Lamotrigine is an oral antiepileptic drug (AED) indicated for adjunctive therapy for partial-onset seizures, primary generalized tonic-clonic seizures, and generalized seizures of Lennox-Gastaut syndrome and conversion to monotherapy in patients with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug. Lamotrigine is also indicated for the maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes in patients treated for acute mood episodes with standard therapy. Treatment of acute manic or mixed episodes with lamotrigine is not recommended; the effectiveness of lamotrigine in the acute treatment of mood episodes has not been established. Cases of life-threatening serious rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, and/or rash-related death have been caused by lamotrigine. The rate of serious rash is greater in pediatric patients than in adults. Benign rashes are also caused by lamotrigine; however, it is not possible to predict which rashes will prove to be serious or life-threatening. Therefore, lamotrigine should be discontinued at the first sign of rash, unless the rash is clearly not drug-related.
General Administration Information
NOTE: Medication errors have been reported with lamotrigine starter kits. Mild to severe side effects, including Stevens-Johnson Syndrome have occurred. There are 3 different starter kits with titration schedules dependant on concurrent medications (see below). Patients must receive the correct kit to avoid over or under dosing.
-A MedGuide is available that discusses the risk of suicidal thoughts and behaviors associated with the use of anticonvulsant medications.
-For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Lamotrigine may be administered without regard to meals.
Oral Solid Formulations
-Orange starter kits: For patients NOT taking carbamazepine, phenytoin, phenobarbital, primidone, rifampin, or valproate.
-Green starter kits: For patients taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin and NOT taking valproate.
-Blue starter kits: For patients taking valproate.
-Immediate-release tablets: Lamotrigine tablets should not be chewed, as the medication is very bitter.
-Tablets for oral suspension: Lamotrigine may be swallowed whole, chewed, or mixed in water or in diluted fruit juice to aid swallowing. To mix the tablets in water or juice, add the tablets to a small amount of liquid (enough to cover the medication) in a glass or spoon. The tablets will dissolve in about 1 minute. Once dissolved, mix or swirl the liquid, and take the entire solution immediately. It is important to have the patient swallow all of the liquid used to prepare the dose. NOTE: The lowest available tablet strength is a 2 mg tablet for oral suspension, and all doses should be rounded to the nearest 2 mg dose. Only whole dispersible tablets should be administered; do not cut in half.
-Orally disintegrating tablets: Lamotrigine tablets should be placed on tongue and moved around in the mouth to facilitate disintegration. The tablet will disintegrate rapidly and may be swallowed with or without water. When dispensing the blisterpack, advise patients to examine it prior to use and do not use if the blisters are torn, broken, or missing.
-Extended-release tablets: Swallow lamotrigine tablets whole. Do not chew, crush, or divide.
A report of attempted suicide with an overdose of lamotrigine 3000 mg resulting in serum concentrations of 18 mcg/ml produced clinical symptoms of unsteady gait, stomach upset, and abnormal eye movements. These symptoms resolved within 2 days. In clinical trials, 4 cases of overdose occurred, all with complete recovery. Two of the overdoses occurred in a 14 year old female and a 4 year old male. They had ingested 3000 mg and 1000 mg of lamotrigine, respectively. The 14 year old lost consciousness and the 4 year old progressed to coma. With supportive therapy, the 4 year old recovered fully in 3 days. The 14 year old child also recovered fully.
Anticonvulsants are thought to carry an increased risk of suicidal ideation and behavior. In a monotherapy controlled clinical trial of immediate-release lamotrigine for the treatment of epilepsy (n = 43 in lamotrigine group), depression and suicidal ideation each occurred in > 2% but < 5% of adult patients. Depression was reported in > 1% but < 5% of patients receiving immediate-release lamotrigine as monotherapy (n = 227) for bipolar disorder in clinical trials. In pediatric bipolar disorder trials (n = 301), suicidal ideation was reported in 5% of lamotrigine-treated patients and 0% of placebo-treated patients. When data from all clinical trials of immediate-release lamotrigine was combined (n = 6694), depression and suicidal ideation were each reported in 0.1-1% of patients. Depression was also reported in 3-4% of patients receiving adjunctive therapy with modified-release lamotrigine formulations in clinical trials. An analysis by the FDA of previously gathered drug data showed that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor. The increased risk of suicidal ideation and behavior occurred between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Depression has been reported during lamotrigine use. All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening suicidal thoughts/behavior or depression. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior.
Adverse reactions to lamotrigine are difficult to interpret because clinical trials of lamotrigine often were conducted in patients receiving other medications concomitantly. Nevertheless, centrally-mediated effects are among the most frequent adverse reactions associated with lamotrigine as monotherapy and in combination with other AEDs. CNS adverse reactions occurring in clinical trials of immediate-release lamotrigine as monotherapy for partial seizures or bipolar disorder in adults at a greater frequency than placebo included: coordination abnormality (7%), dizziness (>= 5%, incidence dose-related), anxiety (>= 5%), insomnia (>= 5%), mania (>= 5%), headache (>= 5%), fatigue (8%), and drowsiness (9%). Fatigue occurred in 6% of patients with epilepsy who received lamotrigine extended-release as adjunctive therapy in clinical trials. In general, the incidences of dizziness and headache are higher during dose titration periods when patients are receiving concomitant medications or when used as adjunctive therapy. Tremor occurred in 4-10% of patients receiving various formulations of lamotrigine in clinical trials for epilepsy and bipolar disorder and was most common in pediatric patients and during conversion to monotherapy. Asthenia was reported in > 2% to 8% of patients who received lamotrigine in clinical trials. Adverse reactions occurring in > 2% but < 5% of patients receiving immediate-release lamotrigine for partial seizures included asthenia, amnesia, ataxia, hypesthesia, hyperreflexia, hyporeflexia, nystagmus, diaphoresis, libido increase, and irritability. Amnesia, agitation, emotional lability, dyspraxia, abnormal thoughts, abnormal dreams, migraine, and hypoesthesia were reported in > 1% but < 5% of patients receiving immediate-release lamotrigine for bipolar disorder. Other CNS adverse reactions reported frequently (>= 1%) in all placebo and non-placebo controlled clinical trials of immediate-release lamotrigine included confusion and paresthesias. Infrequently (0.1-1%) reported CNS adverse reactions included: akathisia, apathy, aphasia, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesis, hypertonia, libido decrease, malaise, memory impairment, mind racing, movement disorder, myoclonus, panic attack, paranoia, personality disorder, psychosis, sleep disorder, and stupor. Rare (< 0.1%) CNS adverse reactions included: choreoathetosis, delirium, dysphoria, dystonic reaction, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, paralysis, and peripheral neuritis. CNS adverse reactions occurring in clinical trials of pediatric patients receiving lamotrigine as adjunctive therapy for epilepsy included: asthenia (8%), drowsiness (17%), dizziness (14%), ataxia (11%), tremor (10%), emotional lability (4%), gait abnormality (4%), abnormal thinking (3%), convulsions (2%), nervousness (2%), and vertigo (2%). In a randomized, comparison study of pediatric patients receiving valproic acid or lamotrigine as monotherapy for absence seizures, nervousness occurred in 1 out of 19 patients in the lamotrigine group. Headache was reported by 2 patients receiving lamotrigine. In a clinical trial of extended-release lamotrigine as an adjunct to other AEDs in the treatment of partial seizures, the following CNS-related effects occurred more frequently in the active treatment group than the placebo group: vertigo (3% vs <1%), asthenia/asthenic conditions (6% vs 4%), gait disturbance (2% vs 0%), dizziness (14% vs 6%), drowsiness (5% vs 3%), tremor (6% vs 1%), cerebellar balance disorder (3% vs 0%), nystagmus (2% vs < 1%), and anxiety (3% vs 0%). Exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson's disease and tics have been reported with post-marketing use of lamotrigine; however, the frequency and causality to the drug have not been established.
Chest pain (unspecified) occurred in 5% and peripheral edema in > 2% but < 5% of adult patients receiving immediate-release lamotrigine as monotherapy for the treatment of partial seizures. Edema was reported in > 1% but < 5% of patients receiving immediate-release lamotrigine as monotherapy for the treatment of bipolar disorder. Edema, facial edema, and hemorrhage were also reported in 2% of pediatric patients receiving immediate-release lamotrigine as adjunctive therapy for epilepsy in clinical trials. Cardiovascular adverse reactions reported infrequently (0.1-1%) in all placebo and non-placebo controlled clinical trials of immediate-release lamotrigine include: flushing, hypertension, palpitations, orthostatic hypotension, syncope, sinus tachycardia, and peripheral vasodilation. Vasculitis has been reported with post-marketing use of lamotrigine; however, the frequency and causality to the drug have not been established.
In a clinical trial of extended-release lamotrigine as an adjunct to other AEDs in the treatment of partial seizures, hot flashes occurred in 2% of the active treatment group (n = 190) compared to 0% in the placebo group (n = 195). When the available data from all clinical trials of lamotrigine were combined (n = 6694), hot flashes were reported in 0.1-1% of patients.
Arthralgia and myalgia were reported in > 1% but < 5% and accidental injury was reported in >= 5% of adult patients receiving immediate-release lamotrigine as monotherapy for bipolar disorder or epilepsy. Accidental injury was reported in 14% of pediatric patients who received lamotrigine as adjunctive treatment for epilepsy. Pain (unspecified) was reported in >= 5% of adult patients receiving immediate-release lamotrigine as monotherapy for partial seizures and in 5% of pediatric patients receiving immediate-release lamotrigine as adjunctive therapy for epilepsy. Back pain (8%), pain (unspecified) (>= 5%), and neck pain (> 1% but < 5%) were also reported in patients receiving immediate-release lamotrigine as monotherapy for bipolar disorder. Other musculoskeletal adverse reactions reported infrequently (0.1-1%) in all placebo and non-placebo controlled trials of immediate-release lamotrigine included: arthritis, leg cramps, myasthenia, and twitching. In a clinical trial of extended-release lamotrigine as an adjunct to other AEDs in the treatment of partial seizures, the following effects occurred more frequently in the active treatment group than the placebo group: pain (unspecified) (2% vs 1%) and myalgia (2% vs 0%). Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions with post-marketing use of lamotrigine; however, the frequency and causality to the drug are unknown.
In a clinical trial of extended-release lamotrigine as adjunct treatment to other AEDs in the treatment of partial seizures, the following types of infection occurred more frequently in the active treatment group than the placebo group: influenza/influenza-like illness (3% vs. 2%) and sinusitis (2% vs. 1%). Related effects included pharyngolaryngeal pain (3% vs. 2%), epistaxis (2% vs. 1%), and sinus congestion (2% vs. 0%). Epistaxis occurred in more than 2% to less than 5% of adults who received immediate-release lamotrigine monotherapy for partial seizures. Respiratory and infectious adverse events occurring in clinical trials of immediate-release lamotrigine as monotherapy for partial seizures or bipolar disorder included: infection (5% or more), influenza (5% or more), rhinitis (7%), and cough (5%). Pharyngitis occurred in 5% to 10% of patients in adult clinical trials. Respiratory and infectious adverse reactions occurring in more than 2% but less than 5% of patients receiving immediate-release lamotrigine as monotherapy for partial seizures included: bronchitis and dyspnea. Sinusitis was reported in more than 1% but less than 5% of patients receiving immediate-release lamotrigine as monotherapy for bipolar disorder, and rhinitis occurred in 5% or more of patients who received lamotrigine monotherapy for epilepsy. Pediatric patients receiving immediate-release lamotrigine as adjunctive therapy for epilepsy experienced the following respiratory and infectious adverse reactions: infection (20%), flu syndrome (7%), pharyngitis (14%), bronchitis (7%), cough (7%), sinusitis (2%), bronchospasm (2%), and urinary tract infection (3%). Influenza (8%) and oropharyngeal pain (8%) were reported in pediatric bipolar disorder trials. In a small controlled trial of pediatric patients 1 to 24 months of age, the immediate-release formulation of lamotrigine was associated with an increased risk of infectious (37% vs. 5% placebo) and respiratory (26% vs. 5% placebo) adverse reactions including bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, viral infection, nasal congestion, cough, and apnea. When the available data from all clinical trials of lamotrigine were combined (n = 6,694), yawning occurred infrequently (0.1% to 1%) and hiccups and hyperventilation rarely (less than 0.1%). Apnea, progressive immunosuppression, lupus-like symptoms, and hypogammaglobulinemia have also been reported with postmarketing use of lamotrigine.
