• UV and IR Spectra. H.-W. Dibbern, R.M. Muller, E. Wirbitzki, 2002 ECV
• NIST / EPA / NIH Mass Spectral Library 2008
• Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman. Academic Press, 2000.
• Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.

Brief background information

Application

Synthesis pathway

Синтез a)
Синтез b)

Trade names

Formulations

Reference

http://www.google.com/patents/EP2128145A2?cl=en

EXAMPLES

• [0047]
  The following examples are for illustrative purposes only and are not intended, nor should they be interpreted to, limit the scope of the invention.

General Experimental Conditions:I. HPLC Assay Method:

• [0048]
  The chromatographic separation was carried out at room temperature (20-25° C) using a Lichrosphere RP-select B, 5 µm,4.0 x 250 mm I.D. column.
• [0049]
  The mobile phase was prepared by mixing 320 mL of acetonitrile with 680 mL of buffer (pH = 5.6) prepared from 3.85 g of ammonium acetate dissolved in 1000 mL of water and by adjusting the pH to 5.6 with glacial acetic acid. The mobile phase was mixed and filtered through a 0.22 µm nylon filter under vacuum.
• [0050]
  The chromatograph was equipped with a 306 nm detector, and the flow rate was 1.0 mL per minute. Test samples (20 µL) were prepared by dissolving the appropriate amount of sample in order to obtain 1 mg/mL of acetonitrile.

Example 1: Preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazineStep 1. Preparation of Lamotrigine

• [0051]
  In a 800 L reactor, 38 kg of 2-(2,3-dichlorophenyl)-2-guanidinyliminoacetonitrile (0.148 kmoles) and 298 kg of isopropanol were combined. The mixture was then heated to reflux temperature (approximately 82° C) and maintained at 82 ± 3° C for 6 hours. Thereafter, the mixture was cooled to 20-25° C and stirred for 1 hour at this temperature. The suspension was then filtered and washed with 8 kg of isopropanol.

Step 2. Removal of Mechanical Impurities

• [0052]
  The crude lamotrigine obtained in Step I and 335 kg of deionized water were combined in the 800 L reactor, and the temperature was adjusted to between 35 and 40° C. Methanesulfonic acid was then added to the mixture until the pH was between 1.5 and 2.0 while maintaining the temperature between 35 to 40° C. The resulting aqueous solution of lamotrigine methane sulfonate was then filtered, and the filter and reactor were washed with 4 kg of deionized water.
• [0053]
  The solution of lamotrigine methanesulfonate was then added to the 800 L reactor, and the pH was adjusted to 6.5 to 7.5 by adding a 50% solution of sodium hydroxide. Next, the temperature was adjusted at 20 to 25° C, and the mixture was stirred at this temperature for 1 hour. Thereafter, the suspension was filtered and washed with 20 kg of deionized water followed by 8 kg of methanol, to obtain wet lamotrigine monohydrate.

Step 3. Conversion of Lamotrigine Hydrate to Anhydrous Lamotrigine

• [0054]
  In the 800 L reactor, the wet lamotrigine hydrate obtained in Step 2 and 255 kg of filtered methanol were combined, and the mixture was heated to reflux temperature. The mixture was then cooled to 20-25° C and stirred at this temperature for 1 hour. Thereafter, the suspension was filtered and washed with 8 kg of methanol.
• [0055]
  The wet product obtained was dried under vacuum for 16 hours at 85 ± 5° C and then was milled and sieved (500 µm to yield 29.11 kg (0.114 kmoles) of lamotrigine (Yield: 76.8%; Purity (HPLC analysis): 99.9%; Melting Point = 216° C).

Example 2: Preparation of Lamotrigine Monohydrate

• [0056]
  Lamotrigine (46 g) and 460 mL of deionized water were combined, and the temperature of the mixture was adjusted at 3 5 to 40° C. Initially, the pH of the mixture was 4.11. Methanesulfonic acid was then added to the mixture until the pH was 1.4 while maintaining the temperature of the mixture at or below 30° C. A light, opaline solution was obtained following addition of the methanesulfonic acid. The obtained solution of lamotrigine methanesulfonate was then filtered and the filter was washed with 4.6 mL of deionized water.
• [0057]
  The pH of the solution of lamotrigine methanesulfonate was next adjusted to 6.8-7.2 by adding a 50% solution of sodium hydroxide while maintaining the temperature at or below 30° C. The temperature was then adjusted to between 20° C and 25° C, and the mixture was stirred at this temperature for 1 hour. Thereafter, the suspension was filtered, and the obtained product was washed with deionized water and dried at 40° C to yield 49.23 g of lamotrigine monohydrate. Analysis: titration (perchloric acid): 99.23%; purity (HPLC analysis): 99%; Water (Karl Fischer) = 6.68%.

