Lamotrigine

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|Lamotrigine

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Lamotrigine

Dosage Form: Tablets, chewable, dispersible

BOXED WARNING

SERIOUS RASHES REQUIRING HOSPITALIZATION AND DISCONTINUATION OF TREATMENT HAVE BEEN REPORTED IN ASSOCIATION WITH THE USE OF Lamotrigine. THE INCIDENCE OF THESE RASHES, WHICH HAVE INCLUDED STEVENS-JOHNSON SYNDROME, IS APPROXIMATELY 0.8% (8 PER 1,000) IN PEDIATRIC PATIENTS (AGE < 16 YEARS) RECEIVING Lamotrigine AS ADJUNCTIVE THERAPY FOR EPILEPSY AND 0.3% (3 PER 1,000) IN ADULTS ON ADJUNCTIVE THERAPY FOR EPILEPSY. IN CLINICAL TRIALS OF BIPOLAR AND OTHER MOOD DISORDERS, THE RATE OF SERIOUS RASH WAS 0.08% (0.8 PER 1,000) IN ADULT PATIENTS RECEIVING Lamotrigine AS INITIAL MONOTHERAPY AND 0.13% (1.3 PER 1,000) IN ADULT PATIENTS RECEIVING Lamotrigine AS ADJUNCTIVE THERAPY. IN A PROSPECTIVELY FOLLOWED COHORT OF 1,983 PEDIATRIC PATIENTS WITH EPILEPSY TAKING ADJUNCTIVE Lamotrigine, THERE WAS 1 RASH-RELATED DEATH. IN WORLDWIDE POSTMARKETING EXPERIENCE, RARE CASES OF TOXIC EPIDERMAL NECROLYSIS AND/OR RASH-RELATED DEATH HAVE BEEN REPORTED IN ADULT AND PEDIATRIC PATIENTS, BUT THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE ESTIMATE OF THE RATE.

BECAUSE THE RATE OF SERIOUS RASH IS GREATER IN PEDIATRIC PATIENTS THAN IN ADULTS, IT BEARS EMPHASIS THAT Lamotrigine IS APPROVED ONLY FOR USE IN PEDIATRIC PATIENTS BELOW THE AGE OF 16 YEARS WHO HAVE SEIZURES ASSOCIATED WITH THE LENNOX-GASTAUT SYNDROME OR IN PATIENTS WITH PARTIAL SEIZURES (SEE INDICATIONS AND USAGE).

OTHER THAN AGE, THERE ARE AS YET NO FACTORS IDENTIFIED THAT ARE KNOWN TO PREDICT THE RISK OF OCCURRENCE OR THE SEVERITY OF RASH ASSOCIATED WITH Lamotrigine. THERE ARE SUGGESTIONS, YET TO BE PROVEN, THAT THE RISK OF RASH MAY ALSO BE INCREASED BY (1) COADMINISTRATION OF Lamotrigine WITH VALPROATE (INCLUDES VALPROIC ACID AND DIVALPROEX SODIUM), (2) EXCEEDING THE RECOMMENDED INITIAL DOSE OF Lamotrigine, OR (3) EXCEEDING THE RECOMMENDED DOSE ESCALATION FOR Lamotrigine. HOWEVER, CASES HAVE BEEN REPORTED IN THE ABSENCE OF THESE FACTORS.

NEARLY ALL CASES OF LIFE-THREATENING RASHES ASSOCIATED WITH Lamotrigine HAVE OCCURRED WITHIN 2 TO 8 WEEKS OF TREATMENT INITIATION. HOWEVER, ISOLATED CASES HAVE BEEN REPORTED AFTER PROLONGED TREATMENT (e.g., 6 MONTHS). ACCORDINGLY, DURATION OF THERAPY CANNOT BE RELIED UPON AS A MEANS TO PREDICT THE POTENTIAL RISK HERALDED BY THE FIRST APPEARANCE OF A RASH.

ALTHOUGH BENIGN RASHES ALSO OCCUR WITH Lamotrigine, IT IS NOT POSSIBLE TO PREDICT RELIABLY WHICH RASHES WILL PROVE TO BE SERIOUS OR LIFE THREATENING. ACCORDINGLY, Lamotrigine SHOULD ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR PERMANENTLY DISABLING OR DISFIGURING.

