1. LAMICTAL HISTORY
How was Lamictal discovered?

Lamictal received U.S. Food and Drug Administration (FDA) approval in June 1999. 

Note: World-drugs.net sells generic version of Lamictal

2.LAMICTAL FACTS

GlaxoSmithKline (GSK) is a reputed research-based pharmaceutical company with a powerful combination of skills and resources that provides a platform for delivering strong growth in today's rapidly changing pharmaceutical environment.

GSK's aim is to improve the quality of human life by helping people to do more, feel better and live longer.

GlaxoSmithKline is headquartered in the UK and has operations based in the US; the new company is one of the industry leaders, with an estimated seven per cent of the world's pharmaceutical market.

GSK also has leadership in four major therapeutic areas - anti-infectives, respiratory, central nervous system (CNS) and gastro-intestinal/metabolic. In addition, it is a leader in the important area of vaccines and has a growing portfolio of oncology products.

GSK also has a Consumer Healthcare portfolio consisting of over-the-counter (OTC) medicines; oral care products and nutritional healthcare drinks, all of which are among the market leaders. 

3.ABOUT LAMICTAL MEDICATION

Lamictal tablets and dispersible tablets contain the active ingredient lamotrigine, which is a medicine used to treat epilepsy. Lamictal works by stabilising electrical activity in the brain.

The brain and nerves are made up of many nerve cells that communicate with each other through electrical signals. These signals must be carefully regulated for the brain and nerves to function properly. When abnormally rapid and repetitive electrical signals are released in the brain, the brain becomes over-stimulated and normal function is disturbed. This results in fits or seizures.

WORKING OF LAMICTAL 

Lamictal prevents epileptic fits by preventing excessive electrical activity in the brain. Lamictal does this by preventing sodium from entering nerve cells when they begin to fire rapid and repetitive electrical signals. A build up of sodium in the nerve cells is necessary for the electrical signal to build up and be passed on to other nerve cells. As Lamictal prevents this, it helps stabilize the electrical activity in the brain.

In addition to its licensed use for treating epilepsy, Lamictal is used off-license by speTadalafilts as a mood stabilizer for treating people with the psychiatric illness, bipolar affective disorder. This use is not licensed, but the medicine has been shown to be effective in people with bipolar disorder who have not responded to the traditional mood stabilizers (lithium, carbamazepine, valproate). It is not fully understood how Lamictal works in this illness, but is thought to be to do with the reduction of glutamate in the brain.

What is Epilepsy?

Epilepsy is a brain disorder in which clusters of nerve cells, or neurons, in the brain sometimes signal abnormally. In Epilepsy, the normal pattern of neuronal activity becomes disturbed, causing strange sensations, emotions, and behavior or sometimes convulsions, muscle spasms, and loss of consciousness. Epilepsy is a disorder with many possible causes. Anything that disturbs the normal pattern of neuron activity - from illness to brain damage to abnormal brain development - can lead to seizures. Epilepsy may develop because of an abnormality in brain wiring, an imbalance of nerve signaling chemicals called neurotransmitters, or some combination of these factors. Having a seizure does not necessarily mean that a person has Epilepsy. Only when a person has had two or more seizures is he or she considered having Epilepsy. EEGs and brain scans are common diagnostic test for Epilepsy.

Is there any treatment?

Once Epilepsy is diagnosed, it is important to begin treatment as soon as possible. For about 80 percent of those diagnosed with Epilepsy, seizures can be controlled with modern medicines and surgical techniques. Some antiepileptic drugs can interfere with the effectiveness of oral contraceptives. In 1997, the FDA approved the vagus nerve stimulator for use in people with seizures that are not well controlled by medication.

What is the prognosis?

