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Product Name
:
LAMITREE
Chemical Name
:
Lamotrigine
Therapeutic Category
:
Central nervous system drugs
Pharmacologic Category
:
Anticonvulsant, Miscellaneous
Pharmaceutical Form
:
Tablets
Composition
:
Lamotrigine 25 mg / 100mg / 150mg
Dosing
 
Dosing: Adult
Note: Only whole tablets should be used for dosing, round calculated dose down to the nearest whole tablet. Enzyme-inducing regimens specifically refer to those containing carbamazepine, phenytoin, phenobarbital, or primidone.
Lennox-Gastaut (adjunctive), primary generalized tonic-clonic seizures (adjunctive) or partial seizures (adjunctive): Oral:
Immediate release formulations:
Regimens not containing carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid: Initial: Week 1 and 2: 25 mg once daily; Week 3 and 4: 50 mg once daily; Week 5 and beyond: Increase by 50 mg/day every 1-2 weeks; Maintenance: 225-375 mg/day in 2 divided doses
Regimens containing valproic acid: Initial: Week 1 and 2: 25 mg every other day; Week 3 and 4: 25 mg once daily; Week 5 and beyond: Increase by 25-50 mg/day every 1-2 weeks; Maintenance: 100-200 mg/day (valproic acid alone) or 100-400 mg/day (valproic acid and other drugs that induce glucuronidation)
Regimens containing carbamazepine, phenytoin, phenobarbital, or primidone and without valproic acid: Initial: Week 1 and 2: 50 mg once daily; Week 3 and 4: 100 mg/day in 2 divided doses; Week 5 and beyond: Increase by 100 mg/day every 1-2 weeks; Maintenance: 300-500 mg/day in 2 divided doses; maximum daily dose: 700 mg
Bipolar disorder: Immediate release formulations:
Regimens not containing carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid: Initial: Week 1 and 2: 25 mg once daily; Week 3 and 4: 50 mg once daily; Week 5: 100 mg once daily; Week 6 and maintenance: 200 mg once daily
Regimens containing valproic acid: Initial: Week 1 and 2: 25 mg every other day; Week 3 and 4: 25 mg once daily; Week 5: 50 mg once daily; Week 6 and maintenance: 100 mg once daily
Regimens containing carbamazepine, phenytoin, phenobarbital, or primidone and without valproic acid: Initial: Week 1 and 2: 50 mg once daily; Week 3 and 4: 100 mg/day in divided doses; Week 5: 200 mg/day in divided doses; Week 6: 300 mg/day in divided doses; Maintenance: up to 400 mg/day in divided doses
Adjustment following discontinuation of psychotropic medication:
Discontinuing valproic acid with current dose of lamotrigine 100 mg/day: 150 mg/day for week 1, then increase to 200 mg/day beginning week 2
Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin with current dose of lamotrigine 400 mg/day: 400 mg/day for week 1, then decrease to 300 mg/day for week 2, then decrease to 200 mg/day beginning week 3
Discontinuing therapy: Children and Adults: Decrease dose by ~50% per week, over at least 2 weeks unless safety concerns require a more rapid withdrawal. Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or rifampin should prolong the half-life of lamotrigine; discontinuing valproic acid should shorten the half-life of lamotrigine
Restarting therapy after discontinuation: If lamotrigine has been withheld for >5 half-lives, consider restarting according to initial dosing recommendations. Note: Concomitant medications may affect the half-life of lamotrigine; consider pharmacokinetic interactions when restarting therapy.
Dosage adjustment with estrogen-containing hormonal contraceptives: Follow initial lamotrigine dosing guidelines, maintenance dose should be adjusted as follows, based on concomitant medications:
Patients taking concomitant carbamazepine, phenytoin, phenobarbital, primidone or rifampin: No dosing adjustment required
Patients not taking concomitant carbamazepine, phenytoin, phenobarbital, primidone or rifampin: Lamotrigine maintenance dose may need increased by twofold over target dose. If already taking a stable dose of lamotrigine and starting contraceptive, maintenance dose may need increased by twofold. Dose increases should start when contraceptive is started and titrated to clinical response increasing no more rapidly than 50-100 mg/day every week. Gradual increases of lamotrigine plasma levels may occur during the inactive “pill-free” week and will be greater when dose increases are made the week before. If increased adverse events consistently occur during “pill-free” week, overall maintenance dose adjustments may be required. When discontinuing estrogen-containing hormonal contraceptive, dose of lamotrigine may need decreased by as much as 50%; do not decrease by more than 25% of total daily dose over a 2-week period unless clinical response or plasma levels indicate otherwise. Dose adjustments during “pill-free” week are not recommended.

