Lamotrigine

Lamotrigine
Systematic (IUPAC) name
6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine
Identifiers
CAS number 84057-84-1
ATC code N03AX09
PubChem CID 3878
DrugBank APRD00570
ChemSpider 3741
Chemical data
Formula C9H7Cl2N5 
Mol. mass 256.091 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 98%
Protein binding 55%
Metabolism Hepatic (mostly UGT1A4-mediated)
Half-life 24–34 hours (healthy adults)
Excretion Renal
Therapeutic considerations
Pregnancy cat. C(US)
Legal status POM (UK) ℞-only (US)
Routes Oral
 YesY(what is this?)  (verify)

Lamotrigine (marketed as Lamictal (pronounced /ləˈmɪktəl/) by GlaxoSmithKline) is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. For epilepsy it is used to treat partial seizures, primary and secondary tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome. Like many other anticonvulsant medications, Lamotrigine also seems to act as an effective mood stabilizer, and in fact has been the only FDA approved drug for this purpose since lithium, a drug approved almost 30 years earlier. It is approved for the maintenance treatment of bipolar type I. Chemically unrelated to other anticonvulsants (due to lamotrigine being a Phenyltriazine), lamotrigine has relatively few side-effects and does not require blood monitoring in monotherapy. The exact way lamotrigine works is unknown. Some think that it is a sodium channel blocker, though it is interesting to note that lamotrigine shares very few side-effects with other, unrelated anticonvulsants known to inhibit sodium channels, (e.g. Oxcarbazepine), which may suggest that lamotrigine has a different mechanism of action . Lamotrigine is inactivated by hepatic glucuronidation.

Contents

U.S. Food and Drug Administration approval history

Therapeutic uses

Epilepsy and seizures

Lamotrigine is approved in the US for the treatment of partial seizures.[1] Lamotrigine is one of a small number of FDA-approved therapies for seizures associated with Lennox-Gastaut syndrome, a severe form of epilepsy. Typically developing before four years of age, LGS is associated with developmental delays. There is no cure, treatment is often complicated, and complete recovery is rare. Symptoms include the atonic seizure (also known as a "drop attack"), during which brief loss of muscle tone and consciousness cause abrupt falls. Lamotrigine significantly reduces the frequency of LGS seizures, and is one of two medications known to decrease the severity of drop attacks.[3] Combination with valproate is common, but this increases the risk of lamotrigine-induced rash, and necessitates reduced dosing due to the interaction of these drugs.[4]

Lamotrigine is also used as first line therapy for childhood absence epilepsy.

Bipolar disorder

While traditional anticonvulsant drugs are predominantly antimanics, the best evidence for lamotrigine’s effectiveness is in the prophylaxis of bipolar depression. Consequently, it is approved in the US for maintenance treatment of Bipolar I disorder.[2] The drug seems ineffective in the maintenance of rapid cycling bipolar disorder.[5] Lamotrigine treats bipolar depression without triggering mania, hypomania, mixed states, or rapid-cycling.

The evidence for lamotrigine’s effectiveness in treating a preexisting mood episode is weaker. It has not demonstrated efficacy in the treatment of acute mania[6] and there is controversy regarding the drug’s effectiveness in treating acute bipolar depression. The 2002 American Psychiatric Association (APA) guidelines recommend lamotrigine as a first-line treatment for acute depression in Bipolar II disorder.[7] In light of the guidelines being more than five years old, the APA’s website notes that the guidelines “can no longer be assumed to be current."[8] A paper written in 2008 by Nasser et al. reviewed evidence from trials that were unpublished and not referenced in the 2002 APA guidelines and concludes that lamotrigine has “very limited, if any, efficacy in the treatment of acute bipolar depression.”[5] A 2008 paper by Calabrese et al. examined much of the same data and found that in four of out five placebo controlled studies, lamotrigine was ineffective in treating acute bipolar depression.[9]

At doses considered sub-therapeutic, lamotrigine is thought to have a mild anti-depressant effect, leading some to question its safety for use in bipolar disorder, as partial remediation of cyclically depressed individuals (especially teens and young adults) has an elevated correlation to suicide until remission attains therapeutically acceptable levels.