……………………………………

Example 6: Preparation of lamotrigine

The 6- (2,3, -dichlorophenyl) -5-chloro-3-thiomethyl-

1, 2,4-triazine prepared in Example 5 was dissolved in ethanol (100 ml) saturated with ammonia gas and heated in a sealed glass tube in an autoclave at 180°C/1930 kPa

(280 p.s.i.) for 72 hours.

The total contents of the tube was evaporated down to give a dark brown crude product. The crude product was recrystallised from methanol and identified as compound (I) , 3, 5-diamino-6- (2,3-dichlorophenyl) -1-2,4-triazine

(lamotrigine) by TLC (Rf = 0.20) . Melting point = 218°C.

 http://www.google.com/patents/WO1996020935A1?cl=en

……………….

3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine of the Formula (I)

also known as lamotrigine, is the active ingredient of several pharmaceutical compositions used for the treatment of different diseases of the central nervous system (e.g. epilepsy).

The synthesis of substituted 3,5-diamino-1,2,4-triazine derivatives is known from the literature. In the following publications the general synthesis of substituted derivatives is described—Agr. Res. Serif. 3 188 (1966) and J. Med. Chem. 859 (1972)—according to which benzoyl cyanide is reacted with aminoguanidine in acidic medium and the so obtained adduct is cyclized under basic conditions. According to the process described in the European Patent No. 21121—analogously to the method described above—2,3-dichlorobenzoyl cyanide is reacted with the hydrogencarbonate salt of aminoguanidine in dimethyl sulfoxide as solvent, in the presence of 8 N nitric acid for 7 days. The obtained adduct is cyclized with methanolic potassium-hydroxide solution to the final product in 15% yield—calculated on the starting material. Basically similar process is described in the European Patent No. 142306. The disadvantages of the above processes are the extremely aggressive reaction medium, the long reaction time as well as the very low yield.

The European Patent No. 247842 describes a process in which 8 M solution of sulfuric acid is used instead of 8 N nitric acid in the condensation reaction, and the reaction time is 48 h. The cyclization reaction is carried out in n-propanol at reflux temperature. The yield is 41%. The disadvantages of this process are the low yield and the aggressive reaction medium.

Basically similar process is described in the U.S. Pat. No. 6,111,101, in which the condensation is carried out in a mixture of diluted sulfuric acid and acetonitrile for 60 h, then the cyclization is carried out with 1% aqueous potassium hydroxide solution. The yield is 44%. The crude product is purified by recrystallization from methanol with the help of clarifier. The disadvantages of the process are the aggressive medium, the low yield and the very long reaction time.

The modification of the above process is described in the European Patent No. 963980, in which the cyclization reaction is carried out in n-propanol at reflux temperature. The yield is 60%. The product is purified by recrystallization from n-propano 1. The disadvantages of this process are also the long reaction time and the aggressive reaction medium.

According to the International Patent Application No. WO96120934 an intermediate, which is prepared with great difficulty, is converted into lamotrigine by cyclizing in a photo-chemical reactor in 80% yield. The disadvantage of the process is that it can not be applied on industrial scale.

The International Patent Application No. WO96120935 describes a six-step synthesis, which is difficult to carry out and hardly realizable on industrial scale, as well as the yield of the final product is very low. The disadvantages of the process are the complicated synthesis, the applied hazardous reagents and the low yield.

 http://www.google.com/patents/US7390899

EXAMPLE 23,5-diamino-6-(2,3-diehlorophenyl)-1,2,4-triazine

A suspension of 24.0 g of methanesulfonic acid and 21.0 g (0.079 mol) of aminoguanidine dimesylate is warmed to 65-70° C. in a 500 ml round bottom flask, equipped with a stirrer, a thermometer and a dropping funnel. The mixture becomes homogenous after 15 min, then a solution of 12.0 g (0.06 mol) of 2,3-dichlorobenzoyl cyanide in 10 ml of acetonitrile is added dropwise. The obtained mixture is stirred at 65-70° C. for 1 h. A mixture of 9 g (0.223 mol) of magnesium oxide and 60 ml of water is stirred for 5 min and the obtained suspension is added to the reaction mixture over a period of 10 min.

