary depending on concomitant AEDs.

The apparent clearance of lamotrigine is affected by the coadministration of certain medications.

The net effects of drug interactions with lamotrigine are summarized in Tables and 15, followed by details of the drug interaction studies below.

Table 15.

Summary of Drug Interactions with Lamotrigine Drug Drug Plasma Concentration with Adjunctive Lamotrigine a Lamotrigine Plasma Concentration with Adjunctive Drugs b Oral contraceptives (e.g., ethinylestradiol/levonorgestrel) c Aripiprazole ↔ d Not assessed ↓ ↔ e Atazanavir/ritonavir ↔ f ↓ Bupropion Not assessed ↔ Carbamazepine ↔ ↓ Carbamazepine epoxide g? Felbamate Not assessed ↔ Gabapentin Not assessed ↔ Lacosamide Not assessed ↔ Levetiracetam ↔ ↔ Lithium Lopinavir/ritonavir ↔.

The drug-therapeutic class: other antiepileptic disorder, ATC code: N03AX09.

Mechanism of action

Pharmacologic studies suggest that lamotrigine preferentially blocks and voltage-dependently the activated sodium channels.

This inhibits the repetitive and sustained activation of the neurons and inhibits the release of glutamate (the neurotransmitter that plays a key role in the generation of epilepsy seizures).

These effects are likely to contribute to the anticonvulsive properties of lamotrigine.

Conversely, the mechanisms by which lamotrigine exerts its therapeutic action on the bipolar disorders were not established, although the sodium-voltage-dependent channel interactions are likely to be significant.

The adverse reactions for indications of epilepsy and bipolar disorders are based on available data from controlled clinical trials and other clinical experiments and are listed in the table below.

Frequency categories are derived from controlled clinical trials (as monotherapy for l-epilepsy (as identified by a cross) and bipolar disorders (as identified by the symbol §)).

When frequency categories differ between clinical trials of l-epilepsy and bipolar disorders, the highest frequency is mentioned.

However, when no controlled clinical trial data are available, frequency categories were obtained from other clinical trials.

The following convention was used for the classification of adverse reactions: very common, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level disorder, low-level.

Overdoses involving quantities up to 15 g have been reported for lamotrigine, some of which have been fatal.

Overdose has resulted in ataxia, nystagmus, seizures (including tonic-clonic seizures), decreased level of consciousness, coma, and intraventricular conduction delay. 10.2 Management of Overdose There are no specific antidotes for lamotrigine.

Following a suspected overdose, hospitalization of the patient is advised.

General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient.

If indicated, emesis should be induced; usual precautions should be taken to protect the airway.

It should be kept in mind that immediate-release lamotrigine is rapidly absorbed.

It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood.

In 6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session.

Center should be contacted for information on the management of overdosage of lamotrigine.

Lamotrigine is contraindicated in patients who have demonstrated hypersensitivity (e.g., rash, angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients.

Hypersensitivity to the drug or its ingredients. ( Boxed Warning, 4 ).

Dosing is based on concomitant medications, indication, and patient age.

To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded.

Lamotrigine Orally Disintegrating Tablets Patient Titration

Kits are available for the first 5 weeks of treatment.

Do not restart lamotrigine orally disintegrating tablets in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks.

Adjustments to maintenance doses will be necessary in most patients starting or stopping estrogen-containing products, including oral contraceptives.

Taper over a period of at least 2 weeks (approximately 50% dose reduction per week).

Adjunctive therapy—See Table for patients older than 12 years and Tables and 3 for patients aged to 12 years.

Conversion to monotherapy—See Table 4.

Bipolar disorde r

See Tables and 6. 2.1 General Dosing Considerations Rash There are suggestions that the risk of severe, potentially life-threatening rash may be increased by coadministration of lamotrigine with valproate, exceeding the recommended initial dose of lamotrigine, or exceeding the recommended dose escalation for lamotrigine.

However, cases have occurred in the absence of these factors.

Therefore, it is important that the dosing recommendations be followed closely.

The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine orally disintegrating tablets are exceeded and in patients with a history of allergy or rash to other AEDs.

Kits provide lamotrigine at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications, for patients with epilepsy (older than 12 years) and bipolar I disorder (adults) and are intended to help reduce the potential for rash.

