Lamdi

Uses

Lamdi is an antiepileptic drug (AED) used for:

Epilepsy (adjunctive therapy in patients aged 2 years and older):

• Partial: Onset seizures.
• Primary generalized tonic: Clonic seizures.
• Generalized seizures of Lennox: Gastaut syndrome.

Epilepsy (monotherapy in patients aged 16 years and older).Bipolar disorder in patients aged 18 years and older.

Lamdi is also used to associated treatment for these conditions: Bipolar 1 Disorder, Grand mal Generalized tonic-clonic seizure, Partial-Onset Seizures, Generalized seizure, Conversion to monotherapy

How Lamdi works

The exact mechanism of action of lamotrigine is not fully elucidated, as it may exert cellular activities that contribute to its efficacy in a range of conditions. Although chemically unrelated, lamotrigine actions resemble those of phenytoin and carbamazepine, inhibiting voltage-sensitive sodium channels, stabilizing neuronal membranes, thereby modulating the release of presynaptic excitatory neurotransmitters.

Lamdi likely acts by inhibiting sodium currents by selective binding to the inactive sodium channel, suppressing the release of the excitatory amino acid, glutamate. The mechanism of action of lamotrigine in reducing anticonvulsant activity is likely the same in managing bipolar disorder. Studies on lamotrigine have identified its binding to sodium channels in a fashion similar to local anesthetics, which could explain the demonstrated clinical benefit of lamotrigine in some neuropathic pain states.

Lamdi displays binding properties to several different receptors. In laboratory binding assays, it demonstrates weak inhibitory effect on the serotonin 5-HT3 receptor. Lamdi also weakly binds to Adenosine A1/A2 receptors, α1/α2/β adrenergic receptors, dopamine D1/D2 receptors, GABA A/B receptors, histamine H1 receptors, κ-opioid receptor (KOR), mACh receptors and serotonin 5-HT2 receptors with an IC50>100 µM. Weak inhibitory effects were observed at sigma opioid receptors. An in vivo study revealed evidence that lamotrigine inhibits Cav2.3 (R-type) calcium currents, which may also contribute to its anticonvulsant effects.

Dosage

Lamdi dosage

Monotherapy of seizures (adult and child over 16 years): Initially 25 mg once daily for 14 days, then 50 mg once daily for further 14 days, then increased by maximum 50 mg/day every 7-14 days; usual maintenance dose 225-375 mg/day in 1-2 divided doses.

Adjunctive therapy of seizures with Valproate:

• Adult and child over 12 years: Initially 25 mg on alternate days for 14 days, then 25 mg once daily for further 14 days, thereafter increased by maximum 25-50 mg/day every 7-14 days; usual maintenance, 100-200 mg/day in 1-2 divided doses.
• Child 2-12 years: Initially 150 mcg/kg/day in 1-2 divided doses for 14 days (those weighing under 13 kg may receive 2 mg on alternate days for first 14 days), then 300 mcg/kg/day in 1-2 divided doses for further 14 days, thereafter increased by maximum 300 mcg/kg/day every 7-14 days; usual maintenance 1-3 mg/kg/day in 1-2 divided doses.

Adjunctive therapy of seizures (with enzyme inducing drugs e.g., Carbamazepine, Phenytoin, Phenobarbital, or Primidone) without Valproate:

• Adult and child over 12 years: Initially 50 mg once daily for 14 days, then 50 mg twice daily for further 14 days, thereafter increased by maximum 100 mg/day in every 7-14 days; usual maintenance 300-500 mg daily in 2 divided doses.
• Child 2-12 years: Initially 600 mcg/kg/day in 2 divided doses for 14 days, then 1.2 mg/kg/day in 2 divided doses for further 14 days, thereafter increased by maximum 1.2 mg/kg/day in every 7-14 days; usual maintenance 5-15 mg/kg/day in 2 divided doses (maximum 400 mg/day in 2 divided doses).

Monotherapy therapy of bipolar disorder (without enzyme inducing Drugs) without Valproate:

• Adult over 18 years: Initially 25 mg once daily for 14 days, then 50 mg once daily for further 14 days, then 100 mg once daily for further 7 days; usual maintenance dose 200 mg once daily; maximum 200 mg daily.

Adjunctive therapy of bipolar disorder with valproate:

• Adult over 18 years: Initially 25 mg on alternate days for 14 days, then 25 mg once daily for further 14 days, then 50 mg once daily for further 7 days; usual maintenance dose 100 mg daily; maximum 100 mg daily.

Adjunctive therapy of bipolar disorder (with enzyme inducing drugs with enzyme inducing drugs e.g., Carbamazepine, Phenytoin, Phenobarbital, or Primidone) without Valproate:

• Adult over 18 years: Initially 50 mg once daily for 14 days, then 50 mg twice daily for further 14 days, then 100 mg twice daily for further 7 days, then 150 mg twice daily for further 7 days; usual maintenance 200 mg twice daily

Side Effects

Adult: Dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis, pharyngitis, and rash.

