Lamotrigine (marketed as
Lamictal by
GlaxoSmithKline GlaxoSmithKline plc is a United Kingdom-based pharmaceutical, biological, and healthcare company. GSK is the world's second largest pharmaceutical company and a research-based company with a wide portfolio of pharmaceutical products covering anti-infectives, central nervous system, respiratory,...
, called
Lamictin in
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,
(
Lamogine) in
IsraelIsrael officially the State of Israel , is a developed state in Western Asia located on the eastern shore of the Mediterranean Sea. It borders Lebanon in the north, Syria in the northeast, Jordan in the east, and Egypt on the southwest, and contains geographically diverse features within its...
, and
in
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and also Lamitor) is an
anticonvulsantThe anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers. The goal of an anticonvulsant is to suppress the rapid and...
drug used in the treatment of
epilepsyEpilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures...
and
bipolar disorderBipolar disorder, also known as manic depressive disorder, manic depression or bipolar affective disorder, is a serious mental disorder that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated mood clinically referred to as mania or, if...
. For epilepsy it is used to treat partial seizures, primary and secondary
tonic-clonic seizureTonic–clonic seizures are a type of generalized seizure that affects the entire brain. Formerly known as grand mal seizures or gran mal seizures, these terms are now discouraged and rarely used in a clinical setting...
s, and seizures associated with
Lennox-Gastaut syndromeLennox–Gastaut syndrome , also known as Lennox syndrome, is a difficult-to-treat form of childhood-onset epilepsy that most often appears between the second and sixth year of life, and is characterized by frequent seizures and different seizure types; it is often accompanied by mental retardation...
. Lamotrigine also acts as a
mood stabilizerA mood stabilizer is a psychiatric medication used to treat mood disorders characterized by intense and sustained mood shifts, which is not the same as "feeling good one minute and then bad the next."-Uses:...
. It is approved for the maintenance treatment of
bipolar type IBipolar disorder, also known as manic depressive disorder, manic depression or bipolar affective disorder, is a serious mental disorder that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated mood clinically referred to as mania or, if...
. Chemically unrelated to other anticonvulsants (due to Lamotrigine being a
PhenyltriazinePhenyltriazines are a class of molecules containing a phenyl group and a triazine group. These molecules are pharmacologically important. Lamotrigine is a phenyltriazine derivative used as an anticonvulsant drug and has been shown to be useful for alleviating bipolar disorder....
), lamotrigine has relatively few side-effects and does not require
bloodBlood is a specialized bodily fluid that delivers necessary substances to the body's cells — such as nutrients and oxygen — and transports waste products away from those same cells....
monitoring in monotherapy. The exact way lamotrigine works is unknown. Some think that it is a Na
+ (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.
OxcarbazepineOxcarbazepine is an anticonvulsant and mood stabilizing drug, used primarily in the treatment of epilepsy. It is also used to treat anxiety and mood disorders, and benign motor tics...
), which may suggest that lamotrigine has a different mechanism of action. The drug information provided at the time of prescription notes that "it is thought to work by restoring the balance of certain natural substances (neurotransmitters) in the brain." Lamotrigine is inactivated by
hepaticThe liver is a vital organ present in vertebrates and some other animals; it has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
glucuronidation.
U.S. Food and Drug Administration approval history
- December 1994 - Lamotrigine was approved for the treatment of partial seizures.
- 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 2 years of age.
- June 2003 - Lamotrigine approved for maintenance treatment of Bipolar I disorder
Bipolar I disorder is a mood disorder that is characterized by at least one manic or mixed episode. There may be episodes of hypomania or major depression as well...
; the first since lithiumLithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number three. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
.
- 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)).
Epilepsy and seizures
Lamotrigine is approved in the US for the treatment of partial seizures. Lamotrigine is one of a small number of FDA-approved therapies for seizures associated with
Lennox-Gastaut syndromeLennox–Gastaut syndrome , also known as Lennox syndrome, is a difficult-to-treat form of childhood-onset epilepsy that most often appears between the second and sixth year of life, and is characterized by frequent seizures and different seizure types; it is often accompanied by mental retardation...