Lamotrigine Description

Lamotrigine, an antiepileptic drug (AED) of the phenyltriazine class, is chemically unrelated to existing antiepileptic drugs. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine. Lamotrigine is a white to pale cream-colored powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M hydrochloride (4.1 mg/mL at 25°C). The structural formula is:

C9H7N5Cl2 M.W. 256.09

Lamotrigine tablets (chewable, dispersible) are supplied for oral administration. The tablets contain 5 mg (white to off-white) or 25 mg (white to off-white) of Lamotrigine and the following inactive ingredients: artificial cherry flavor, colloidal silicon dioxide, croscarmellose sodium, mannitol, microcrystalline cellulose, pregelatinized starch, saccharin sodium, sodium starch glycolate, and sodium stearyl fumarate.

Lamotrigine - Clinical Pharmacology

Mechanism of Action

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. 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).

The mechanisms by which Lamotrigine exerts its therapeutic action in Bipolar Disorder have not been established.

Pharmacological Properties

Although the relevance for human use is unknown, the following data characterize the performance of Lamotrigine in receptor binding assays. Lamotrigine had a weak inhibitory effect on the serotonin 5-HT3 receptor (IC50 = 18 μM). It does not exhibit high affinity binding (IC50 > 100 μM) to the following neurotransmitter receptors: adenosine A1 and A2; adrenergic α1, α2, and β; dopamine D1 and D2; γ-aminobutyric acid (GABA) A and B; histamine H1; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT2. Studies have failed to detect an effect of Lamotrigine on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid receptors (IC50 = 145 μM). Lamotrigine did not inhibit the uptake of norepinephrine, dopamine, or serotonin (IC50 > 200 μM) when tested in rat synaptosomes and/or human platelets in vitro.

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 IC50 for Lamotrigine effects on NMDA-induced currents (in the presence of 3 μM of glycine) in cultured hippocampal neurons exceeded 100 μM.

Folate Metabolism

In vitro, Lamotrigine was shown to be an inhibitor of 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 (see PRECAUTIONS, Pregnancy). 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.

Accumulation in Kidneys

Lamotrigine was found to accumulate 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.

Melanin Binding

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.

Cardiovascular

In dogs, Lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongations of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular effects 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 (see Drug Disposition). 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).

Pharmacokinetics and Drug Metabolism

The pharmacokinetics of Lamotrigine have been studied in patients with epilepsy, healthy young and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine pharmacokinetic parameters for adult and pediatric patients and healthy normal volunteers are summarized in Tables 1 and 2.

Table 1: Mean*1 Pharmacokinetic Parameters in Healthy Volunteers and Adult Patients With Epilepsy
Adult Study Population Number of Subjects Tmax: Time of Maximum Plasma Concentration (h) t½: 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 12.0) 32.8 (14.0 to 103.0) 0.44 (0.12 to 1.10)
Multiple-dose Lamotrigine 36 1.7 (0.5 to 4.0) 25.4 (11.6 to 61.6) 0.58 (0.24 to 1.15)
Healthy volunteers taking valproate:
Single-dose Lamotrigine 6 1.8 (1.0 to 4.0) 48.3 (31.5 to 88.6) 0.30 (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)
Patients 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 0.40)
Patients with epilepsy taking enzyme-inducing antiepileptic drugs (EIAEDs)2 plus valproate:
Single-dose Lamotrigine 25 3.8 (1.0 to 10.0) 27.2 (11.2 to 51.6) 0.53 (0.27 to 1.04)
Patients with epilepsy taking EIAEDs:
Single-dose Lamotrigine 24 2.3 (0.5 to 5.0) 14.4 (6.4 to 30.4) 1.10 (0.51 to 2.22)
Multiple-dose Lamotrigine 17 2.0 (0.75 to 5.93) 12.6 (7.5 to 23.1) 1.21 (0.66 to 1.82)
1
* 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 Tmax. The overall mean values were calculated from individual study means that were weighted based on the number of volunteers/patients in each study. The numbers in parentheses below each parameter mean represent the range of individual volunteer/patient values across studies.
2
† Examples of EIAEDs are carbamazepine, phenobarbital, phenytoin, and primidone.

Absorption

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 (chewable, dispersible) were found to be equivalent, whether they were administered as dispersed in water, chewed and swallowed, or swallowed as whole, to the Lamotrigine compressed tablets in terms of rate and extent of absorption.

Distribution

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.

Protein Binding

Data from in vitro studies indicate that Lamotrigine is approximately 55% bound to human plasma proteins at plasma Lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 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.

Drug Disposition

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 14C-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-glucurodine (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).

Drug Interactions

The apparent clearance of Lamotrigine is affected by the coadministration of AEDs. Lamotrigine is eliminated more rapidly in patients who have been taking hepatic EIAEDs, including carbamazepine, phenytoin, phenobarbital, and primidone. Most clinical experience is derived from this population.

