84057-84-1 Usage
Uses
Used in Pharmaceutical Industry:
Lamotrigine is used as an anticonvulsant for the treatment of refractory partial seizures, as it significantly reduces their incidence. It is also used as an add-on therapy for the treatment of generalized seizures not satisfactorily controlled by other anti-epileptics.
Used in Mental Health Treatment:
Lamotrigine is used as a mood stabilizer for the adjunctive treatment of bipolar I disorder, helping to maintain treatment and manage depressive episodes.
Used in Antimicrobial Applications:
Lamotrigine is used as an antibacterial agent, contributing to the fight against bacterial infections.
Indications
Epilepsy: monotherapy and adjunctive therapy of focal and generalized seizures.
Recommendations summarized from NICE (2012)
Seizure types: first line (generalized tonic- clonic seizures, tonic/ atonic seizures, absence seizures, focal seizures), adjunctive (generalized tonicclonic seizures, absence seizures, focal seizures).
Epilepsy types: first line (absence syndromes, juvenile myoclonic epilepsy, epilepsy with generalized tonic- clonic seizures only, idiopathic generalized epilepsy, benign epilepsy with centrotemporal spikes, Panayiotopoulos syndrome, late-onset childhood occipital epilepsy), adjunctive (absence syndromes, juvenile myoclonic epilepsy, epilepsy with generalized tonic- clonic seizures only, idiopathic generalized epilepsy, benign epilepsy with centrotemporal spikes, Panayiotopoulos syndrome, late- onset childhood occipital epilepsy, Lennox- Gastaut syndrome), contraindicated (Dravet syndrome)
Psychiatry: prevention of depressive episodes associated with bipolar disorder (not indicated for manic phase)
Dose titration
Epilepsy— monotherapy
25 mg od for 14 days, 50 mg od for 14 days, then increased to a maximum of 100 mg every 7– 14 days; usual maintenance 100– 200 mg daily, divided into 1– 2 doses (max. 500 mg daily).
Epilepsy— adjunctive therapy (with valproate)
25 mg on alternate days for 14 days, 25 mg od for 14 days, then increased by a maximum of 50 mg every 7– 14 days; usual maintenance 100– 200 mg daily, divided into 1– 2 doses (max. 500 mg daily).
Epilepsy— adjunctive therapy (with enzyme- inducing AED and without valproate)
50 mg od for 14 days, 50 mg bd for 14 days, then increased by a maximum of 100 mg every 7– 14 days; usual maintenance 200– 400 mg daily, divided into two doses (max. 700 mg daily).
Epilepsy— adjunctive therapy (without enzyme- inducing AED and without valproate)
25 mg od for 14 days, 50 mg od for 14 days, then increased by a maximum of 100 mg every 7– 14 days; usual maintenance 100– 200 mg daily, divided into 1 or 2 doses.
Bipolar disorder— monotherapy or adjunctive therapy (without enzyme- inducing AED and without valproate)
25 mg od for 14 days, 50 mg daily, divided into 1 or 2 doses for 14 days, 100 mg daily, divided into 1 or 2 doses for 7 days; usual maintenance 200 mg daily, divided into 1 or 2 doses (max. 400 mg daily).
Bipolar disorder— adjunctive therapy (with valproate)
25 mg on alternate days for 14 days, 25 mg od for 14 days, 50 mg daily, divided into 1 or 2 doses; usual maintenance 100 mg daily, divided into 1 or 2 doses (max. 200 mg daily).
Bipolar disorder— adjunctive therapy (with enzyme- inducing AED and without valproate)
50 mg od for 14 days, 50 mg bd for 14 days, 100 mg bd for 7 days; 150 mg bd for 7 days; usual maintenance 200 mg bd.
If stopping lamotrigine, patients with epilepsy need to reduce the dose gradually over about 2 weeks to minimize the risk of relapse. This does not apply to patients who take lamotrigine for bipolar disorder, although NICE (2015) recommend that it be reduced gradually over at least 4 weeks to minimize the risk of relapse.
Plasma levels monitoring
Although plasma levels can be measured, and a therapeutic range has been postulated (2.5– 15 mg/ L), there is only a loose relationship between serum concentration and clinical effectiveness/ adverse effects. The routine measurement of plasma levels in clinical practice is therefore unnecessary, although it can sometimes be useful in guiding dosage adjustments in situations associated with changes in lamotrigine pharmacokinetics, such as pregnancy, puerperium, and polymedication.