, a severe form of
epilepsyEpilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures...
. 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 seizureAtonic seizures , are a minor type of seizure. They consist of a brief lapse in muscle tone that are caused by temporary alterations in brain function. The seizures are brief - usually less than fifteen seconds. They begin in childhood and may persist into adulthood...
(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. 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.
Lamotrigine is also used as first line therapy for childhood absence epilepsy.
Bipolar disorder
Lamotrigine is approved in the US for maintenance treatment of
Bipolar I disorderBipolar I disorder is a mood disorder that is characterized by at least one manic or mixed episode. There may be episodes of hypomania or major depression as well...
. While traditional
anticonvulsantThe anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers. The goal of an anticonvulsant is to suppress the rapid and...
drugs are predominantly antimanics, lamotrigine is most effective in the treatment and prophylaxis of bipolar depression. Lamotrigine treats bipolar depression without triggering
maniaMania is a severe medical condition characterized by extremely elevated mood, energy, unusual thought patterns and sometimes psychosis...
, hypomania, mixed states, or
rapid-cyclingBipolar disorder, also known as manic depressive disorder, manic depression or bipolar affective disorder, is a serious mental disorder that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated mood clinically referred to as mania or, if...
. It has not demonstrated efficacy in the treatment of acute mania. The 2002 American Psychiatric Association guidelines recommended lamotrigine as a first-line treatment for acute depression in bipolar disorder as well as a maintenance therapy.
However, lamotrigine is not indicated
on label for the treatment of acute bipolar symptoms. Because the dosage must be slowly increased from a sub-therapeutic level to the therapeutic level, the drug's utility in the management of acute manic symptoms is debatable; typically
benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s or another anticonvulsant will be used to manage the acute mania until the lamotrigine reaches therapeutic blood concentration.
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 corelation to suicide until remission attains therapeutically acceptable levels.
Other uses
Off-label uses include the treatment of
peripheral neuropathyPeripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of the nerve or from the side-effects of systemic illness....
,
trigeminal neuralgiaSee also: Atypical trigeminal neuralgiaTrigeminal neuralgia , "The Suicide Disease" or tic douloureux is a neuropathic disorder of one or both of the facial trigeminal nerves. It causes episodes of intense pain in any or all of the following: the ear, eye, lips, nose, scalp, forehead, teeth or jaw...
,
cluster headacheCluster headache, nicknamed "suicide headache", is a neurological disease that involves, as its most prominent feature, an immense degree of pain. "Cluster" refers to the tendency of these headaches to occur periodically, with active periods interrupted by spontaneous remissions. The cause of the...
s,
migraineMigraine is a neurological syndrome characterized by altered bodily perceptions, severe headaches, and nausea. Physiologically, the migraine headache is a neurological condition more common to women than to men. The word migraine was borrowed from Old French migraigne...
s, and reducing neuropathic pain.
Off-label psychiatric usage includes the treatment of
depersonalization disorderDepersonalization disorder is a dissociative disorder in which the sufferer is affected by persistent or recurrent feelings of depersonalization and/or derealization...
,
bipolar IIBipolar disorder, also known as manic depressive disorder, manic depression or bipolar affective disorder, is a serious mental disorder that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated mood clinically referred to as mania or, if...
disorders,
schizoaffective disorderSchizoaffective disorder is a psychiatric diagnosis that describes a mental disorder characterized by recurring episodes of mood disorder and psychosis. Distortions in perception alternate with and occur simultaneously with elevated or depressed mood...
,
borderline personality disorderBorderline personality disorder is a psychiatric diagnosis in the Diagnostic and Statistical Manual of Mental Disorders that describes a prolonged disturbance of personality function characterized by depth and variability of moods...
, Post Traumatic Stress Disorder
, and as adjunctive therapy for treatment refractory
unipolar depressionMajor depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and loss of interest or pleasure in normally enjoyable activities...
.
Mechanism of action
One proposed mechanism of action for lamotrigine involves an effect on sodium channels, 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).
