Bipolar Disorder: Lamotrigine is indicated for the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes).

CONTRAINDICATIONS: Lamotrigine is contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients.

DESCRIPTION: Lamotrigine, an antiepileptic drug (AED) of the phenyltriazine class, is chemically unrelated to existing antiepileptic drugs.

CLINICAL PHARMACOLOGY:

Mechanism of Action: 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 (e.g., glutamate and aspartate).

Pharmacological Properties:  Lamotrigine had a weak inhibitory effect on the serotonin 5-HT ₃ receptor (IC ₅₀ = 18 µM). It does not exhibit high affinity binding (IC ₅₀ >100 µM) to the following neurotransmitter receptors: adenosine A ₁ and A ₂ ; adrenergic (alpha)1, (alpha)2, and (beta); dopamine D ₁ and D ₂ ; (gamma)-aminobutyric acid (GABA) A and B; histamine H ₁ ; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT ₂ .

Folate Metabolism:    In vitro, Lamotrigine was shown to be an inhibitor of dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins.

Absorption: Lamotrigine 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. Distribution: Estimates of the mean apparent volume of distribution (Vd/F) of Lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Protein Binding: Data from in vitro studies indicate that Lamotrigine is approximately 55% bound to human plasma proteins. Drug Disposition: Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate.

Patients With Renal Insufficiency:

Hepatic Disease:

Age: Pediatric Patients: Population pharmacokinetic analyses involving patients aged 2 to 18 years demonstrated that Lamotrigine clearance was influenced predominantly by total body weight and concurrent AED therapy.

WARNINGS:

Serious Rash: The incidence of serious rash associated with hospitalization and discontinuation of Lamotrigine in pediatric patients with epilepsy receiving adjunctive therapy was approximately 0.8% (16 of 1,983). There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients. Adult Population: Serious rash associated with hospitalization and discontinuation of Lamotrigine occurred in 0.3% (11 of 3,348).

There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults. ACCORDINGLY, LAMOTRIGINE SHOULD ORDINARILY BE DISCONTINUED AT THE FIRST SIGN OF RASH, UNLESS THE RASH IS CLEARLY NOT DRUG RELATED. DISCONTINUATION OF TREATMENT MAY NOT PREVENT A RASH FROM BECOMING LIFE THREATENING OR PERMANENTLY DISABLING OR DISFIGURING.

Hypersensitivity Reactions: Hypersensitivity reactions, some fatal or life threatening, have also occurred.

Acute Multiorgan Failure: Multiorgan failure, which in some cases has been fatal or irreversible, has been observed in patients receiving Lamotrigine.

Blood Dyscrasias: There have been reports of blood dyscrasias that may or may not be associated with the hypersensitivity syndrome.

Withdrawal Seizures: In patients with epilepsy there is a possibility of increasing seizure frequency.

PRECAUTIONS:

Serious rashes: There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of Lamotrigine with valproate, (2) exceeding the recommended initial dose of Lamotrigine, or (3) exceeding the recommended dose escalation for Lamotrigine. Although most rashes resolved even with continuation of treatment with Lamotrigine, it is not possible to predict reliably which rashes will prove to be serious or life threatening.

Sudden Unexplained Death in Epilepsy (SUDEP): Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night.

Suicide: The possibility of a suicide attempt is inherent in Bipolar Disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for Lamotrigine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Use in Patients With Concomitant Illness: Caution is advised when using Lamotrigine in patients with diseases or conditions that could affect metabolism or elimination of the drug, such as renal, hepatic, or cardiac functional impairment.

Binding in the Eye and Other Melanin-Containing Tissues: Because Lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that Lamotrigine may cause toxicity in these tissues after extended use.

Information for Patients: Prior to initiation of treatment with Lamotrigine, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately. In addition, the patient should notify his or her physician if worsening of seizure control occurs.

Patients should be advised that Lamotrigine may cause dizziness, somnolence, and other symptoms and signs of central nervous system (CNS) depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on Lamotrigine to gauge whether or not it adversely affects their mental and/or motor performance.

Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physicians if they intend to breast-feed or are breast-feeding an infant.

Laboratory Tests: In general, clinical judgment should be exercised regarding monitoring of plasma levels of Lamotrigine and other anti-seizure drugs and whether or not dosage adjustments are necessary.

Pregnancy: Pregnancy Category C.

Nursing Mothers: Preliminary data indicate that Lamotrigine passes into human milk.Breast-feeding while taking Lamotrigine is not recommended.

Pediatric Use: Safety and effectiveness for other uses in patients with epilepsy below the age of 16 years have not been established.