During clinical trials, nausea/vomiting was among the most frequent adverse reactions associated with immediate-release lamotrigine in combination with other AEDs and was considered to be a dose-related side effect. GI adverse reactions occurring in clinical trials of immediate-release lamotrigine as monotherapy for partial seizures or bipolar disorder included: vomiting (5-9%), dyspepsia (7%), nausea (7-14%), weight loss (5%), abdominal pain (6%), xerostomia (> 2% to 6%), diarrhea (>= 5%), and constipation (5%). Anorexia, rectal hemorrhage, and peptic ulcer occurred in > 2% but < 5% of patients receiving immediate-release lamotrigine as monotherapy for partial seizures. Flatulence and weight gain occurred in > 1% but < 5% of patients receiving immediate-release lamotrigine as monotherapy for bipolar disorder. GI adverse reactions reported infrequently (0.1-1%) in all placebo- and non-placebo controlled clinical trials (n = 6694) included: dysphagia, eructation, gastritis, gingivitis, appetite stimulation, hypersalivation, liver function tests abnormal (e.g., elevated hepatic enzymes), and mouth ulceration. GI adverse reactions reported rarely (< 0.1%) included: gastrointestinal hemorrhage, glossitis, hematemesis, hemorrhagic colitis, hepatitis, melena, and stomatitis. In a randomized, comparison study of pediatric patients receiving valproic acid or lamotrigine as monotherapy for absence seizures, increased appetite occurred in 1 out of 19 patients in the lamotrigine group. Additional GI adverse reactions reported in pediatric patients include: vomiting (6-20%), diarrhea (11%), abdominal pain (5-10%), nausea (10%), constipation (4%), and dyspepsia (2%). In a clinical trial of extended-release lamotrigine as an adjunct to other AEDs in the treatment of partial seizures, the following GI effects occurred more frequently in the active treatment group than the placebo group: diarrhea (5% vs. 3%), nausea (7% vs. 4%), abdominal pain (6% vs. 4%), vomiting (6% vs. 3%), constipation (2% vs. < 1%), anorexia/decreased appetite (3% vs. 2%), weight gain (2% vs. 1%), and xerostomia (2% vs. 1%). Esophagitis and pancreatitis have been reported with post-marketing use of lamotrigine; however, the frequencies and causality to the drug are unknown.
During clinical trials, diplopia (5% pediatrics, 24% to 49% adults), blurred vision (4% pediatrics, 11% to 25% adults), and vision abnormality (2% pediatrics, 3% adults) were among the most frequent adverse reactions associated with immediate-release lamotrigine in combination with other AEDs. Both diplopia and blurred vision were considered to be dose-related effects. Vision abnormality (visual impairment) was also reported in more than 2% but less than 5% of patients receiving immediate-release lamotrigine in clinical trials as monotherapy for partial seizures. Amblyopia was reported frequently (1% or more) in all placebo and non-placebo controlled clinical trials of immediate-release lamotrigine (n = 6,694). Infrequently (0.1% to 1%) reported adverse reactions of the senses included: abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, and tinnitus. Rarely (less than 0.1%) reported adverse reactions included: deafness, oscillopsia, parosmia, ptosis, strabismus, uveitis, and visual field defect. In a randomized, comparison study of pediatric patients receiving valproic acid or lamotrigine as monotherapy for absence seizures, diplopia occurred in 1 out of 19 patients in the lamotrigine group. In a clinical trial of extended-release lamotrigine as an adjunct to other AEDs in the treatment of partial seizures, the following effects occurred more frequently in the active treatment group than the placebo group: blurred vision (3%) and diplopia (5%). Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time, and theoretically may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in 1 controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, is unknown. Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.
Rash is the most common cause for discontinuation of lamotrigine therapy. Lamotrigine-associated rash may be relatively benign and uncomplicated, but it may also be serious and potentially life-threatening. Counsel all patients to promptly report any signs of rash or symptoms of a hypersensitivity reaction, such as fever or lymphadenopathy, even in the absence of rash. To make the diagnosis of a serious reaction even more challenging, fever is a relatively common adverse reaction occurring in more than 1% to 15% of patients who receive lamotrigine, and lymphadenopathy occurs in approximately 2% of pediatric patients. Lymphadenopathy that is not associated with hypersensitivity has also been reported during postmarketing experience. Because it is not possible to reliably predict which rashes are benign and which will lead to a life-threatening situation, it is generally recommended that lamotrigine be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Approximately 7% to 14% of patients develop some type of rash; however, rashes associated with lamotrigine do not have specific identifying characteristics. Rash was reported in 14% of pediatric patients receiving immediate-release lamotrigine as adjunctive therapy for epilepsy. The rash usually develops during the first 2 to 8 weeks of therapy; however, isolated cases occurring after prolonged treatment (e.g., 6 months) have been reported. Non-serious rashes associated with lamotrigine administration have occurred 3 times more frequently in patients with a history of rash or allergy to other anticonvulsants than in those without this history. Serious rashes associated with hospitalization have occurred in approximately 0.3% to 0.8% of pediatric patients in clinical trials and in 0.08% to 0.3% of patients in adult trials. Other than age, there are no proven risk factors known to predict the severity or risk of occurrence of rash. However, rash appears to be more common in patients receiving valproic acid concomitantly or when the recommended dose escalation schedule is exceeded. Rash has occurred, however, when these factors were not present. Initiating therapy at the lowest dosage possible and escalating slowly appears to minimize the occurrence of skin rash. Some reports suggest that with strict adherence to lamotrigine dose titrations and dose reduction in patients receiving concomitant valproate that the incidence of serious and life-threatening rash is rare. Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and exfoliative dermatitis have been reported rarely (less than 0.1%). In addition, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), a multi-organ hypersensitivity reaction, has occurred. Manifestations of DRESS typically include fever, rash, and/or lymphadenopathy in conjunction with other organ system abnormalities including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. Eosinophilia is often present. Early manifestations such as fever and lymphadenopathy may be present without evidence of a rash. Cases of isolated hepatic failure without rash or other organ involvement have also been reported. Within 14 days of adding lamotrigine to an existing antiepileptic drug regimen, 3 cases of multiorgan dysfunction and disseminated intravascular coagulation (DIC) occurred with subsequent resolution of symptoms after discontinuation of the drug. Fatalities associated with hepatic failure or multiorgan failure occurred in 2 of 3,796 adults and 4 of 2,435 pediatric patients during clinical trials. Fatalities have also been reported rarely during postmarketing use. Pruritus was reported in 2% of pediatric patients and 5% or more of adult patients during clinical trials. Maculopapular rash and urticaria were reported infrequently (0.1% to 1%). Angioedema, erythema, and eosinophilia occurred rarely (less than 0.1%).
Hematological reactions observed during immediate-release lamotrigine therapy have included anemia (< 0.1%), eosinophilia (< 0.1%), ecchymosis (0.1-1%), leukopenia (0.1-1%), leukocytosis (< 0.1%), lymphocytosis (< 0.1%), petechiae (< 0.1%), and thrombocytopenia (< 0.1%). Although, lamotrigine has weak antifolate activity, no clinically significant alterations in serum or erythrocyte folate concentrations have been identified. Iron deficiency anemia and macrocytic anemia, however, has been reported rarely (< 0.1%). Decreased fibrin and fibrinogen have also been rarely reported (< 0.1%). Agranulocytosis, aplastic anemia, hemolytic anemia, neutropenia, pancytopenia, and pure red cell aplasia have been reported with post-marketing use of lamotrigine; however, the frequencies and casualty to the drug are unknown. Abnormal laboratory values that have been associated with administration of extended-release lamotrigine include decreased total white blood cells and monocytes.
In clinical trials of immediate-release lamotrigine as monotherapy, dysmenorrhea occurred in 5% of patients, and increased urinary frequency occurred in more than 1% but less than 5% of patients. During add-on placebo-controlled trials, female patients taking immediate-release lamotrigine reported dysmenorrhea (7% vs. 6% placebo), vaginitis (4% vs. 1% placebo), and amenorrhea (2% vs. 1% placebo) compared to 1% of patients given placebo. Other adverse reactions reported infrequently (0.1% to 1%) in all placebo and non-placebo-controlled clinical trials of immediate-release lamotrigine included ejaculation dysfunction, hematuria, impotence (erectile dysfunction), menorrhagia, polyuria, and urinary incontinence. Rarely (less than 0.1%) occurring adverse reactions included breast neoplasm, cystitis, dysuria, epididymitis, female lactation, renal failure (unspecified), nocturia, urinary retention, and urinary urgency. Tubulo-interstitial nephritis (alone and in association with uveitis) has been observed during postmarketing experience with lamotrigine.
Lamotrigine may cause hyponatremia. Lamotrigine decreases calcium conductance and may act at voltage-sensitive sodium channels to stabilize neuronal membranes. Both actions are also provided by carbamazepine, which has been associated with the syndrome of inappropriate antidiuretic hormone (SIADH). Decreasing synthetic ADH requirements have been documented in 2 patients who received lamotrigine (see Drug Interactions). Other endocrine and metabolic adverse reactions reported rarely (< 0.1%) in all placebo- and non-placebo controlled clinical trials (n = 6694) included: goiter, hypothyroidism, hyperglycemia, and hyperbilirubinemia.
Therapy with lamotrigine increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, evaluate patients for other causes of meningitis and treat as appropriate. Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking lamotrigine. Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to 1.5 months after the initiation of treatment. In most cases, symptoms were reported to resolve after discontinuation of lamotrigine. Reexposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day after reinitiation of treatment) that were frequently more severe. Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild to moderate pleocytosis, normal glucose concentrations, and mild to moderate increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one-third of the cases. Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction.
Dermatologic adverse reactions occurring in > 2% but < 5% of patients receiving immediate-release lamotrigine as monotherapy for partial seizures included contact dermatitis and xerosis. Infrequently (0.1-1%) reported dermatologic adverse reactions in all placebo and non-placebo controlled trials of immediate-release lamotrigine included: acne vulgaris, hirsutism, alopecia, and skin discoloration. Other rarely (< 0.1%) reported dermatologic adverse reactions included fungal dermatitis, herpes zoster, and leukoderma. Atopic dermatitis (2%) and contact dermatitis (5%) were reported in pediatric patients at a greater frequency than placebo receiving immediate-release lamotrigine. Lamotrigine-associated rash may be relatively benign and uncomplicated, but it may also be serious and potentially life threatening (see serious skin rash and hypersensitivity adverse reactions content). Counsel all patients to promptly report any signs of rash or symptoms of a hypersensitivity reaction, such as fever or lymphadenopathy, even in the absence of rash.
