Lamotrigine
Clinical data | |||
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Pronunciation | /ləˈmoʊtrɪˌdʒiːn/ | ||
Trade names | Lamictal, others[1] | ||
Other names | BW-430C; BW430C; 3,5-Diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine | ||
AHFS/Drugs.com | Monograph | ||
MedlinePlus | a695007 | ||
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Phenyltriazine | |||
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Pharmacokinetic data | |||
Bioavailability | 98% | ||
Protein binding | 55% | ||
Metabolism | Liver (mostly UGT1A4-mediated) | ||
Elimination half-life | 29 hours | ||
Excretion | Urine (65%), feces (2%) | ||
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Lamotrigine, sold under the brand name Lamictal among others, is a
Common side effects include nausea, sleepiness, headache, vomiting, trouble with coordination, and rash.
Lamotrigine was first marketed in Ireland in 1991,[12] and approved for use in the United States in 1994.[8][13] It is on the World Health Organization's List of Essential Medicines.[14] In 2021, it was the 50th most commonly prescribed medication in the United States, with more than 13 million prescriptions.[15][16]
Medical uses
Epilepsy
Lamotrigine is considered a first-line drug for primary generalized
Lennox–Gastaut syndrome
Lamotrigine is one of a small number of FDA-approved therapies for the form of epilepsy known as Lennox–Gastaut syndrome.[21] It reduces the frequency of LGS seizures, and is one of two medications known to decrease the severity of drop attacks.[22] Combination with valproate is common, but this increases the risk of lamotrigine-induced severe skin reaction Stevens–Johnson syndrome, and necessitates reduced dosing due to the interaction of these drugs.[23]
Bipolar disorder
Lamotrigine is approved in the US for maintenance treatment of
Lamotrigine has not demonstrated clear efficacy in treating acute mood episodes, either mania or depression. It has not demonstrated effectiveness in treating acute mania,[27] and there is controversy regarding the drug's effectiveness in treating acute bipolar depression.[28] A paper written in 2008 by Nassir et al. reviewed evidence from trials that were unpublished and not referenced in the 2002 APA guidelines, and it concludes that lamotrigine has "very limited, if any, efficacy in the treatment of acute bipolar depression".[25] A 2008 paper by Calabrese et al. examined much of the same data, and found that in five placebo-controlled studies, lamotrigine did not significantly differ from placebo in the treatment of bipolar depression.[29] However, in a meta-analysis of these studies conducted in 2008, Geddes, Calabrese and Goodwin found that lamotrigine was effective in individuals with bipolar depression, with a number needed to treat (NNT) of 11, or 7 in severe depression.[30]
A 2013 review concluded that lamotrigine is recommended in bipolar maintenance when depression is prominent and that more research is needed in regard to its role in the treatment of acute bipolar depression and unipolar depression. No information to recommend its use in other psychiatric disorders was found.[31]
Schizophrenia
Lamotrigine, as a monotherapy, is not substantially effective against schizophrenia. However, various publications[32][33] and textbooks[34][35] have expressed that lamotrigine could be added to clozapine as augmentation therapy against partial or non-responding schizophrenic patients. Patients had statistically significant improvements in positive, negative and affective symptoms. Lamotrigine does not have a statistically significant effect with antipsychotics other than clozapine, such as: olanzapine, risperidone, haloperidol, zuclopenthixol, etc.[36]
Other uses
Side effects
Side effects such as rash, fever, and fatigue are very serious, as they may indicate incipient SJS, TEN, DRESS syndrome, or aseptic meningitis.[50]
Lamotrigine prescribing information has a
In 2018, the FDA required a new warning for the risk of hemophagocytic lymphohistiocytosis. This serious reaction can occur between days to weeks after starting the treatment.[52]
Other side effects include alopecia (hair loss), loss of balance or coordination,
Lamotrigine has been associated with a decrease in white blood cell count (leukopenia).[53] Lamotrigine does not prolong QT/QTc in TQT studies in healthy subjects.[54]
In people taking antipsychotics, cases of lamotrigine-precipitated neuroleptic malignant syndrome have been reported.[55][56]
Women
Women are more likely than men to have side effects.[5]
Some evidence shows interactions between lamotrigine and female hormones, which can be of particular concern for women on estrogen-containing
Pregnancy and breastfeeding
Many studies have found no association between lamotrigine exposure in utero and birth defects, while those that have found an association have found only slight associations with minor malformations such as
Lamotrigine is expressed in breast milk; the manufacturer recommends carefully weighing the benefits and risks of taking Lamotrigine while breastfeeding.[61] However, some studies suggest that lamotrigine is safe to use while breastfeeding.[62] A frequently updated review of scientific literature rates lamotrigine as L3: moderately safe.[63]
Other types of effects
Lamotrigine binds to melanin-containing tissues such as the iris of the eye or melanin-rich skin. The long-term consequences of this are unknown.[64]
Lamotrigine is known to affect sleep. Studies with small numbers of patients (10–15) reported that lamotrigine increases the duration of REM sleep, decreases the number of phase shifts, and decreases the duration of slow-wave sleep,[65] and that there was no effect on vigilance,[66] daytime somnolence and cognitive function.[67] 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.[68]
Lamotrigine can induce a type of seizure known as a
In overdose, lamotrigine can cause uncontrolled seizures in most people. Reported results in overdoses involving up to 15 g include increased seizures, coma, and death.[5]