The temperature of the reaction mixture is raised to 70° C. and kept at this temperature for 3 h. The hot reaction mixture is filtered, 90 ml of water is added to the filtrate and concentrated. 60 ml of water is added to the residue, the suspension is stirred at 0-5° C., then filtered off. The product is washed with water and dried at 60-70° C. to yield 14.3 g (93.1%) of the crude title compound. Melting point: 212-216° C.

EXAMPLE 3Crystallization of 3,5-diamino-6-(2,3-diehlorophenyl)-1,2,4-triazine

10 g of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine is dissolved in 400 ml of acetone at reflux temperature, then 0.5 g of charcoal is added and the mixture is refluxed for 5 min. The clarifier is filtered off and the filtrate is cooled to 0-5° C. The precipitated crystals are filtered off and dried at 90° C. in vacuum to yield 7.0 g (70%) of the product. Melting point: 215-219° C.

………………………………………….

Lamotrigine 3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine, is an antiepileptic drug, and its analogues were first disclosed in British Patent No. 759,014 (1956). Subsequently, Lamotrigine and its analogues were described in Canadian Patent Nos. 1,112,643 and 1,133,938, and in United States Patent No. 4,602,017. Processes for the preparation of Lamotrigine are also disclosed in international publications and patents WO 96/20934, WO 96/20935, WO 00/35888 and European Patent No. 963,980.

Lamotrigine 1

The process (as disclosed in Canadian Patent Nos. 1,112,643 and 1,133,938, United States Patent No. 4,602,017 and in British Patent No. 759,014) for the preparation of Lamotrigine involves reaction of 2,3-dichlorobenzoyl cyanide 2 and aminoguanidine bicarbonate in dimethylsulfoxide and 8N aqueous nitric acid (scheme 1). The above process uses drastic conditions (20 eq. 8N HNO3), excess reagents and requires 7 days for completion of the reaction. The overall yield of the process from 2,3-dichlorobenzoyl cyanide is 15.6%.

Scheme 1

2. MeOH, KOH, heat Lamotrigine 1 15.6% yield

The process reported in WO 00/35888 for this reaction uses H₂S0₄ instead of 8N HNO3. However, it also suffers from lower yield (40%) and longer reaction time (2.5 days). The process also uses a large excess (-11 times) of sulfuric acid.

It is accordingly an object of the present invention to provide an improved process for the manufacture of lamotrigine which overcome the problems associated with poor efficiency described in the prior art. More broadly, it is an object of the present invention to provide novel processes for the production of 3,5-diamino-6-substituted-l,2,4-triazines.

SUMMARY OF THE INVENTION

In accordance with one aspect of the present invention, there is provided a process for the manufacture of an intermediate compound of formula IV

formula IV useful for manufacturing 3,5-diamino-6-substituted-l,2,4-triazines, wherein R is an optionally substituted C1-C4 alkyl or aryl group, which process comprises reacting a compound of formula II:

formula II

with aminoguanidine in the presence of an acid in an organic solvent under anhydrous conditions followed by treatment with a dehydrating reagent.

In accordance with another aspect of the present invention there is provided a process for the manufacture of 3,5-diamino-6-substituted-l,2,4-triazines of formula I:

formula I

comprising the steps of:

(a) reacting a compound of formula (II):

formula II

with aminoguanidine salts, or equivalent thereof, in the presence of an acid in an organic solvent under anhydrous conditions to form a cyanohydrin of formula III:

formula III

(b) dehydrating the cyanohydrin of formula III to form a compound of formula IV by treatment with a dehydrating reagent,

formula IV

and

(c) cyclization of the compound of formula IV into a 3,5-diamino-6- substituted-l,2,4-triazine of compound of formula I or into a hydrated form thereof.

Suitably the substituted Ci-Q alkyl group is methyl, ethyl, propyl or butyl and the substituted aryl group is preferably 2,3-dichlorophenyl.

