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Lamictal Side Effects, and Drug Interactions - Lamotrigine

Lamictal Side Effects, and Drug Interactions - Lamotrigine

SIDE EFFECTS

SERIOUS RASH REQUIRING HOSPITALIZATION AND DISCONTINUATION OF LAMICTAL, INCLUDING STEVENS-JOHNSON SYNDROME AND TOXIC

EPIDERMAL NECROLYSIS, HAVE OCCURRED IN ASSOCIATION WITH THERAPY WITH LAMICTAL. RARE DEATHS HAVE BEEN REPORTED, BUT THEIR NUMBERS ARE TOO FEW TO PERMIT A PRECISE ESTIMATE OF THE RATE (see BOX WARNING).

Epilepsy:

Most Common Adverse Events in All Clinical Studies: Adjunctive Therapy in Adults With Epilepsy: The most commonly observed (=5%) adverse experiences seen in association with LAMICTAL during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with LAMICTAL than in patients receiving other EIAEDs with LAMICTAL. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate (see WARNINGS).

Approximately 11% of the 3,378 adult patients who received LAMICTAL as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse experience. The adverse events most commonly associated with discontinuation were rash (3.0%), dizziness (2.8%), and headache (2.5%).

In a dose response study in adults, the rate of discontinuation of LAMICTAL for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related.

Monotherapy in Adults With Epilepsy: The most commonly observed (³5%) adverse experiences seen in association with the use of LAMICTAL during the monotherapy phase of the controlled trial in adults not seen at an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed (³5%) adverse experiences associated with the use of LAMICTAL during the conversion to monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia, nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.

Approximately 10% of the 420 adult patients who received LAMICTAL as monotherapy in premarketing clinical trials discontinued treatment because of an adverse experience. The adverse events most commonly associated with discontinuation were rash (4.5%), headache (3.1%), and asthenia (2.4%).

Adjunctive Therapy in Pediatric Patients With Epilepsy: The most commonly observed (³5%) adverse experiences seen in association with the use of LAMICTAL as adjunctive treatment in pediatric patients and not seen at an equivalent rate in the control group were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia.

In 339 patients age 2 to 16 years, 4.2% of patients on LAMICTAL and 2.9% of patients on placebo discontinued due to adverse experiences. The most commonly reported adverse experiences that led to discontinuation were rash for patients treated with LAMICTAL and deterioration of seizure control for patients treated with placebo.

Approximately 11.5% of the 1,081 pediatric patients who received LAMICTAL as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse experience. The adverse events most commonly associated with discontinuation were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%).

Incidence in Controlled Clinical Studies of Epilepsy: The prescriber should be aware that the figures in Tables 4, 5, 6, and 7 cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied.

Incidence in Controlled Adjunctive Clinical Studies in Adults With Epilepsy:

Table 4 lists treatment-emergent signs and symptoms that occurred in at least 2% of adult patients with epilepsy treated with LAMICTAL in placebo-controlled trials and were numerically more common in the patients treated with LAMICTAL. In these studies, either LAMICTAL or placebo was added to the patient's current AED therapy. Adverse events were usually mild to moderate in intensity.

