LAMOTRIG

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.

The epilepsy is a neurological disorder, and the lamotrgen affects this electrical activity, preventing seizures.

Diarrhoeal seizures of patients with bipolar disorders.

Arrhythmia, panic disorder, analgesic disorder, and triple-team neuropain.

The blood of the child is also treated in the form of a pulmonary disease, and the disease of the child is immediately stopped.

The disease of the child is considered to be an immediate result of the disease of the child.

It is important to make some adjustments to the doses of the medicine in case of any of these disorders.

The heart problems, such as heart blockage, or heart failure, may increase the risk of infection in the heartbeat.

The disease of the disease is accompanied by suicidal ideas, since the complications of the use of the drug increase the risk of the drug being repeated by the patient.

The disease of the disease is also observed in the form of a non-pulsemological disease, and the disease of the child is not affected.

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 ↔.

Lamotrigene is one of the anti-infusion drugs used to treat many epilepsy types, and is also used to control a range of other psychological disorders, given its wide-ranging effect on the brain and the central nervous system.

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The following serious adverse reactions are described in more detail in the Warnings and Precautions section of the labeling: Serious Skin Rashes Hemophagocytic Lymphohistiocytosis Multiorgan Hypersensitivity Reactions and Organ Failure Cardiac Rhythm and Conduction Abnormalities Blood Dyscrasias Suicidal Behavior and Ideation Aseptic Meningitis Withdrawal Seizures Status Epilepticus Epilepsy: Most common adverse reactions (incidence ≥10%) in adults were dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis, pharyngitis, and rash.

Additional adverse reactions (incidence ≥10%) reported in children included vomiting, infection, fever, accidental injury, diarrhea, abdominal pain, and tremor.

Bipolar disorder

Most common adverse reactions (incidence >5%) in adults were nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal pain, and xerostomia.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Epilepsy Most Common Adverse Reactions in All Clinical Trials: Adjunctive Therapy in Adults w ith Epilepsy: The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with lamotrigine during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash.

Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose related.

Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with lamotrigine.

Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate.

Approximately 11% of the 3,378 adult patients who received lamotrigine as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction.

The adverse reactions most commonly associated with discontinuation were rash (3%), dizziness (2.8%), and headache (2.5%).

In a dose-response trial in adults, the rate of discontinuation of lamotrigine for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related.

Monotherapy in Adults w ith Epilepsy

The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with the use of lamotrigine during the monotherapy phase of the controlled trial in adults not seen at an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and dysmenorrhea.

The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions associated with the use of lamotrigine during the conversion to monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia, nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.

Approximately 10% of the 420 adult patients who received lamotrigine as monotherapy in premarketing clinical trials discontinued treatment because of an adverse reaction.

The adverse reactions most commonly associated with discontinuation were rash (4.5%), headache (3.1%), and asthenia (2.4%).

Adjunctive Therapy in Pediatric Patients w ith Epilepsy: The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with the use of lamotrigine as adjunctive treatment in pediatric patients aged to 16 years and not seen at an equivalent rate in the control group were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia.

In 339 patients aged to 16 years with partial-onset seizures or generalized seizures of Lennox-Gastaut syndrome, 4.2% of patients on lamotrigine and 2.9% of patients on placebo discontinued due to adverse reactions.

The most commonly reported adverse reaction that led to discontinuation of lamotrigine was rash.

Approximately 11.5% of the 1,081 pediatric patients aged to 16 years who received lamotrigine as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction.

The adverse reactions most commonly associated with discontinuation were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%).

Controlled Adjunctive Clinical Trials in Adults w ith Epilepsy: Table 8 lists adverse reactions that occurred in adult patients with epilepsy treated with lamotrigine in placebo-controlled trials.

In these trials, either lamotrigine or placebo was added to the patient’s current AED therapy.

Table 8.

Adverse Reactions in

Pooled, Placebo-Controlled Adjunctive Trials in Adult Patients with Epilepsy a,b Body System/ Adverse Reaction Percent of Patients Receiving Adjunctive Lamotrigine (n = 711) Percent of Patients Receiving Adjunctive Placebo (n = 419) Body as a whole Headache 29 19 Flu syndrome 7 6 Fever 6 4 Abdominal pain 5 4 Neck pain 2 1 Reaction aggravated (seizure exacerbation) 2 1 Digestive Nausea 19 10 Vomiting 9 4 Diarrhea 6 4 Dyspepsia 5 2 Constipation 4 3 Anorexia 2 1 Musculoskeletal Arthralgia 2 0 Nervous Dizziness 38 13 Ataxia 22 6 Somnolence 14 7 Incoordination 6 2 Insomnia 6 2 Tremor 4 1 Depression 4 3 Anxiety 4 3 Convulsion 3 1 Irritability 3 2 Speech disorder 3 0 Concentration disturbance 2 1 Respiratory Rhinitis 14 9 Pharyngitis 10 9 Cough increased 8 6 Skin and appendages Rash 10 5 Pruritus 3 2 Special senses Diplopia 28 7 Blurred vision 16 5 Vision abnormality 3 1 Urogenital Female patients only (n = 365) (n = 207) Dysmenorrhea 7 6 Vaginitis 4 1 Amenorrhea 2 1 a Adverse reactions that occurred in at least 2% of patients treated with lamotrigine and at a greater incidence than placebo. b Patients in these adjunctive trials were receiving to 3 of the concomitant AEDs carbamazepine, phenytoin, phenobarbital, or primidone in addition to lamotrigine or placebo.

Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than 1 category.

In a randomized, parallel trial comparing placebo with and 500 mg/day of lamotrigine, some of the more common drug-related adverse reactions were dose related.

Table 9.

Dose-Related Adverse Reactions from a

Randomized, Placebo-Controlled, Adjunctive Trial in Adults with Epilepsy Adverse Reaction Percent of Patients Experiencing Adverse Reactions Placebo (n = 73) Lamotrigine 300 mg (n = 71) Lamotrigine 500 mg (n = 72) Ataxia 10 10 28 a,b Blurred vision 10 11 25 a,b Diplopia 8 24 a 49 a,b Dizziness 27 31 54 a,b Nausea 11 18 25 a Vomiting 4 11 18 a a Significantly greater than placebo group ( P <0.05). b Significantly greater than group receiving lamotrigine 300 mg ( P <0.05).

The overall adverse reaction profile for lamotrigine was similar between females and males and was independent of age.

Because the largest non-Caucasian racial subgroup was only 6% of patients exposed to lamotrigine in placebo-controlled trials, there are insufficient data to support a statement regarding the distribution of adverse reaction reports by race.

Generally, females receiving either lamotrigine as adjunctive therapy or placebo were more likely to report adverse reactions than males.

The only adverse reaction for which the reports on lamotrigine were >10% more frequent in females than males (without a corresponding difference by gender on placebo) was dizziness (difference = 16.5%).

There was little difference between females and males in the rates of discontinuation of lamotrigine for individual adverse reactions.

Controlled Monotherapy Trial in Adults w ith Partial-Onset Seizures: Table 10 lists adverse reactions that occurred in patients with epilepsy treated with monotherapy with lamotrigine in a double-blind trial following discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent frequency in the control group.

Table 10.

Adverse Reactions in a Controlled Monotherapy Trial in Adult Patients with Partial-Onset Seizures a,b Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine c as Monotherapy (n = 43) Percent of Patients Receiving Low-Dose Valproate d Monotherapy (n = 44) Body as a whole Pain 5 0 Infection 5 2 Chest pain 5 2 Digestive Vomiting 9 0 Dyspepsia 7 2 Nausea 7 2 Metabolic and nutritional Weight decrease 5 2 Nervous Coordination abnormality 7 0 Dizziness 7 0 Anxiety 5 0 Insomnia 5 2 Respiratory Rhinitis 7 2 Urogenital (female patients only) (n = 21) (n = 28) Dysmenorrhea 5 0 a Adverse reactions that occurred in at least 5% of patients treated with lamotrigine and at a greater incidence than valproate-treated patients. b Patients in this trial were converted to lamotrigine or valproate monotherapy from adjunctive therapy with carbamazepine or phenytoin.

Patients may have reported multiple adverse reactions during the trial; thus, patients may be included in more than 1 category. c Up to 500 mg/day. d 1,000 mg/day. Adverse reactions that occurred with a frequency of <5% and >2% of patients receiving lamotrigine and numerically more frequent than placebo were: Body as a Whole: Asthenia, fever.

Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.

Peripheral edema.

Amnesia, ataxia, depression, hypesthesia, libido increase, decreased reflexes, increased reflexes, nystagmus, irritability, suicidal ideation.

Epistaxis, bronchitis, dyspnea.

Contact dermatitis, dry skin, sweating.

Vision abnormality.

Incidence in Controlled Adjunctive Trials in Pediatric Patients w ith Epilepsy: Table 11 lists adverse reactions that occurred in 339 pediatric patients with partial-onset seizures or generalized seizures of Lennox-Gastaut syndrome who received lamotrigine up to 15 mg/kg/day or a maximum of 750 mg/day. Table 11.

Pooled, Placebo-Controlled, Adjunctive Trials in Pediatric Patients with Epilepsy a Body System/ Adverse Reaction Percent of Patients Receiving Lamotrigine (n = 168) Percent of Patients Receiving Placebo (n = 171) Body as a whole Infection 20 17 Fever 15 14 Accidental injury 14 12 Abdominal pain 10 5 Asthenia 8 4 Flu syndrome 7 6 Pain 5 4 Facial edema 2 1 Photosensitivity 2 0 Cardiovascular Hemorrhage 2 1 Digestive Vomiting 20 16 Diarrhea 11 9 Nausea 10 2 Constipation 4 2 Dyspepsia 2 1 Hemic and lymphatic Lymphadenopathy 2 1 Metabolic and nutritional Edema 2 0 Nervous system Somnolence 17 15 Dizziness 14 4 Ataxia 11 3 Tremor 10 1 Emotional lability 4 2 Gait abnormality 4 2 Thinking abnormality 3 2 Convulsions 2 1 Nervousness 2 1 Vertigo 2 1 Respiratory Pharyngitis 14 11 Bronchitis 7 5 Increased cough 7 6 Sinusitis 2 1 Bronchospasm 2 1 Skin Rash 14 1.

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.