Other uses

Off-label uses include the treatment of peripheral neuropathy, trigeminal neuralgia, cluster headaches, migraines, and reducing neuropathic pain. [10][11][12] Off-label psychiatric usage includes the treatment of depersonalization disorder, bipolar II disorders, schizoaffective disorder, borderline personality disorder, Post Traumatic Stress Disorder , and as adjunctive therapy for treatment refractory unipolar depression.[13]

Mechanism of action

One proposed mechanism of action for lamotrigine involves an effect on sodium channels,[14] although this remains to be established in humans. 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 (for example glutamate and aspartate).[15]

Pharmacokinetics

The pharmacokinetics of lamotrigine follow first order kinetics, with a half-life of 13.5 hours and volume of distribution of 1.36l/kg.[16]. Lamotrigine has fewer drug interactions than many anticonvulsant drugs, although pharmacokinetic interactions with Sodium Valproate and other enzyme inducing medications may shorten half-life. Dose adjustments should be made on clinical response, but monitoring may be of benefit in assessing compliance.

Side effects

Lamotrigine prescribing information has a black box warning about life threatening skin reactions, including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.[15] The manufacturer states that nearly all cases appear in the first 2 to 8 weeks of therapy and if medication is suddenly stopped then resumed at the normal dosage. Patients should seek medical attention for any unexpected skin rash as its presence is an indication of a possible serious or even deadly side effect of the drug. Not all rashes that occur while taking lamotrigine progress to Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. It is estimated that 5 to 10 % of patients will develop a rash, but that only one in a thousand patients will develop a serious rash. It is thought that one in 50,000 exposed patients may die from a rash.

Common side effects include headaches, body aches and cramps, muscle aches, abdominal pain, back pain; dizziness and lack of coordination; acne, rash and skin irritation; sleepiness, insomnia, vivid dreams or nightmares, night sweats; dry mouth, mouth ulcers, damage to tooth enamel; fatigue, memory and cognitive problems; blurred or double vision; irritability, weight changes, hair loss, changes in libido, frequent urination, nausea, fever, tremor, appetite changes and other side effects. In very rare cases, lamotrigine has been known to cause the dangerous drug eruptions DRESS syndrome, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The rash is more common in children, so this medication is often reserved for adults. There is also an increased incidence of these eruptions in patients who are currently on, or recently discontinued a valproate-type anticonvulsant drug, as these medications interact in such a way that the clearance of both is decreased and the effective dose of lamotrigine is increased.

Lamotrigine has been associated with a decrease in white blood cell count (leucopenia).[17]

Effects in women

In clinical trials women were more likely than men to have side effects. This is the opposite of most other anticonvulsants and antipsychotics.

There is evidence showing interactions between lamotrigine and female hormones, which can be of particular concern for women on estrogen-containing hormonal contraceptives. Ethinyl estradiol, the ingredient of such contraceptives, has been shown to decrease serum levels of lamotrigine[18]. Women starting an estrogen-containing oral contraceptive may need to increase the dosage of lamotrigine to maintain its level of efficacy. Similarly, women may experience an increase in lamotrigine side effects upon discontinuation of the pill. This may include the "pill free" week where lamotrigine serum levels have been shown to increase twofold[15]. Another study showed a significant increase in follicle stimulating hormone (FSH) and luteinizing hormone (LH) in women taking lamotrigine with oral contraceptive compared to women taking oral contraceptives alone[19]. However, these increases were not in conjunction with increased progesterone, indicating that oral contraceptives maintained suppression of ovulation[19].