Pharmacokinetics
The
pharmacokineticsPharmacokinetics is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
of lamotrigine are quite complicated, with highly varying
half-lifeHalf-life is the period of time, for a substance undergoing decay, to decrease by half. The name originally was used to describe a characteristic of unstable atoms , but may apply to any quantity which follows a set-rate decay....
and
blood plasmaBlood plasma is the yellow liquid component of blood, in which the blood cells in whole blood would normally be suspended. It makes up about 55% of the total blood volume. It is mostly water and contains dissolved proteins, glucose, clotting factors, mineral ions, hormones and carbon dioxide...
levels.
Lamotrigine has fewer drug interactions than many
anticonvulsantThe anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers. The goal of an anticonvulsant is to suppress the rapid and...
drugs, although pharmacokinetic interactions with
Sodium ValproateSodium valproate or valproate sodium is the sodium salt of valproic acid and is an anticonvulsant used in the treatment of epilepsy and bipolar disorder, as well as other psychiatric conditions requiring the administration of a mood stabilizer...
in particular is an indication for blood monitoring.
Side effects
Lamotrigine prescribing information has a
black box warningIn the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
about life threatening skin reactions, including
Stevens-Johnson SyndromeStevens–Johnson syndrome is a life-threatening condition affecting the skin in which cell death causes the epidermis to separate from the dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes...
and
Toxic Epidermal NecrolysisToxic epidermal necrolysis , also known as Lyell's syndrome, is a life-threatening dermatological condition that is frequently induced by a reaction to medications...
. 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 SyndromeStevens–Johnson syndrome is a life-threatening condition affecting the skin in which cell death causes the epidermis to separate from the dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes...
or
Toxic Epidermal NecrolysisToxic epidermal necrolysis , also known as Lyell's syndrome, is a life-threatening dermatological condition that is frequently induced by a reaction to medications...
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
headacheIn medicine a headache or cephalalgia is a symptom of a number of different conditions of the head. Some of the causes are benign while others are medical emergencies.There are a number of different classification systems for headaches...
s,
dizzinessDizziness refers to an impairment in spatial perception and stability. It is considered imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or for a non-specific feeling such as giddiness or foolishness....
and
insomniaInsomnia is a symptom of any of several sleep disorders, characterized by persistent difficulty falling asleep or staying asleep despite the opportunity. Insomnia is a symptom, not a stand-alone diagnosis or a disease. By definition, insomnia is "difficulty initiating or maintaining sleep, or both"...
. Other side effects may include
acneAcne is a group of skin rashes that have different causes.* Acne vulgaris - most commonly experienced around puberty, typically of the face and shoulders/chest* Cystic acne, a severe form of acne wherein small cysts form...
and skin irritation, vivid dreams or
nightmareA nightmare is an unpleasant dream. Nightmares cause a strong unpleasant emotional response from the sleeper, typically fear or horror. The dream may contain a situation of extreme danger, or sensations of pain, bad events, falling, drowning, being raped, becoming disabled, losing loved ones,...
s, night sweats, body aches and cramps,
muscle achesMyalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections...
, dry mouth, mouth ulcers, damage to tooth enamel, fatigue,
memoryIn psychology, memory is an organism's mental ability to store, retain, and recall information. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing the memory....
and cognitive problems,
irritabilityIrritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli....
, weight changes, hair loss, changes in
libidoLibido in its common usage means sexual desire; however, more technical definitions, such as those found in the work of Carl Jung, are more general, referring to libido as the free creative—or psychic—energy an individual has to put toward personal development or individuation.- History of the...
, frequent urination,
nauseaNausea is the sensation of unease and discomfort in the stomach with an urge to vomit.-Causes:...
, appetite changes and other side effects. In very rare cases, Lamotrigine has been known to cause the development of a dangerous
rashA rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, dry, cracked or blistered, swell and may be painful. The causes, and therefore...
called
Stevens-Johnson syndromeStevens–Johnson syndrome is a life-threatening condition affecting the skin in which cell death causes the epidermis to separate from the dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes...
(or SJS). The rash is more common in children, so this medication is often reserved for adults. There is also an increased incidence of this rash 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.