Children: Vomiting, diarrhea, infection, fever, abdominal pain, and tremor.

Toxicity

The oral LD50 in mouse and rat is 205 mg/kg and 245 mg/kg, respectively.

Fatal cases of overdose of up to 15g of lamotrigine have been reported. Overdose with lamotrigine has been manifested by ataxia, nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular conduction delay. Though no known antidote exists for lamotrigine, hospitalization and general supportive measures should be employed in the case of a suspected lamotrigine overdose. Gastric lavage and emesis may be warranted with simultaneous protection of the airway. It is uncertain at this time whether hemodialysis is an effective means of removing lamotrigine from the sytemic circulation.

Precaution

• Discontinue at the first sign of rash.
• Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia): May occur, either with or without an associated hypersensitivity syndrome. Monitor for signs of anemia, unexpected infection, or bleeding.
• Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors.
• Aseptic meningitis: Monitor for signs of meningitis.

Interaction

• Valproate increases lamotrigine concentrations more than 2-fold.
• Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin decrease lamotrigine concentrations by approximately 40%.
• Estrogen-containing oral contraceptives decrease lamotrigine concentrations by approximately 50%.
• Protease inhibitors lopinavir/ritonavir and atazanavir/lopinavir decrease lamotrigine exposure by approximately 50% and 32%, respectively.

Food Interaction

• Take with or without food. The absorption is unaffected by food.

[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.

Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Lamdi Drug Interaction

Moderate: aripiprazole, aripiprazole, duloxetine, duloxetine, escitalopram, escitalopram, pregabalin, pregabalin, alprazolam, alprazolamUnknown: amphetamine / dextroamphetamine, amphetamine / dextroamphetamine, quetiapine, quetiapine, cyanocobalamin, cyanocobalamin, cholecalciferol, cholecalciferol, lisdexamfetamine, lisdexamfetamine

Lamdi Disease Interaction

Major: depression, rashModerate: suicidal tendency, blood dyscrasias, heart disease, meningitis, renal/liver disease, PKU

Volume of Distribution

The mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranges from 0.9 to 1.3 L/kg and is independent of dose administered. Lamdi accumulated in the kidney of the male rat, and likely behaves in a similar fashion in humans. Lamdi also binds to tissues containing melanin, such as the eyes and pigmented skin.

Elimination Route

Lamdi is rapidly and entirely absorbed with minimal first-pass metabolism effects, with a bioavailability estimated at 98%. Cmax is reached in the range of 1.4 to 4.8 hours post-dose, but this depends on the dose administered, concomitant medications, and epileptic status. The rate and extent of lamictal absorption is considered equivalent between the compressed tablet form taken with water to that of the chewable dispersible tablets, taken with or without water.

Half Life

The average elimination half-life of lamotrigine ranges from approximately 14-59 hours. The value is dependent on the dose administered, concomitant drug therapy, as well as disease status. One pharmacokinetic study revealed a half-life of 22.8 to 37.4 hours in healthy volunteers. It also reported that enzyme-inducing antiepileptic drugs such as pheobarbital, phenytoin, or carbamazepine decrease the half-life of lamotrigine. On the other hand, valproic acid increases the half-life of lamotrigine (in the range of 48-59 hours).

Clearance

The mean apparent plasma clearance (Cl/F) ranges from 0.18 to 1.21 mL/min/kg. The values vary depending on dosing regimen, concomitant antiepileptic medications, and disease state of the individual. In one study, healthy volunteers on lamictal monotherapy showed a clearance of about 0.44 mL/min/kg after a single dose.

Elimination Route

Lamdi is excreted in both the urine and feces. Following oral administration of 240 mg radiolabelled lamotrigine, about 94% of total drug and its metabolites administered is recovered in the urine and 2% is recovered in the feces. One pharmacokinetic study recovered 43 to 87% of a lamotrigine dose in the urine mainly as glucuronidated metabolites. 2-N-glucuronide is mainly excreted in the urine.

Pregnancy & Breastfeeding use

Pregnancy category C. Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: Lamdi is present in milk from lactating women taking Lamdi.

Contraindication

Hypersensitivity (e.g., rash, angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients.

Special Warning

Hepatic impairment: Dosage adjustments required in patients with moderate and severe liver impairment.

Renal impairment: Reduced maintenance doses may be effective for patients with significant renal impairment.

Acute Overdose

Symptoms: Nystagmus and muscle hypertonicity, QRS interval prolongation, low-grade fever, erythema, and periorbital oedema, generalised tonic-clonic seizures, tremor, muscle weakness, ataxia, hypertonia.

Management: Gastric lavage and activated charcoal.

Storage Condition

Store below 30°C. Protect from light and moisture. Keep out of the reach of children

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