Dosing: Pediatric

Note: Only whole tablets should be used for dosing, round calculated dose down to the nearest whole tablet. Extended release tablets not approved for use in children ≤12 years of age. Enzyme-inducing regimens specifically refer to those containing carbamazepine, phenytoin, phenobarbital, or primidone.
Lennox-Gastaut (adjunctive), primary generalized tonic-clonic seizures (adjunctive), or partial seizures (adjunctive): Oral: Note: Children <30 kg will likely require maintenance doses to be increased as much as 50% based on clinical response regardless of regimen below:
Immediate release formulations:
Children 2-12 years:
Regimens not containing carbamazepine, phenytoin, phenobarbital, primidone, or valproic acid: Initial: Week 1 and 2: 0.3 mg/kg/day in 1-2 divided doses; Week 3 and 4: 0.6 mg/kg/day in 2 divided doses; Week 5 and beyond: Increase by 0.6 mg/kg/day every 1-2 weeks; Maintenance: 4.5-7.5 mg/kg/day (maximum: 300 mg/day) in 2 divided doses
Regimens containing valproic acid : Initial: Week 1 and 2: 0.15 mg/kg/day in 1-2 divided doses; Week 3 and 4: 0.3 mg/kg/day in 1-2 divided doses; Week 5 and beyond: Increase by 0.3 mg/kg/day every 1-2 weeks; Maintenance: 1-5 mg/kg/day (maximum: 200 mg/day) in 1 or 2 divided doses or 1-3 mg/kg/day (maximum: 200 mg/day) (valproic acid alone)
Regimens containing carbamazepine, phenytoin, phenobarbital, or primidone and without valproic acid: Initial: Week 1 and 2: 0.6 mg/kg/day in 2 divided doses; Week 3 and 4: 1.2 mg/kg/day in 2 divided doses; Week 5 and beyond: Increase by 1.2 mg/kg/day every 1-2 weeks; Maintenance: 5-15 mg/kg/day (maximum: 400 mg/day) in 2 divided doses
Children ≥13 years: Refer to adult dosing.
Conversion from adjunctive therapy with a single enzyme-inducing AED regimen for partial seizures to monotherapy with lamotrigine:
Immediate release formulations: Children ≥16 years: Refer to adult dosing.
Discontinuing therapy: Refer to adult dosing.
Restarting therapy after discontinuation: Refer to adult dosing.
Dosage adjustment with estrogen-containing hormonal contraceptives: Refer to adult dosing.

Dosing: Geriatric
Refer to adult dosing.

Dosing: Renal Impairment

Decreased maintenance dosage may be effective in patients with significant renal impairment; has not been adequately studied; use with caution.

Dosing: Hepatic Impairment

Mild impairment: No adjustment required.
Moderate-to-severe impairment without ascites: Decrease initial, escalation, and maintenance doses by ~25%; adjust according to clinical response.
Moderate-to-severe impairment with ascites: Decrease initial, escalation, and maintenance doses by ~50%; adjust according to clinical response.
Use
 
Adjunctive therapy in the treatment of generalized seizures of Lennox-Gastaut syndrome, primary generalized tonic-clonic seizures, and partial seizures; conversion to monotherapy in patients with partial seizures who are receiving treatment with valproic acid or a single enzyme-inducing antiepileptic drug (specifically carbamazepine, phenytoin, phenobarbital or primidone); maintenance treatment of bipolar I disorder
Adverse Reactions
 