Pregnancy and breastfeeding

Lamotrigine is rated Pregnancy Category Risk C. Use during pregnancy is recommended only if benefits outweigh potential risks. In September 2006, the FDA issued a warning that taking lamotrigine during the first trimester of pregnancy may increase the risk for cleft lip and palate malformation in newborns.[20] Since then, review studies have found that overall rates of congenital malformations in infants exposed to lamotrigine in utero are relatively low (1-4%).[21][22] This compares to a typical 3% rate in the untreated population. However, a dose-dependence of the malformation rate has been reported.[23] A prospective study on cognition in children (mean age = 4.2 years) exposed to lamotrigine in utero did not indicate any adverse effects.[24]

Lamotrigine is found in breast milk; the manufacturer does not recommend breastfeeding during treatment. In "Medications and Mothers' Milk", a frequently updated review of scientific literature, lamotrigine is rated as L3: moderately safe.[25]

Other types of effects

Lamotrigine binds to melanin-containing tissues such as the iris of the eye. The long-term consequences of this are unknown.[26]

Some patients have reported experiencing a loss of concentration, even with very small doses, while some others have actually reported an increase in alertness and concentration. GlaxoSmithKline investigated lamotrigine for the treatment of ADHD. The results were inconclusive. No detrimental effects on cognitive function were observed, however, the only statistical improvement in core ADHD symptoms was an improvement on a test, PASAT (Paced Auditory Serial Addition Test), that measures auditory processing speed and calculation ability.[27]

Lamotrigine is known to affect sleep. Studies with small numbers (10-15) of patients reported that lamotrigine increases sleep stability (increases the duration of REM sleep, decreases the number of phase shifts, and decreases the duration of slow-wave sleep),[28] and that there was no effect on vigilance,[29] and daytime somnolence and cognitive function.[30] However, a retrospective study of 109 patients' medical records found that 6.7% of patients experienced an 'alerting effect' resulting in intolerable insomnia, for which the treatment had to be discontinued.[31]

Lamotrigine can induce a type of seizure known as a Myoclonic Jerk, which tends to happen soon after the use of the medication.[32] When used in the treatment of myoclonic epilepsies such as Juvenile myoclonic epilepsy, lower doses (and lower plasma levels) are usually needed, as even moderate doses of this drug can lead to induction of seizures, including tonic-clonic seizures, which can develop into Status epilepticus (a medical emergency). It can also cause Myoclonic Status Epilepticus.

In overdose, lamotrigine can cause uncontrolled seizures in most patients regardless of the reason they were prescribed the drug.

Some of the side effects are quite surprising. Those such as herpes zoster and Candida. There are many life-threatening adverse reactions that are important for anyone considering taking the drug Lamictal.[33]

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 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.[34] On 23 July 2008 Teva began offering the full line of generic lamotrigine in the US.[35] Lamotrigine is also available in generic form[36] 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.

GlaxoSmithKline has also recently received FDA Approval for an extended release version of lamotrigine called Lamictal XR[37].

Lamotrigine is marketed as Lamictin in South Africa, למוג'ין (Lamogine)[38] in Israel, and 라믹탈 in South Korea and generally named as Lamitor.

