CLASSES

Anticonvulsants, Miscellaneous
Mood Stabilizers

BOXED WARNING

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.[28451] [63107]

DEA CLASS

Rx

DESCRIPTION

Oral antiepileptic drug (AED)
Used for adjunctive therapy for partial-onset seizures, primary generalized tonic-clonic seizures, and generalized seizures of Lennox-Gastaut syndrome; conversion to monotherapy in patients with partial-onset seizures who are receiving treatment with certain other AEDs; and maintenance treatment of bipolar I disorder
Associated with life-threatening serious rashes and/or rash-related death, more frequently in pediatric patients

COMMON BRAND NAMES

Lamictal, Lamictal CD, Lamictal ODT, Lamictal XR, Subvenite

HOW SUPPLIED

Lamictal CD/Lamotrigine Oral Tab Chew: 5mg, 25mg
Lamictal ODT/Lamotrigine Oral Tab Orally Dis: 25mg, 50mg, 100mg, 200mg, 25-50mg, 25-50-100mg, 50-100mg
Lamictal XR/Lamotrigine Oral Tab ER: 25mg, 50mg, 100mg, 200mg, 250mg, 300mg, 25-50mg, 25-50-100mg, 50-100-200mg
Lamictal/Lamotrigine/Subvenite Oral Tab: 25mg, 100mg, 150mg, 200mg, 25-100mg

DOSAGE & INDICATIONS

†Indicates off-label use

MAXIMUM DOSAGE

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.

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.

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.

>= 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.

DOSING CONSIDERATIONS

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.

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.

ADMINISTRATION

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.

STORAGE

Lamictal:
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
- Store in a dry place
Lamictal CD:
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
- Store in a dry place
Lamictal ODT:
- Store at controlled room temperature (between 68 and 77 degrees F)
Lamictal XR:
- Store at 20 to 25 degrees C (68 to 77 degrees F); excursions permitted between 15 to 30 degrees C (59 to 86 degrees F) USP Controlled Room Temperature
Subvenite:
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
- Store in a dry place

CONTRAINDICATIONS / PRECAUTIONS

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.[28451] [63107]

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 patients 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 in the geriatric patient 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 patients 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.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; the use of any anticonvulsant for any condition should be based on confirmation of the condition and its potential cause(s). Determine effectiveness and tolerability by evaluating symptoms, and use these as the basis for dosage adjustment for most patients. Therapeutic drug monitoring is not required or available for most anticonvulsants. Serum medication concentrations (when available) may assist in identifying toxicity. Monitor the treated patient for drug efficacy and side effects. Anticonvulsants can cause a variety of side effects; some adverse reactions can increase the risk of falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity as outlined in the OBRA guidelines.[60742]

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.[28451] 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.[28451] [48875] [63108] 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.[28451]

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.[28451] 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.[32574] 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.[28451] 

ADVERSE REACTIONS

suicidal ideation / Delayed / 0.1-5.0
peptic ulcer / Delayed / 2.1-4.9
visual impairment / Early / 2.0-4.9
bronchospasm / Rapid / 2.0-2.0
hematemesis / Delayed / 0-0.1
uveitis / Delayed / 0-0.1
exfoliative dermatitis / Delayed / 0-0.1
toxic epidermal necrolysis / Delayed / 0-0.1
angioedema / Rapid / 0-0.1
erythema multiforme / Delayed / 0-0.1
Stevens-Johnson syndrome / Delayed / 0-0.1
renal failure (unspecified) / Delayed / 0-0.1
epididymitis / Delayed / 0-0.1
vasculitis / Delayed / Incidence not known
rhabdomyolysis / Delayed / Incidence not known
apnea / Delayed / Incidence not known
lupus-like symptoms / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
myocarditis / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
red cell aplasia / Delayed / Incidence not known
pancytopenia / Delayed / Incidence not known
hemolytic anemia / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
interstitial nephritis / Delayed / Incidence not known
aseptic meningitis / Delayed / Incidence not known
hemophagocytic lymphohistiocytosis / Delayed / Incidence not known