Valproate decreases the apparent clearance of Lamotrigine (i.e., more than doubles the elimination half-life of Lamotrigine), whether given with or without EIAEDs. Accordingly, if Lamotrigine is to be administered to a patient receiving valproate, Lamotrigine must be given at a reduced dosage, no more than half the dose used in patients not receiving valproate (see DOSAGE AND ADMINISTRATION and PRECAUTIONS, Drug Interactions).

In vitro inhibition experiments indicated that the formation of the primary metabolite of Lamotrigine, the 2-N-glucuronide, was not significantly affected by co-incubation with clozapine, fluoxetine, phenelzine, risperidone, sertraline, or trazodone, and was minimally affected by co-incubation with amitriptyline, bupropion, clonazepam, haloperidol, or lorazepam. In addition, bufuralol metabolism data from human liver microsomes suggested that Lamotrigine does not inhibit the metabolism of drugs eliminated predominantly by CYP2D6.

Lamotrigine has no effects on the pharmacokinetics of lithium (see PRECAUTIONS, Drug Interactions).

The pharmacokinetics of Lamotrigine were not changed by coadministration of bupropion (see PRECAUTIONS, Drug Interactions).

Enzyme Induction

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 t½and a 37% increase in Cl/F at steady state compared to 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 EIAEDs.

Dose Proportionality

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 50 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 50 to 350 mg twice daily.

Elimination

(See Table 1.)

Special Populations

Patients With Renal Insufficiency

Twelve volunteers with chronic renal failure (mean creatinine clearance = 13 mL/min; range = 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100 mg dose of Lamotrigine. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared to 26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the amount of Lamotrigine present in the body was eliminated by hemodialysis during a 4 hour session.

Hepatic Disease

The pharmacokinetics of Lamotrigine in patients with impaired liver function have not been studied.

Age

Pediatric patients

The pharmacokinetics of Lamotrigine following a single 2 mg/kg dose were evaluated in 2 studies of pediatric patients (n = 29 for patients aged 10 months to 5.9 years and n = 26 for patients aged 5 to 11 years). Forty-three patients received concomitant therapy with other AEDs and 12 patients received Lamotrigine as monotherapy. Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 2.

Population pharmacokinetic analyses involving patients aged 2 to 18 years demonstrated that Lamotrigine clearance was influenced predominantly by total body weight and concurrent AED therapy. The oral clearance of Lamotrigine was higher, on a body weight basis, in pediatric patients than in adults. Weight-normalized Lamotrigine clearance was higher in those subjects weighing less than 30 kg, compared with those weighing greater than 30 kg. Accordingly, patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses, based on clinical response, as compared with subjects weighing more than 30 kg being administered the same AEDs (see DOSAGE AND ADMINISTRATION). These analyses also revealed that, after accounting for body weight, Lamotrigine clearance was not significantly influenced by age. Thus, the same weight-adjusted doses should be administered to children irrespective of differences in age. Concomitant AEDs which influence Lamotrigine clearance in adults were found to have similar effects in children.

Table 2: Mean Pharmacokinetic Parameters in Pediatric Patients With Epilepsy
Pediatric Study Population Number of Subjects Tmax (h) t½ (h) Cl/F (mL/min/kg)
Ages 10 months to 5.3 years
Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) 10 3.0 (1.0 to 5.9) 7.7 (5.7 to 11.4) 3.62 (2.44 to 5.28)
Patients taking antiepileptic drugs (AEDs) with no known effect on drug-metabolizing enzymes 7 5.2 (2.9 to 6.1) 19.0 (12.9 to 27.1) 1.2 (0.75 to 2.42)
Patients taking valproate only 8 2.9 (1.0 to 6.0) 44.9 (29.5 to 52.5) 0.47 (0.23 to 0.77)
Ages 5 to 11 years
Patients taking EIAEDs 7 1.6 (1.0 to 3.0) 7.0 (3.8 to 9.8) 2.54 (1.35 to 5.58)
Patients taking EIAEDs plus valproate 8 3.3 (1.0 to 6.4) 19.1 (7.0 to 31.2) 0.89 (0.39 to 1.93)
Patients taking valproate only3 3 4.5 (3.0 to 6.0) 65.8 (50.7 to 73.7) 0.24 (0.21 to 0.26)
Ages 13 to 18 years    
Patients taking EIAEDs 11 4 4 1.3
Patients taking EIAEDs plus valproate 8 4 4 0.5
Patients taking valproate only 4 4 4 0.3
3
Two subjects were included in the calculation for mean Tmax.
4
Parameter not estimated.