Geriatric Use: 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.

Drug Interactions:

Other Psychotropic Drugs Added to Lamotrigine: Results of in vitro experiments suggest that clearance of Lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone.

Interactions With Folate Inhibitors: Lamotrigine is an inhibitor of dihydrofolate reductase.

Interactions With Oral Contraceptives: In women taking Lamotrigine, there have been reports of decreased Lamotrigine concentrations following introduction of oral contraceptives and reports of increased Lamotrigine concentrations following withdrawal of oral contraceptives.

SIDE EFFECTS:

Treatment-Emergent Adverse Event Incidence in Placebo-Controlled Adjunctive Trials in Adult Patients With Epilepsy (n = 711)  Percent of Patients Receiving Adjunctive Lamotrigine:
   Headache 29,  Flu syndrome 7,  Fever 6,  Abdominal pain 5, Neck pain         2,

  Reaction aggravated (seizure exacerbation) 2,  Nausea 19, Vomiting 9,

  Diarrhea 6, Dyspepsia 5, Constipation 4, Tooth disorder 3, Anorexia 2, Arthralgia 2,

  Dizziness 38, Ataxia 22, Somnolence 14, Incoordination          6, Insomnia 6, Tremor         4,

  Depression 4, Anxiety 4, Convulsion 3, Irritability 3, Speech disorder 3, Concentration disturbance 2, Rhinitis 14, Pharyngitis 10,  Cough increased 8,

  Rash 10, Pruritus 3, Diplopia        28, Blurred vision 16, Vision abnormality     3,

  Female patients only (n = 365) Dysmenorrhea 7, Vaginitis 4, Amenorrhea 2.

Treatment-Emergent Adverse Event Incidence in Pediatric Patients With Epilepsy (n = 168):

Infection 20, Fever 15, Accidental injury 14, Abdominal pain 10, Asthenia 8, Flu syndrome 7, Pain 5, Vomiting 20, Diarrhea 11, Nausea 10, Constipation 4, Somnolence 17, Dizziness 14, Ataxia 11, Tremor 10, Emotional lability 4,

Gait abnormality 4, Thinking abnormality 3, Pharyngitis 14, Bronchitis 7,

Increased cough 7, Rash 14, Diplopia 5, Blurred vision 4, Urinary tract infection          3,

Penis disorder 4.

Treatment-Emergent Adverse Event Incidence  in Adults With Bipolar I Disorder

Back pain 8, Fatigue 8, Abdominal pain 6, Nausea 14, Constipation 5, Vomiting 5

Insomnia 10, Somnolence 9, Xerostomia (dry mouth) 6, Rhinitis 7, Exacerbation of cough 5, Pharyngitis 5, Rash (non serious) 7

OVERDOSAGE:

Human Overdose Experience: Overdoses involving quantities up to 15 g have been reported for Lamotrigine, some of which have been fatal. Overdose has resulted in ataxia, nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular conduction delay.

Management of Overdose: There are no specific antidotes for Lamotrigine. Following a suspected overdose, hospitalization of the patient is advised. General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient. If indicated, emesis should be induced or gastric lavage should be performed; usual precautions should be taken to protect the airway. It should be kept in mind that Lamotrigine is rapidly absorbed. It is uncertain whether hemodialysis is an effective means of removing Lamotrigine from the blood.

DOSAGE AND ADMINISTRATION:

 Adults in epilepsy; 50 mg daily for 2 weeks, then a total of 100 mg Bid for 2 weeks. The dose is usually not more than 500 mg a day. Adults taking other anticonvulsant drugs 25 mg once every other day for 2 weeks, then 25 mg daily for 2 weeks. The dose is usually not more than 400 mg a day. In Bipolar; Weeks 1 and 2, 25 mg daily and increase 25 mg/day every week, maximum daily 200 mg. In taking other anticonvulsant drugs half dosage of this.

Children 2 to 12 years of age: 0.6 mg/kg daily for 2 weeks, then 1.2 mg/kg Bid for 2 weeks. The dose is usually not more than 400 mg a day. Children taking other anticonvulsant drugs 0.15 mg/kg daily Bid for 2 weeks, then 0.3 mg/kg daily or Bid for 2 weeks. The dose is usually not more than 200 mg a day.  

How Supplied: Each Pack of Ruz-Lamotrigine 25 mg or 50 mg or 100 mg tablets contain 100 tablets in 10 blisters.

storage: Store at 25°C in a dry place.

Reference: PDR 2000, page 1208-14

                  USPDI Vol for Professional Health Care, 2004, Page 1720-4

                  Martindale 2005, Page 363-6