Cautions
Patients with a history of allergy or rash from other AEDs.
Patients with Parkinson disease.
Patients with myoclonic seizures.
Interactions
With AEDs
Plasma concentration of lamotrigine is increased by the glucuronidation inhibitor valproate (reduce lamotrigine dose to avoid increased risk of toxicity).
Plasma concentration of lamotrigine is reduced by the glucuronidation inducers carbamazepine, phenytoin, phenobarbital and primidone.
Lamotrigine can raise concentration of active metabolite of carbamazepine (conflicting evidence).
With other drugs
Plasma concentration of lamotrigine is reduced by the glucuronidation inducers oestrogens, rifampicin, and ritonavir (consider increasing the dose of lamotrigine).
Plasma concentration of lamotrigine is possibly increased by desogestrel.
With alcohol/food
There are no known specific interactions between alcohol and lamotrigine, and there are no specific foods that must be excluded from diet when taking lamotrigine.
Special populations
Hepatic impairment
Halve dose in moderate impairment.
Quarter dose in severe impairment.
Renal impairment
Reduce maintenance dose in significant impairment.
Pregnancy
A large amount of data on pregnant women exposed to lamotrigine during the first trimester of pregnancy do not suggest a substantial increase in the teratogenity risk. However, if therapy with lamotrigine is considered necessary during pregnancy, the lowest possible therapeutic dose is recommended.
Lamotrigine doses may need to be doubled during pregnancy, as its plasma clearance can greatly increase towards the end of pregnancy (dose adjustments made in pregnancy should be rapidly reversed in the few days after delivery).
Should a woman on lamotrigine decide to breastfeed, the infant should be monitored for possible adverse effects, as lamotrigine can be excreted in considerable amounts in breastmilk. In combination with slow infantile elimination can result in plasma concentrations at which pharmacological effects occur.
Behavioural and cognitive effects in patients with epilepsy
Lamotrigine is characterized by an overall positive psychotropic profile, especially in terms of antidepressant properties. There are mixed findings about its possible effects on anxiety symptoms. The main adverse behavioural effects include irritability, agitation, and aggression (especially in patients with learning disability). However, these are not very common. There is no evidence of a significantly increased risk of thought disorders or cognitive deficits (at least at commonly used therapeutic doses). Positive effects on cognitive functions seem to be associated with EEG changes, rather than enhanced cognition.
Psychiatric use
The use of lamotrigine for the treatment of behavioural symptoms emerged from the observation of mood improvement in patients taking this medication for partial epilepsy. The main use of lamotrigine in psychiatry settings is for the maintenance therapy of bipolar disorder (prevention of depressive episodes), for which there is an approved indication from both FDA and EMA. There is evidence of a modest benefit in acute bipolar depression and unipolar depression (especially in more severely depressed patients). Reassuring data show no increased risk for switch- over placebo, indicating that lamotrigine is a reasonable choice for the treatment of acute bipolar depression in patients already on mood stabilizers, including those who have demonstrated adverse effects, such as switching on commonly used antidepressants. Other off- label uses have been investigated with preliminary positive results in borderline personality disorder (anger, affective lability, impulsivity), whereas supportive evidence is limited for use in obsessive- compulsive disorder (augmentation therapy), post- traumatic stress disorder, schizophrenia, schizoaffective disorder, alcohol and opiate withdrawal, cocaine dependence, behavioural, and psychological symptoms of dementia.
Manufacturing Process
A mixture of 2,3-dichlorophenylglyoxylamide (54.5 g, 0.25 mol),
aminoguanidine hydrochloride (33.15 g, 0.30 mol), ethanol (1 liter) and
concentrated hydrochloric acid (4 ml) were heated under reflux for 6 hours at
pH 1.5. The resulting solution was evaporated to dryness, the solid was
dissolved in water (2 L; resulting pH 2.5) and the solution was basified to pH
13 by the addition of 50% aqueous sodium hydroxide (45 ml) at <15°C. The
mixture was filtered, the solid washed with 0.88 N ammonia solution and
dried to give (E)-2-(2',3'-dichlorophenyl)-2-(guanidinylimino)acetamide (59.5
g, 87%) m.p. 231-233°C. Recrystallisation of this product (2.2 g) from npropanol (60 ml) afforded pure material (1.83 g, 83%), m.p. 238-239°C
(decomp.).(E)-2-(2',3'-dichlorophenyl)-2-(guanidinylimino)acetamide (0.3 g) was
dissolved in ethanol (10 ml) and was irradiated by exposure to sunlight. After
5 days 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine (Lamotrigine) was
detected by TLC in the liquor material. Melting point of lamotrigine 218°C.