Lamotrigine may cause hemophagocytic lymphohistiocytosis (HLH), which is a rare but serious uncontrolled immune system response that may result in hospitalization and death. Severe inflammation occurs throughout the body leading to severe problems with blood cells and organs throughout the body. Between December 1994 to September 2017, 8 cases of confirmed or suspected HLH were identified. All cases resulted in hospitalization and 1 death occurred. HLH may occur days to weeks after starting treatment; each of the reported cases occurred within 24 days of treatment initiation. Lamotrigine dosages ranged from 25 mg every other day to 250 mg once daily. In 7 cases, HLH improved after lamotrigine discontinuation. Treatments included steroids, IV immunoglobulin, blood products, and chemotherapy. Although all cases reported concomitant medications, none of the concomitant medications are associated with HLH. HLH typically presents with a fever (more than 101 degrees F) and rash. Other signs and symptoms may include enlarged liver with pain, tenderness, or unusual swelling over the liver area in the upper right belly, swollen lymph nodes, yellow skin or eyes, unusual bleeding, hypertriglyceridemia, or nervous system problems (seizures, trouble walking, difficulty seeing, or other visual disturbances). A diagnosis may be established if 5 of the following symptoms from the HLH-2004 diagnostic criteria are present: fever or rash, enlarged spleen (splenomegaly), cytopenias, elevated concentrations of triglycerides or low blood concentrations of fibrinogen, high concentrations of blood ferritin, hemophagocytosis identified through bone marrow, spleen, or lymph node biopsy, decreased or absent natural killer cell activity, and elevated blood concentrations of CD25 showing prolonged immune cell activation. Evaluate patients who present with fever or rash promptly, as early recognition is necessary to improve outcomes and reduce mortality. HLH may be confused with other serious immune-system reactions such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
Lamotrigine use is contraindicated in patients who have demonstrated hypersensitivity to lamotrigine (e.g., rash, history of angioedema, acute urticaria, extensive pruritus, mucosal ulceration) or other life-threatening hypersensitivity or serious immune-related events. Due to the potential for life-threatening serious rash (including Stevens-Johnson syndrome and toxic epidermal necrolysis), discontinue lamotrigine if rash occurs at any time during treatment. It is important to note that discontinuation of lamotrigine may not prevent progression to a higher level of severity; therefore, monitor patients closely. Age is the only factor currently known to predict the occurrence or severity of a rash, with pediatric patients at increased risk. Other possible but unproven factors include concurrent use of valproate, exceeding the initial recommended dose, or exceeding the recommended dose titration. Almost all cases of life-threatening rash have occurred within the first 2 to 8 weeks of treatment. However, prolonged duration of therapy does not preclude the possibility of an association to the drug. Also, caution is advised when administering lamotrigine to patients with a history of rash or allergy to other anticonvulsants, since non-serious rashes have occurred 3 times more frequently in these patients during treatment with lamotrigine than in those without this history. Do not resume lamotrigine after prior discontinuation due to rash unless the benefits outweigh the risks. If the drug is reintroduced and it has been 5 half-lives or longer since the last dose, reinitiate using initial dosing recommendations. Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms (DRESS), have occurred. Some have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, evaluate the patient immediately. Discontinue lamotrigine if an alternative etiology for the signs or symptoms cannot be established. Lamotrigine may also cause hemophagocytic lymphohistiocytosis (HLH), which is a rare but serious uncontrolled immune system response that may result in hospitalization and death. Severe inflammation occurs throughout the body leading to severe problems with blood cells and organs throughout the body. HLH typically presents with a fever (more than 101 degrees F) and rash. Other signs and symptoms may include enlarged liver with pain, tenderness, or unusual swelling over the liver area in the upper right belly, swollen lymph nodes, yellow skin or eyes, unusual bleeding, hypertriglyceridemia, or nervous system problems (seizures, trouble walking, difficulty seeing, or other visual disturbances). A diagnosis may be established if 5 of the following symptoms from the HLH-2004 diagnostic criteria are present: fever or rash, enlarged spleen (splenomegaly), cytopenias, elevated concentrations of triglycerides or low blood concentrations of fibrinogen, high concentrations of blood ferritin, hemophagocytosis identified through bone marrow, spleen, or lymph node biopsy, decreased or absent natural killer cell activity, and elevated blood concentrations of CD25 showing prolonged immune cell activation. Evaluate patients who present with fever or rash promptly, as early recognition is necessary to improve outcomes and reduce mortality. HLH may be confused with other serious immune-system reactions such as DRESS.
There have been reports of blood dyscrasias with lamotrigine that may or may not be associated with multiorgan hypersensitivity (also known as DRESS). These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia. Monitor for signs of anemia, unexpected infection, or bleeding that may indicate a blood dyscrasia.
All patients beginning treatment with anticonvulsants or currently receiving lamotrigine should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior or suicidal ideation. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence of new or worsening of depression, suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. Anticonvulsants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. In January 2008, the FDA alerted healthcare professionals of an increased risk of suicidal ideation and behavior in patients receiving anticonvulsants to treat epilepsy (AEDs), psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). This alert followed an initial request by the FDA in March 2005 for manufacturers of marketed AEDs to provide data from existing controlled clinical trials for analysis. Prior to this request, preliminary evidence had suggested a possible link between AED use and suicidality. The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (5 years of age and older). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Data were analyzed from AEDs with adequately designed clinical trials including carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. However, this is considered to be a class effect.
Lamotrigine commonly causes blurred vision, dizziness, and drowsiness. Patients should be advised to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of whether lamotrigine adversely affects their mental and/or motor performance.
There is limited data on the use of lamotrigine in hepatic disease; dosages should be adjusted in patients with moderate to severe hepatic impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response. No dosage adjustment is needed in patients with mild liver impairment.
Should be used with caution in patients with renal impairment or renal failure. Initial doses of lamotrigine in patients with renal impairment should be based on patient's medication regimen; reduced maintenance doses may be effective for patients with significant renal impairment. Few patients with severe renal impairment, renal failure, or receiving dialysis have been evaluated during chronic treatment with lamotrigine.
Patients receiving lamotrigine for any indication, including bipolar disorder, should not undergo abrupt discontinuation if possible due to the potential for withdrawal seizures. A gradual taper of lamotrigine over 2 weeks is recommended unless safety concerns require a more rapid discontinuation.
Clinical studies of lamotrigine for epilepsy and for bipolar disorder did not include sufficient numbers of geriatric subjects 65 years of age or older to determine whether they respond differently or exhibit a different safety profile than younger adults. Geriatric individuals exhibit a lower clearance and longer lamotrigine half-life when compared to young adults. It is recommended that older adults receive initial dosages at the low end of the normal adult range. Liver and kidney function should be assessed prior to lamotrigine initiation since dosages should be adjusted for organ function impairments. According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric adults with a history of falls or fractures and should be avoided in these patient populations, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If lamotrigine must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.
Lamotrigine is not indicated for use in the adjunctive treatment of epilepsy in neonates, infants, and children less than 2 years of age. A clinical trial evaluating the use of lamotrigine in partial seizures in pediatric patients aged 1 to 24 months of age was stopped early because the incidence of infectious (37% for lamotrigine and 5% for placebo) and respiratory (26% lamotrigine and 5% placebo) adverse reactions were significantly higher. Safety and efficacy of lamotrigine for the maintenance treatment of bipolar disorder were not established in a double-blind, randomized withdrawal, placebo-controlled trial that evaluated 301 pediatric patients aged 10 to 17 years with a current manic/hypomanic, depressed, or mixed mood episode as defined by DSM-IV-TR. Lamotrigine is associated with a potentially life-threatening serious rash, the incidence of which is higher in pediatric patients than adults. The incidence of serious rash is approximately 0.3 to 0.8% in pediatric patients (2 to 17 years of age) compared to 0.08 to 0.3% in adults. In a juvenile animal study in which lamotrigine (oral doses of 5, 15, or 30 mg/kg) was administered to young rats (postnatal days 7 to 62), decreased viability and growth were seen at the highest dose tested and long-term behavioral abnormalities (decreased locomotor activity, increased reactivity, and learning deficits in animals tested as adults) were observed at the 2 highest doses. The no-effect dose for adverse effects on neurobehavioral development is less than the human dose of 400 mg/day on a mg/m2 basis.
Lamotrigine therapy increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, evaluate patients for other causes of meningitis and treat as appropriate. Symptoms have been reported to occur within 1 day to 1.5 months after the initiation of treatment. In most cases, symptoms resolved after discontinuation of lamotrigine. Some patients treated with lamotrigine who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus (SLE) or other autoimmune disease. Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction.
Weigh the benefits of treatment with lamotrigine against the risks for serious arrhythmias and/or sudden death in patients with clinically important structural or functional cardiac disease (i.e., patients with heart failure, valvular heart disease, congenital heart disease, conduction system disease, ventricular arrhythmias, cardiac channelopathies [e.g., Brugada syndrome], clinically important ischemic heart disease, or multiple risk factors for coronary artery disease). Consultation with a cardiologist before lamotrigine initiation may be warranted in these patients. Consider obtaining a baseline ECG in all patients over 60 years, as the likelihood of undiagnosed cardiac conduction abnormalities may be increased in this patient population, and in patients younger than 60 years with known cardiac disease or significant cardiac risk factors, such as diabetes, hypertension, familial hypercholesterolemia, or smoking. In most cases the initial ECG can be obtained while titrating lamotrigine (i.e., when the patient is at the first dose of 25 mg/day) because lamotrigine must be titrated slowly and cardiac adverse events are dose-related. If lamotrigine is used in patients at risk, consider a repeat ECG when the target dose is reached, particularly when the target dose or lamotrigine serum concentrations are near or above the upper limit of the therapeutic range. Always obtain an ECG before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction. Consider obtaining an ECG and cardiology consultation in patients who experience sudden-onset syncope or presyncope with loss of muscular tone without a clear vasovagal or orthostatic cause while taking lamotrigine. Nonspecific ST and T wave abnormalities should not preclude treatment with lamotrigine. In vitro testing showed that lamotrigine exhibits Class IB antiarrhythmic activity at therapeutically relevant concentrations, indicating lamotrigine could slow ventricular conduction (widen QRS) and induce proarrhythmia in patients with clinically significant cardiac disease.
Lamotrigine has been reported to cause laboratory test interference with the assay used in some rapid urine drug screens, which can result in false-positive readings, particularly for phencyclidine (PCP). Use a more specific analytical method to confirm a positive result.
Physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of prepartum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response. Data from several pregnancy registries and epidemiological studies of pregnant women have not detected an increased risk for major congenital malformations or a consistent pattern of malformations among women exposed to lamotrigine compared to the general population. After first-trimester maternal exposure to lamotrigine monotherapy, the International Lamotrigine Pregnancy Registry reported major congenital malformations in 2.2% (95% CI: 1.6%, 3.1%) of 1,558 infants, and the EURAP (an international registry focused outside of North America) reported major birth defects in 2.9% (95% CI: 2.3%, 3.7%) of 2,514 infants. The North American Antiepileptic Drug (NAAED) Pregnancy Registry reported major congenital malformations in 2% of 1,562 infants exposed to lamotrigine monotherapy during the first trimester. The NAAED Pregnancy Registry observed a 3-fold increased risk of isolated oral clefts among 2,200 infants exposed to lamotrigine early in pregnancy compared to unexposed healthy controls; the risk of oral clefts was 3.2 per 1,000 (95% CI: 1.4, 6.3). An increased risk of oral clefts has not been observed in other large international pregnancy registries. An adjusted odds ratio of 1.45 (95% CI: 0.8, 2.63) for isolated oral clefts with lamotrigine exposure was reported from a case-control study based on 21 congenital anomaly registries covering over 10 million births in Europe. Meta-analyses have not demonstrated any increased risk of fetal death, stillbirths, preterm births, small for gestational age, or neurodevelopmental delays in infants born to mothers with lamotrigine exposure. Use lamotrigine cautiously in patients with folate deficiency. In vitro data reveal that lamotrigine inhibits dihydrofolate reductase, and animal data show that lamotrigine decreased fetal, placental, and maternal folate concentrations. Significant reductions in folate concentrations are associated with teratogenesis (e.g., neural tube defects). Sufficient dietary supplementation with folic acid is recommended during pregnancy to maintain normal folate concentrations. Guidelines for the management of epilepsy during pregnancy make general recommendations to optimize treatment prior to conception, which include using monotherapy during pregnancy if possible, choosing the most effective AED for seizure type and syndrome, using the lowest effective dose, and supplementing the pregnant mother with folate. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to lamotrigine; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.
Lamotrigine is present in milk from breast-feeding women taking lamotrigine. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for lamotrigine and any potential adverse effects on the breast-fed child from lamotrigine or the underlying maternal condition. Neonates and young infants are at risk for high serum concentrations because maternal serum and milk concentrations can rise to high concentrations postpartum if the lamotrigine dosage has been increased during pregnancy but is not reduced after delivery to the pre-pregnancy dosage. Monitor human breast milk-fed infants closely for adverse events resulting from lamotrigine. Perform measurement of infant serum concentrations to rule out toxicity if concerns arise. Discontinue breast-feeding in infants with lamotrigine toxicity. Data from multiple small studies indicate that lamotrigine plasma concentrations in human milk-fed infants have been reported to be as high as 50% of the maternal serum concentrations. Immature glucuronidation capacity in the infant may also lead to greater drug exposure. The median milk/maternal plasma concentration ratio was 0.61 (range, 0.47 to 0.77) 2 to 3 weeks after delivery in a single study. The median lamotrigine plasma concentration in the neonates was approximately 30% (range, 23% to 50%) of the mother's plasma concentrations. Rash, apnea, drowsiness, poor sucking, and poor weight gain (requiring hospitalization in some cases) have been reported in nursing infants of mothers using lamotrigine; drug causality is not established. No data are available on the effects of lamotrigine on milk production.
Medication errors have been reported with lamotrigine starter kits. Mild to severe side effects, including Stevens-Johnson Syndrome have occurred. There are 3 different starter kits with titration schedules dependent on concurrent medications. Patients must receive the correct kit to avoid over or under dosing.