Percentages reported in adults on monotherapy for epilepsy or bipolar disorder.
>10%: Gastrointestinal: Nausea (7% to 14%)
1% to 10%:
Cardiovascular: Chest pain (5%), peripheral edema (2% to 5%), edema (1% to 5%)
Central nervous system: Insomnia (5% to 10%), somnolence (9%), fatigue (8%), coordination impaired (7%), dizziness (7%), anxiety (5%), pain (5%), ataxia (2% to 5%), irritability (2% to 5%), suicidal ideation (2% to 5%), agitation (1% to 5%), amnesia (1% to 5%), depression (1% to 5%), dream abnormality (1% to 5%), emotional lability (1% to 5%), fever (1% to 5%), hypoesthesia (1% to 5%), migraine (1% to 5%), thought abnormality (1% to 5%), confusion (1%)
Dermatologic: Rash (nonserious: 7%), dermatitis (2% to 5%), dry skin (2% to 5%)
Endocrine & metabolic: Dysmenorrhea (5%), libido increased (2% to 5%)
Gastrointestinal: Vomiting (5% to 9%), dyspepsia (7%), abdominal pain (6%), xerostomia (2% to 6%), constipation (5%), weight loss (5%), anorexia (2% to 5%), peptic ulcer (2% to 5%), rectal hemorrhage (2% to 5%), flatulence (1% to 5%), weight gain (1% to 5%)
Genitourinary: Urinary frequency (1% to 5%)
Neuromuscular & skeletal: Back pain (8%), weakness (2% to 5%), arthralgia (1% to 5%), myalgia (1% to 5%), neck pain (1% to 5%), paresthesia (1%)
Ocular: Nystagmus (2% to 5%), vision abnormal (2% to 5%), amblyopia (1%)
Respiratory: Rhinitis (7%), cough (5%), pharyngitis (5%), bronchitis (2% to 5%), dyspnea (2% to 5%), epistaxis (2% to 5%), sinusitis (1% to 5%)
Miscellaneous: Infection (5%), diaphoresis (2% to 5%), reflexes increased/decreased (2% to 5%), dyspraxia (1% to 5%)
<1%: Any indication (limited to important or life-threatening): Accommodation abnormality, agranulocytosis, alcohol intolerance, allergic reaction, alopecia, anemia, angina, angioedema, aphasia, aplastic anemia, apnea, appetite increased, arthritis, aseptic meningitis, atrial fibrillation, bruising, cerebellar syndrome, cerebral sinus thrombosis, cerebrovascular accident, chills, choreoathetosis, CNS depression/stimulation, conjunctivitis, deafness, deep thrombophlebitis, delirium, delusions, dermatitis (exfoliative, fungal), disseminated intravascular coagulation, dysphagia, dysphoria, dystonia, ECG abnormality, ejaculation abnormal, eructation, erythema multiforme, esophagitis, euphoria, extrapyramidal syndrome, flushing, gastritis, gingivitis, goiter, hallucinations, hematuria, hemiplegia, hemolytic anemia, hemorrhage, hepatitis, hiccup, hirsutism, hot flashes, hyperalgesia, hyperglycemia, hypersensitivity reactions, hypertension, hyperventilation, hypokinesia, hypothyroidism, hypotonia, impotence, kidney failure (acute), leg cramps, leukopenia, liver function tests abnormal, lupus-like reaction, lymphadenopathy, maculopapular rash, menorrhagia, MI, mouth ulceration, movement disorder, multiorgan failure, muscle spasm, myasthenia, neuralgia, neurosis, neutropenia, palpitation, pancreatitis, pancytopenia, paralysis, parkinsonian exacerbation, peripheral neuritis, photophobia, polyuria, postural hypotension, progressive immunosuppression, pruritus, pure red cell aplasia, rhabdomyolysis, salivation increased, skin discoloration, status epilepticus, Stevens-Johnson syndrome, sudden unexplained death in epilepsy (SUDEP), suicidal behavior, suicide, syncope, tachycardia, taste loss/perversion, thrombocytopenia, tic, tinnitus, tongue edema, toxic epidermal necrolysis, twitching, urinary incontinence, urticaria, vasculitis, vasodilation, withdrawal seizures
Also observed: Rash requiring hospitalization: Children <16 years 0.8% (epilepsy adjunctive therapy), 1.2 % (with concurrent valproic acid use); Adults 0.3% (epilepsy adjunctive therapy), 0.13% (epilepsy monotherapy), 1% (with concurrent valproic acid use), 0.8% (bipolar disorder, monotherapy)
Contraindications
 
Hypersensitivity to lamotrigine or any component of the formulation
Warnings / Precautions Drug
 