The process of the present invention provides a high yielding and cost- effective process for the preparation of 3,5-diamino-6-substituted-l,2,4- triazines in general and Lamotrigine in particular. This result is obtained through the use of an additive, namely a dehydrating agent, such as thionyl chloride, POCI3 or PCI5, and by employing organic acid in combination with a polar organic solvent, which stabilizes the cyanohydrin of formula III. The cyanohydrin of formula III upon addition of a dehydrating agent affords the intermediate iminoguanidine of formula IV (scheme 2). The acid used in this process can be dry organosulfonic acids such as methanesulfonic acid or para-toluenesulfonic acid, either in combination with dry polar organic solvents, such as dimethylformamide (DMF), N-methyl-2- pyrrolidinone (NMP) or dimethylsulfoxide (DMSO), or combinations of a polar solvent with nonpolar solvents such as tetrahydrofuran (THF). The dehydrating reagents used in the process can be SOCl₂, POCI3 or PCI5, oxalyl chloride, phosgene or equivalents thereof.

Scheme 2

dehydration ,

f

ormula II formula III

cyclisation

formula IV

The process, as shown in Scheme 2, involves the reaction of aryl cyanide, preferably 2,3-dichlorobenzoyl cyanide 2 (in which R = 2,3-dichlorophenyl), with an organic acid, for example para-toluenesulfonic acid or methanesulfonic acid, and dry organic solvents, for example DMSO, NMP or DMF, at suitable temperatures to form an intermediate of formula III. The reaction mixture is treated with dehydrates for example SOCl₂, POCI3 or PCI5, oxalyl chloride, phosgene or equivalent thereof at a suitable temperature to form the iminoguanidine of formula IV. The iminoguanidine salt in the reaction mixture is cyclized upon basification and heating. The in inoguanidine salt can be basified and isolated by filtration. The isolated iminoguanidine can be cyclized to form Lamotrigine using a base (such as NaOH, NH3 or KOH) in a protic solvent (such as methanol, ethanol, isopropanol or water). Lamotrigine 1 can be isolated as the monohydrate when the cyclization of the intermediate is carried out using base and isopropanol/ water mixture or NMP/ water. The lamotrigine monohydrate is a new compound and is further characterized in having the following peaks in powder X-ray diffraction pattern at an angle of two theta (2Θ) is found to be: 10.34, 11.53, 12.46, 13.36, 13.86, 14.15, 14.94, 16.43, 16.65, 17.44, 17.97, 18.77, 18.91, 19.11, 19.52, 20.58, 22.11, 22.31, 23.09, 23.61, 24.18, 24.99, 25.52, 26.31, 26.83, 27.68, 28.53, 29.07, 29.24, 29.86, 30.09, 30.63, 31.01, 31.37, 31.78, 32.82, 33.25, 34.35, 34.96, 36.23, 36.92, 37.97, 38.60, 38.90. The positions of the peaks in powder X-ray diffraction pattern studies of anhydrous lamotrigine at an angle of two theta (2Θ) to be 9.80, 11.39, 12,46, 13.29, 13.86, 14.13, 15.62, 16.66, 17.44, 17.97, 19.54, 20.56, 22.30, 22.89, 23.61, 24.81, 25.50, 26.31, 26.74, 27.87, 28.42, 28.86, 29.38, 29.66, 30.95, 31.66, 32.59, 33.23, 33.61, 33.83, 34.21, 35.20, 36.27, 37.16, 37.90, 38.35, 38.92, 39.17, 39.45.

The overall yield of lamotrigine is high (molar yield: 80 – 85%). The above described process is very cost-effective, operationally simple and completed in a short time period (6 to 10 hours).

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is the powder X-ray diffraction pattern of lamotrigine monohydrate.

Figure 2 is a differential scanning calorimetry thermogram (DSC) of lamotrigine monohydrate.

Figure 3 is a Fourier transform infrared spectrum (FTIR) of lamotrigine monohydrate.

Figure 4 is the powder X-ray diffraction pattern of anhydrous lamotrigine. Figure 5 is a differential scanning calorimetry thermogram (DSC) of anhydrous lamotrigine.

Figure 6 is a Fourier transform infrared spectrum (FTIR) of anhydrous lamotrigine.

The following examples serve to illustrate embodiments of the present invention in a manner in which they can be practiced but, as such, should not be considered in a limiting sense.

EXAMPLES

Procedure I

To a round bottomed flask was added aminoguanidine hydrochloride (116.1 g, 1.05 mol) and dimethylformamide (900 mL). To this mixture was added methanesulfonic acid (130.4 g, 1.36 mol) followed by adding 2,3- dichlorobenzoylcyanide (150.0 g, 0.75 mol). The reaction mixture was stirred for 1 hour and then the dehydrating reagent, thionyl chloride, (45.2g, 0.38 mol) was added. The reaction mixture was stirred for another hour and then basified with KOH solution (4N). The precipitate was filtered and washed with water.