Table 4. Treatment-Emergent Adverse Event Incidence in Placebo-Controlled Adjunctive Trials in Adult Patients With Epilepsy* (Events in at least 2% of patients treated with LAMICTAL and numerically more frequent than in the placebo group.)
Body System/ Adverse Experience †		Percent of Patients Receiving Adjunctive LAMICTAL (n = 711)		Percent of Patients Receiving Adjunctive Placebo (n = 419)
Body as a whole
Headache		29		19
Flu syndrome		7		6
Fever		6		4
Abdominal pain		5		4
Neck pain		2		1
Reaction aggravated(seizure exacerbation)		2		1
Digestive
Nausea		19		10
Vomiting		9		4
Diarrhea		6		4
Dyspepsia		5		2
Constipation		4		3
Tooth disorder		3		2
Anorexia		2		1
Musculoskeletal
Arthralgia		2		0
Nervous
Dizziness	38		13
Ataxia	22		6
Somnolence	14		7
Incoordination	6		2
Insomnia	6		2
Tremor	4		1
Depression	4		3
Anxiety	4		3
Convulsion	3		1
Irritability	3		2
Speech disorder	3		0
Concentration disturbance	2		1
Respiratory
Rhinitis	14		9
Pharyngitis	10		9
Cough increased	8		6
Skin and appendages
Rash	10		5
Pruritus	3		2
Special senses
Diplopia	28		7
Blurred vision	16		5
Vision abnormality	3		1
Urogenital
Female patients only	(n = 365)		(n = 207)
Dysmenorrhea	7		6
Vaginitis	4		1
Amenorrhea	2		1
* Patients in these adjunctive studies were receiving 1 to 3 concomitant EIAEDs in addition to LAMICTAL or placebo. Patients may have reported multiple adverse experiences during the study or at discontinuation; thus, patients may be included in more than one category.
†Adverse experiences reported by at least 2% of patients treated with LAMICTAL are included.

In a randomized, parallel study comparing placebo and 300 and 500 mg/day of LAMICTAL, some of the more common drug-related adverse events were dose related (see Table 5).

Table 5. Dose-Related Adverse Events From a Randomized, Placebo-Controlled Trial in Adults With Epilepsy
	Percent of Patients Experiencing Adverse Experiences
Adverse Experience	Placebo (n = 73)	LAMICTAL 300 mg (n = 71)	LAMICTAL 500 mg (n = 72)
Ataxia	10	10	28*†
Blurred vision	10	11	25*†
Diplopia	8	24*	49*†
Dizziness	27	31	54*†
Nausea	11	18	25*
Vomiting	4	11	18*
*Significantly greater than placebo group (p<0.05).
†Significantly greater than group receiving LAMICTAL 300 mg (p<0.05).

Other events that occurred in more than 1% of patients but equally or more frequently in the placebo group included: asthenia, back pain, chest pain, flatulence, menstrual disorder, myalgia, paresthesia, respiratory disorder, and urinary tract infection.

The overall adverse experience profile for LAMICTAL was similar between females and males, and was independent of age. Because the largest non-Caucasian racial subgroup was only 6% of patients exposed to LAMICTAL in placebo-controlled trials, there are insufficient data to support a statement regarding the distribution of adverse experience reports by race. Generally, females receiving either adjunctive LAMICTAL or placebo were more likely to report adverse experiences than males. The only adverse experience for which the reports on LAMICTAL were greater than 10% more frequent in females than males (without a corresponding difference by gender on placebo) was dizziness (difference = 16.5%). There was little difference between females and males in the rates of discontinuation of LAMICTAL for individual adverse experiences.

Incidence in a Controlled Monotherapy Trial in Adults With Partial Seizures: Table 6 lists treatment-emergent signs and symptoms that occurred in at least 5% of patients with epilepsy treated with monotherapy with LAMICTAL in a double-blind trial following discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent frequency in the control group.

Table 6. Treatment-Emergent Adverse Event Incidence in Adults With Partial Seizures in a Controlled Monotherapy Trial* (Events in at least 5% of patients treated with LAMICTAL and numerically more frequent than in the valproate group.)
Body System/ Adverse Experience †	Percent of Patients Receiving LAMICTAL Monotherapy ‡ (n = 43)	Percent of Patients Receiving Low-Dose Valproate§ Monotherapy (n = 44)
Body as a whole
Pain	5	0
Infection	5	2
Chest pain	5	2
Digestive
Vomiting	9	0
Dyspepsia	7	2
Nausea	7	2
Metabolic and nutritional
Weight decrease	5	2
Nervous
Coordination abnormality	7	0
Dizziness	7	0
Anxiety	5	0
Insomnia	5	2
Respiratory
Rhinitis	7	2
Urogenital (female patients only)	(n = 21)	(n = 28)
Dysmenorrhea	5	0
* Patients in these studies were converted to LAMICTAL or valproate monotherapy from adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple adverse experiences during the study; thus, patients may be included in more than one category.
† Adverse experiences reported by at least 5% of patients are included.
‡ Up to 500 mg/day.
§ 1,000 mg/day.