blurred vision / Early / 4.0-25.0
ataxia / Delayed / 2.0-11.0
chest pain (unspecified) / Early / 5.0-5.0
constipation / Delayed / 2.0-5.0
contact dermatitis / Delayed / 2.1-5.0
depression / Delayed / 0.1-4.9
migraine / Early / 1.1-4.9
nystagmus / Delayed / 2.0-4.9
amnesia / Delayed / 1.1-4.9
hyperreflexia / Delayed / 2.1-4.9
peripheral edema / Delayed / 2.1-4.9
edema / Delayed / 1.1-4.9
dyspnea / Early / 2.1-4.9
vaginitis / Delayed / 4.0-4.0
hot flashes / Early / 0.1-2.0
lymphadenopathy / Delayed / 2.0-2.0
atopic dermatitis / Delayed / 2.0-2.0
hallucinations / Early / 0.1-1.0
aphasia / Delayed / 0.1-1.0
memory impairment / Delayed / 0.1-1.0
dyskinesia / Delayed / 0.1-1.0
hypertonia / Delayed / 0.1-1.0
akathisia / Delayed / 0.1-1.0
hostility / Early / 0.1-1.0
psychosis / Early / 0.1-1.0
dysarthria / Delayed / 0.1-1.0
euphoria / Early / 0.1-1.0
hypertension / Early / 0.1-1.0
palpitations / Early / 0.1-1.0
sinus tachycardia / Rapid / 0.1-1.0
peripheral vasodilation / Rapid / 0.1-1.0
orthostatic hypotension / Delayed / 0.1-1.0
myasthenia / Delayed / 0.1-1.0
dysphagia / Delayed / 0.1-1.0
elevated hepatic enzymes / Delayed / 0.1-1.0
gastritis / Delayed / 0.1-1.0
photophobia / Early / 0.1-1.0
conjunctivitis / Delayed / 0.1-1.0
leukopenia / Delayed / 0.1-1.0
impotence (erectile dysfunction) / Delayed / 0.1-1.0
urinary incontinence / Early / 0.1-1.0
hematuria / Delayed / 0.1-1.0
ejaculation dysfunction / Delayed / 0.1-1.0
neuritis / Delayed / 0-0.1
dystonic reaction / Delayed / 0-0.1
dysphoria / Early / 0-0.1
delirium / Early / 0-0.1
hyperalgesia / Delayed / 0-0.1
hyperesthesia / Delayed / 0-0.1
choreoathetosis / Delayed / 0-0.1
hypotonia / Delayed / 0-0.1
hepatitis / Delayed / 0-0.1
melena / Delayed / 0-0.1
colitis / Delayed / 0-0.1
stomatitis / Delayed / 0-0.1
glossitis / Early / 0-0.1
erythema / Early / 0-0.1
eosinophilia / Delayed / 0-0.1
anemia / Delayed / 0-0.1
lymphocytosis / Delayed / 0-0.1
thrombocytopenia / Delayed / 0-0.1
urinary retention / Early / 0-0.1
dysuria / Early / 0-0.1
cystitis / Delayed / 0-0.1
hyperbilirubinemia / Delayed / 0-0.1
hypothyroidism / Delayed / 0-0.1
hyperglycemia / Delayed / 0-0.1
goiter / Delayed / 0-0.1
mania / Early / 5.0
confusion / Early / 1.0
amblyopia / Delayed / 1.0
esophagitis / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
hyponatremia / Delayed / Incidence not known
splenomegaly / Delayed / Incidence not known