Most people with Epilepsy lead outwardly normal lives. While Epilepsy cannot currently be cured, for some people it does eventually go away. Most seizures do not cause brain damage. It is not uncommon for people with Epilepsy, especially children, to develop behavioral and emotional problems, sometimes the consequence of embarrassment and frustration or bullying, teasing, or avoidance in school and other social setting. For many people with Epilepsy, the risk of seizures restricts their independence (some states refuse drivers licenses to people with Epilepsy) and recreational activities. People with Epilepsy are at special risk for two life-threatening conditions: status epilepticus and sudden unexplained death. Most women with Epilepsy can become pregnant, but they should discuss their Epilepsy and the medications they are taking with their doctors. Women with Epilepsy have a 90 percent or better chance of having a normal, healthy baby.

Antiepileptics or Anticonvulsants can be divided into older medications (called first-generation Anticonvulsants) and more recently developed medications (second-generation Anticonvulsants). 

First-Generation anticonvulsants
Phenytoin: This is one of the more commonly used agents and often is considered the first-line drug to treat partial and generalized tonic-clonic (grand mal) seizures and status epilepticus.

Phenytoin is thought to work by suppressing electrical activity in brain nerve cells. It can be given orally or intravenously (IV), and a newer form of the drug, fosphenytoin, can be injected into muscle. The oral form has the benefit of once-a-day dosing.

Carbamazepine : This drug is commonly prescribed for the treatment of partial and generalized tonic-clonic (grand mal) seizures. The mechanism by which it works is not well understood. In oral form, it can be taken 2 to 3 times a day; a recent development of the drug in sustained-release form allows for twice-a-day dosing.

Phenobarbital : This drug is used to treat both partial and generalized seizures. It also is used as part of the protocol after phenytoin use in status epilepticus as well as in neonatal Epilepsy. It is available in oral and intravenous forms.

Valproate : This is prescribed for partial seizures, generalized tonic-clonic (grand mal) seizures, absence (petit mal) seizures, and myoclonic Epilepsy. Its mechanism of action is thought to be related to the effect of a brain substance known as GABA (gamma-aminobutyric acid). It is available in oral form and must be taken 2 to 3 times per day for adequate dosing. 

Second-Generation anticonvulsants
Topiramate : This drug is used with other Anticonvulsant drugs in the treatment of partial seizures and generalized tonic-clonic seizures in adults and children aged 2 to 16. Its precise mechanism of action is unknown, but its Anticonvulsant activity may be due in part to increasing GABA (gamma-aminobutyric acid), a neurotransmitter that inhibits excitation of nerve cells in the brain. It is available in oral form, including sprinkles for children, and is taken twice daily. There are few drug interactions between topiramate and other medications or other Anticonvulsants.

Gabapentin : This drug is indicated for the adjunct treatment of partial seizures, with or without secondary generalization. Although it is structurally related to the substance GABA (gamma-aminobutyric acid), it does not interact with GABA receptors in the brain, and its mechanism of action is unknown. It is available in oral form and is taken 3 times daily. 

Lamotrigine: This drug is used for the adjunct treatment of partial seizures. Its precise mechanism of action is unknown. It is presently available in oral form and is taken twice daily. No laboratory monitoring of drug levels are necessary.

Tiagabine: This drug is indicated for adjunct therapy in adults with partial seizures. Its mechanism of action may be related to its effect on the brain substance GABA (gamma-aminobutyric acid). It is available in oral form and should be given in divided doses 2 to 4 times daily. Its metabolism may be altered when taken with other Anticonvulsants.

Levetiracetam : This drug is approved for use in adults as adjunct therapy for the treatment of partial seizure disorders. It is available in tablet form and as an oral solution for patients who prefer a liquid or cannot swallow tablets. Side effects can include fatigue, imbalance, and behavioral changes, which often dissipate after the first month of treatment.

Oxcarbazepine : This drug is indicated for monotherapy (used alone) and adjunct therapy (in addition to other medications) in adults who have partial seizures and as adjunct therapy in children aged 4 and older who have partial seizures. When used as monotherapy, Trileptal causes very few of the side effects associated with other AEDs.

Zonisamide : This drug is approved for use in adults as adjunct therapy for partial seizures. It has however, been used fairly extensively in other countries for use in other seizure types including generalized seizures, myoclonic seizures, and absence seizures. Patients who are allergic to sulfonamide drugs should not use zonisamide because it is a derivative of this class of drug.