Chemistry

Lamotrigine synth.png

U.S. Patent 4,560,687

References

  1. ↑ 1.0 1.1 anonymous (19 March 2004). "EFFICACY SUPPLEMENTS APPROVED IN CALENDAR YEAR 2003". FDA/Center for Drug Evaluation and Research. http://www.fda.gov/cder/rdmt/ESCY03AP.HTM. Retrieved 2008-04-09. 
  2. ↑ 2.0 2.1 GlaxoSmithKline, 2003
  3. ↑ French, J.A. et al. (2004). Efficacy and tolerability of the new antiepileptic drugs II: Treatment of refractory epilepsy [electronic version]. Neurology. 62:1261–1273.
  4. ↑ Pellock, J.M. (1999). Managing pediatric epilepsy syndromes with new antiepileptic drugs [Special issue, electronic version]. Pediatrics. 104(5): 1106–1116.
  5. ↑ 5.0 5.1 Ghaemi, S.N., Shirzadi, A.A., Filkowski, M. (2008). "Publication Bias and the Pharmaceutical Industry: The Case of Lamotrigine in Bipolar Disorder". Medscape J Med 10 (9): 211. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2580079/. 
  6. ↑ Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM (2003). "Lamotrigine: a review of its use in bipolar disorder". Drugs 63 (19): 2029–50. PMID 12962521. 
  7. ↑ "Acute Treatment - Formula and Implementation of a Treatment Plan". Practice Guideline for the Treatment of Patients With Bipolar Disorder Second Edition. American Psychiatric Association. http://www.psychiatryonline.com/content.aspx?aID=50136. Retrieved 15 August 2010. 
  8. ↑ "Main page". Practice Guideline for the Treatment of Patients With Bipolar Disorder Second Edition. American Psychiatric Association. http://www.psychiatryonline.com/pracGuide/pracGuideTopic_8.aspx. Retrieved 15 August 2010. 
  9. ↑ Calabrese JR, Huffman RF, White RL, Edwards S, Thompson TR, Ascher JA, Monaghan ET, Leadbetter RA (2008). "Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials". Bipolar disorders 10 (2): 323–333. 
  10. ↑ Backonja, M. (2004). Neuromodulating drugs for the symptomatic treatment of neuropathic pain. Cur Pain Headache Rep. 8(3):212–6
  11. ↑ Jensen, T.S. (2002). Anticonvulsants in neuropathic pain: rationale and clinical evidence. [Abstract]. Eur J Pain. 6 Suppl A:61–68.
  12. ↑ Pappagallo, M. (2003). Newer antiepileptic drugs: possible uses in the treatment of neuropathic pain and migraine. [Abstract]. Clin. Ther. 25(10):2506–38.
  13. ↑ Barbosa, L. Berk, M. Vorster, M. (2003). A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. [Abstract]. J Clin Psychiatry. 64(4):403–407.
  14. ↑ Curia G, Biagini G, Perucca E, Avoli M (2009). "Lacosamide: a new approach to target voltage-gated sodium currents in epileptic disorders". CNS Drugs 23 (7): 555–68. doi:10.2165/00023210-200923070-00002. PMID 19552484. 
  15. ↑ 15.0 15.1 15.2 anonymous (May 2007). "LAMICTAL PRESCRIBING INFORMATION" (PDF). GlaxoSmithKline.. http://us.gsk.com/products/assets/us_lamictal.pdf. Retrieved 2008-04-09. 
  16. ↑ Pharmacokinetics and safety of lamotrigine in patients with epilepsy. Epilepsy Res 1991:10:191-200
  17. ↑ Nicholson, R J; Kelly, K P; Grant, I S (25 February 1995). "Leucopenia associated with lamotrigine". BMJ. http://www.bmj.com/cgi/content/full/310/6978/504/b. Retrieved 16 June 2010. 
  18. ↑ Reimers A, A; Helde G, Brodtkorb E (September 2005). "Ethinyl estradiol, not progestogens, reduces lamotrigine serum concentrations". Epilepsia (Blackwell Science) 46 (9): 1414–7. doi:10.1111/j.1528-1167.2005.10105.x. PMID 16146436. 
  19. ↑ 19.0 19.1 Sidhu J, J; Job S, Singh S, Philipson R (February 2006). "The pharmacokinetic and pharmacodynamic consequences of the co-administration of lamotrigine and a combined oral contraceptive in healthy female subjects.". Br J Clin Pharmacol. 61 (2): 191–9. doi:10.1111/j.1365-2125.2005.02539.x. PMID 16433873. 
  20. ↑ FDA: Safety Alerts: Lamotrigine