-Orange starter kits: For patients NOT taking carbamazepine, phenytoin, phenobarbital, primidone, rifampin, or valproate.
-Green starter kits: For patients taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin and NOT taking valproate.
-Blue starter kits: For patients taking valproate.
For the treatment of partial seizures:
-for the treatment of partial-onset seizures when converting to monotherapy from adjunctive therapy with carbamazepine, phenobarbital, phenytoin, or primidone:
Oral dosage (immediate-release):
Adults: 50 mg PO once daily for 2 weeks, then 50 mg PO twice daily for 2 weeks, and then increase the dose by 100 mg/day every 1 to 2 weeks to a dose of 250 mg PO twice daily. After achieving a dose of lamotrigine 500 mg/day, withdraw the concomitant enzyme-inducing antiepileptic drug (AED) by 20% decrements weekly over a 4-week period. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The safety and effectiveness of immediate-release lamotrigine as initial monotherapy, for conversion to monotherapy from AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate, or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs have not been established.
Adolescents 16 to 17 years: 50 mg PO once daily for 2 weeks, then 50 mg PO twice daily for 2 weeks, and then increase the dose by 100 mg/day every 1 to 2 weeks to a dose of 250 mg PO twice daily. After achieving a dose of lamotrigine 500 mg/day, withdraw the concomitant enzyme-inducing antiepileptic drug (AED) by 20% decrements weekly over a 4-week period. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The safety and effectiveness of immediate-release lamotrigine as initial monotherapy, for conversion to monotherapy from AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate, or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs have not been established.
Oral dosage (extended-release):
Adults: 50 mg PO once daily for 2 weeks, then 100 mg PO once daily for 2 weeks, then 200 mg PO once daily for 1 week, then 300 mg PO once daily for 1 week, then 400 mg PO once daily for 1 week, and then 500 mg PO once daily. After achieving a dose of lamotrigine 500 mg/day, withdraw the concomitant enzyme-inducing antiepileptic drug (AED) by 20% decrements weekly over a 4-week period. At 2 weeks after completion of withdrawal of the enzyme-inducing AED, decrease the lamotrigine dose by no faster than 100 mg/day weekly to a dose of 250 to 300 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The safety and effectiveness of extended-release lamotrigine as initial monotherapy or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs have not been established.
Adolescents: 50 mg PO once daily for 2 weeks, then 100 mg PO once daily for 2 weeks, then 200 mg PO once daily for 1 week, then 300 mg PO once daily for 1 week, then 400 mg PO once daily for 1 week, and then 500 mg PO once daily. After achieving a dose of lamotrigine 500 mg/day, withdraw the concomitant enzyme-inducing antiepileptic drug (AED) by 20% decrements weekly over a 4-week period. At 2 weeks after completion of withdrawal of the enzyme-inducing AED, decrease the lamotrigine dose by no faster than 100 mg/day weekly to a dose of 250 to 300 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The safety and effectiveness of extended-release lamotrigine as initial monotherapy or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs have not been established.
-for the treatment of partial-onset seizures when converting to monotherapy from adjunctive therapy with valproate:
Oral dosage (immediate-release):
Adults: 25 mg PO every other day for 2 weeks, then 25 mg PO once daily for 2 weeks, and then increase the dose by 25 to 50 mg/day every 1 to 2 weeks to a dose of 200 mg/day in 1 or 2 divided doses. After achieving a dose of lamotrigine 200 mg/day, decrease the valproate dose by no more than 500 mg/day weekly to a dose of 500 mg/day; maintain for 1 week. Then, increase the lamotrigine dose to 300 mg/day in 1 or 2 divided doses and simultaneously decrease valproate to 250 mg/day; maintain for 1 week. Then, increase the lamotrigine dose by 100 mg/day weekly to a dose of 500 mg/day in 1 or 2 divided doses and discontinue valproate. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The safety and effectiveness of immediate-release lamotrigine as initial monotherapy, for conversion to monotherapy from AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate, or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs have not been established.
Adolescents 16 to 17 years: 25 mg PO every other day for 2 weeks, then 25 mg PO once daily for 2 weeks, and then increase the dose by 25 to 50 mg/day every 1 to 2 weeks to a dose of 200 mg/day in 1 or 2 divided doses. After achieving a dose of lamotrigine 200 mg/day, decrease the valproate dose by no more than 500 mg/day weekly to a dose of 500 mg/day; maintain for 1 week. Then, increase the lamotrigine dose to 300 mg/day in 1 or 2 divided doses and simultaneously decrease valproate to 250 mg/day; maintain for 1 week. Then, increase the lamotrigine dose by 100 mg/day weekly to a dose of 500 mg/day in 1 or 2 divided doses and discontinue valproate. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The safety and effectiveness of immediate-release lamotrigine as initial monotherapy, for conversion to monotherapy from AEDs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate, or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs have not been established.
Oral dosage (extended-release):
Adults: 25 mg PO every other day for 2 weeks, then 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 1 week, then 100 mg PO once daily for 1 week, and then 150 mg PO once daily. After achieving a dose of lamotrigine 150 mg/day, decrease the valproate dose by no more than 500 mg/day weekly to a dose of 500 mg/day; maintain for 1 week. Then, increase the lamotrigine dose to 200 mg/day and simultaneously decrease valproate to 250 mg/day; maintain for 1 week. Then, increase the lamotrigine dose to 250 or 300 mg/day and discontinue valproate. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The safety and effectiveness of extended-release lamotrigine as initial monotherapy or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs have not been established.
Adolescents: 25 mg PO every other day for 2 weeks, then 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 1 week, then 100 mg PO once daily for 1 week, and then 150 mg PO once daily. After achieving a dose of lamotrigine 150 mg/day, decrease the valproate dose by no more than 500 mg/day weekly to a dose of 500 mg/day; maintain for 1 week. Then, increase the lamotrigine dose to 200 mg/day and simultaneously decrease valproate to 250 mg/day; maintain for 1 week. Then, increase the lamotrigine dose to 250 or 300 mg/day and discontinue valproate. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The safety and effectiveness of extended-release lamotrigine as initial monotherapy or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs have not been established.
-for the treatment of partial-onset seizures when converting to monotherapy from adjunctive therapy with a single anti-epileptic drug other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate:
Oral dosage (extended-release):
Adults: 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 2 weeks, then 100 mg PO once daily for 1 week, then 150 mg PO once daily, then 200 to 250 mg PO once daily, and then increase the dose by no more than 100 mg/day to a dose of 250 or 300 mg/day. After achieving a dose of lamotrigine 250 or 300 mg/day, withdraw the concomitant enzyme-inducing antiepileptic drug (AED) by 20% decrements weekly over a 4-week period. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The safety and effectiveness of extended-release lamotrigine as initial monotherapy or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs have not been established.
Adolescents 13 to 17 years: 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 2 weeks, then 100 mg PO once daily for 1 week, then 150 mg PO once daily, then 200 to 250 mg PO once daily, and then increase the dose by no more than 100 mg/day to a dose of 250 or 300 mg/day. After achieving a dose of lamotrigine 250 or 300 mg/day, withdraw the concomitant enzyme-inducing antiepileptic drug (AED) by 20% decrements weekly over a 4-week period. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The safety and effectiveness of extended-release lamotrigine as initial monotherapy or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs have not been established.
-for the treatment of partial-onset seizures as adjunctive therapy with carbamazepine, phenobarbital, phenytoin, or primidone:
Oral dosage (immediate-release):
Adults: 50 mg PO once daily for 2 weeks, then 50 mg PO twice daily for 2 weeks, and then increase the dose by 100 mg/day every 1 to 2 weeks to a dose of 300 to 500 mg/day in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 50 mg PO once daily for 2 weeks, then 50 mg PO twice daily for 2 weeks, and then increase the dose by 100 mg/day every 1 to 2 weeks to a dose of 300 to 500 mg/day in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 30 kg or more: 0.3 mg/kg/dose PO twice daily for 2 weeks, then 0.6 mg/kg/dose PO twice daily for 2 weeks, and then increase the dose by 1.2 mg/kg/day every 1 to 2 weeks to a dose of 5 to 15 mg/kg/day in 2 divided doses. Max: 400 mg/day. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing less than 30 kg: 0.3 mg/kg/dose PO twice daily for 2 weeks, then 0.6 mg/kg/dose PO twice daily for 2 weeks, and then increase the dose by 1.2 mg/kg/day every 1 to 2 weeks to a dose of 5 to 15 mg/kg/day in 2 divided doses. Max: 400 mg/day. The maintenance dose may need to be increased by as much as 50% based on clinical response. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Oral dosage (extended-release):
Adults: 50 mg PO once daily for 2 weeks, then 100 mg PO once daily for 2 weeks, then 200 mg PO once daily for 1 week, then 300 mg PO once daily for 1 week, then 400 mg PO once daily for 1 week, and then increase the dose by 100 mg/day weekly to a dose of 400 to 600 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 50 mg PO once daily for 2 weeks, then 100 mg PO once daily for 2 weeks, then 200 mg PO once daily for 1 week, then 300 mg PO once daily for 1 week, then 400 mg PO once daily for 1 week, and then increase the dose by 100 mg/day weekly to a dose of 400 to 600 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for the treatment of partial-onset seizures as adjunctive therapy with valproate:
Oral dosage (immediate-release):
Adults: 25 mg PO every other day for 2 weeks, then 25 mg PO once daily for 2 weeks, and then increase the dose by 25 to 50 mg/day every 1 to 2 weeks to a dose of 100 to 200 mg/day in 2 divided doses with valproate alone and 100 to 400 mg/day in 2 divided doses with valproate and other drugs that induce glucuronidation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 25 mg PO every other day for 2 weeks, then 25 mg PO once daily for 2 weeks, and then increase the dose by 25 to 50 mg/day every 1 to 2 weeks to a dose of 100 to 200 mg/day in 2 divided doses with valproate alone and 100 to 400 mg/day in 2 divided doses with valproate and other drugs that induce glucuronidation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 40 kg or more: 0.15 mg/kg/day PO in 1 or 2 divided doses for 2 weeks, then 0.3 mg/kg/day PO in 1 or 2 divided doses for 2 weeks, and then increase the dose by 0.3 mg/kg/day every 1 to 2 weeks to a dose of 1 to 3 mg/kg/day in 1 or 2 divided doses with valproate alone and 1 to 5 mg/day in 1 or 2 divided doses with valproate and other anti-epileptic drugs. Max: 200 mg/day. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 34.1 to 40 kg: 5 mg PO once daily for 2 weeks, then 10 mg PO once daily for 2 weeks, and then increase the dose by 0.3 mg/kg/day every 1 to 2 weeks to a dose of 1 to 3 mg/kg/day in 1 or 2 divided doses with valproate alone and 1 to 5 mg/day in 1 or 2 divided doses with valproate and other anti-epileptic drugs. Max: 200 mg/day. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 27.1 to 34 kg: 4 mg PO once daily for 2 weeks, then 8 mg PO once daily for 2 weeks, and then increase the dose by 0.3 mg/kg/day every 1 to 2 weeks to a dose of 1 to 3 mg/kg/day in 1 or 2 divided doses with valproate alone and 1 to 5 mg/day in 1 or 2 divided doses with valproate and other anti-epileptic drugs. Max: 200 mg/day. The maintenance dose may need to be increased by as much as 50% in children weighing less than 30 kg based on clinical response. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 14.1 to 27 kg: 2 mg PO once daily for 2 weeks, then 4 mg PO once daily for 2 weeks, and then increase the dose by 0.3 mg/kg/day every 1 to 2 weeks to a dose of 1 to 3 mg/kg/day in 1 or 2 divided doses with valproate alone and 1 to 5 mg/day in 1 or 2 divided doses with valproate and other anti-epileptic drugs. Max: 200 mg/day. The maintenance dose may need to be increased by as much as 50% based on clinical response. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 6.7 to 14 kg: 2 mg PO every other day for 2 weeks, then 2 mg PO once daily for 2 weeks, and then increase the dose by 0.3 mg/kg/day every 1 to 2 weeks to a dose of 1 to 3 mg/kg/day in 1 or 2 divided doses with valproate alone and 1 to 5 mg/day in 1 or 2 divided doses with valproate and other anti-epileptic drugs. Max: 200 mg/day. The maintenance dose may need to be increased by as much as 50% based on clinical response. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Oral dosage (extended-release):