Ethosuximide: This agent is used to treat absence (petit mal) seizures. It is thought to work by suppressing brain cell activity that is associated with lapses of consciousness. It is given orally and is available as a tablet or flavored syrup.

Primidone : This drug is a barbiturate that contains phenobarbitol. It is used to control generalized tonic-clonic (grand mal) seizures and partial seizures and is used in adults and children over 8 years old. Primidone is not known to interact with other drugs. It is present in breast milk and is associated with neonatal hemorrhage and coagulation defects similar to vitamin K deficiency. Patients hypersensitive to phenobarbital should not take primidone. 

4.LAMICTAL EFFECTIVENESS
When is Lamictal best taken?

The pharmacokinetics of Lamictal have been studied in patients with Epilepsy, healthy young and elderly volunteers, and volunteers with chronic renal failure. 

Lamictal is rapidly and completely absorbed after oral administration with negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration. The Lamictal chewable/dispersible tablets were found to be equivalent, whether they were administered as dispersed in water, chewed and swallowed, or swallowed as whole, to the lamotrigine compressed tablets in terms of rate and extent of absorption.

Estimates of the mean apparent volume of distribution (Vd/F) of Lamictal following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with Epilepsy and in healthy volunteers.

5.LAMICTAL EFFECTS ON SPECIAL POPULATION
(How do different people react to Lamictal?)

Pregnancy : Lamictal should not be used during pregnancy.

Labor and Delivery: The effect of Lamictal on labor and delivery in humans is unknown.

Use in Nursing Mothers : Preliminary data indicate that lamotrigine passes into human milk. Because the effects on the infant exposed to Lamictal by this route are unknown, breast-feeding while taking Lamictal is not recommended.

Pediatric Use : Lamictal is indicated as adjunctive therapy for partial seizures in patients above 2 years of age and for the generalized seizures of Lennox-Gastaut syndrome. Safety and effectiveness for other uses in patients with Epilepsy below the age of 16 years have not been established.

Safety and effectiveness in patients below the age of 18 years with Bipolar Disorder has not been established.

Geriatric Use : Clinical studies of Lamictal for Epilepsy and in Bipolar Disorder did not include sufficient numbers of subject's aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy

6.LAMICTAL EFFECTS ON MEDICAL CONDITIONS
(How does Lamictal affect your existing condition/ailment?)

Patients With Renal Insufficiency: Twelve volunteers with chronic renal failure (mean creatinine clearance = 13 mL/min; range = 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100-mg dose of Lamictal. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared to 26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the amount of Lamictal present in the body was eliminated by hemodialysis during a 4-hour session.

Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose of Lamictal were evaluated in 24 subjects with moderate to severe hepatic dysfunction and compared with 12 subjects without hepatic impairment. The median apparent clearance of Lamictal was 0.31, 0.24, or 0.10 mL/kg/min in patients with Grade A, B, or C (Child-Pugh Classification) hepatic impairment, respectively, compared to 0.34 mL/kg/min in the healthy controls. Median half-life of Lamictal was 36, 60, or 110 hours in patients with Grade A, B, or C hepatic impairment, respectively, versus 32 hours in healthy controls. 

7.OTHER/ALTERNATE USES OF LAMICTAL
(What else does Lamictal treat?)

Lamictal is also used for treating episodes of high or low mood and for helping to prevent episodes of ill health in these people.

8.ADVERSE/SIDE EFFECTS of LAMICTAL
What are the side effects of Lamictal?

Serious rash requiring hospitalization and discontinuation of Lamictal, including Stevens-Johnson syndrome and toxic Epidermal necrolysis, have occurred in association with therapy with Lamictal. Rare deaths have been reported, but their numbers are too few to permit a precise estimate of the rate.

Most Common Adverse Events in All Clinical Studies:
Adjunctive Therapy in Adults With Epilepsy: The most commonly observed (=5%) adverse experiences seen in association with Lamictal during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with Lamictal than in patients receiving other EIAEDs with Lamictal. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate.