Yield: 401.3 g damp cake (KF = 39.2%).

Analytically pure sample of the intermediate is prepared as following:

20.0 g of the damp cake was suspended in 60 ml MeOH and stirred at room temperature for 3 hours. The solid was filtered and dried in vacuum at room temperature to give 5.4 g analytic pure iminoguanidine as a yellow solid.

m.p.: 179 ~ 180° C (corrected).

MS (m/z): 256.3 [M⁺] IR: 3491.8; 3457.1 (Amine N-H stretching); 2207.5 (CN stretching); 1681.9 (Imine C=N stretching); 1055.5 (C_aryi-Cl stretching).

Η-NMR (300 MHz, DMSO-D6): 7.66 (ad, J = 7.9 Hz, 2H), 7.41 (dd, J = 7.9; 7.9 Hz, 1H), 6.70 (br s, NH₂).

^C-NMR (75 MHz, DMSO-D6): 163.6, 135.3, 132.4, 130.0, 129.5, 129.0, 128.2, 114.4, 113.8.

Elemental analysis: C H N

Calculated: 42.21 2.76 27.35

Found: 42.10 2.49 27.69

Procedure II:

A round bottomed flask was charged with iminoguanidine (401.3 g from procedure I), isopropanol (1000.0 ml) and KOH (85%, 12.0 g, 0.18 mol). The reaction mixture was refluxed for 3 hours. Isopropanol was distilled and water (800 ml) was added. The reaction mixture was stirred for 3 hours, the solid was filtered and washed with water. The damp cake is dried under vacuum to yield 168.5 grams of lamotrigine monohydrate as crystalline solid (82% based on 2,3-dichlorobenzoyl cyanide).

Procedure III (without isolation of intermediate of formula IV):

To a round bottomed flask was added aminoguanidine hydrochloride (116.1 g, 1.05 mol) and dimethylformamide (900 ml). To this mixture was added methanesulfonic acid (130.4 g, 1.36 mol) followed by 2,3-dichlorobenzoyl cyanide (150.0 g, 0.75 mol). The reaction mixture was stirred for 1 hour and then dehydrating reagent thionyl chloride (45.2g, 0.38 mol) was added slowly. The reaction mixture was stirred for another hour and then basified with KOH solution (4 N). The Reaction mixture was heated under reflux (100 ~ 105° C) for 3 ~ 4 hours and cooled slowly to room temperature. The solid was filtered and washed with water. After drying, 160.7g of lamotrigine monohydrate as a crystalline solid (78% based on 2,3-dichlorobenzoyl cyanide) was obtained.

See also FIG. 1, 2, 3.

Karl Fischer (water content): 5.92 – 6.03%

DSC: 106.86, 216.65° C (onset).

MS (m/z): 256.3 [M⁺]

IR: 3496.9; 3450.3; 3338.5; 3211.0; 1658.7; 1524.0; 1328.8; 1027.1.

ⁱH-NMR (300 MHz, DMSO-D6): 7.66 (ad, J = 7.9 Hz, 2H), 7.41 (dd, J = 7.9; 7.9 Hz, 1H), 6.70 (br s, NH₂).

¹³C-NMR (75 MHz, DMSO-D6): 163.6, 135.3, 132.4, 130.0, 129.5, 129.0, 128.2, 114.4, 113.8.

Procedure IV (preparation of anhydrous lamotrigine from lamotrigine monohydrate):

150 g lamotrigine monohydrate (from procedure II or III) was recrystallized in 900 mL isopropanol giving 132 g (94%) of anhydrous lamotrigine as a crystalline solid.

See also FIG. 4, 5, 6.

m.p.: 216 – 217° C (corrected).

MS (m/z): 256.3 [M⁺]

Η-NMR (300 MHz, DMSO-D6): 7.69 (dd, J = 1.7; 7.9 Hz, 1H), 7.43 (dd, J = 7.9; 7.6 Hz, 1H), 7.35 (dd, J = 1.7; 7.6 Hz, 1H), 6.70 (br s, NH₂), 6.44 (br s, NH₂).