The use of lamotrigine ODT Patient Titration Kits is recommended for appropriate patients who are starting or restarting lamotrigine orally disintegrating tablets.

It is recommended that lamotrigine orally disintegrating tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks.

If the decision is made to restart a patient who has discontinued lamotrigine orally disintegrating tablets, the need to restart with the initial dosing recommendations should be assessed.

The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations.

If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed.

The half-life of lamotrigine is affected by other concomitant medications.

Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine.

Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing products, including oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.

Valproate inhibits glucuronidation.

For dosing considerations for lamotrigine orally disintegrating tablets in patients on estrogen-containing products, including contraceptives, and atazanavir/ritonavir, see below and Table 13.

For dosing considerations for lamotrigine orally disintegrating tablets in patients on other drugs known to induce or inhibit glucuronidation, see Tables to 6, and 13.

Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder A therapeutic plasma concentration range has not been established for lamotrigine.

Dosing of lamotrigine orally disintegrating tablets should be based on therapeutic response.

Women Taking Estrogen-Containing Oral Contraceptives Starting

Lamotrigine orally disintegrating tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine, no adjustments to the recommended dose-escalation guidelines for lamotrigine orally disintegrating tablets should be necessary solely based on the use of estrogen-containing oral contraceptives.

Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine orally disintegrating tablets based on the concomitant AED or other concomitant medications.

See below for adjustments to maintenance doses of lamotrigine orally disintegrating tablets in women taking estrogen-containing oral contraceptives.

Adjustments to the Maintenance Dose of Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives: Taking Estrogen-Containing Oral Contraceptives: In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose of lamotrigine orally disintegrating tablets will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level.

Starting Estrogen-Containing Oral Contraceptives

In women taking a stable dose of lamotrigine orally disintegrating tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level.

The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than to 100 mg/day every week.

Dose increases should not exceed the recommended rate unless lamotrigine plasma levels or clinical response support larger increases.

Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation.

Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia.

If adverse reactions attributable to lamotrigine orally disintegrating tablets consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary.

Dose adjustments limited to the pill-free week are not recommended.

For women taking lamotrigine orally disintegrating tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, no adjustment to the dose of lamotrigine orally disintegrating tablets should be necessary.

Stopping Estrogen-Containing Oral Contraceptives

In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose of lamotrigine orally disintegrating tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level.

The decrease in dose of lamotrigine orally disintegrating tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise.

In women taking lamotrigine orally disintegrating tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, no adjustment to the dose of lamotrigine orally disintegrating tablets should be necessary.

Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy The effect of other hormonal contraceptive preparations or hormone replacement therapy (HRT) on the pharmacokinetics of lamotrigine has not been systematically evaluated.

Other estrogen-containing therapies, such as HRT, may interfere with lamotrigine.

Therefore, close clinical monitoring on effectiveness of lamotrigine orally disintegrating tablets with dose adjustment may be necessary.

It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels.

Therefore, adjustments to the dosage of lamotrigine orally disintegrating tablets in the presence of progestogens alone will likely not be needed.

Atazanavir/Ritonavir While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for lamotrigine orally disintegrating tablets should be necessary solely based on the use of atazanavir/ritonavir.

Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine orally disintegrating tablets based on concomitant AED or other concomitant medications.

In patients already taking maintenance doses of lamotrigine orally disintegrating tablets and not taking glucuronidation inducers, the dose of lamotrigine orally disintegrating tablets may need to be increased if atazanavir/ritonavir is added or decreased if atazanavir/ritonavir is discontinued.

Experience in patients with hepatic impairment is limited.

Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment, the following general recommendations can be made.

No dosage adjustment is needed in patients with mild liver impairment.

Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites.

Escalation and maintenance doses may be adjusted according to clinical response.

Initial doses of lamotrigine orally disintegrating tablets should be based on patients’ concomitant medications; reduced maintenance doses may be effective for patients with significant renal impairment.

Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine orally disintegrating tablets.

Because there is inadequate experience in this population, lamotrigine orally disintegrating tablets.

Tablets 25-mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “NT” on one side and “123” on the other side.

Packs of 30 (NDC 49884-484-11). 50-mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “EP” on one side and “191” on the other side.

Packs of 30 (NDC 49884-485-11). 100-mg, Peach colored, round shaped, flat-faced, bevel-edged tablets debossed with “E” on one side and “432” on the other side.