Approximately 11% of the 3,378 adult patients who received Lamictal as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse experience. The adverse events most commonly associated with discontinuation were rash (3.0%), dizziness (2.8%), and headache (2.5%).

In a dose response study in adults, the rate of discontinuation of Lamictal for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related. 

Monotherapy in Adults With Epilepsy:
The most commonly observed adverse experiences seen in association with the use of Lamictal during the monotherapy phase of the controlled trial in adults not seen at an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed adverse experiences associated with the use of Lamictal during the conversion to monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia, nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.

Approximately 10% of the 420 adult patients who received Lamictal as monotherapy in premarketing clinical trials discontinued treatment because of an adverse experience. The adverse events most commonly associated with discontinuation were rash (4.5%), headache (3.1%), and asthenia (2.4%).

Adjunctive Therapy in Pediatric Patients With Epilepsy:
The most commonly observed (³5%) adverse experiences seen in association with the use of Lamictal as adjunctive treatment in pediatric patients and not seen at an equivalent rate in the control group were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia.

In 339 patients age 2 to 16 years, 4.2% of patients on Lamictal and 2.9% of patients on placebo discontinued due to adverse experiences. The most commonly reported adverse experiences that led to discontinuation were rash for patients treated with Lamictal and deterioration of seizure control for patients treated with placebo.

Approximately 11.5% of the 1,081 pediatric patients who received Lamictal as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse experience. The adverse events most commonly associated with discontinuation were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%).

Incidence in Controlled Clinical Studies of Epilepsy:
The prescriber should be aware that the figures in Tables 1, 2, 3, and 4 cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied.

Incidence in Controlled Adjunctive Clinical Studies in Adults With Epilepsy:
Table 1 lists treatment-emergent signs and symptoms that occurred in at least 2% of adult patients with Epilepsy treated with Lamictal in placebo-controlled trials and were numerically more common in the patients treated with Lamictal. In these studies, either Lamictal or placebo was added to the patient's current AED therapy. Adverse events were usually mild to moderate in intensity.

In a randomized, parallel study comparing placebo and 300 and 500 mg/day of Lamictal, some of the more common drug-related adverse events were dose related (see Table 2).

Other events that occurred in more than 1% of patients but equally or more frequently in the placebo group included: asthenia, back pain, chest pain, flatulence, menstrual disorder, myalgia, paresthesia, respiratory disorder, and urinary tract infection.

The overall adverse experience profile for Lamictal was similar between females and males, and was independent of age. Because the largest non-Caucasian racial subgroup was only 6% of patients exposed to Lamictal in placebo-controlled trials, there are insufficient data to support a statement regarding the distribution of adverse experience reports by race. Generally, females receiving either adjunctive Lamictal or placebo were more likely to report adverse experiences than males. The only adverse experience for which the reports on Lamictal were greater than 10% more frequent in females than males (without a corresponding difference by gender on placebo) was dizziness (difference = 16.5%). There was little difference between females and males in the rates of discontinuation of Lamictal for individual adverse experiences.

Other events that occurred in 5% or more patients but equally or more frequently in the placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury, diarrhea, and dyspepsia.

Adverse events that occurred with a frequency of less than 5% and greater than 1% of patients receiving Lamictal and numerically more frequent than placebo were:

General : Fever, neck pain.
Cardiovascular : Migraine.
Digestive : Flatulence.
Metabolic and Nutritional : Weight gain, edema.
Musculoskeletal: Arthralgia, myalgia.
Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal thoughts, dream abnormality, hypoesthesia.
Urogenital : Urinary frequency.
Endocrine System: Rare: Goiter and hypothyroidism.
Respiratory System: Infrequent: Yawn. Rare: Hiccup and hyperventilation. Special Senses: Frequent: Amblyopia. Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, and tinnitus. Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, and visual field defect.
Urogenital System: Infrequent: Abnormal ejaculation, breast pain, hematuria, impotence, menorrhagia, polyuria, urinary incontinence, and urine abnormality. Rare: Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency, and vaginal moniliasis.