Elderly

The pharmacokinetics of Lamotrigine following a single 150 mg dose of Lamotrigine were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance = 61 mL/min, range = 33 to 108 mL/min). The mean half-life of Lamotrigine in these subjects was 31.2 hours (range, 24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range, 0.26 to 0.48 mL/min/kg).

Gender

The clearance of Lamotrigine is not affected by gender. However, during dose escalation of Lamotrigine in one clinical trial in patients with epilepsy on a stable dose of valproate (n = 77), mean trough Lamotrigine concentrations, unadjusted for weight, were 24 to 45% higher (0.3 to 1.7 mcg/mL) in females than in males.

Race

The apparent oral clearance of Lamotrigine was 25% lower in non-Caucasians than Caucasians.

Clinical Studies

Epilepsy

The results of controlled clinical trials established the efficacy of Lamotrigine as monotherapy in adults with partial onset seizures already receiving treatment with a single enzyme-inducing antiepileptic drug (EIAED), as adjunctive therapy in adults and pediatric patients age 2 to 16 with partial seizures, and as adjunctive therapy in the generalized seizures of Lennox-Gastaut syndrome in pediatric and adult patients.

Monotherapy With Lamotrigine in Adults With Partial Seizures Already Receiving Treatment With a Single EIAED

The effectiveness of monotherapy with Lamotrigine was established in a multicenter, double-blind clinical trial enrolling 156 adult outpatients with partial seizures. The patients experienced at least 4 simple partial, complex partial, and/or secondarily generalized seizures during each of 2 consecutive 4 week periods while receiving carbamazepine or phenytoin monotherapy during baseline. Lamotrigine (target dose of 500 mg/day) or valproate (1,000 mg/day) was added to either carbamazepine or phenytoin monotherapy over a 4 week period. Patients were then converted to monotherapy with Lamotrigine or valproate during the next 4 weeks, then continued on monotherapy for an additional 12 week period.

Study endpoints were completion of all weeks of study treatment or meeting an escape criterion. Criteria for escape relative to baseline were: (1) doubling of average monthly seizure count, (2) doubling of highest consecutive 2 day seizure frequency, (3) emergence of a new seizure type (defined as a seizure that did not occur during the 8 week baseline) that is more severe than seizure types that occur during study treatment, or (4) clinically significant prolongation of generalized-tonic-clonic (GTC) seizures. The primary efficacy variable was the proportion of patients in each treatment group who met escape criteria.

The percentage of patients who met escape criteria was 42% (32/76) in the Lamotrigine group and 69% (55/80) in the valproate group. The difference in the percentage of patients meeting escape criteria was statistically significant (p= 0.0012) in favor of Lamotrigine. No differences in efficacy based on age, sex, or race were detected.

Patients in the control group were intentionally treated with a relatively low dose of valproate; as such, the sole objective of this study was to demonstrate the effectiveness and safety of monotherapy with Lamotrigine, and cannot be interpreted to imply the superiority of Lamotrigine to an adequate dose of valproate.

Adjunctive Therapy With Lamotrigine in Adults With Partial Seizures

The effectiveness of Lamotrigine as adjunctive therapy (added to other AEDs) was established in 3 multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial seizures. The patients had a history of at least 4 partial seizures per month in spite of receiving one or more AEDs at therapeutic concentrations and, in 2 of the studies, were observed on their established AED regimen during baselines that varied between 8 to 12 weeks. In the third, patients were not observed in a prospective baseline. In patients continuing to have at least 4 seizures per month during the baseline, Lamotrigine or placebo was then added to the existing therapy. In all 3 studies, change from baseline in seizure frequency was the primary measure of effectiveness. The results given below are for all partial seizures in the intent-to-treat population (all patients who received at least one dose of treatment) in each study, unless otherwise indicated. The median seizure frequency at baseline was 3 per week while the mean at baseline was 6.6 per week for all patients enrolled in efficacy studies.

One study (n = 216) was a double-blind, placebo-controlled, parallel trial consisting of a 24 week treatment period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. Patients were randomized to receive placebo, a target dose of 300 mg/day of Lamotrigine, or a target dose of 500 mg/day of Lamotrigine. The median reductions in the frequency of all partial seizures relative to baseline were 8% in patients receiving placebo, 20% in patients receiving 300 mg/day of Lamotrigine, and 36% in patients receiving 500 mg/day of Lamotrigine. The seizure frequency reduction was statistically significant in the 500 mg/day group compared to the placebo group, but not in the 300 mg/day group.