¹³C-NMR (75 MHz, DMSO-D6): 162.1, 154.1, 138.3, 136.8, 132.0, 131.6, 130.6, 128.5. Elemental analysis: C H N

Calculated: 42.21 2.76 27.35

Found: 42.10 2.58 27.46

 http://www.google.com/patents/WO2003078407A1?cl=en

Lamotrigine

Systematic (IUPAC) name
6-(2,3-Dichlorophenyl)-1,2,4-triazine-3,5-diamine
Clinical data
Trade names	Lamictal
AHFS/Drugs.com	monograph
MedlinePlus	a695007
Licence data	US FDA:link
Pregnancy cat.	AU: D US: C
Legal status	AU: Prescription Only (S4) CA: ℞-only UK: POM US: ℞-only
Routes	Oral
Pharmacokinetic data
Bioavailability	98%
Protein binding	55%
Metabolism	Hepatic (mostly UGT1A4-mediated)
Half-life	29 hours
Excretion	Urine (65%), faeces (2%)
Identifiers
CAS number	84057-84-1
ATC code	N03AX09
PubChem	CID 3878
IUPHAR ligand	2622
DrugBank	DB00555
ChemSpider	3741
UNII	U3H27498KS
KEGG	D00354
ChEBI	CHEBI:6367
ChEMBL	CHEMBL741
Chemical data
Formula	C9H7Cl2N5
Mol. mass	256.091 g/mol

History

• December 1994 — Lamotrigine was approved for the treatment of partial seizures.^[5]
• August 1998 — for use as adjunctive treatment of Lennox-Gastaut syndrome in pediatric and adult patients, new dosage form: chewable dispersible tablets.
• December 1998 — for use as monotherapy for treatment of partial seizures in adult patients when converting from a single enzyme-inducing anti-epileptic drug (EIAED).
• January 2003 — for use as adjunctive therapy for partial seizures in pediatric patients as young as two years of age.
• June 2003 — approved for maintenance treatment of Bipolar I disorder; the first such medication since lithium.^[10]
• January 2004 — for use as monotherapy for treatment of partial seizures in adult patients when converting from the anti-epileptic drug valproate [including valproic acid (Depakene); sodium valproate (Epilim) and divalproex sodium (Depakote)].

Availability

Lamictal 200 mg tablets

GlaxoSmithKline’s trademarked brand of lamotrigine, Lamictal, is manufactured in scored tablets (25 mg, 50 mg, 100 mg, 150 mg and 200 mg) and chewable dispersible tablets (2 mg, 5 mg and 25 mg). Five-week sample kits are also available; these include titration ^[66]instructions and scored tablets (25 mg for patients taking valproate, 25 mg and 100 mg for patients not taking valproate). Lamotrigine is also available in un-scored tablet form. In 2005, Teva Pharmaceutical Industries Ltd. began selling generic lamotrigine in the United States, but only in 5 mg and 25 mg chewable dispersible tablets.^[67] On 23 July 2008 Teva began offering the full line of generic lamotrigine in the US.^[68]Lamotrigine is also available in generic form^[69] in the United States, the United Kingdom, Canada and Australia. It should be noted that brand name Lamictal is not available in 200 mg tablets in Canada, at all registered pharmacies (while 25, 100, and 150 mg are all offered). Starter kits are also not available in Canada.

Lamotrigine is marketed as Lamotrine in Egypt, Lamitrin in Bangladesh [1], Lamictin in South Africa, למוג’ין (Lamogine)^[70] in Israel, and 라믹탈 in South Korea and generally named as Lamitor.

Lamictal XR

In 2009 GlaxoSmithKline received FDA Approval for an extended-release version of lamotrigine branded Lamictal XR.^[71] Lamictal XR tablets are a novel preparation of lamotrigine, delivered in a tablet with an enteric coating that GlaxoSmithKline has branded DiffCORE. The extended release formulation is analogous to the instant release version, such that treatment may begin without titration^[66] or recalibration of the dosage.

References

External links

• FAQ: Psychiatric Uses of Lamotrigine (Lamictal), by Ivan K. Goldberg, MD. Includes many references from the medical literature.
• Center for Drug Evaluation and Research: Lamictal — documents related to the FDA approval process, including medical reviews and correspondence letters.
• Epilepsy South Africa: MEDICATION FOR EPILEPSY — an Epilepsy FAQ with a list of medicines for treatment thereof, includes lamotrigine with South African trade name Lamictin
• Adverse Reactions — Reported adverse reactions and side-effects.
• U.S. National Library of Medicine: Drug Information Portal — Lamotrigine