Adults: 25 mg PO every other day for 2 weeks, then 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 1 week, then 100 mg PO once daily for 1 week, then 150 mg PO once daily for 1 week, and then increase the dose by 100 mg/day weekly to a dose of 200 to 250 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 25 mg PO every other day for 2 weeks, then 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 1 week, then 100 mg PO once daily for 1 week, then 150 mg PO once daily for 1 week, and then increase the dose by 100 mg/day weekly to a dose of 200 to 250 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for the treatment of partial-onset seizures as adjunctive therapy with anti-epileptic drugs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate:
Oral dosage (immediate-release):
Adults: 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 2 weeks, and then increase the dose by 50 mg/day every 1 to 2 weeks to a dose of 225 to 375 mg/day in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 2 weeks, and then increase the dose by 50 mg/day every 1 to 2 weeks to a dose of 225 to 375 mg/day in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 30 kg or more: 0.3 mg/kg/day PO in 1 or 2 divided doses for 2 weeks, then 0.3 mg/kg/dose PO twice daily for 2 weeks, then increase the dose by 0.6 mg/kg/day every 1 to 2 weeks to a dose of 4.5 to 7.5 mg/kg/day in 2 divided doses. Max: 300 mg/day. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing less than 30 kg: 0.3 mg/kg/day PO in 1 or 2 divided doses for 2 weeks, then 0.3 mg/kg/dose PO twice daily for 2 weeks, then increase the dose by 0.6 mg/kg/day every 1 to 2 weeks to a dose of 4.5 to 7.5 mg/kg/day in 2 divided doses. Max: 300 mg/day. The maintenance dose may need to be increased by as much as 50% based on clinical response. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Oral dosage (extended-release):
Adults: 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 2 weeks, then 100 mg PO once daily for 1 week, then 150 mg PO once daily for 1 week, then 200 mg PO once daily for 1 week, and then increase the dose by 100 mg/day weekly to a dose of 300 to 400 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 2 weeks, then 100 mg PO once daily for 1 week, then 150 mg PO once daily for 1 week, then 200 mg PO once daily for 1 week, and then increase the dose by 100 mg/day weekly to a dose of 300 to 400 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For the treatment of primary generalized tonic-clonic seizures as adjunctive therapy:
-for the treatment of primary generalized tonic-clonic seizures as adjunctive therapy with carbamazepine, phenobarbital, phenytoin, or primidone:
Oral dosage (immediate-release):
Adults: 50 mg PO once daily for 2 weeks, then 50 mg PO twice daily for 2 weeks, and then increase the dose by 100 mg/day every 1 to 2 weeks to a dose of 300 to 500 mg/day in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 50 mg PO once daily for 2 weeks, then 50 mg PO twice daily for 2 weeks, and then increase the dose by 100 mg/day every 1 to 2 weeks to a dose of 300 to 500 mg/day in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 30 kg or more: 0.3 mg/kg/dose PO twice daily for 2 weeks, then 0.6 mg/kg/dose PO twice daily for 2 weeks, and then increase the dose by 1.2 mg/kg/day every 1 to 2 weeks to a dose of 5 to 15 mg/kg/day in 2 divided doses. Max: 400 mg/day. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing less than 30 kg: 0.3 mg/kg/dose PO twice daily for 2 weeks, then 0.6 mg/kg/dose PO twice daily for 2 weeks, and then increase the dose by 1.2 mg/kg/day every 1 to 2 weeks to a dose of 5 to 15 mg/kg/day in 2 divided doses. Max: 400 mg/day. The maintenance dose may need to be increased by as much as 50% based on clinical response. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Oral dosage (extended-release):
Adults: 50 mg PO once daily for 2 weeks, then 100 mg PO once daily for 2 weeks, then 200 mg PO once daily for 1 week, then 300 mg PO once daily for 1 week, then 400 mg PO once daily for 1 week, and then increase the dose by 100 mg/day weekly to a dose of 400 to 600 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 50 mg PO once daily for 2 weeks, then 100 mg PO once daily for 2 weeks, then 200 mg PO once daily for 1 week, then 300 mg PO once daily for 1 week, then 400 mg PO once daily for 1 week, and then increase the dose by 100 mg/day weekly to a dose of 400 to 600 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for the treatment of primary generalized tonic-clonic seizures as adjunctive therapy with valproate:
Oral dosage (immediate-release):
Adults: 25 mg PO every other day for 2 weeks, then 25 mg PO once daily for 2 weeks, and then increase the dose by 25 to 50 mg/day every 1 to 2 weeks to a dose of 100 to 200 mg/day in 2 divided doses with valproate alone and 100 to 400 mg/day in 2 divided doses with valproate and other drugs that induce glucuronidation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 25 mg PO every other day for 2 weeks, then 25 mg PO once daily for 2 weeks, and then increase the dose by 25 to 50 mg/day every 1 to 2 weeks to a dose of 100 to 200 mg/day in 2 divided doses with valproate alone and 100 to 400 mg/day in 2 divided doses with valproate and other drugs that induce glucuronidation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 40 kg or more: 0.15 mg/kg/day PO in 1 or 2 divided doses for 2 weeks, then 0.3 mg/kg/day PO in 1 or 2 divided doses for 2 weeks, and then increase the dose by 0.3 mg/kg/day every 1 to 2 weeks to a dose of 1 to 3 mg/kg/day in 1 or 2 divided doses with valproate alone and 1 to 5 mg/day in 1 or 2 divided doses with valproate and other anti-epileptic drugs. Max: 200 mg/day. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 34.1 to 40 kg: 5 mg PO once daily for 2 weeks, then 10 mg PO once daily for 2 weeks, and then increase the dose by 0.3 mg/kg/day every 1 to 2 weeks to a dose of 1 to 3 mg/kg/day in 1 or 2 divided doses with valproate alone and 1 to 5 mg/day in 1 or 2 divided doses with valproate and other anti-epileptic drugs. Max: 200 mg/day. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 27.1 to 34 kg: 4 mg PO once daily for 2 weeks, then 8 mg PO once daily for 2 weeks, and then increase the dose by 0.3 mg/kg/day every 1 to 2 weeks to a dose of 1 to 3 mg/kg/day in 1 or 2 divided doses with valproate alone and 1 to 5 mg/day in 1 or 2 divided doses with valproate and other anti-epileptic drugs. Max: 200 mg/day. The maintenance dose may need to be increased by as much as 50% in children weighing less than 30 kg based on clinical response. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 14.1 to 27 kg: 2 mg PO once daily for 2 weeks, then 4 mg PO once daily for 2 weeks, and then increase the dose by 0.3 mg/kg/day every 1 to 2 weeks to a dose of 1 to 3 mg/kg/day in 1 or 2 divided doses with valproate alone and 1 to 5 mg/day in 1 or 2 divided doses with valproate and other anti-epileptic drugs. Max: 200 mg/day. The maintenance dose may need to be increased by as much as 50% based on clinical response. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 6.7 to 14 kg: 2 mg PO every other day for 2 weeks, then 2 mg PO once daily for 2 weeks, and then increase the dose by 0.3 mg/kg/day every 1 to 2 weeks to a dose of 1 to 3 mg/kg/day in 1 or 2 divided doses with valproate alone and 1 to 5 mg/day in 1 or 2 divided doses with valproate and other anti-epileptic drugs. Max: 200 mg/day. The maintenance dose may need to be increased by as much as 50% based on clinical response. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Oral dosage (extended-release):
Adults: 25 mg PO every other day for 2 weeks, then 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 1 week, then 100 mg PO once daily for 1 week, then 150 mg PO once daily for 1 week, and then increase the dose by 100 mg/day weekly to a dose of 200 to 250 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 25 mg PO every other day for 2 weeks, then 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 1 week, then 100 mg PO once daily for 1 week, then 150 mg PO once daily for 1 week, and then increase the dose by 100 mg/day weekly to a dose of 200 to 250 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for the treatment of primary generalized tonic-clonic seizures as adjunctive therapy with anti-epileptic drugs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate:
Oral dosage (immediate-release):
Adults: 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 2 weeks, and then increase the dose by 50 mg/day every 1 to 2 weeks to a dose of 225 to 375 mg/day in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 2 weeks, and then increase the dose by 50 mg/day every 1 to 2 weeks to a dose of 225 to 375 mg/day in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 30 kg or more: 0.3 mg/kg/day PO in 1 or 2 divided doses for 2 weeks, then 0.3 mg/kg/dose PO twice daily for 2 weeks, then increase the dose by 0.6 mg/kg/day every 1 to 2 weeks to a dose of 4.5 to 7.5 mg/kg/day in 2 divided doses. Max: 300 mg/day. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing less than 30 kg: 0.3 mg/kg/day PO in 1 or 2 divided doses for 2 weeks, then 0.3 mg/kg/dose PO twice daily for 2 weeks, then increase the dose by 0.6 mg/kg/day every 1 to 2 weeks to a dose of 4.5 to 7.5 mg/kg/day in 2 divided doses. Max: 300 mg/day. The maintenance dose may need to be increased by as much as 50% based on clinical response. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Oral dosage (extended-release):
Adults: 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 2 weeks, then 100 mg PO once daily for 1 week, then 150 mg PO once daily for 1 week, then 200 mg PO once daily for 1 week, and then increase the dose by 100 mg/day weekly to a dose of 300 to 400 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 2 weeks, then 100 mg PO once daily for 1 week, then 150 mg PO once daily for 1 week, then 200 mg PO once daily for 1 week, and then increase the dose by 100 mg/day weekly to a dose of 300 to 400 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For the treatment of generalized seizures of Lennox-Gastaut syndrome as adjunctive therapy:
-for the treatment of generalized seizures of Lennox-Gastaut syndrome as adjunctive therapy with carbamazepine, phenobarbital, phenytoin, or primidone:
Oral dosage (immediate-release):
Adults: 50 mg PO once daily for 2 weeks, then 50 mg PO twice daily for 2 weeks, and then increase the dose by 100 mg/day every 1 to 2 weeks to a dose of 300 to 500 mg/day in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 50 mg PO once daily for 2 weeks, then 50 mg PO twice daily for 2 weeks, and then increase the dose by 100 mg/day every 1 to 2 weeks to a dose of 300 to 500 mg/day in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 30 kg or more: 0.3 mg/kg/dose PO twice daily for 2 weeks, then 0.6 mg/kg/dose PO twice daily for 2 weeks, and then increase the dose by 1.2 mg/kg/day every 1 to 2 weeks to a dose of 5 to 15 mg/kg/day in 2 divided doses. Max: 400 mg/day. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing less than 30 kg: 0.3 mg/kg/dose PO twice daily for 2 weeks, then 0.6 mg/kg/dose PO twice daily for 2 weeks, and then increase the dose by 1.2 mg/kg/day every 1 to 2 weeks to a dose of 5 to 15 mg/kg/day in 2 divided doses. Max: 400 mg/day. The maintenance dose may need to be increased by as much as 50% based on clinical response. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for the treatment of generalized seizures of Lennox-Gastaut syndrome as adjunctive therapy with valproate:
Oral dosage (immediate-release):
Adults: 25 mg PO every other day for 2 weeks, then 25 mg PO once daily for 2 weeks, and then increase the dose by 25 to 50 mg/day every 1 to 2 weeks to a dose of 100 to 200 mg/day in 2 divided doses with valproate alone and 100 to 400 mg/day in 2 divided doses with valproate and other drugs that induce glucuronidation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 25 mg PO every other day for 2 weeks, then 25 mg PO once daily for 2 weeks, and then increase the dose by 25 to 50 mg/day every 1 to 2 weeks to a dose of 100 to 200 mg/day in 2 divided doses with valproate alone and 100 to 400 mg/day in 2 divided doses with valproate and other drugs that induce glucuronidation. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 40 kg or more: 0.15 mg/kg/day PO in 1 or 2 divided doses for 2 weeks, then 0.3 mg/kg/day PO in 1 or 2 divided doses for 2 weeks, and then increase the dose by 0.3 mg/kg/day every 1 to 2 weeks to a dose of 1 to 3 mg/kg/day in 1 or 2 divided doses with valproate alone and 1 to 5 mg/day in 1 or 2 divided doses with valproate and other anti-epileptic drugs. Max: 200 mg/day. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 34.1 to 40 kg: 5 mg PO once daily for 2 weeks, then 10 mg PO once daily for 2 weeks, and then increase the dose by 0.3 mg/kg/day every 1 to 2 weeks to a dose of 1 to 3 mg/kg/day in 1 or 2 divided doses with valproate alone and 1 to 5 mg/day in 1 or 2 divided doses with valproate and other anti-epileptic drugs. Max: 200 mg/day. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 27.1 to 34 kg: 4 mg PO once daily for 2 weeks, then 8 mg PO once daily for 2 weeks, and then increase the dose by 0.3 mg/kg/day every 1 to 2 weeks to a dose of 1 to 3 mg/kg/day in 1 or 2 divided doses with valproate alone and 1 to 5 mg/day in 1 or 2 divided doses with valproate and other anti-epileptic drugs. Max: 200 mg/day. The maintenance dose may need to be increased by as much as 50% in children weighing less than 30 kg based on clinical response. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 14.1 to 27 kg: 2 mg PO once daily for 2 weeks, then 4 mg PO once daily for 2 weeks, and then increase the dose by 0.3 mg/kg/day every 1 to 2 weeks to a dose of 1 to 3 mg/kg/day in 1 or 2 divided doses with valproate alone and 1 to 5 mg/day in 1 or 2 divided doses with valproate and other anti-epileptic drugs. Max: 200 mg/day. The maintenance dose may need to be increased by as much as 50% based on clinical response. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 6.7 to 14 kg: 2 mg PO every other day for 2 weeks, then 2 mg PO once daily for 2 weeks, and then increase the dose by 0.3 mg/kg/day every 1 to 2 weeks to a dose of 1 to 3 mg/kg/day in 1 or 2 divided doses with valproate alone and 1 to 5 mg/day in 1 or 2 divided doses with valproate and other anti-epileptic drugs. Max: 200 mg/day. The maintenance dose may need to be increased by as much as 50% based on clinical response. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for the treatment of generalized seizures of Lennox-Gastaut syndrome as adjunctive therapy with anti-epileptic drugs other than carbamazepine, phenobarbital, phenytoin, primidone, or valproate:
Oral dosage (immediate-release):
Adults: 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 2 weeks, and then increase the dose by 50 mg/day every 1 to 2 weeks to a dose of 225 to 375 mg/day in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Adolescents: 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 2 weeks, and then increase the dose by 50 mg/day every 1 to 2 weeks to a dose of 225 to 375 mg/day in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing 30 kg or more: 0.3 mg/kg/day PO in 1 or 2 divided doses for 2 weeks, then 0.3 mg/kg/dose PO twice daily for 2 weeks, then increase the dose by 0.6 mg/kg/day every 1 to 2 weeks to a dose of 4.5 to 7.5 mg/kg/day in 2 divided doses. Max: 300 mg/day. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children 2 to 12 years weighing less than 30 kg: 0.3 mg/kg/day PO in 1 or 2 divided doses for 2 weeks, then 0.3 mg/kg/dose PO twice daily for 2 weeks, then increase the dose by 0.6 mg/kg/day every 1 to 2 weeks to a dose of 4.5 to 7.5 mg/kg/day in 2 divided doses. Max: 300 mg/day. The maintenance dose may need to be increased by as much as 50% based on clinical response. Round the dose down to the nearest whole tablet. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For the treatment of absence seizures*:
Oral dosage (immediate-release):
Children and Adolescents 3 to 13 years: 0.25 mg/kg/dose PO twice daily for 2 weeks, then 0.5 mg/kg/day PO twice daily for 2 weeks, and then increase the dose by 1 mg/kg/day every 5 days until an effective dose is reached, side effects prohibit further titration, or to a maximum of 12 mg/kg/day. At 1 month, significantly more children were seizure free with valproic acid (52.6%) than lamotrigine (5.3%). There was no statistical difference by month 3 (63.1% vs. 36.8%). After 12 months, 68.4% and 52.6% of those receiving valproic acid and lamotrigine, respectively, were seizure free. Adverse effects (headache, skin rash, diplopia, nervousness, or increased appetite) were reported in 6 subjects receiving lamotrigine. The delayed response to lamotrigine may in part be due to the slow titration schedule. However, safety issues, such as the risk of a serious skin rash, must be taken into consideration when selecting a dosage titration. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For the treatment of bipolar disorder (bipolar I disorder) to delay the occurrence of mood episodes (i.e., depression, mania, hypomania, mixed episodes) in persons treated for acute mood episodes with standard therapy:
-for the treatment of bipolar disorder in persons not taking carbamazepine (or other enzyme-inducing drugs) or valproate:
Oral dosage (immediate-release):
Adults: 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 2 weeks, then 100 mg PO once daily for 1 week, and then 200 mg PO once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children* and Adolescents* 12 to 17 years: 25 mg PO once daily for 2 weeks, then 50 mg/day PO in 1 or 2 divided doses for 2 weeks, then 100 mg/day PO in 1 or 2 divided doses, initially. May further increase the dose by 25 to 50 mg/week based on clinical response and tolerability. Max: 500 mg/day in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children* 6 to 11 years: 0.35 mg/kg/day PO in 2 divided doses for 2 weeks, then 0.7 mg/kg/day PO in 2 divided doses for 2 weeks, then 1.4 mg/kg/day PO in 2 divided doses for 2 weeks, initially. May further increase the dose by 1 mg/kg/day in 2 divided doses every week based on clinical response and tolerability. Usual dose: 5 to 15 mg/kg/day. Max: 400 mg/day in 2 divided doses. Round dose down to the nearest 5 mg. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for the treatment of bipolar disorder in persons taking carbamazepine (or other enzyme-inducing drugs):
Oral dosage (immediate-release):
Adults: 50 mg PO once daily for 2 weeks, then 50 mg PO twice daily for 2 weeks, then 100 mg PO twice daily for 1 week, then 150 mg PO twice daily for 1 week, then up to 200 mg PO twice daily. Upon discontinuation of carbamazepine (or other enzyme inducing drug), maintain lamotrigine 400 mg/day for 1 week, then decrease dose by 100 mg/day every week to a dose of 200 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
-for the treatment of bipolar disorder in persons taking valproate:
Oral dosage (immediate-release):
Adults: 25 mg PO every other day for 2 weeks, then 25 mg PO once daily for 2 weeks, than 50 mg PO once daily for 1 week, then 100 mg PO once daily. Upon discontinuation of valproate, increase the lamotrigine dose to 150 mg/day for 1 week, and then 200 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children* and Adolescents* 12 to 17 years: 12.5 mg PO once daily for 2 weeks, initially. Increase the dose gradually based on clinical response and tolerability. Usual dose: 50 to 100 mg/day in 2 divided doses. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For long-term prophylaxis of short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT)*:
Oral dosage:
Adults: Limited case series and report suggest doses of 100 to 600 mg/day PO are effective in reducing or eliminating symptoms of SUNCT. Lamotrigine was initiated at 25 mg PO once daily and titrated every 4 to 5 days until patients experienced relief. While doses as high as 600 mg/day were allowed and required by some patients, most patients responded to doses of 100 mg to 400 mg/day. In a patient, a combination of carbamazepine and lamotrigine was required for cessation of SUNCT symptoms. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
For the treatment of trigeminal neuralgia*:
Oral dosage (immediate-release):
Adults: 50 mg PO twice daily for 1 week, then 100 mg PO twice daily for 1 week, then 200 mg PO twice daily or alternatively, 25 mg PO once daily for 2 weeks, then 50 mg PO once daily for 2 weeks, then increase the dose by 50 mg/day every 2 weeks up to 200 mg PO twice daily. Max: 400 mg/day.
Maximum Dosage Limits:
-Adults
In seizure disorders, individualize to the patient's age, weight, indication, concurrent medication, and clinical response. In bipolar disorder, maximum monotherapy dosage is 200 mg/day PO; 100 mg/day PO if taking valproate; 400 mg/day PO if taking enzyme-inducing drugs.
-Elderly
In seizure disorders, individualize to the patient's age, weight, indication, concurrent medication, and clinical response. In bipolar disorder, maximum monotherapy dosage is 200 mg/day PO; 100 mg/day PO if taking valproate; 400 mg/day PO if taking enzyme-inducing drugs.
-Adolescents
In seizure disorders, individualize to the patient's age, weight, indication, concurrent medication, and clinical response. Safe and effective use in bipolar disorder has not been established.
-Children
>= 2 years: In seizure disorders, individualize to the patient's age, weight, indication, concurrent medication, and clinical response. Safe and effective use in bipolar disorder has not been established. Safe and effective use of extended-release formulation has not been established. Guidelines: Children receiving valproate: 200 mg/day PO as adjunct treatment. Children receiving enzyme-inducing AEDs (e.g., carbamazepine, phenobarbital, phenytoin, primidone) WITHOUT valproate: 400 mg/day PO as adjunct treatment. Children receiving AEDs OTHER than carbamazepine, phenobarbital, phenytoin, primidone, or valproate: 300 mg/day PO as adjunct treatment.
< 2 years: Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Initial, escalation, and maintenance doses should generally be reduced by 25% in patients with moderate hepatic impairment or severe impairment without ascites, and by 50% in patients with severe hepatic impairment with ascites. Adjust doses as needed according to clinical response.
Patients with Renal Impairment Dosing
Dosage should be modified depending on clinical response and degree of renal impairment. A reduced maintenance dosage may be effective, but due to limited experience, no quantitative recommendations are available.
Intermittent hemodialysis
Hemodialysis lowers the apparent elimination half-life of lamotrigine by 70% to 80%. The half-life decreases from 43 to 57 hours in anuric subjects between dialysis treatments to 13 hours during dialysis treatments. Approximately 20% of lamotrigine present in the body is removed after a standard 4-hour dialysis session. No quantitative recommendations are available for adjustments.
*non-FDA-approved indication
Acetaminophen: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Aspirin: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Caffeine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Chlorpheniramine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Codeine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Dextromethorphan: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Diphenhydramine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Hydrocodone: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Ibuprofen: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Oxycodone: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Phenylephrine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Acetaminophen; Pseudoephedrine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Alogliptin; Metformin: (Moderate) Concomitant administration of metformin and lamotrigine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; lamotrigine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, including anticonvulsants, can potentiate the CNS effects of either agent.
Amitriptyline: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as tricyclic antidepressants. Concomitant use of tricyclic antidepressants with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Apalutamide: (Moderate) Adjustments in lamotrigine escalation and maintenance dose regimens may be necessary with concomitant apalutamide use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and apalutamide induces glucuronidation.
Aripiprazole: (Minor) Coadministration of aripiprazole and lamotrigine may slightly decrease lamotrigine plasma concentrations; however, this interaction is not expected to be clinically meaningful. During clinical trials, lamotrigine exposure was reduced approximately 10% in patients (n = 18) on a stable regimen of lamotrigine 100 mg/day to 400 mg/day who received ariprazole 10 mg/day to 30 mg/day for 7 days, followed by 30 mg/day for an additional 7 days.
Atazanavir: (Major) Adjustments in lamotrigine maintenance dose regimens may be necessary with concomitant use of atazanavir boosted with ritonavir. No dose adjustments during dose escalation are necessary. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and atazanavir with ritonavir induces glucuronidation. Daily doses of atazanavir/ritonavir (300 mg/100 mg) in healthy volunteers reduced the AUC and Cmax of a single lamotrigine dose (100 mg) by approximately 32% and 6%, respectively. The lamotrigine half-life decreased by 27%. Concurrent use of lamotrigine and unboosted atazanavir is not expected to alter the plasma concentration of lamotrigine, and no dose adjustment of lamotrigine is necessary when administered without ritonavir.
Atazanavir; Cobicistat: (Major) Adjustments in lamotrigine maintenance dose regimens may be necessary with concomitant use of atazanavir boosted with ritonavir. No dose adjustments during dose escalation are necessary. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and atazanavir with ritonavir induces glucuronidation. Daily doses of atazanavir/ritonavir (300 mg/100 mg) in healthy volunteers reduced the AUC and Cmax of a single lamotrigine dose (100 mg) by approximately 32% and 6%, respectively. The lamotrigine half-life decreased by 27%. Concurrent use of lamotrigine and unboosted atazanavir is not expected to alter the plasma concentration of lamotrigine, and no dose adjustment of lamotrigine is necessary when administered without ritonavir.