A second study (n = 98) was a double-blind, placebo-controlled, randomized, crossover trial consisting of two 14 week treatment periods (the last 2 weeks of which consisted of dose tapering) separated by a 4 week washout period. Patients could not be on more than 2 other anticonvulsants and valproate was not allowed. The target dose of Lamotrigine was 400 mg/day. When the first 12 weeks of the treatment periods were analyzed, the median change in seizure frequency was a 25% reduction on Lamotrigine compared to placebo (p < 0.001).

The third study (n = 41) was a double-blind, placebo-controlled, crossover trial consisting of two 12 week treatment periods separated by a 4 week washout period. Patients could not be on more than 2 other anticonvulsants. Thirteen patients were on concomitant valproate; these patients received 150 mg/day of Lamotrigine. The 28 other patients had a target dose of 300 mg/day of Lamotrigine. The median change in seizure frequency was a 26% reduction on Lamotrigine compared to placebo (p < 0.01).

No differences in efficacy based on age, sex, or race, as measured by change in seizure frequency, were detected.

Adjunctive Therapy With Lamotrigine in Pediatric Patients With Partial Seizures

The effectiveness of Lamotrigine as adjunctive therapy in pediatric patients with partial seizures was established in a multicenter, double-blind, placebo-controlled trial in 199 patients aged 2 to 16 years (n = 98 on Lamotrigine, n = 101 on placebo). Following an 8 week baseline phase, patients were randomized to 18 weeks of treatment with Lamotrigine or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg per day for patients taking valproate (maximum dose, 250 mg/day) and 15 mg/kg per day for patients not taking valproate (maximum dose, 750 mg per day). The primary efficacy endpoint was percentage change from baseline in all partial seizures. For the intent-to-treat population, the median reduction of all partial seizures was 36% in patients treated with Lamotrigine and 7% on placebo, a difference that was statistically significant (p < 0.01).

Adjunctive Therapy With Lamotrigine in Pediatric and Adult Patients With Lennox-Gastaut Syndrome

The effectiveness of Lamotrigine as adjunctive therapy in patients with Lennox-Gastaut syndrome was established in a multicenter, double-blind, placebo-controlled trial in 169 patients aged 3 to 25 years (n = 79 on Lamotrigine, n = 90 on placebo). Following a 4 week single-blind, placebo phase, patients were randomized to 16 weeks of treatment with Lamotrigine or placebo added to their current AED regimen of up to 3 drugs. Patients were dosed on a fixed-dose regimen based on body weight and valproate use. Target doses were designed to approximate 5 mg/kg per day for patients taking valproate (maximum dose, 200 mg/day) and 15 mg/kg per day for patients not taking valproate (maximum dose, 400 mg/day). The primary efficacy endpoint was percentage change from baseline in major motor seizures (atonic, tonic, major myoclonic, and tonic-clonic seizures). For the intent-to-treat population, the median reduction of major motor seizures was 32% in patients treated with Lamotrigine and 9% on placebo, a difference that was statistically significant (p < 0.05). Drop attacks were significantly reduced by Lamotrigine (34%) compared to placebo (9%), as were tonic-clonic seizures (36% reduction versus 10% increase for Lamotrigine and placebo, respectively).

Bipolar Disorder

The effectiveness of Lamotrigine in the maintenance treatment of Bipolar I Disorder was established in 2 multicenter, double-blind, placebo-controlled studies in adult patients who met DSM-IV criteria for Bipolar I Disorder. Study 1 enrolled patients with a current or recent (within 60 days) depressive episode as defined by DSM-IV and Study 2 included patients with a current or recent (within 60 days) episode of mania or hypomania as defined by DSM-IV. Both studies included a cohort of patients (30% of 404 patients in Study 1 and 28% of 171 patients in Study 2) with rapid cycling Bipolar Disorder (4 to 6 episodes per year).

In both studies, patients were titrated to a target dose of 200 mg of Lamotrigine, as add-on therapy or as monotherapy, with gradual withdrawal of any psychotropic medications during an 8 to 16 week open-label period. Overall 81% of 1,305 patients participating in the open-label period were receiving 1 or more other psychotropic medications, including benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics (including olanzapine), valproate, or lithium, during titration of Lamotrigine. Patients with a CGI-severity score of 3 or less maintained for at least 4 continuous weeks, including at least the final week on monotherapy with Lamotrigine, were randomized to a placebo-controlled, double-blind treatment period for up to 18 months. The primary endpoint was TIME (time to intervention for a mood episode or one that was emerging, time to discontinuation for either an adverse event that was judged to be related to Bipolar Disorder, or for lack of efficacy). The mood episode could be depression, mania, hypomania, or a mixed episode.