diplopia / Early / 5.0-49.0
vomiting / Early / 5.0-20.0
drowsiness / Early / 5.0-17.0
fever / Early / 1.1-15.0
dizziness / Early / 5.0-14.0
pharyngitis / Delayed / 5.0-14.0
nausea / Early / 7.0-14.0
rash / Early / 7.0-14.0
diarrhea / Early / 5.0-11.0
tremor / Early / 4.0-10.0
abdominal pain / Early / 5.0-10.0
asthenia / Delayed / 2.1-8.0
fatigue / Early / 6.0-8.0
back pain / Delayed / 8.0-8.0
cough / Delayed / 5.0-7.0
dyspepsia / Early / 2.0-7.0
dysmenorrhea / Delayed / 5.0-7.0
xerostomia / Early / 2.0-6.0
weight loss / Delayed / 5.0-5.0
diaphoresis / Early / 2.1-4.9
libido increase / Delayed / 2.1-4.9
agitation / Early / 1.1-4.9
irritability / Delayed / 2.1-4.9
emotional lability / Early / 1.1-4.9
hypoesthesia / Delayed / 1.1-4.9
hyporeflexia / Delayed / 2.1-4.9
arthralgia / Delayed / 1.1-4.9
myalgia / Early / 1.1-4.9
epistaxis / Delayed / 2.0-4.9
sinusitis / Delayed / 1.1-4.9
flatulence / Early / 1.1-4.9
weight gain / Delayed / 1.1-4.9
anorexia / Delayed / 2.0-4.9
increased urinary frequency / Early / 1.1-4.9
xerosis / Delayed / 2.1-4.9
vertigo / Early / 2.0-3.0
amenorrhea / Delayed / 2.0-2.0
libido decrease / Delayed / 0.1-1.0
hyperkinesis / Delayed / 0.1-1.0
malaise / Early / 0.1-1.0
paranoia / Early / 0.1-1.0
flushing / Rapid / 0.1-1.0
syncope / Early / 0.1-1.0
yawning / Early / 0.1-1.0
eructation / Early / 0.1-1.0
hypersalivation / Early / 0.1-1.0
gingivitis / Delayed / 0.1-1.0
appetite stimulation / Delayed / 0.1-1.0
tinnitus / Delayed / 0.1-1.0
urticaria / Rapid / 0.1-1.0
ecchymosis / Delayed / 0.1-1.0
polyuria / Early / 0.1-1.0
menorrhagia / Delayed / 0.1-1.0
acne vulgaris / Delayed / 0.1-1.0
alopecia / Delayed / 0.1-1.0
hirsutism / Delayed / 0.1-1.0
skin discoloration / Delayed / 0.1-1.0
hiccups / Early / 0-0.1
hyperventilation / Early / 0-0.1
parosmia / Delayed / 0-0.1
ptosis / Delayed / 0-0.1
maculopapular rash / Early / 0-0.1
leukocytosis / Delayed / 0-0.1
petechiae / Delayed / 0-0.1
nocturia / Early / 0-0.1
urinary urgency / Early / 0-0.1
headache / Early / 5.0
paresthesias / Delayed / 1.0
insomnia / Early / 5.0
anxiety / Delayed / 3.0
rhinitis / Early / 5.0
influenza / Delayed / 3.0
infection / Delayed / 5.0
pruritus / Rapid / 2.0
nasal congestion / Early / Incidence not known

DRUG INTERACTIONS

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: (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; Dichloralphenazone; Isometheptene: (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; Pentazocine: (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%.
Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS or psychotropic activity, such as lamotrigine. Use with caution.
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.
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%.
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.
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.
Dasabuvir; Ombitasvir; Paritaprevir; 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%. (Moderate) If coadministration of lamotrigine and dasabuvir; ombitasvir; paritaprevir; ritonavir is warranted, use caution and carefully monitor lamotrigine concentrations; lamotrigine dosage adjustments may be needed. Ritoanvir may increase the hepatic metabolism of lamotrigine via glucuronidation, resulting in decreased lamotrigine concentrations. Additionally, lamotrigine interactions are thought to be mediated by uridine diphosphate glucuronyltransferase (UGT), and dasabuvir, ombitasvir, and paritaprevir are UGT1A1 inhibitors. Further alterations to lamotrigine concentrations could occur.
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.
Diethylstilbestrol, DES: (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.
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.
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.
Encainide: (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.
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 Cypionate; 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.
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: (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; Levonorgestrel; Folic Acid; 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.
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.
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.
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.
Mestranol; 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.
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; Rosiglitazone: (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.
Ombitasvir; Paritaprevir; 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%. (Moderate) If coadministration of lamotrigine and dasabuvir; ombitasvir; paritaprevir; ritonavir is warranted, use caution and carefully monitor lamotrigine concentrations; lamotrigine dosage adjustments may be needed. Ritoanvir may increase the hepatic metabolism of lamotrigine via glucuronidation, resulting in decreased lamotrigine concentrations. Additionally, lamotrigine interactions are thought to be mediated by uridine diphosphate glucuronyltransferase (UGT), and dasabuvir, ombitasvir, and paritaprevir are UGT1A1 inhibitors. Further alterations to lamotrigine concentrations could occur.
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.
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.
Procaine: (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 procaine. Concomitant use of procaine 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.
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.
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.

PREGNANCY AND LACTATION

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.[28451] 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.[28451] [48875] [63108] 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.[28451]

MECHANISM OF ACTION

Mechanism of Action: 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.

PHARMACOKINETICS

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.