Packs of 30 (NDC 49884-486-11). 200-mg, White colored, round shaped, flat-faced, bevel-edged tablets debossed with “EP” on one side and “433” on the other side.

Packs of 30 (NDC 49884-487-11).

Store at 20° to 25°C (68° to 77°F); with excursions permitted to 15° to 30°C (59° to 86°F). .

Lamotrigine Orally Disintegrating Tablets Patient Titration Kit for Patients Taking Valproate (Blue ODT Kit) 25-mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “NT” on one side and “123” on the other side and 50 mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “EP” on one side and “191” on the other side, blister pack of 28 tablets (21/25-mg tablets and 7/50-mg tablets) (NDC 49884-880-99).

Lamotrigine Orally Disintegrating Tablets Patient Titration Kit for Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone and Not Taking Valproate (Green ODT Kit) 50-mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “EP” on one side and “191” on the other side and 100 mg, Peach colored, round shaped, flat-faced, bevel-edged tablets debossed with “E” on one side and “432” on the other side, blister pack of 56 tablets (42/50-mg tablets and 14/100-mg tablets) (NDC 49884-881-99).

Lamotrigine Orally Disintegrating Tablets Patient Titration Kit for Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate (Orange ODT Kit) 25-mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “NT” on one side and “123” on the other side, 50 mg, white colored, round shaped, flat-faced, bevel-edged tablets debossed with “EP” on one side and “191” on the other side, and 100 mg, Peach colored, round shaped, flat-faced, bevel-edged tablets debossed with “E” on one side and “432” on the other side, blister pack of 35 tablets (14/25-mg tablets, 14/50-mg tablets, and 7/100-mg tablets) (NDC 49884-882-99).

If the product is dispensed in a blister pack, the patient should be advised to examine the blister pack before use and not use if blisters are torn, broken, or missing.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including lamotrigine, during pregnancy.

Encourage women who are taking lamotrigine during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting.

Data from several prospective pregnancy exposure registries and epidemiological studies of pregnant women have not detected an increased frequency of major congenital malformations or a consistent pattern of malformations among women exposed to lamotrigine compared with the general population.

The majority of lamotrigine pregnancy exposure data are from women with epilepsy.

In animal studies, administration of lamotrigine during pregnancy resulted in developmental toxicity (increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities) at doses lower than those administered clinically.

Lamotrigine decreased fetal folate concentrations in rats, an effect known to be associated with adverse pregnancy outcomes in animals and humans.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Maternal and/or Embryofetal Risk Epilepsy, with or without exposure to antiepileptic drugs, has been associated with several adverse outcomes during pregnancy, including preeclampsia, preterm labor, antepartum and postpartum hemorrhage, placental abruption, poor fetal growth, prematurity, fetal death, and maternal mortality.

The risk of maternal or fetal injury may be greatest for patients with untreated or poorly controlled convulsive seizures.

Women with epilepsy who become pregnant should not abruptly discontinue antiepileptic drugs, including lamotrigine, due to the risk of status epilepticus or severe seizures, which may be life-threatening.

Dose Adjustments During Pregnancy and the Postpartum Period As with other AEDs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect.

There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-pregnancy concentrations after delivery.

Dose adjustments may be necessary to maintain clinical response.

Data from several international pregnancy registries have not shown an increased risk for malformations overall.

Registry reported major congenital malformations in 2.2% (95% CI: 1.6%, 3.1%) of 1,558 infants exposed to lamotrigine monotherapy in the first trimester of pregnancy.

Registry reported major congenital malformations among 2% of 1,562 infants exposed to lamotrigine monotherapy in the first trimester.

EURAP, a large international pregnancy registry focused outside of North America, reported major birth defects in 2.9% (95% CI: 2.3%, 3.7%) of 2,514 exposures to lamotrigine monotherapy in the first trimester.

The frequency of major congenital malformations was similar to estimates from the general population.

Registry observed an increased risk of isolated oral clefts: among 2,200 infants exposed to lamotrigine early in pregnancy, the risk of oral clefts was 3.2 per 1,000 (95% CI: 1.4, 6.3), a 3-fold increased risk versus unexposed healthy controls.

This finding has not been observed in other large international pregnancy registries.