  21. ↑ Berwaerts, K; Sienaert P, De Fruyt J (2009). "Teratogenic effects of lamotrigine in women with bipolar disorder." (in Dutch). Tijdschr Psychiatr 51 (10): 741–50. PMID 19821242. 
  22. ↑ Prakash; Prabhu LV, Nasar MA et al. (October 2007). "Lamotrigine in pregnancy: safety profile and the risk of malformations.". Singapore Med J 48 (10): 880–3. PMID 17909669. 
  23. ↑ Meador, KJ; Baker GA, Finnel RH et al. (August 2006). "In utero antiepileptic drug exposure: fetal death and malformations.". Neurology 67 (3): 407–12. doi:10.1212/01.wnl.0000227919.81208.b2. PMID 16894099. 
  24. ↑ McVearry, KM; Gaillard WD, VanMeter J, Meador KJ (December 2009). "A prospective study of cognitive fluency and originality in children exposed in utero to carbamazepine, lamotrigine, or valproate monotherapy.". Epilepsy Behav 16 (4): 609–16. doi:10.1016/j.yebeh.2009.09.024. PMID 19892603. 
  25. ↑ Hale, TW (2008). Medications and Mothers' Milk (13th ed.). Hale Publishing. p. 532. ISBN 978-0-9815257-2-3. 
  26. ↑ anonymous. "Lamictal, Warnings & Precautions". RxList Inc.. http://www.rxlist.com/cgi/generic/lamotrigine_wcp.htm. Retrieved 2008-04-09. 
  27. ↑ anonymous. "lamotrigine studies". GlaxoSmithKline. http://ctr.gsk.co.uk/Summary/lamotrigine/studylist.asp. Retrieved 2008-04-09. 
  28. ↑ Foldvary, N; Perry M, Lee J et al. (December 2001). "The effects of lamotrigine on sleep in patients with epilepsy.". Epilepsia 42 (12): 1569–73. doi:10.1046/j.1528-1157.2001.46100.x. PMID 11879368. 
  29. ↑ Bonanni, E; Galli R, Gori S et al. (June 2001). "Neurophysiological evaluation of vigilance in epileptic patients on monotherapy with lamotrigine.". Clin Neurophysiol 112 (6): 1018–22. doi:10.1016/S1388-2457(01)00537-5. PMID 11377260. 
  30. ↑ Placidi, F; Marciani MG, Diomedi M et al. (August 2000). "Effects of lamotrigine on nocturnal sleep, daytime somnolence and cognitive functions in focal epilepsy.". Acta Neurol Scand 102 (2): 81–6. doi:10.1034/j.1600-0404.2000.102002081.x. PMID 10949523. 
  31. ↑ Sadler, M (March 1999). "Lamotrigine associated with insomnia.". Epilepsia 40 (3): 322–5. doi:10.1111/j.1528-1157.1999.tb00712.x. PMID 10080513. 
  32. ↑ http://www.ehealthme.com/ds/lamictal/myoclonic+jerks Retrieved August 19, 2010. Myoclonic Jerk in the use of Lamictal.
  33. ↑ http://www.druglib.com/druginfo/lamictal/side-effects_adverse-reactions/ Retrieved April 15, 2010. analysis of side effects
  34. ↑ anonymous (17 February 2005). "Press Release, Teva Announces Settlement Of Lamictal Litigation With Glaxosmithkline". Teva Pharmaceutical Industries Ltd.. http://www.tevapharm.com/pr/2005/pr_513.asp. Retrieved 2008-04-09. 
  35. ↑ http://www.tevapharm.com/pr/2008/pr_779.asp
  36. ↑ anonymous (2 March 2005). "Treatment for epilepsy: generic lamotrigine". Department of Health (UK). http://www.dh.gov.uk/en/Healthcare/Medicinespharmacyandindustry/Prescriptions/DH_4104966. Retrieved 2008-04-09. 
  37. ↑ Waknine Y (2009). "FDA Approves Extended-Release Lamotrigine for Adjunctive Treatment of Epilepsy". MedScape. http://www.medscape.com/viewarticle/703853. Retrieved 2010-05-18. 
  38. ↑ anonymous (2007). "LAMOTRIGINE". www.drug.co.il. http://www.drug.co.il/bygeneric.asp?gen_id=775&drugID=7007&wel=. Retrieved 2008-04-14. 

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Emil Kraepelin · Karl Leonhard · John Cade · Mogens Schou · Frederick K. Goodwin · Kay Redfield Jamison
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Hallucination · Delusion · Emotional dysregulation (Anhedonia, Dysphoria, Suicidal ideation) · sleep disorder (Hypersomnia, Insomnia) · Psychosis · Racing thoughts
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