Benzalkonium Chloride; Benzocaine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as benzocaine. Concomitant use of benzocaine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Benzhydrocodone; Acetaminophen: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Benzocaine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as benzocaine. Concomitant use of benzocaine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Benzocaine; Butamben; Tetracaine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as benzocaine. Concomitant use of benzocaine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Bupivacaine Liposomal: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as bupivacaine. Concomitant use of bupivacaine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Bupivacaine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as bupivacaine. Concomitant use of bupivacaine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Bupivacaine; Epinephrine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as bupivacaine. Concomitant use of bupivacaine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Bupivacaine; Lidocaine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as bupivacaine. Concomitant use of bupivacaine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations. (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IB antiarrhythmics. Concomitant use of class IB antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Bupivacaine; Meloxicam: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as bupivacaine. Concomitant use of bupivacaine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Butalbital; Acetaminophen: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Butalbital; Acetaminophen; Caffeine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Canagliflozin; Metformin: (Moderate) Concomitant administration of metformin and lamotrigine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; lamotrigine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Cannabidiol: (Moderate) Consider a dose reduction of lamotrigine, as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Increased lamotrigine exposure is possible. Lamotrigine is a UGT2B7 substrate. In vitro data predicts inhibition of UGT2B7 by cannabidiol potentially resulting in clinically significant interactions.
Carbamazepine: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant carbamazepine use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and carbamazepine induces glucuronidation. During concurrent use of lamotrigine with carbamazepine, lamotrigine steady-state concentration decreased by approximately 40%. Lamotrigine may increase the concentration of the 10, 11-epoxide metabolite of carbamazepine; small studies have demonstrated mixed results when evaluating carbamazepine-epoxide concentrations in the presence of lamotrigine. Limited data suggest that there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving lamotrigine with carbamazepine than in patients receiving lamotrigine with other AEDs; the mechanism of the interaction is not known.
Cenobamate: (Major) Increase the dosage of lamotrigine as needed when coadministered with cenobamate due to the potential for reduced efficacy of lamotrigine. Coadministration of cenobamate and lamotrigine is expected to decrease lamotrigine concentrations by 21% to 52%.
Chlordiazepoxide; Amitriptyline: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as tricyclic antidepressants. Concomitant use of tricyclic antidepressants with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Chloroprocaine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as chloroprocaine. Concomitant use of chloroprocaine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Cimetidine: (Minor) Coadministration of cimetidine and lamotrigine may decrease cimetidine clearance, resulting in increased plasma concentrations and the potential for cimetidine-related adverse events. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and cimetidine is excreted via this route.
Class IA Antiarrhythmics: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IA antiarrhythmics. Concomitant use of class IA antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Class IB Antiarrhythmics: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IB antiarrhythmics. Concomitant use of class IB antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Class IC Antiarrhythmics: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IC antiarrhythmics. Concomitant use of class IC antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Clomipramine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as tricyclic antidepressants. Concomitant use of tricyclic antidepressants with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Clozapine: (Major) One report has described an interaction between lamotrigine and clozapine. A 3-fold increase in clozapine concentrations occurred in a patient after lamotrigine was added to the drug regimen. The patient experienced drowsiness and dizziness that were clinically significant. Measurement of clozapine plasma concentrations during the time of the interaction and after lamotrigine was discontinued indicated a probable interaction, although the mechanism of the interaction is not certain. Clozapine may interact with anticonvulsants in several ways; therefore concurrent use of clozapine in patients on antiepileptic medications is not recommended if seizures are not controlled. Clozapine lowers the seizure threshold in a dose-dependent manner and thus may induce seizures. Dosage adjustments of clozapine should be cautious.
Cocaine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as cocaine. Concomitant use of cocaine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Colesevelam: (Moderate) Colesevelam may decrease the bioavailability of lamotrigine. To minimize potential for interactions, consider administering oral anticonvulsants such as lamotrigine at least 1 hour before or at least 4 hours after colesevelam.
Conjugated Estrogens: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced.
Conjugated Estrogens; Bazedoxifene: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced.
Conjugated Estrogens; Medroxyprogesterone: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Dapagliflozin; Metformin: (Moderate) Concomitant administration of metformin and lamotrigine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; lamotrigine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Desipramine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as tricyclic antidepressants. Concomitant use of tricyclic antidepressants with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Desmopressin: (Major) Caution is recommended if a drug that may increase the risk of water intoxication with hyponatremia, such as lamotrigine, is administered with desmopressin acetate. Two children with diabetes insipidus had decreasing desmopressin requirements with lamotrigine initiation.
Desogestrel; Ethinyl Estradiol: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Dextromethorphan; Quinidine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IA antiarrhythmics. Concomitant use of class IA antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Dienogest; Estradiol valerate: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Disopyramide: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IA antiarrhythmics. Concomitant use of class IA antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Dofetilide: (Major) Coadministration of lamotrigine and dofetilide is not recommended. Coadministration may decrease dofetilide clearance, resulting in increased plasma concentrations and the potential for serious adverse events, including QT prolongation and cardiac arrhythmias. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and dofetilide is excreted via this route.
Doxepin: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as tricyclic antidepressants. Concomitant use of tricyclic antidepressants with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Drospirenone: (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Drospirenone; Estetrol: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Drospirenone; Estradiol: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Drospirenone; Ethinyl Estradiol: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis. (Minor) L-methylfolate concentrations may be reduced when administered concomitantly with lamotrigine. Patients should be monitored closely for decreased efficacy of L-methylfolate if these agents are used together.
Elagolix; Estradiol; Norethindrone acetate: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Empagliflozin; Linagliptin; Metformin: (Moderate) Concomitant administration of metformin and lamotrigine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; lamotrigine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Empagliflozin; Metformin: (Moderate) Concomitant administration of metformin and lamotrigine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; lamotrigine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Ertugliflozin; Metformin: (Moderate) Concomitant administration of metformin and lamotrigine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; lamotrigine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Eslicarbazepine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as eslicarbazepine. Concomitant use of eslicarbazepine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Esterified Estrogens: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced.
Esterified Estrogens; Methyltestosterone: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced.
Estradiol: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced.
Estradiol; Levonorgestrel: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Estradiol; Norethindrone: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Estradiol; Norgestimate: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Estradiol; Progesterone: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Estrogens: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced.
Estropipate: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced.
Ethinyl Estradiol; Norelgestromin: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Ethinyl Estradiol; Norethindrone Acetate: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Ethinyl Estradiol; Norgestrel: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Etonogestrel: (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Etonogestrel; Ethinyl Estradiol: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Flecainide: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IC antiarrhythmics. Concomitant use of class IC antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Fluorouracil, 5-FU: (Moderate) Lamotrigine inhibits dihydrofolate reductase. Caution should be exercised when administering fluorouracil, 5-FU, which may inhibit this enzyme.
Fosphenytoin: (Moderate) A lamotirigine dosage increase may be necessary during coadministration of fosphenytoin and lamotrigine. When phenytoin or fosphenytoin is added to lamotrigine therapy, phenytoin decreases the steady state concentrations of lamotrigine by approximately 40 percent. If enzyme inducing antiepileptic drugs are discontinued, lamotrigine doses may need to be adjusted downward. Phenytoin can decrease lamotrigine half-life, presumably through induction of the hepatic enzyme uridine diphosphate glucuronyltransferase (UGT).
Glipizide; Metformin: (Moderate) Concomitant administration of metformin and lamotrigine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; lamotrigine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Glyburide; Metformin: (Moderate) Concomitant administration of metformin and lamotrigine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; lamotrigine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Hydroxychloroquine: (Moderate) Monitor for seizures during concomitant use of hydroxychloroquine and lamotrigine. Hydroxychloroquine can lower the seizure threshold and the activity of antiepileptics may be impaired during concomitant use.
Imipramine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as tricyclic antidepressants. Concomitant use of tricyclic antidepressants with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant rifampin use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and rifampin induces glucuronidation. During concurrent use of lamotrigine with rifampin in 10 volunteers, rifampin (600 mg/day for 5 days) decreased the AUC of lamotrigine (25 mg single dose) by approximately 40%.
Isoniazid, INH; Rifampin: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant rifampin use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and rifampin induces glucuronidation. During concurrent use of lamotrigine with rifampin in 10 volunteers, rifampin (600 mg/day for 5 days) decreased the AUC of lamotrigine (25 mg single dose) by approximately 40%.
Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction including those that prolong PR interval, such as sodium channel blocking anticonvulsants (e.g., lamotrigine), because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
Leuprolide; Norethindrone: (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Levomefolate: (Minor) L-methylfolate concentrations may be reduced when administered concomitantly with lamotrigine. Patients should be monitored closely for decreased efficacy of L-methylfolate if these agents are used together.
Levonorgestrel: (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Levonorgestrel; Ethinyl Estradiol: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Lidocaine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IB antiarrhythmics. Concomitant use of class IB antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Lidocaine; Epinephrine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IB antiarrhythmics. Concomitant use of class IB antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Lidocaine; Prilocaine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IB antiarrhythmics. Concomitant use of class IB antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations. (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as prilocaine. Concomitant use of prilocaine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Linagliptin; Metformin: (Moderate) Concomitant administration of metformin and lamotrigine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; lamotrigine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Lopinavir; Ritonavir: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant lopinavir; ritonavir use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and lopinavir; ritonavir induces glucuronidation. During concurrent use of lamotrigine with lopinavir; ritonavir in 18 healthy subjects, induction of glucuronidation by lopinavir (400 mg twice daily); ritonavir (100 mg twice daily) decreased lamotrigine AUC, Cmax, and half-life by approximately 50% to 55.4%.
Maprotiline: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
Medroxyprogesterone: (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Mefloquine: (Moderate) Coadministration of mefloquine and anticonvulsants may result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the anticonvulsant serum concentration, if the drug is monitored via therapeutic drug monitoring, is recommended. Mefloquine may cause CNS side effects that may cause seizures or alter moods or behaviors. Some, but not all anticonvulsants, induce CYP3A4 and may increase the metabolism of mefloquine. Use of enzyme-inducing anticonvulsants can reduce the clinical efficacy of mefloquine, increasing the risk of Plasmodium falciparum resistance during treatment of malaria.
Mepivacaine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as mepivacaine. Concomitant use of mepivacaine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Metformin: (Moderate) Concomitant administration of metformin and lamotrigine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; lamotrigine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Metformin; Repaglinide: (Moderate) Concomitant administration of metformin and lamotrigine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; lamotrigine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Metformin; Saxagliptin: (Moderate) Concomitant administration of metformin and lamotrigine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; lamotrigine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Metformin; Sitagliptin: (Moderate) Concomitant administration of metformin and lamotrigine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; lamotrigine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Methotrexate: (Moderate) Monitor for increased methotrexate-related adverse reactions during concomitant lamotrigine use. Concomitant use may have additive antifolate effects. Methotrexate inhibits dihydrofolate reductase, and lamotrigine is a weak inhibitor of dihydrofolate reductase.
Methsuximide: (Major) Methsuximide may reduce serum concentrations of lamotrigine by up to 70%. Conversely, if methsuximide is discontinued, lamotrigine doses may need to be adjusted downward. The mechanism by which this interaction occurs has not been established.
Mexiletine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IB antiarrhythmics. Concomitant use of class IB antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
Nirmatrelvir; Ritonavir: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant lopinavir; ritonavir use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and lopinavir; ritonavir induces glucuronidation. During concurrent use of lamotrigine with lopinavir; ritonavir in 18 healthy subjects, induction of glucuronidation by lopinavir (400 mg twice daily); ritonavir (100 mg twice daily) decreased lamotrigine AUC, Cmax, and half-life by approximately 50% to 55.4%.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Norethindrone: (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Norethindrone; Ethinyl Estradiol: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Norgestimate; Ethinyl Estradiol: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Norgestrel: (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Nortriptyline: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as tricyclic antidepressants. Concomitant use of tricyclic antidepressants with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Oxcarbazepine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as oxcarbazepine. Concomitant use of oxcarbazepine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Perphenazine; Amitriptyline: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as tricyclic antidepressants. Concomitant use of tricyclic antidepressants with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Phenobarbital: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant phenobarbital use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and phenobarbital induces glucuronidation. During concurrent use of lamotrigine with phenobarbital, lamotrigine steady-state concentration decreased by approximately 40%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant phenobarbital use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and phenobarbital induces glucuronidation. During concurrent use of lamotrigine with phenobarbital, lamotrigine steady-state concentration decreased by approximately 40%.