Therapeutic Function
Anticonvulsant
World Health Organization (WHO)
Lamotrigine is a relatively new antiepilepsy agent acting through
stabilization of neuronal membranes and preventing liberation of neurotransmitters.
Biological Functions
Lamotrigine has a broad spectrum of action and is effective
in generalized and partial epilepsies. Its primary
mechanism of action appears to be blockage of voltagedependent
sodium channels, although its effectiveness
against absence seizures indicates that additional mechanisms
may be active. Lamotrigine is almost completely absorbed from the gastrointestinal tract, and peak
plasma levels are achieved in about 2 to 5 hours. The
plasma half-life after a single dose is about 24 hours.
Unlike most drugs, lamotrigine is metabolized primarily
by glucuronidation. Therefore, it appears likely that
lamotrigine will not induce or inhibit cytochrome P450
isozymes, in contrast to most AEDs.
Severe skin rashes appear to be the major concern
with lamotrigine use.The incidence of rash is greater in
children than in adults.Other adverse effects are similar
to those of drugs with the same mechanism of action,
such as cerebellovestibular changes leading to dizziness,
diplopia, ataxia, and blurred vision. Disseminated intravascular
coagulation has been reported.
Biological Activity
Anticonvulsant. Inhibits glutamate release, possibly through inhibition of Na + , K + and Ca 2+ currents.
Biochem/physiol Actions
Anticonvulsant.
Mechanism of action
The most probable explanation for lamotrigine's efficacy is its ability to produce a blockade of sodium channel repetitive firing.
In addition, lamotrigine appears to reduce glutaminergic excitatory transmission, although the mechanism for this action
remains unclear.
Pharmacokinetics
Following oral administration, lamotrigine is absorbed rapidly and completely, exhibiting linear pharmacokinetics and modest
protein binding (55%). Lamotrigine is metabolized predominantly by N-glucuronidation and subsequent urinary elimination of its
major metabolite, the quaternary 2-N-glucuronide (80–90%), the minor 5-amino-N-glucuronide (8–10%), and unchanged drug
(8–10%). Lamotrigine's usual elimination half-life of 24–35 hours is reduced to 13–15 hours in patients taking enzymeinducing AEDs. The presence of valproate increases the lamotrigine half-life substantially by inhibiting N-glucuronidation,
necessitating a reduction in dose to avoid toxicity. Hepatic disease patients may demonstrate a reduced capacity to for
lamotrigine glucuronidation, thus reducing its rate of clearance.
Clinical Use
Lamotrigine is a 5-phenyl-1,2,4-triazine derivative indicated as monotherapy or as an adjunct for partial seizures in adults, as
adjunct in patients with Lennox-Gastaut syndrome, and as adjunct for partial seizures in children 2 years of age and older.
Lamotrigine may have additional benefit in combating myoclonic and typical absence seizures. It is approved for use in the
maintenance treatment of bipolar disorder.
Side effects
The usefulness of lamotrigine is limited by the increased incidence of serious rashes, particularly in children or patients taking
valproate. This increase, however, may be attenuated by very slow dose escalation, because most rashes appear within
the first 8 weeks of treatment. The drug should be discontinued if a rash appears at any time. Additionally, lamotrigine may be
associated with development of myoclonus after 2 to 3 years of drug treatment. Additional common side effects associated
with lamotrigine therapy include dizziness, diplopia, headache, ataxia, blurred vision, somnolence, and nausea.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin.
Antidepressants: antagonism of anticonvulsant
effect; avoid with St John’s wort.