In Study 1, patients received double-blind monotherapy with Lamotrigine, 50 mg/day (n = 50), Lamotrigine 200 mg/day (n = 124), Lamotrigine 400 mg/day (n = 47), or placebo (n = 121). Lamotrigine (200 and 400 mg/day treatment groups combined) was superior to placebo in delaying the time to occurrence of a mood episode. Separate analyses of the 200 and 400 mg/day dose groups revealed no added benefit from the higher dose.

In Study 2, patients received double-blind monotherapy with Lamotrigine (100 to 400 mg/day, n = 59), or placebo (n = 70). Lamotrigine was superior to placebo in delaying the time to occurrence of a mood episode. The mean Lamotrigine dose was about 211 mg/day.

Although these studies were not designed to separately evaluate time to the occurrence of depression or mania, a combined analysis for the two studies revealed a statistically significant benefit for Lamotrigine over placebo in delaying the time to occurrence of both depression and mania, although the finding was more robust for depression.

Indications and Usage for Lamotrigine

Epilepsy

Adjunctive Use

Lamotrigine tablets (chewable, dispersible) are indicated as adjunctive therapy for partial seizures in adults and pediatric patients (≥ 2 years of age).

Lamotrigine tablets (chewable, dispersible) are also indicated as adjunctive therapy for the generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients (≥ 2 years of age).

Monotherapy Use

Lamotrigine tablets (chewable, dispersible) are indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with a single EIAED or valproate.

Safety and effectiveness of Lamotrigine have not been established (1) as initial monotherapy, (2) for conversion to monotherapy from non-enzyme-inducing AEDs except valproate, or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs (see DOSAGE AND ADMINISTRATION).

Safety and effectiveness in patients below the age of 16 other than those with partial seizures and the generalized seizures of Lennox-Gastaut syndrome have not been established (see BOX WARNING).

Bipolar Disorder

Lamotrigine tablets (chewable, dispersible) are indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. The effectiveness of Lamotrigine in the acute treatment of mood episodes has not been established.

The effectiveness of Lamotrigine as maintenance treatment was established in 2 placebo-controlled trials of 18 months’ duration in patients with Bipolar I Disorder as defined by DSM-IV (see CLINICAL STUDIES, Bipolar Disorder). The physician who elects to use Lamotrigine tablets (chewable, dispersible) for periods extending beyond 18 months should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Contraindications

Lamotrigine tablets (chewable, dispersible) are contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

Warnings

SEE BOX WARNING REGARDING THE RISK OF SERIOUS RASHES REQUIRING HOSPITALIZATION AND DISCONTINUATION OF Lamotrigine.

ALTHOUGH BENIGN RASHES ALSO OCCUR WITH Lamotrigine, IT IS NOT POSSIBLE TO PREDICT RELIABLY WHICH RASHES WILL PROVE TO BE SERIOUS OR LIFE THREATENING. ACCORDINGLY, Lamotrigine SHOULD ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR PERMANENTLY DISABLING OR DISFIGURING.

Serious Rash

Pediatric Population

The incidence of serious rash associated with hospitalization and discontinuation of Lamotrigine in a prospectively followed cohort of pediatric patients with epilepsy receiving adjunctive therapy was approximately 0.8% (16 of 1,983). When 14 of these cases were reviewed by 3 expert dermatologists, there was considerable disagreement as to their proper classification. To illustrate, one dermatologist considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death in this 1,983 patient cohort. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in U.S. and foreign postmarketing experience. It bears emphasis, accordingly, that Lamotrigine is only approved for use in those patients below the age of 16 who have partial seizures or generalized seizures associated with the Lennox-Gastaut syndrome (see INDICATIONS AND USAGE).

There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared to 0.6% (6 of 952) patients not taking valproate.

Adult Population

Serious rash associated with hospitalization and discontinuation of Lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received Lamotrigine in premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received Lamotrigine as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received Lamotrigine as adjunctive therapy. No fatalities occurred among these individuals. However, in worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate.

Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and a rash associated with a variable number of the following systemic manifestations: fever, lymphadenopathy, facial swelling, hematologic, and hepatologic abnormalities.

There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered Lamotrigine with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered Lamotrigine in the absence of valproate were hospitalized.

Other examples of serious and potentially life-threatening rash that did not lead to hospitalization also occurred in premarketing development. Among these, 1 case was reported to be Stevens-Johnson-like.