Boxed warnings:
• Skin reactions: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Aseptic meningitis: Increased risk of developing aseptic meningitis has been reported; symptoms (eg, headache, nuchal rigidity, fever, nausea/vomiting, rash, photophobia) have generally occurred within 1-45 days following therapy initiation. In some cases, new onset hepatic, renal and/or other organ involvement has also occurred with symptoms, possibly suggesting aseptic meningitis is associated with a hypersensitivity reaction (eg, anticonvulsant hypersensitivity syndrome). Symptoms of aseptic meningitis generally resolve following discontinuation. In some cases, re-exposure has resulted in a rapid return of symptoms (often more severe).
• Blood dyscrasias: A spectrum of hematologic effects have been reported with use (eg, neutropenia, leukopenia, thrombocytopenia, pancytopenia, anemias, and rarely, aplastic anemia and pure red cell aplasia); patients with a previous history of adverse hematologic reaction to any drug may be at increased risk. Early detection of hematologic change is important; advise patients of early signs and symptoms including fever, sore throat, mouth ulcers, infections, easy bruising, petechial or purpuric hemorrhage. May be associated with hypersensitivity syndrome.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Hypersensitivity reactions: Potentially serious, sometimes fatal hypersensitivity reactions, including multiorgan hypersensitivity, have been reported; monitor for signs and symptoms of possible disparate manifestations associated with lymphatic, hepatic, renal, and/or hematologic organ systems; discontinuation and conversion to alternate therapy may be required.
• Skin reactions: [U.S. Boxed Warning]: Severe and potentially life-threatening skin rashes requiring hospitalization have been reported; incidence of serious rash is higher in pediatric patients than adults; risk may be increased by coadministration with valproic acid, higher than recommended starting doses, and exceeding recommended dose titration. The majority of cases occur in the first 8 weeks; however, isolated cases may occur after prolonged treatment or in patients without these risk factors; discontinue at first sign of rash and do not reinitiate therapy unless rash is clearly not drug related. Rare cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and angioedema have been reported.
• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment may be required.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be required.
Concurrent drug therapy issues:
• Hormonal contraceptives: May cause a decrease in lamotrigine levels; dose adjustment of the lamotrigine maintenance dose may be required when initiating or discontinuing estrogen-containing oral contraceptives.
• Sedatives: Effects with other sedative drugs or ethanol may be potentiated.
• Valproic acid: May cause an increase in lamotrigine levels requiring dose adjustment.
Special populations:
• Pediatrics: Children are at increased risk for developing serious skin rashes during therapy.
Other warnings/precautions:
• Appropriate use: Bipolar disorder use: Patients treated for bipolar disorder should be monitored closely for clinical worsening or suicidality; prescriptions should be written for the smallest quantity consistent with good patient care.
• Medication error potential: Medication errors have occurred; potential for medication errors with similar-sounding medications and between different lamotrigine formulations.
• Melanin binding: Binds to melanin and may accumulate in the eye and other melanin-rich tissues; the clinical significance of this is not known.
• Monotherapy: Safety and efficacy have not been established for use as initial monotherapy, conversion to monotherapy from antiepileptic drugs (AED) other than carbamazepine, phenytoin, phenobarbital, primidone or valproic acid or conversion to monotherapy from two or more AEDs.
• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. Taper over at least 2 weeks if possible.
Interactions
 