Pharmacology
Mechanism of action
Lamotrigine is a member of the
It is a
Lamotrigine does not have pronounced effects on any of the usual neurotransmitter receptors that anticonvulsants affect (
These studies suggested that lamotrigine acts presynaptically on voltage-gated sodium channels to decrease glutamate release. Several electrophysiological studies have investigated the effects of lamotrigine on voltage-gated sodium channels. For example, lamotrigine blocked sustained repetitive firing in cultured mouse spinal cord neurons in a concentration-dependent manner, at concentrations that are therapeutically relevant in the treatment of human seizures. In cultured hippocampal neurons, lamotrigine reduced sodium currents in a voltage-dependent manner, and at depolarised potentials showed a small frequency-dependent inhibition. These and a variety of other results indicate that the antiepileptic effect of lamotrigine, like those of phenytoin and
The basis for this broader spectrum of activity of lamotrigine is unknown, but could relate to actions of the drug on
It antagonises these receptors with the following IC50 values:[5]
- 5-HT3, IC50 = 18 μM
- σ receptors, IC50 = 145 μM
Pharmacokinetics
The
Lamotrigine is inactivated by
Lamotrigine has fewer drug interactions than many anticonvulsant drugs, although pharmacokinetic interactions with carbamazepine, phenytoin and other hepatic enzyme inducing medications may shorten half-life.[83] Dose adjustments should be made on clinical response, but monitoring may be of benefit in assessing compliance.[5]
The capacity of available tests to detect potentially adverse consequences of melanin binding is unknown. Clinical trials excluded subtle effects and optimal duration of treatment. There are no specific recommendations for periodic ophthalmological monitoring. Lamotrigine binds to the eye and melanin-containing tissues which can accumulate over time and may cause toxicity. Prescribers should be aware of the possibility of long-term ophthalmologic effects and base treatment on clinical response. Patient compliance should be periodically reassessed with lab and medical testing of liver and kidney function to monitor progress or side effects.[5]
Chemistry
The first synthesis of lamotrigine was disclosed in a patent filed by the Wellcome Foundation in 1980.[84][85] 2,3-Dichlorobenzoyl chloride is treated with
History
- 1980 — initial patent filings are made by the Wellcome Foundation.[84]
- 1990 — lamotrigine is approved for use in Ireland to treat epilepsy.[12]
- 1991 — lamotrigine is used in the United Kingdom as an anticonvulsant medication[87]
- December 1994 — lamotrigine was approved for use in the United States for the treatment of partial seizures.[88]
- August 1998 — for use as adjunctive treatment of Lennox-Gastaut syndrome in pediatric and adult patients, new dosage form: chewable dispersible tablets.[citation needed]
- December 1998 — for use as monotherapy for treatment of partial seizures in adult patients when converting from a single enzyme-inducing anticonvulsant drug.[citation needed]
- 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 lithium.[citation needed]
- January 2004 — for use as monotherapy for treatment of partial seizures in adult patients when converting from the anti-epileptic drug valproic acid)[citation needed]
Society and culture
Brand names
Lamotrigine is sold under the original brand name Lamictal[5] and it is available in generic form under many brand names worldwide.[1][89]
Regulatory advisory in 2021
In March 2021, the United States Food and Drug Administration (FDA) issued a warning regarding the potential for cardiac arrhythmias in people with pre-existing structural or conduction heart defects.[90][91] The warning provoked consternation and controversy within the professional community.[92] An in-vitro study conducted in 2011 predicted Class IB antiarrhythmic activity at therapeutic concentrations of lamotrigine, due to its sodium channel-blocking activity.[93] Thus, lamotrigine use in at-risk populations could prolong the QRS interval on the electrocardiogram, and increase the risk of arrhythmias and sudden death. No references to human studies or postmarket data in at-risk populations (i.e., people with structural heart disease) were cited to support the warning. A study in dogs is mentioned in the prescribing information brochure by the manufacturer.[90] A rapid systematic review concluded that "there is insufficient evidence to support or refute that lamotrigine is associated with sudden death or electrocardiogram changes..."[94] The FDA has recommended that further studies are conducted with lamotrigine and other sodium-channel blocking antiseizure medications.[91]
In March 2023, a FAERS (FDA Adverse Event Reporting System) analysis demonstrated signals of cardiac arrest, but not of tachyarrhythmia or bradyarrhythmia nor their clinical manifestation as fainting in lamotrigine. The study stratified the epileptic and psychiatric indications, explaining that the nature of the signal for cardiac arrest seems to be confounded by the psychiatric indication, which included 2.5 times more concomitant medications with cardiac adverse events, such as QT-prolonging drugs. Additionally, a 1.5-fold greater reports on overdose and suicide attempts was recorded in the psychiatric reports. Although lamotrigine blocks the cardiac sodium channels at therapeutically relevant concentrations, owing to its short-fast kinetics at the channel level, this blockage did not translate into a disproportionality signal in this study.[95]
Research
Though lamotrigine has been used to treat seizures in infants, as of 2023, its effectiveness in this age group has been evaluated in only one study. Adverse effects were rarely severe enough for the medication to be discontinued in this age group, however, its effectiveness in reducing seizures was inconclusive.[96]
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