Adverse events that occurred with a frequency of less than 5% and greater than 2% of patients receiving LAMICTAL and numerically more frequent than placebo were:

Body as a Whole: Asthenia, fever.

Digestive: Anorexia, dry mouth, rectal hemorrhage, peptic ulcer.

Metabolic and Nutritional: Peripheral edema.

Nervous System: Amnesia, ataxia, depression, hypesthesia, libido increase, decreased reflexes, increased reflexes, nystagmus, irritability, suicidal ideation.

Respiratory: Epistaxis, bronchitis, dyspnea.

Skin and Appendages: Contact dermatitis, dry skin, sweating. Special Senses: Vision abnormality.

Incidence in Controlled Adjunctive Trials in Pediatric Patients With Epilepsy:

Table 7 lists adverse events that occurred in at least 2% of 339 pediatric patients who received LAMICTAL up to 15 mg/kg per day or a maximum of 750 mg per day. Reported adverse events were classified using COSTART terminology.

Table 7. Treatment-Emergent Adverse Event Incidence in Placebo-Controlled Adjunctive Trials in Pediatric Patients With Epilepsy (Events in at least 2% of patients treated with LAMICTAL and numerically more frequent than in the placebo group.)
Body System/ Adverse Experience		Percent of Patients Receiving LAMICTAL (n =168)			Percent of Patients Receiving Placebo (n =171)
Body as a whole
Infection		20			17
Fever		15			14
Accidental injury		14			12
Abdominal pain		10			5
Asthenia		8			4
Flu syndrome		7			6
Pain		5			4
Facial edema		2			1
Photosensitivity		2			0
Cardiovascular
Hemorrhage		2			1
Digestive
Vomiting	20			16
Diarrhea	11			9
Nausea	10			2
Constipation	4			2
Dyspepsia	2			1
Tooth disorder	2			1
Hemic and lymphatic
Lymphadenopathy	2			1
Metabolic and nutritional
Edema	2			0
Nervous system
Somnolence	17			15
Dizziness	14			4
Ataxia	11			3
Tremor	10			1
Emotional lability	4			2
Gait abnormality	4			2
Thinking abnormality	3			2
Convulsions	2			1
Nervousness	2			1
Vertigo	2			1
Respiratory
Pharyngitis	14			11
Bronchitis	7			5
Increased cough	7			6
Sinusitis	2			1
Bronchospasm	2			1
Skin
Rash	14		12
Eczema	2		1
Pruritus	2		1
Special senses
Diplopia	5		1
Blurred vision	4		1
Ear disorder	2		1
Visual abnormality	2		0
Urogenital
Male and female patients Urinary tract infection	3		0
Male patients only	n = 93		n = 92
Penis disorder	2		0

Bipolar Disorder: The most commonly observed (³5%) adverse experiences seen in association with the use of LAMICTAL as monotherapy (100 to 400 mg/day) in Bipolar Disorder in the 2 double-blind, placebo-controlled trials of 18 months duration, and numerically more frequent than in placebo-treated patients are included in Table 8. Adverse events that occurred in at least 5% of patients and were numerically more common during the dose escalation phase of LAMICTAL in these trials (when patients may have been receiving concomitant medications) compared to the monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruitus (6%).

During the monotherapy phase of the double-blind, placebo-controlled trials of 18 months duration, 13% of 227 patients who received LAMICTAL (100 to 400 mg/day), 16% of 190 patients who received placebo, and 23% of 166 patients who received lithium discontinued therapy because of an adverse experience. The adverse events which most commonly led to discontinuation of LAMICTAL were rash (3%) and mania/hypomania/mixed mood adverse events (2%). Approximately 16% of 2,401 patients who received LAMICTAL (50 to 500 mg/day) for Bipolar Disorder in premarketing trials discontinued therapy because of an adverse experience; most commonly due to rash (5%) and mania/hypomania/mixed mood adverse events (2%).