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Barbiturates: May decrease the serum concentration of LamoTRIgine. Management: See lamotrigine prescribing information for specific age-dependent dosing guidelines regarding concurrent use with a barbiturate, as well as for adjusting lamotrigine dosing if concurrent barbiturate therapy is discontinued. Risk D: Consider therapy modification
CarBAMazepine: LamoTRIgine may enhance the adverse/toxic effect of CarBAMazepine. CarBAMazepine may increase the metabolism of LamoTRIgine. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Risk C: Monitor therapy
Contraceptives (Estrogens): May decrease the serum concentration of LamoTRIgine. Management: Monitor for increased serum concentrations/effects of lamotrigine in patients in whom a hormonal contraceptive is discontinued/dose decreased (this includes during a pill-free week). A reduced dosage of lamotrigine may be needed. Risk D: Consider therapy modification
Contraceptives (Progestins): LamoTRIgine may decrease the serum concentration of Contraceptives (Progestins). Management: Women using progestin-only “minipill” products may be at risk for contraceptive failure; it is unclear if other progestin-containing products would be significantly impacted. Alternative, non-hormonal, means of contraception are recommended. Risk D: Consider therapy modification
Desmopressin: LamoTRIgine may enhance the adverse/toxic effect of Desmopressin. LamoTRIgine may enhance the therapeutic effect of Desmopressin. Risk C: Monitor therapy
Divalproex: May enhance the adverse/toxic effect of LamoTRIgine. Divalproex may increase the serum concentration of LamoTRIgine. Risk D: Consider therapy modification
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Fosphenytoin: May decrease the serum concentration of LamoTRIgine. Risk D: Consider therapy modification
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ketorolac: May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Ketorolac (Nasal): May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Ketorolac (Systemic): May diminish the therapeutic effect of Anticonvulsants. Risk C: Monitor therapy
Mefloquine: May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants. Management: Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
OLANZapine: LamoTRIgine may enhance the sedative effect of OLANZapine. Risk C: Monitor therapy
Phenytoin: May decrease the serum concentration of LamoTRIgine. Risk D: Consider therapy modification
Primidone: May decrease the serum concentration of LamoTRIgine. Management: Adjust dose per lamotrigine prescribing information guidelines during primidone treatment. Monitor for decreased concentration/effect if primidone is initiated/dose increased or increased concentration/effect if primidone is discontinued/dose decreased. Risk D: Consider therapy modification
Rifampin: May increase the metabolism of LamoTRIgine. Risk C: Monitor therapy
Ritonavir: May decrease the serum concentration of LamoTRIgine. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy
Valproic Acid: May enhance the adverse/toxic effect of LamoTRIgine. Valproic Acid may increase the serum concentration of LamoTRIgine. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Food: Has no effect on absorption.
Herb/Nutraceutical: Avoid evening primrose (seizure threshold decreased).
Pregnancy
 
C
Lactation
 
Enters breast milk/not recommended (AAP rates “of concern”; AAP 2001 update pending)
Breast-Feeding Considerations
Lamotrigine is found in breast milk. In one study, the relative dose to the infant was 9% (range: 2% to 20%) of the weight-adjusted maternal dose. Lamotrigine was measurable in the plasma of nursing infants; adverse events were not observed.
Monitoring Parameters
 
Seizure, frequency and duration; serum levels of concurrent anticonvulsants, hypersensitivity reactions (especially rash); suicidality (eg, suicidal thoughts, depression, behavioral changes); signs/symptoms of aseptic meningitis
Reference Range
A therapeutic serum concentration range has not been established for lamotrigine. Dosing should be based on therapeutic response. Lamotrigine plasma concentrations of 0.25-29.1 mcg/mL have been reported in the literature.
Mechanism of Action
 
A triazine derivative which inhibits release of glutamate (an excitatory amino acid) and inhibits voltage-sensitive sodium channels, which stabilizes neuronal membranes. Lamotrigine has weak inhibitory effect on the 5-HT3 receptor; in vitro inhibits dihydrofolate reductase.
Pharmacodynamics / Kinetics
 
Absorption: Immediate release: Rapid and complete
Distribution: Vd: 0.9-1.3 L/kg
Protein binding: ~55%
Metabolism: Hepatic and renal; metabolized primarily by glucuronic acid conjugation to inactive metabolites
Bioavailability: Immediate release: 98%; Note: AUCs were similar for immediate release and extended release preparations in patients receiving nonenzyme-inducing AEDs. In subjects receiving concomitant enzyme-inducing AEDs, bioavailability of extended release product was ~21% lower than immediate release product; in some of these subjects, a decrease in AUC of up to 70% was observed when switching from immediate release to extended release tablets.
Half-life elimination: Immediate release: Adults: 25-33 hours, Elderly: 25-43 hours; Extended release: Similar to immediate release
Concomitant valproic acid therapy: 48-70 hours
Concomitant phenytoin, phenobarbital, primidone, or carbamazepine therapy: 13-14 hours
Chronic renal failure: 43 hours
Hemodialysis: 13 hours during dialysis; 57 hours between dialysis (~20% of a dose is eliminated in a 4-hour dialysis session)
Hepatic impairment:
Mild: 26-66 hours
Moderate: 28-116 hours
Severe without ascites: 56-78 hours
Severe with ascites: 52-148 hours
Time to peak, plasma: Immediate release: 1-1.5 hours; Extended release: 4-11 hours (dependent on adjunct therapy)
Excretion: Urine (94%, ~90% as glucuronide conjugates and ~10% unchanged); feces (2%)
 
   
 
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