Effects in women
In clinical trials women were more likely than men to have side effects. This is the opposite of most other
anticonvulsantThe anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers. The goal of an anticonvulsant is to suppress the rapid and...
s and
antipsychoticAntipsychotics are a group of psychoactive drugs commonly but not exclusively used to treat psychosis, which is typified by schizophrenia, but can also be present in severe bipolar disorder, as well as many other conditions. Over time a wide range of antipsychotics have been developed...
s.
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. Women starting an estrogen-containing oral contraceptive may need to increase the dosage of lamotrigine to maintain its level of efficacy. Similarily, 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 two-fold. Another study showed a significant increase in follicle stimulating hormone (FSH) and
luteinizing hormoneLuteinizing hormone is a hormone produced by the anterior pituitary gland.* In the female, an acute rise of LH – the LH surge – triggers ovulation and corpus luteum development....
(LH) in women taking lamotrigine with oral contraceptive compared to women taking oral contraceptives alone. However, these increases were not in conjunction with increased progesterone, indicating that oral contraceptives maintained suppression of ovulation.
Use during pregnancy is recommended only if benefits outweigh potential risks. It was also reported on
CNNCable News Network, almost always referred to by its initialism CNN, is an U.S. cable news network founded in 1980 by Ted Turner. Upon its launch, CNN was the first network to provide 24-hour television news coverage, and the first all-news television network in the United States...
in September 2006 that taking Lamictal during the first trimester of pregnancy can lead to a cleft palate in babies. Lamotrigine is found in
breast milkHuman breast milk refers to the milk produced by a mother to feed her baby. It provides the primary source of nutrition for newborns before they are able to eat and digest other foods; older infants and toddlers may continue to be breastfed...
;
breastfeedingBreastfeeding is the feeding of an infant or young child with breast milk directly from human breasts rather than from a baby bottle or other container. Babies have a sucking reflex that enables them to suck and swallow milk...
is not recommended during treatment.
Lamotrigine can inhibit sleep. It is best taken in the morning.
Other types of effects
Lamotrigine binds to
melaninMelanin is a class of compounds found in plants, animals, and protists, where it serves predominantly as a pigment. The class of pigments are derivatives of the amino acid tyrosine. Many melanins are insoluble salts and show affinity to water...
-containing tissues such as the iris of the eye. The long-term consequences of this are unknown.
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 GlaxoSmithKline plc is a United Kingdom-based pharmaceutical, biological, and healthcare company. GSK is the world's second largest pharmaceutical company and a research-based company with a wide portfolio of pharmaceutical products covering anti-infectives, central nervous system, respiratory,...
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.
Lamotrigine can induce a type of seizure known as a Myoclonic Jerk. When used in the treatment of myoclonic epilepsies such as
Juvenile myoclonic epilepsyJuvenile myoclonic epilepsy , also known as Janz syndrome, is a fairly common form of idiopathic generalized epilepsy, representing 5-10% of all epilepsies. This disorder typically first manifests itself between the ages of 12 and 18 with myoclonus occurring early in the morning. Most patients also...
, 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 epilepticusStatus epilepticus refers to a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 30 minutes , or recurrent seizures without regaining consciousness between...
(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.
Availability
GlaxoSmithKline's trademarked brand of Lamotrigine, Lamictal, is manufactured in scored tablets (25 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
titrationTitration is a common laboratory method of quantitative chemical analysis that is used to determine the unknown concentration of a known reactant...
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.Teva Pharmaceutical Industries Ltd. , is an international pharmaceutical company headquartered in Petah Tikva, Israel. It specializes in generic and proprietary pharmaceuticals and active pharmaceutical ingredients. It is the largest generic drug manufacturer in the world and one of the 20 largest...
began selling generic Lamotrigine in the United States, but only in 5 mg and 25 mg chewable dispersible tablets. On 23 July 2008 Teva began offering the full line of generic Lamotrigine in the US. Lamotrigine is also available in generic form in the United States, the
United KingdomThe United Kingdom of Great Britain and Northern Ireland is a sovereign state located off the northwestern coast of continental Europe. It is an island country, spanning an archipelago including Great Britain, the northeastern part of Ireland, and many small islands...
and Canada.
External links