Incidence in Controlled Clinical Studies of LAMICTAL for the Maintenance Treatment of Bipolar I Disorder: Table 8 lists treatment-emergent signs and symptoms that occurred in at least 5% of patients with Bipolar Disorder treated with LAMICTAL monotherapy (100 to 400 mg/day), following the discontinuation of other psychotropic drugs, in 2 double-blind, placebo-controlled trials of 18 months duration and were numerically more frequent than in the placebo group.

Table 8. Treatment-Emergent Adverse Event Incidence in 2 Placebo-Controlled Trials in Adults With Bipolar I Disorder* (Events in at least 5% of patients treated with LAMICTAL monotherapy and numerically more frequent than in the placebo group.)
Body System/ Adverse Experience†	Percent of Patients Receiving LAMICTAL n = 227	Percent of Patients Receiving Placebo n = 190
General
Back pain	8	6
Fatigue	8	5
Abdominal pain	6	3
Digestive
Nausea	14	11
Constipation	5	2
Vomiting	5	2
Nervous System
Insomnia	10	6
Somnolence	9	7
Xerostomia (dry mouth)	6	4
Respiratory
Rhinitis	7	4
Exacerbation of cough	5	3
Pharyngitis	5	4
Skin
Rash (non serious)‡	7	5
* Patients in these studies were converted to LAMICTAL (100 to 400 mg/day) or placebo monotherapy from add-on therapy with other psychotropic medications. Patients may have reported multiple adverse experiences during the study; thus, patients may be included in more than one category.
†Adverse experiences reported by at least 5% of patients are included.
‡In the overall bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received LAMICTAL as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received LAMICTAL as adjunctive therapy (see WARNINGS).

These adverse events were usually mild to moderate in intensity.

Other events that occurred in 5% or more patients but equally or more frequently in the placebo group included: dizziness, mania, headache, infection, influenza, pain, accidental injury, diarrhea, and dyspepsia.

Adverse events that occurred with a frequency of less than 5% and greater than 1% of patients receiving LAMICTAL and numerically more frequent than placebo were:

General: Fever, neck pain.

Cardiovascular: Migraine.

Digestive: Flatulence.

Metabolic and Nutritional: Weight gain, edema.

Musculoskeletal: Arthralgia, myalgia.

Nervous System: Amnesia, depression, agitation, emotional lability, dyspraxia, abnormal thoughts, dream abnormality, hypoesthesia.

Respiratory: Sinusitis.

Urogenital: Urinary frequency.

Adverse Events Following Abrupt Discontinuation: In the 2 maintenance trials, there was no increase in the incidence, severity or type of adverse events in Bipolar Disorder patients after abruptly terminating LAMICTAL therapy. In clinical trials in patients with Bipolar Disorder, 2 patients experienced seizures shortly after abrupt withdrawal of LAMICTAL. However, there were confounding factors that may have contributed to the occurrence of seizures in these bipolar patients (see DOSAGE AND ADMINISTRATION).

Mania/Hypomania/Mixed Episodes: During the double-blind, placebo-controlled clinical trials in Bipolar I Disorder in which patients were converted to LAMICTAL monotherapy (100 to 400 mg/day) from other psychotropic medications and followed for durations up to 18 months, the rate of manic or hypomanic or mixed mood episodes reported as adverse experiences was 5% for patients treated with LAMICTAL (n = 227), 4% for patients treated with lithium (n = 166), and 7% for patients treated with placebo (n = 190). In all bipolar controlled trials combined, adverse events of mania (including hypomania and mixed mood episodes) were reported in 5% of patients treated with LAMICTAL (n = 956), 3% of patients treated with lithium (n = 280), and 4% of patients treated with placebo (n = 803).

The overall adverse event profile for LAMICTAL was similar between females and males, between elderly and nonelderly patients, and among racial groups.

