Lamotrigine (Page 12 of 19)


10.1 Human Overdose Experience

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 [see Clinical Pharmacology (12.3)] . It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood. In six renal failure patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A Poison Control Center should be contacted for information on the management of overdosage of lamotrigine.


Lamotrigine, 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 is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural formula is:

Lamotrigine Structural Formula

Lamotrigine tablets, USP are supplied for oral administration as 25 mg, 100 mg, 150 mg or 200 mg tablets. Each tablet contains the labeled amount of lamotrigine and the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, pregelatinized starch (corn) and sodium lauryl sulfate. In addition, the 200 mg tablets contain D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake.

Meets USP Dissolution Test 3.


12.1 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. 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 50 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 [see Use in Specific Populations (8.1)]. 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 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.

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.


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. 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 Clinical Pharmacology (12.3)]. 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).

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 14 and 16.

Table 14. Mean Pharmacokinetic Parameters * in Healthy Volunteers and Adult Subjects with Epilepsy
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.
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 [see Drug Interactions (7)].

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



(0.25 to 12)


(14 to 103)


(0.12 to 1.10)

Multiple-dose lamotrigine



(0.5 to 4)


(11.6 to 61.6)


(0.24 to 1.15)

Healthy volunteers taking valproate:

Single-dose lamotrigine



(1 to 4)


(31.5 to 88.6)


(0.14 to 0.42)

Multiple-dose lamotrigine



(0.5 to 3.5)


(41.9 to 113.5)


(0.12 to 0.33)

Subjects with epilepsy taking valproate only:

Single-dose lamotrigine



(1.8 to 8.4)


(30.5 to 88.8)


(0.16 to 0.40)

Subjects with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone plus valproate:

Single-dose lamotrigine



(1 to 10)


(11.2 to 51.6)


(0.27 to 1.04)

Subjects with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone :

Single-dose lamotrigine





(0.5 to 5)

(6.4 to 30.4)

(0.51 to 2.22)

Multiple-dose lamotrigine



(0.75 to 5.93)


(7.5 to 23.1)


(0.66 to 1.82)

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