Furthermore, a case-control study based on 21 congenital anomaly registries covering over 10 million births in Europe reported an adjusted odds ratio for isolated oral clefts with lamotrigine exposure of 1.45 (95% CI: 0.8, 2.63).

Several meta-analyses have not reported an increased risk of major congenital malformations following lamotrigine exposure in pregnancy compared with healthy and disease-matched controls.

No patterns of specific malformation types were observed.

The same meta-analyses evaluated the risk of additional maternal and infant outcomes including fetal death, stillbirth, preterm birth, small for gestational age, and neurodevelopmental delay.

Although there are no data suggesting an increased risk of these outcomes with lamotrigine monotherapy exposure, differences in outcome definition, ascertainment methods, and comparator groups limit the conclusions that can be drawn.

When lamotrigine was administered to pregnant mice, rats, or rabbits during the period of organogenesis (oral doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal body weight and increased incidences of fetal skeletal variations were seen in mice and rats at doses that were also maternally toxic.

The no-effect doses for embryofetal developmental toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and rabbits) or less than (rats) the human dose of 400 mg/day on a body surface area (mg/m 2 ) basis.

In a study in which pregnant rats were administered lamotrigine (oral doses of 0, 5, or 25 mg/kg) during the period of organogenesis and offspring were evaluated postnatally, neurobehavioral abnormalities were observed in exposed offspring at both doses.

The lowest effect dose for developmental neurotoxicity in rats is less than the human dose of 400 mg/day on a mg/m 2 basis.

Maternal toxicity was observed at the higher dose tested.

When pregnant rats were administered lamotrigine (oral doses of 0, 5, 10, or 20 mg/kg) during the latter part of gestation and throughout lactation, increased offspring mortality (including stillbirths) was seen at all doses.

The lowest effect dose for pre.

• and post-natal developmental toxicity in rats is less than the human dose of 400 mg/day on a mg/m 2 basis.

Maternal toxicity was observed at the 2 highest doses tested.

When administered to pregnant rats, lamotrigine decreased fetal folate concentrations at doses greater than or equal to 5 mg/kg/day, which is less than the human dose of 400 mg/day on a mg/m 2 basis.

Lamotrigine is indicated as adjunctive therapy in patients aged 2 years and older for partial-onset seizures, the generalized seizures of Lennox-Gastaut syndrome, and PGTC seizures.

Safety and efficacy of lamotrigine used as adjunctive treatment for partial-onset seizures were not demonstrated in a small, randomized, double-blind, placebo-controlled withdrawal trial in very young pediatric patients (aged to 24 months).

Lamotrigine was associated with an increased risk for infectious adverse reactions (lamotrigine 37%, placebo 5%), and respiratory adverse reactions (lamotrigine 26%, placebo 5%).

Infectious adverse reactions included bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and viral infection.

Respiratory adverse reactions included nasal congestion, cough, and apnea.

Safety and efficacy of lamotrigine for the maintenance treatment of bipolar disorder were not established in a double-blind, randomized withdrawal, placebo-controlled trial that evaluated 301 pediatric patients aged to 17 years with a current manic/hypomanic, depressed, or mixed mood episode as defined by DSM-IV-TR.

In the randomized phase of the trial, adverse reactions that occurred in at least 5% of patients taking lamotrigine (n = 87) and were twice as common compared with patients taking placebo (n = 86) were influenza (lamotrigine 8%, placebo 2%), oropharyngeal pain (lamotrigine 8%, placebo 2%), vomiting (lamotrigine 6%, placebo 2%), contact dermatitis (lamotrigine 5%, placebo 2%), upper abdominal pain (lamotrigine 5%, placebo 1%), and suicidal ideation (lamotrigine 5%, placebo 0%).

In a juvenile animal study in which lamotrigine (oral doses of 0, 5, 15, or 30 mg/kg) was administered to young rats from postnatal day to 62, decreased viability and growth were seen at the highest dose tested and long-term neurobehavioral abnormalities (decreased locomotor activity, increased reactivity, and learning deficits in animals tested as adults) were observed at the 2 highest doses.

The no-effect dose for adverse developmental effects in juvenile animals is less than the human dose of 400 mg/day on a mg/m 2 basis.

Clinical trials of lamotrigine for epilepsy and bipolar disorder did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients or exhibit a different safety profile than that of younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.