Other Adverse Events Observed During All Clinical Trials For Pediatric and Adult Patients With Epilepsy or Bipolar Disorder and Other Mood Disorders: LAMICTAL has been administered to 6,694 individuals for whom complete adverse event data was captured during all clinical trials, only some of which were placebo controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. The frequencies presented represent the proportion of the 6,694 individuals exposed to LAMICTAL who experienced an event of the type cited on at least one occasion while receiving LAMICTAL. All reported events are included except those already listed in the previous tables or elsewhere in the labeling, those too general to be informative, and those not reasonably associated with the use of the drug.

Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare adverse events are those occurring in fewer than 1/1,000 patients.

Body as a Whole: Infrequent: Allergic reaction, chills, halitosis, and malaise. Rare: Abdomen enlarged, abscess, and suicide/suicide attempt.

Cardiovascular System: Infrequent: Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope, tachycardia, and vasodilation. Rare: Angina pectoris, atrial fibrillation, deep thrombophlebitis, ECG abnormality, and myocardial infarction.

Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, and urticaria. Rare: Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash, seborrhea, Stevens-Johnson syndrome, and vesiculobullous rash.

Digestive System: Infrequent: Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation, liver function tests abnormal, and mouth ulceration. Rare: Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, thirst, and tongue edema.

Endocrine System: Rare: Goiter and hypothyroidism.

Hematologic and Lymphatic System: Infrequent: Ecchymosis and leukopenia. Rare:

Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic anemia, petechia, and thrombocytopenia.

Metabolic and Nutritional Disorders: Infrequent: Aspartate transaminase increased.

Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase, bilirubinemia, general edema, gamma glutamyl transpeptidase increase, and hyperglycemia.

Musculoskeletal System: Infrequent: Arthritis, leg cramps, myasthenia, and twitching. Rare: Bursitis, joint disorder, muscle atrophy, pathological fracture, and tendinous contracture.

Nervous System: Frequent: Confusion and paresthesia.

Infrequent: Akathisia, apathy, aphasia, CNS depression, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, sleep disorder, stupor, and suicidal ideation. Rare: Cerebellar syndrome, cerebrovascular accident, cerebral sinus thrombosis, choreoathetosis, CNS stimulation, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia, neurosis, paralysis, and peripheral neuritis.

Respiratory System: Infrequent: Yawn. Rare: Hiccup and hyperventilation. Special Senses: Frequent: Amblyopia. Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, and tinnitus. Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, and visual field defect.

Urogenital System: Infrequent: Abnormal ejaculation, breast pain, hematuria, impotence, menorrhagia, polyuria, urinary incontinence, and urine abnormality. Rare: Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency, and vaginal moniliasis.

Postmarketing and Other Experience: In addition to the adverse experiences reported during clinical testing of LAMICTAL, the following adverse experiences have been reported in patients receiving marketed LAMICTAL and from worldwide noncontrolled investigational use. These adverse experiences have not been listed above, and data are insufficient to support an estimate of their incidence or to establish causation.

Blood and Lymphatic: Agranulocytosis, aplastic anemia, disseminated intravascular coagulation, hemolytic anemia, neutropenia, pancytopenia, red cell aplasia.

Gastrointestinal: Esophagitis.

Hepatobiliary Tract and Pancreas: Pancreatitis.

Immunologic: Lupus-like reaction, vasculitis.

Lower Respiratory: Apnea.

Musculoskeletal: Rhabdomyolysis has been observed in patients experiencing hypersensitivity reactions.

Neurology: Exacerbation of parkinsonian symptoms in patients with pre-existing Parkinson s disease, tics.

Non-site Specific: Hypersensitivity reaction, multiorgan failure, progressive immunosuppression.

DRUG ABUSE AND DEPENDENCE

The abuse and dependence potential of LAMICTAL have not been evaluated in human studies.

DRUG INTERACTIONS

Effects of Lamotrigine on the Pharmacokinetics of Other Drugs: (see Table 3).