Antiepileptics: concentration reduced by
carbamazepine, phenobarbital and phenytoin, also
possibility of increased concentration of active
carbamazepine metabolite; concentration increased
by valproate - reduce lamotrigine dose.
Antimalarials: mefloquine antagonises
anticonvulsant effect
Antipsychotics: anticonvulsant effect antagonised.
Oestrogens and progestogens: concentration of
lamotrigine reduced and the dose may need to
be increased by as much as 2-fold; may affect
contraceptive effect.
Orlistat: possibly increased risk of convulsions
Metabolism
Potentially hazardous interactions with other drugs
Antibacterials: concentration reduced by rifampicin.
Antidepressants: antagonism of anticonvulsant
effect; avoid with St John’s wort.
Antiepileptics: concentration reduced by
carbamazepine, phenobarbital and phenytoin, also
possibility of increased concentration of active
carbamazepine metabolite; concentration increased
by valproate - reduce lamotrigine dose.
Antimalarials: mefloquine antagonises
anticonvulsant effect
Antipsychotics: anticonvulsant effect antagonised.
Oestrogens and progestogens: concentration of
lamotrigine reduced and the dose may need to
be increased by as much as 2-fold; may affect
contraceptive effect.
Orlistat: possibly increased risk of convulsions
Check Digit Verification of cas no
The CAS Registry Mumber 84057-84-1 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 8,4,0,5 and 7 respectively; the second part has 2 digits, 8 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 84057-84:
(7*8)+(6*4)+(5*0)+(4*5)+(3*7)+(2*8)+(1*4)=141
141 % 10 = 1
So 84057-84-1 is a valid CAS Registry Number.
InChI:InChI=1/C9H7Cl2N5/c10-5-3-1-2-4(6(5)11)7-8(12)14-9(13)16-15-7/h1-3H,(H4,12,13,14,16)
84057-84-1Relevant articles and documents
Improved method for synthetizing lamotrigine
-
Paragraph 0049-0061, (2018/07/06)
The invention discloses an improved method for synthetizing lamotrigine. The method comprises the following steps: step I, carrying out helogenating reaction through 3-amino-1,2,4-triazine (I) and a halogenating reagent in the presence of an organic solvent to obtain 3-amino 6-halogeno-1,2,4-triazine (II); step II, carrying out amination reaction of a compound II to prepare 3,5-diamino 6-halogeno-1,2,4-triazine (compound III); and step III, carrying out suzuki coupling reaction through the compound III and 2,3-dichlorobenzene boric acid derivative in the solvent under catalysis of palladium/[N,N] pyridine amidino ligand/alkali to prepare lamotrigine (IV). Through the method, metal cyanide is not used; meanwhile, the method is high in reaction selectivity and high in reaction yield.
Improved synthesis process for lamotrigine
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Paragraph 0033, (2017/07/21)
The invention discloses an improved synthesis process for lamotrigine. The process comprises the following steps: (1) synthesizing 2,3-dichlorobenzoyl cyanide: adding 2,3-dichlorobenzoic acid and thionyl chloride into a reactor, carrying out depressurized evaporating to remove thionyl chloride after a reaction is completed, adding cuprous cyanide into the reactor, and filtering out solids after a reaction is completed, so as to obtain a 2,3-dichlorobenzoyl cyanide solution; (2) preparing a condensate: adding aminoguanidine carbonate and an entrainer into a reactor, dropwise adding concentrated sulfuric acid, distilling off the entrainer and water, carrying out suction filtration, enabling solids to enter a reaction bottle, carrying out depressurized pumping, then, adding the 2,3-dichlorobenzoyl cyanide solution obtained in the step (1) into the reaction bottle, cooling the reaction bottle to room temperature after a reaction is completed, and carrying out suction filtration, so as to obtain the condensate; and (3) preparing cyclics: adding liquid alkali into the condensate obtained in the step (2), and carrying out crystallizing, filtering, washing and baking after a reaction, thereby obtaining the lamotrigine. According to the improved synthesis process for the lamotrigine, the quality and yield of the product, i.e., the lamotrigine can be remarkably increased, and the yield reaches 90% or more.
AN IMPROVED PROCESS FOR THE PREPARATION OF LAMOTRIGINE
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Page/Page column 3; 5, (2009/07/03)
The present invention relates to an improved process for the preparation of Lamotrigine (I) comprising a step of cyclizing 2-(2,3-Dichlorophenyl)-2-(guanidinoimino)acetonitrile(III) in the presence of an alcohol and an acid.