Phentermine; Topiramate: (Moderate) Monitor for loss of topiramate efficacy and/or an increase in topiramate-related adverse events during coadministration. Coadministration has resulted in both a 13% decrease and 15% increase in topiramate concentrations.
Phenytoin: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant phenytoin use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and phenytoin induces glucuronidation. During concurrent use of lamotrigine with phenytoin, lamotrigine steady-state concentration decreased by approximately 40%.
Pioglitazone; Metformin: (Moderate) Concomitant administration of metformin and lamotrigine may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is an OCT2 substrate; lamotrigine is an OCT2 inhibitor that may decrease metformin elimination by blocking renal tubular secretion.
Prilocaine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as prilocaine. Concomitant use of prilocaine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Prilocaine; Epinephrine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as prilocaine. Concomitant use of prilocaine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Primidone: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant primidone use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and primidone induces glucuronidation. During concurrent use of lamotrigine with primidone, lamotrigine steady-state concentration decreased by approximately 40%.
Procainamide: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IA antiarrhythmics. Concomitant use of class IA antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Progesterone: (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Progestins: (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Propafenone: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IC antiarrhythmics. Concomitant use of class IC antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Protriptyline: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as tricyclic antidepressants. Concomitant use of tricyclic antidepressants with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Pyrimethamine: (Moderate) Lamotrigine inhibits dihydrofolate reductase. Caution should be exercised when administering pyrimethamine, which also inhibits this enzyme.
Quinidine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as class IA antiarrhythmics. Concomitant use of class IA antiarrhythmics with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Relugolix; Estradiol; Norethindrone acetate: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Rifampin: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant rifampin use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and rifampin induces glucuronidation. During concurrent use of lamotrigine with rifampin in 10 volunteers, rifampin (600 mg/day for 5 days) decreased the AUC of lamotrigine (25 mg single dose) by approximately 40%.
Ritonavir: (Major) Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant lopinavir; ritonavir use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and lopinavir; ritonavir induces glucuronidation. During concurrent use of lamotrigine with lopinavir; ritonavir in 18 healthy subjects, induction of glucuronidation by lopinavir (400 mg twice daily); ritonavir (100 mg twice daily) decreased lamotrigine AUC, Cmax, and half-life by approximately 50% to 55.4%.
Rufinamide: (Moderate) Shortening of the QT interval has occurred during treatment with rufinamide. Therefore, caution is advisable during co-administration with other drugs associated with QT-shortening including lamotrigine. In addition, a population pharmacokinetic analysis showed a 7% to 13% decrease in lamotrigine concentrations and no effect on rufinamide concentrations during concurrent use.
Segesterone Acetate; Ethinyl Estradiol: (Major) A lamotrigine maintenance dose increase of up to 2-fold may be required during concomitant use of estrogen hormones. Increase the dose no more rapidly than 50 to 100 mg/day every week based on clinical response. Coadministration of an oral contraceptive containing 30 mcg of ethinyl estradiol has been observed to decrease the AUC and Cmax of lamotrigine by 52% and 39%, respectively. During the oral contraceptive pill-free week, trough lamotrigine concentrations have been observed to increase an average of 2-fold which may transiently increase the risk for lamotrigine-related adverse effects. If lamotrigine-related adverse effects consistently occur during the pill-free week, the overall lamotrigine maintenance dose may need to be reduced. (Moderate) Patients taking progestin hormones for contraception may consider an alternate or additional form of contraception, such as nonhormonal and/or barrier methods, during and for at least 1 month after discontinuation of lamotrigine. Higher-dose hormonal regimens may also be considered. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on lamotrigine with dose adjustments made based on clinical efficacy. The AUC and Cmax of levonorgestrel decreased by 19% and 12%, respectively, among 16 volunteers during concurrent use with lamotrigine 300 mg/day. Serum progesterone concentrations did not suggest ovulation, however, serum FSH, LH, and estradiol concentrations suggested some loss of suppression of the hypothalamic-pituitary-ovarian axis.
Tetracaine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as tetracaine. Concomitant use of tetracaine with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Topiramate: (Moderate) Monitor for loss of topiramate efficacy and/or an increase in topiramate-related adverse events during coadministration. Coadministration has resulted in both a 13% decrease and 15% increase in topiramate concentrations.
Tramadol; Acetaminophen: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
Tricyclic antidepressants: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as tricyclic antidepressants. Concomitant use of tricyclic antidepressants with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Trimipramine: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as tricyclic antidepressants. Concomitant use of tricyclic antidepressants with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
Valproic Acid, Divalproex Sodium: (Major) Coadministration of valproic acid with lamotrigine can decrease the elimination of lamotrigine. Valproic acid more than doubles the elimination half-life of lamotrigine in both pediatric and adult patients. In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate coadministration (a 165% increase). The decrease in apparent clearance of lamotrigine may occur via inhibition of lamotrigine metabolism through competition for liver glucuronidation sites. Serious skin reactions (such as Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. In any patient receiving valproic acid, lamotrigine must be initiated at a reduced dosage that is less than half the dose used in patients not receiving valproic acid. In controlled clinical trials, lamotrigine had no appreciable effect on plasma valproic acid concentrations when added to existing valproic acid therapies. If valproic acid therapy is discontinued, lamotrigine doses may need to be adjusted upward. The inhibitory effects of valproic acid on lamotrigine elimination may offset the actions of other anticonvulsants with known hepatic enzyme-inducing properties on lamotrigine clearance.
Zonisamide: (Moderate) Consider ECG monitoring before and during concomitant use of lamotrigine with other sodium channel blockers known to impair atrioventricular and/or intraventricular cardiac conduction, such as zonisamide. Concomitant use of zonisamide with lamotrigine may increase the risk of proarrhythmia, especially in patients with clinically important structural or functional heart disease. In vitro testing showed that lamotrigine exhibits class IB antiarrhythmic activity at therapeutically relevant concentrations.
The exact mechanism of anticonvulsant activity is not known, but studies suggest lamotrigine may stabilize neuronal membranes by acting at voltage-sensitive sodium channels. The blocking of sodium channels can decrease the presynaptic release of glutamate and aspartate, resulting in decreased seizure frequency. This mechanism is similar to that of carbamazepine and phenytoin. Lamotrigine appears to have little or no effect on the release of GABA, dopamine, acetylcholine, or norepinephrine. Lamotrigine is also a weak dihydrofolate reductase inhibitor in vitro and in animal studies. In clinical studies, however, no effect of lamotrigine on folate concentrations has been noted, although it is possible that folate concentrations may decrease during gestation.
Lamotrigine is administered orally as conventional tablets, chewable tablets, orally disintegrating tablets (ODT), and extended-release tablets. The volume of distribution is independent of dose and duration of therapy. Distribution into the CNS is not known. Extensive placental transfer appears to occur. In 9 women, the maternal plasma concentrations immediately after delivery were similar to concentrations found in the umbilical cords. Further, lamotrigine is distributed into breast milk. Two to three weeks after delivery, the median milk:maternal plasma concentration ratio was 0.61 (range, 0.47 to 0.77); the median plasma concentration in the neonates was approximately 30% (range, 23% to 50%) of the mother's plasma concentrations. Protein binding is 55% at plasma concentrations up to 10 mcg/ml.
Lamotrigine has a negligible first-pass effect, and undergoes glucuronidation in the liver. Carbamazepine, phenytoin, phenobarbital, and primidone can decrease lamotrigine half-life, presumably through induction of the hepatic enzyme uridine diphosphate glucuronyltransferase (UGT). Valproic acid decreases lamotrigine clearance and more than doubles elimination half-life, whether given with or without the other antiepileptic drugs. After multiple dosing in normal adult volunteers receiving no other medications, lamotrigine may induce its own metabolism which may decrease the half-life by 25% and increase plasma clearance by 37%. The mean plasma half-life in adults is approximately 24 hours (range 14-59 hours). Overall, 70% of a dose is excreted by the kidneys, 75% to 90% as metabolites. Less than 10% of a dose is eliminated unchanged by the kidney.
Affected cytochrome P450 isoenzymes and drug transporters: UGT1A4, UGT2B7, and OCT2
Lamotrigine is predominately metabolized by glucuronic acid conjugation; hence, drugs that are known to inhibit or induce glucuronidation may alter its clearance. Carbamazepine, phenytoin, phenobarbital, and primidone can decrease lamotrigine half-life, presumably through induction of the hepatic enzyme uridine diphosphate glucuronyltransferase (UGT). In addition, lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins at potentially clinically relevant concentrations, and may increase plasma concentrations of agents substantially excreted by this route.
-Route-Specific Pharmacokinetics
Oral Route
After oral administration, lamotrigine is rapidly and almost completely absorbed (98%). The relative bioavailability of the extended-release tablets is about 21% lower than immediate-release lamotrigine in patients receiving enzyme-inducing AEDs. In some patients, a reduction in exposure of up to 70% has been observed when switching from the immediate-release to the extended-release formulation. Food does not affect extent of absorption, but it can slightly slow the rate of absorption. All of the immediate-release oral formulations have a similar rate and extent of absorption. Peak plasma concentrations occur 1.4 to 2.3 hours after an oral dose of immediate-release lamotrigine in normal adult volunteers or in adult patients receiving enzyme-inducing anticonvulsants and up to 4.8 hours after an oral dose in patients on concomitant valproic acid. A second peak may be seen 4 to 6 hours after administration; this may suggest entero-hepatic circulation. The median peak plasma concentration occurs 4 to 6 hours after the administration of the extended-release formulation in patients taking carbamazepine, phenytoin, phenobarbital, or primidone, 9 to 11 hours after administration in patients taking valproic acid, and 6 to 10 hours after administration in patients taking other AEDs. The therapeutic range of lamotrigine has not been established; however, plasma concentrations associated with adult doses of 300 to 500 mg/day ranged from 2 to 5 mcg/mL. Plasma concentrations after the administration of extended-release lamotrigine are characterized by lower peaks, longer time to peaks, and lower peak-to-trough fluctuations compared to immediate-release lamotrigine; however, there are not significant changes in trough plasma concentrations between the two formulations.
-Special Populations
Hepatic Impairment
Because lamotrigine is hepatically metabolized, dosage adjustments in patients with hepatic impairment may be necessary.
Renal Impairment
Based on limited data, hemodialysis lowers the apparent elimination half-life of lamotrigine in adults roughly 70% to 80%. The half-life decreases from 43 to 57 hours in anuric subjects between dialysis treatments to 13 hours during dialysis treatments. Based on this data, approximately 20% of lamotrigine present in the body is removed after a standard 4-hour hemodialysis session.
Pediatrics
Lamotrigine clearance and elimination half-life are shorter in children than in adults. Adolescents and adults have shown similar mean clearances. As in adults, the elimination of lamotrigine in children is greatly affected by the type of concomitant AED treatment. Elimination of lamotrigine in neonates whose mothers took lamotrigine during pregnancy is slow. The median plasma lamotrigine concentrations in the neonates 72 hours after delivery were 75% (range, 50% to 100%) of the cord plasma concentrations.
Geriatric
Limited data in elderly patients suggest that the elderly exhibit a lower clearance, higher peak concentrations, higher AUC, and longer elimination half-life of lamotrigine when compared to young adults. The manufacturer recommends that elderly patients receive dosages at the low end of the normal range.
Other
Pregnancy
Increased clearance of lamotrigine occurs during pregnancy. Of 14 women who were taking lamotrigine monotherapy and not on drugs known to affect lamotrigine metabolism, the mean relative clearance was 0.71 +/- 0.24 (daily lamotrigine dose in mg /patient weight in kg)/(serum lamotrigine concentration in mg/L) before conception, 1.55 +/- 1.02 (mg/kg)/(mg/L) during the first trimester, 1.93 +/- 1.22 (mg/kg)/(mg/L) during the second trimester, 2.19 +/- 1.09 (mg/kg)/(mg/L) during the third trimester, and 0.74 +/- 0.11 (mg/kg)/(mg/L) after delivery. Although left to the discretion of each patient's caregiver, all patients had a lamotrigine dosage adjustment due to substantial changes in lamotrigine concentrations. Several patients called with reports of toxicity in the first 2 postpartum weeks. Wide inter-patient variability in lamotrigine concentrations was noted, but at least a 2-fold increase in clearance during pregnancy was noted in each woman.