LAMICTAL Added to Carbamazepine: LAMICTAL has no appreciable effect on steady-state carbamazepine plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving carbamazepine with LAMICTAL than in patients receiving other EIAEDs with LAMICTAL (see ADVERSE REACTIONS). The mechanism of this interaction is unclear. The effect of lamotrigine on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels were seen to increase.

LAMICTAL Added to Valproate: When LAMICTAL was administered to 18 healthy volunteers receiving valproate in a pharmacokinetic study, the trough steady-state valproate concentrations in plasma decreased by an average of 25% over a 3-week period, and then stabilized. However, adding LAMICTAL to the existing therapy did not cause a change in plasma valproate concentrations in either adult or pediatric patients in controlled clinical trials.

LAMICTAL Added to Lithium: The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by co-administration of 100 mg/day lamotrigine for 6 days.

LAMICTAL Added to Phenytoin: LAMICTAL has no appreciable effect on steady-state phenytoin plasma concentrations in patients with epilepsy.

Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6 (see CLINICAL PHARMACOLOGY).

Effects of Other Drugs on the Pharmacokinetics of Lamotrigine: (see Table 3).

Valproate Added to LAMICTAL: The addition of valproate increases lamotrigine steady-state concentrations in normal volunteers by slightly more than 2-fold.

Enzyme-Inducing Antiepileptic Drugs (e.g., carbamazepine, phenytoin, phenobarbital, primidone) Added to LAMICTAL: The addition of EIAEDs decreases lamotrigine steady-state concentrations by approximately 40%.

Bupropion Added to LAMICTAL: The pharmacokinetics of a 100-mg single dose of lamotrigine in 12 healthy volunteers were not changed by co-administration of bupropion at 300 mg/day starting 11 days before the lamotrigine dose.

Other Psychotropic Drugs Added to LAMICTAL: Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, risperidone, sertraline, or trazodone (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Drug Metabolism).

Interactions With Folate Inhibitors: Lamotrigine is an inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism.

Interactions With Oral Contraceptives: In women taking lamotrigine, there have been reports of decreased lamotrigine concentrations following introduction of oral contraceptives and reports of increased lamotrigine concentrations following withdrawal of oral contraceptives. Dosage adjustments may be necessary to maintain clinical response when starting or stopping oral contraceptives during lamotrigine therapy.

The net effects of drug interactions with LAMICTAL are summarized in Table 3.

Table 3. Summary of Drug Interactions With LAMICTAL
Drug	Drug Plasma Concentration With Adjunctive LAMICTAL*	Lamotrigine Plasma Concentration With Adjunctive Drugs
Phenytoin (PHT)	«	¯
Carbamazepine (CBZ)	«	¯
CBZ epoxide	?
Valproate	¯	­
Valproate + PHT and/or CBZ	Not assessed	«
Lithium	«	Not assessed
Bupropion	Not assessed	«
*From adjunctive clinical trials and volunteer studies.
Net effects were estimated by comparing the mean clearance values obtained in adjunctive clinical trials and volunteers studies.
Not administered, but an active metabolite of carbamazepine.
« = No significant effect.
? = Conflicting data.

Drug/Laboratory Test Interactions: None known.

Carcinogenesis, Mutagenesis, Impairment of Fertility: No evidence of carcinogenicity was seen in 1 mouse study or 2 rat studies following oral administration of lamotrigine for up to 2 years at maximum tolerated doses (30 mg/kg per day for mice and 10 to 15 mg/kg per day for rats, doses that are equivalent to 90 mg/m² and 60 to 90 mg/m², respectively). Steady-state plasma concentrations ranged from 1 to 4 mcg/mL in the mouse study and 1 to 10 mcg/mL in the rat study. Plasma concentrations associated with the recommended human doses of 300 to 500 mg/day are generally in the range of 2 to 5 mcg/mL, but concentrations as high as 19 mcg/mL have been recorded.

Lamotrigine was not mutagenic in the presence or absence of metabolic activation when tested in 2 gene mutation assays (the Ames test and the in vitro mammalian mouse lymphoma assay). In 2 cytogenetic assays (the in vitro human lymphocyte assay and the in vivo rat bone marrow assay), lamotrigine did not increase the incidence of structural or numerical chromosomal abnormalities.