Improved method for synthesizing lamotrigine
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Page/Page column 7, (2009/12/23)
The invention relates, in general, to an improved process for preparing lamotrigine and related compounds. Processes for preparing and purifying lamotrigine, including lamotrigine hydrate, lamotrigine monohydrate and anhydrous lamotrigine, are described.
A PROCESS FOR THE PREPARATION OF LAMOTRIGINE
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Page/Page column 13, (2008/06/13)
A novel process for the preparation of lamotrigine and its intermediates is devised.
A NOVEL PROCESS FOR THE SYNTHESIS OF LAMOTRIGINE AND ITS INTERMEDIATE
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Example 2; 3, (2010/11/27)
This invention discloses a process for the preparation of 3,5-Diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine of a formula (I), commonly known as Lamotrigine which comprises the step of reacting aminoguanidine bicarbonarte and 2,3- dichlorobenzocynide with a reagent prepared by dissolving phosphorus pentoxide and methane sulfonic acid, to produce a novel intermediate 2-(2,3-dichlorophenyl)-2-(aminoguanidine)-acetonitrile monomesylate which is further cyclized to lamotrigine without basification.
METHOD FOR PREPARING LAMOTRIGINE AND ITS INTERMEDIATE 2,3-DICHLOROBENZOYL CHLORIDE
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Page/Page column 16-17, (2010/11/29)
The invention relates to an improved method for preparing 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, also commonly known as lamotrigine. The present invention also relates to a method for preparing the intermediate 2,3-dichlorobenzoyl chloride, which comprises the synthesis by photochlorination of 2,3-dichlorobenzotrichloride followed by hydrolysis thereof. Said 2,3-dichlorobenzoyl chloride intermediate is useful for preparing lamotrigine.
LAMOTRIGINE MONOHYDRATE
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Page 13, (2008/06/13)
The invention relates to lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) monohydrate (Ia) and anhydrous lamotrigine, and a process for preparing the same. An improved process is provided for manufacturing the lamotrigine (I). The process comprises of reacting 2,3-dichlorobenzoyl cyanide (II) with aminoguanidine bicarbonate in aqueous mineral acid, optionally together with a water miscible organic solvent, at 30 - 80 °C to produce the 2-(2,3-dichlorophenyl)-2-(guanidinylamino)acetonitrile (Schiff base). The Schiff base is further cyclised in aqueous alcohol to produce pure lamotrigine of a pharmaceutically acceptable quality which on further drying at 45 - 50 °C under vacuum yields lamotrigine monohydrate, and/or on further drying at 100 - 110 °C yields anhydrous lamotrigine. The lamotrigine monohydrate or anhydrous lamotrigine thereby produced may then be brought into association with a pharmaceutically acceptable carrier for administration to a patient in need thereof.
A new approach to the synthesis of lamotrigine and other 3,5-diamino-1,2,4-triazine derivatives
Ulomskii,Shestakova,Deev,Rusinov,Chupakhin
, p. 726 - 732 (2007/10/03)
A new in principle method for the synthesis of 6-aryl(hetaryl)-3,5-diamino- 1,2,4-triazines by decomposition of pre-synthesized tetrazolo[1,5-b][1,2,4] triazines was developed. The advantages of this method over traditional methods were demonstrated using the synthesis of a modern antiepileptic preparation lamotrigine, as an example.
NEW PROCESS FOR THE SYNTHESIS OF HIGH PURITY 3,5-DIAMINO-6-(2, 3-DICHLOROPHENYL)-1,2,4-TRIAZINE
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Page 5, (2008/06/13)
The present invention relates to a new process for the synthesis of high purity 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine of formula (I) using 2,3-dichlorobenzoyl cyanide and an aminoguanidine salt as starting materials. 2,3-dichlorobenzoyl cyanide is reacted with 1-2 mol equivalent of aminoguanidine salt in 3-6 mol equivalent of methanesulfonic acid, then the obtained adduct of formula (IV) is transformed without isolation into the product with magnesium oxide. In given case the obtained crude product can be recrystallized from a proper organic solvent.