Hypersensitivity Reactions

Hypersensitivity reactions, some fatal or life threatening, have also occurred. Some of these reactions have included clinical features of multiorgan failure/dysfunction, including hepatic abnormalities and evidence of disseminated intravascular coagulation. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patients should be evaluated immediately. Lamotrigine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Prior to initiation of treatment with Lamotrigine, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately.

Acute Multiorgan Failure

Multiorgan failure, which in some cases has been fatal or irreversible, has been observed in patients receiving Lamotrigine. Fatalities associated with multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received Lamotrigine in clinical trials. No such fatalities have been reported in bipolar patients in clinical trials. Rare fatalities from multiorgan failure have also been reported in compassionate plea and postmarketing use. The majority of these deaths occurred in association with other serious medical events, including status epilepticus and overwhelming sepsis, and hantavirus making it difficult to identify the initial cause.

Additionally, 3 patients (a 45-year-old woman, a 3.5-year-old boy, and an 11-year-old girl) developed multiorgan dysfunction and disseminated intravascular coagulation 9 to 14 days after Lamotrigine was added to their AED regimens. Rash and elevated transaminases were also present in all patients and rhabdomyolysis was noted in 2 patients. Both pediatric patients were receiving concomitant therapy with valproate, while the adult patient was being treated with carbamazepine and clonazepam. All patients subsequently recovered with supportive care after treatment with Lamotrigine was discontinued.

Blood Dyscrasias

There have been reports of blood dyscrasias that may or may not be associated with the hypersensitivity syndrome. These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia and, rarely, aplastic anemia and pure red cell aplasia.

Withdrawal Seizures

As with other AEDs, Lamotrigine should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of Lamotrigine. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients. Unless safety concerns require a more rapid withdrawal, the dose of Lamotrigine should be tapered over a period of at least 2 weeks (see DOSAGE AND ADMINISTRATION).

Precautions

Dermatological Events (see BOX WARNING, WARNINGS)

Serious rashes associated with hospitalization and discontinuation of Lamotrigine have been reported. Rare deaths have been reported, but their numbers are too few to permit a precise estimate of the rate. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of Lamotrigine with valproate, (2) exceeding the recommended initial dose of Lamotrigine, or (3) exceeding the recommended dose escalation for Lamotrigine. However, cases have been reported in the absence of these factors.

In epilepsy clinical trials, approximately 10% of all patients exposed to Lamotrigine developed a rash. In the Bipolar Disorder clinical trials, 14% of patients exposed to Lamotrigine developed a rash. Rashes associated with Lamotrigine do not appear to have unique identifying features. Typically, rash occurs in the first 2 to 8 weeks following treatment initiation. However, isolated cases have been reported after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as a means to predict the potential risk heralded by the first appearance of a rash.

Although most rashes resolved even with continuation of treatment with Lamotrigine, it is not possible to predict reliably which rashes will prove to be serious or life threatening. ACCORDINGLY, Lamotrigine SHOULD ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR PERMANENTLY DISABLING OR DISFIGURING.

Use in Patients With Epilepsy

Sudden Unexplained Death in Epilepsy (SUDEP)

During the premarketing development of Lamotrigine, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).

Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving Lamotrigine (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for Lamotrigine, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon to the cohort receiving Lamotrigine and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving Lamotrigine and those receiving another antiepileptic drug that underwent clinical testing in a similar population at about the same time. Importantly, that drug is chemically unrelated to Lamotrigine. This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect.

Status Epilepticus

Valid estimates of the incidence of treatment emergent status epilepticus among patients treated with Lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries, etc.) were made.

Use in Patients With Bipolar Disorder

Acute Treatment of Mood Episodes

Safety and effectiveness of Lamotrigine in the acute treatment of mood episodes has not been established.

Children and Adolescents (Less Than 18 Years of Age)

Treatment with antidepressants is associated with an increased risk of suicidal thinking and behavior in children and adolescents with major depressive disorder and other psychiatric disorders. It is not known whether Lamotrigine is associated with a similar risk in this population (see PRECAUTIONS, Clinical Worsening and Suicide Risk Associated with Bipolar Disorder).

Clinical Worsening and Suicide Risk Associated with Bipolar Disorder

Patients with bipolar disorder may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviors (suicidality) whether or not they are taking medications for bipolar disorder. Patients should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes.

In addition, patients with a history of suicidal behavior or thoughts, those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, and young adults, are at an increased risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.

Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms) and /or the emergence of suicidal ideation/behavior or thoughts of harming themselves and to seek medical advice immediately if these symptoms present.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behavior especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Prescriptions for Lamotrigine tablets (chewable, dispersible) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Overdoses have been reported for Lamotrigine, some of which have been fatal (see OVERDOSAGE).