No evidence of impairment of fertility was detected in rats given oral doses of lamotrigine up to 2.4 times the highest usual human maintenance dose of 8.33 mg/kg per day or 0.4 times the human dose on a mg/m² basis. The effect of lamotrigine on human fertility is unknown.

Pregnancy: Teratogenic Effects: Pregnancy Category C. No evidence of teratogenicity was found in mice, rats, or rabbits when lamotrigine was orally administered to pregnant animals during the period of organogenesis at doses up to 1.2, 0.5, and 1.1 times, respectively, on a mg/m² basis, the highest usual human maintenance dose (i.e., 500 mg/day). However, maternal toxicity and secondary fetal toxicity producing reduced fetal weight and/or delayed ossification were seen in mice and rats, but not in rabbits at these doses. Teratology studies were also conducted using bolus intravenous administration of the isethionate salt of lamotrigine in rats and rabbits. In rat dams administered an intravenous dose at 0.6 times the highest usual human maintenance dose, the incidence of intrauterine death without signs of teratogenicity was increased.

A behavioral teratology study was conducted in rats dosed during the period of organogenesis. At day 21 postpartum, offspring of dams receiving 5 mg/kg per day or higher displayed a significantly longer latent period for open field exploration and a lower frequency of rearing. In a swimming maze test performed on days 39 to 44 postpartum, time to completion was increased in offspring of dams receiving 25 mg/kg per day. These doses represent 0.1 and 0.5 times the clinical dose on a mg/m² basis, respectively.

Lamotrigine did not affect fertility, teratogenesis, or postnatal development when rats were dosed prior to and during mating, and throughout gestation and lactation at doses equivalent to 0.4 times the highest usual human maintenance dose on a mg/m² basis.

When pregnant rats were orally dosed at 0.1, 0.14, or 0.3 times the highest human maintenance dose (on a mg/m² basis) during the latter part of gestation (days 15 to 20), maternal toxicity and fetal death were seen. In dams, food consumption and weight gain were reduced, and the gestation period was slightly prolonged (22.6 vs. 22.0 days in the control group). Stillborn pups were found in all 3 drug-treated groups with the highest number in the high-dose group. Postnatal death was also seen, but only in the 2 highest doses, and occurred between day 1 and 20. Some of these deaths appear to be drug-related and not secondary to the maternal toxicity. A no-observed-effect level (NOEL) could not be determined for this study.

Although LAMICTAL was not found to be teratogenic in the above studies, lamotrigine decreases fetal folate concentrations in rats, an effect known to be associated with teratogenesis in animals and humans. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Non-Teratogenic Effects: As with other antiepileptic drugs, 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 pre-partum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response.

Pregnancy Exposure Registry: To facilitate monitoring fetal outcomes of pregnant women exposed to lamotrigine, physicians are encouraged to register patients, before fetal outcome (e.g., ultrasound, results of amniocentesis, birth, etc.) is known, and can obtain information by calling the Lamotrigine Pregnancy Registry at (800) 336-2176 (toll-free). Patients can enroll themselves in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334 (toll-free).

Labor and Delivery: The effect of LAMICTAL on labor and delivery in humans is unknown.

Use in Nursing Mothers: Preliminary data indicate that lamotrigine passes into human milk. Because the effects on the infant exposed to LAMICTAL by this route are unknown, breast-feeding while taking LAMICTAL is not recommended.

Pediatric Use: LAMICTAL is indicated as adjunctive therapy for partial seizures in patients above 2 years of age and for the generalized seizures of Lennox-Gastaut syndrome. Safety and effectiveness for other uses in patients with epilepsy below the age of 16 years have not been established (see BOX WARNING).

Safety and effectiveness in patients below the age of 18 years with Bipolar Disorder has not been established.

Geriatric Use: Clinical studies of LAMICTAL for epilepsy and in Bipolar Disorder did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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