Addition of Lamotrigine to a Multidrug Regimen That Includes Valproate (Dosage Reduction)

Because valproate reduces the clearance of Lamotrigine, the dosage of Lamotrigine in the presence of valproate is less than half of that required in its absence (see DOSAGE AND ADMINISTRATION).

Use in Patients With Concomitant Illness

Clinical experience with Lamotrigine in patients with concomitant illness is limited. Caution is advised when using Lamotrigine in patients with diseases or conditions that could affect metabolism or elimination of the drug, such as renal, hepatic, or cardiac functional impairment.

Hepatic metabolism to the glucuronide followed by renal excretion is the principal route of elimination of Lamotrigine (see CLINICAL PHARMACOLOGY).

A study in individuals with severe chronic renal failure (mean creatinine clearance = 13 mL/min) not receiving other AEDs indicated that the elimination half-life of unchanged Lamotrigine is prolonged relative to individuals with normal renal function. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with Lamotrigine, it should be used with caution in these patients, generally using a reduced maintenance dose for patients with significant impairment.

Because there is no experience with the use of Lamotrigine in patients with impaired liver function, the use in such patients may be associated with as yet unrecognized risks.

Binding in the Eye and Other Melanin-Containing Tissues

Because Lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that Lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in one controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of Lamotrigine’s binding to melanin is unknown.

Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.

Information for Patients

Prior to initiation of treatment with Lamotrigine, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately. In addition, the patient should notify his or her physician if worsening of seizure control occurs.

Patients should be advised that Lamotrigine may cause dizziness, somnolence, and other symptoms and signs of central nervous system (CNS) depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on Lamotrigine to gauge whether or not it adversely affects their mental and/or motor performance.

Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they intend to breastfeed or are breastfeeding an infant.

Patients should be informed of the availability of a patient information leaflet, and they should be instructed to read the leaflet prior to taking Lamotrigine. See PATIENT INFORMATION at the end of this labeling for the text of the leaflet provided for patients.

Laboratory Tests

The value of monitoring plasma concentrations of Lamotrigine has not been established. Because of the possible pharmacokinetic interactions between Lamotrigine and other AEDs being taken concomitantly (see Table 3), monitoring of the plasma levels of Lamotrigine and concomitant AEDs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of Lamotrigine and other anti-seizure drugs and whether or not dosage adjustments are necessary.

Drug Interactions

Effects of Lamotrigine on the Pharmacokinetics of Other Drugs

(See Table 3.)

Lamotrigine added to carbamazepine

Lamotrigine has no appreciable effect on steady-state carbamazepine plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving carbamazepine with Lamotrigine than in patients receiving other EIAEDs with Lamotrigine (see ADVERSE REACTIONS). The mechanism of this interaction is unclear. The effect of Lamotrigine on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, Lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels were seen to increase.

Lamotrigine added to valproate

When Lamotrigine was administered to 18 healthy volunteers receiving valproate in a pharmacokinetic study, the trough steady-state valproate concentrations in plasma decreased by an average of 25% over a 3 week period, and then stabilized. However, adding Lamotrigine to the existing therapy did not cause a change in plasma valproate concentrations in either adult or pediatric patients in controlled clinical trials.

Lamotrigine added to lithium

The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by coadministration of 100 mg/day Lamotrigine for 6 days.

Lamotrigine added to phenytoin

Lamotrigine has no appreciable effect on stead-state phenytoin plasma concentrations in patients with epilepsy.

Results of in vitro experiment suggest that Lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6 (see CLINICAL PHARMACOLOGY).

Effects of Other Drugs on the Pharmacokinetics of Lamotrigine

(See Table 3.)

Valproate added to Lamotrigine

The addition of valproate increases Lamotrigine steady-state concentrations in normal volunteers by slightly more than 2 fold. In one study, maximal inhibition of Lamotrigine clearance was reached at valproate doses between 250 mg/day and 500 mg/day and did not increase as the valproate dose was further increased.

Enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin, phenobarbital, or primidone) added to Lamotrigine

The addition of EIAEDs decreases Lamotrigine steady-state concentrations by approximately 40%.

Bupropion added to Lamotrigine

The pharmacokinetics of a 100 mg single dose of Lamotrigine in 12 healthy volunteers were not changed by coadministration of buproion at 300 mg/day starting 11 days before the Lamotrigine dose.

Other psychotropic drugs added to Lamotrigine

Results of in vitro experiments suggest that clearance of Lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone (see CLINIC




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