Lamotrigine Extended Release Tablet
Name: Lamotrigine Extended Release Tablet
- Lamotrigine Extended Release Tablet 500 mg
- Lamotrigine Extended Release Tablet tablet
- Lamotrigine Extended Release Tablet drug
- Lamotrigine Extended Release Tablet 200 mg
- Lamotrigine Extended Release Tablet dosage
- Lamotrigine Extended Release Tablet oral dose
- Lamotrigine Extended Release Tablet action
- Lamotrigine Extended Release Tablet effects of
- Lamotrigine Extended Release Tablet the effects of
- Lamotrigine Extended Release Tablet dosage forms
- Lamotrigine Extended Release Tablet adverse effects
Adverse Reactions
The following adverse reactions are described in more detail in the Warnings and Precautions section of the label:
• Serious skin rashes [see Warnings and Precautions (5.1)] • Multiorgan hypersensitivity reactions and organ failure [see Warnings and Precautions (5.2)] • Blood dyscrasias [see Warnings and Precautions (5.3)] • Suicidal behavior and ideation [see Warnings and Precautions (5.4)] • Aseptic meningitis [see Warnings and Precautions (5.5)] • Withdrawal seizures [see Warnings and Precautions (5.8)] • Status epilepticus [see Warnings and Precautions (5.9)] • Sudden unexplained death in epilepsy [see Warnings and Precautions (5.10)]Clinical Trial Experience with LAMOTRIGINE EXTENDED-RELEASE TABLETS for Treatment of Primary Generalized Tonic-Clonic and Partial-Onset Seizures
Most Common Adverse Reactions in Clinical Trials
Adjunctive Therapy in Patients with Epilepsy : Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In these 2 trials, adverse reactions led to withdrawal of 4 (2%) patients in the group receiving placebo and 10 (5%) patients in the group receiving LAMOTRIGINE EXTENDED-RELEASE TABLETS. Dizziness was the most common reason for withdrawal in the group receiving LAMOTRIGINE EXTENDED-RELEASE TABLETS (5 patients [3%]). The next most common adverse reactions leading to withdrawal in 2 patients each (1%) were rash, headache, nausea, and nystagmus.
Table 4 displays the incidence of adverse reactions in these two 19-week, double-blind, placebo-controlled trials of patients with PGTC and partial-onset seizures.
| Body System/Adverse Reaction | Percent of Patients Receiving Adjunctive LAMOTRIGINE EXTENDED-RELEASE TABLETS (n = 190) % | Percent of Patients Receiving Adjunctive Placebo (n = 195) % |
| Ear and labyrinth disorders Vertigo | 3 | <1 |
| Eye disorders Diplopia Vision blurred | 5 3 | <1 2 |
| Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Dry mouth | 7 6 5 2 2 | 4 3 3 <1 1 |
| General disorders and administration site conditions Asthenia and fatigue | 6 | 4 |
| Infections and infestations Sinusitis | 2 | 1 |
| Metabolic and nutritional disorders Anorexia | 3 | 2 |
| Musculoskeletal and connective tissue disorder Myalgia | 2 | 0 |
| Nervous system Dizziness Tremor and intention tremor Somnolence Cerebellar coordination and balance disorder Nystagmus | 14 6 5 3 2 | 6 1 3 0 <1 |
| Psychiatric disorders Depression Anxiety | 3 3 | <1 0 |
| Respiratory, thoracic, and mediastinal disorders Pharyngolaryngeal pain | 3 | 2 |
| Vascular disorder Hot flush | 2 | 0 |
a Adverse reactions that occurred in at least 2% of patients treated with LAMOTRIGINE EXTENDED-RELEASE TABLETS and at a greater incidence than placebo.
Note: In these trials the incidence of nonserious rash was 2% for LAMOTRIGINE EXTENDED-RELEASE TABLETS and 3% for placebo. In clinical trials evaluating immediate-release lamotrigine, the rate of serious rash was 0.3% in adults on adjunctive therapy for epilepsy [see Boxed Warning].
Adverse reactions were also analyzed to assess the incidence of the onset of an event in the titration period, and in the maintenance period, and if adverse reactions occurring in the titration phase persisted in the maintenance phase.
The incidence for many adverse reactions caused by treatment with LAMOTRIGINE EXTENDED-RELEASE TABLETS was increased relative to placebo (i.e., treatment difference between LAMOTRIGINE EXTENDED-RELEASE TABLETS and placebo ≥2%) in either the titration or maintenance phases of the trial. During the titration phase, an increased incidence (shown in descending order of percent treatment difference) was observed for diarrhea, nausea, vomiting, somnolence, vertigo, myalgia, hot flush, and anxiety. During the maintenance phase, an increased incidence was observed for dizziness, tremor, and diplopia. Some adverse reactions developing in the titration phase were notable for persisting (>7 days) into the maintenance phase. These persistent adverse reactions included somnolence and dizziness
There were inadequate data to evaluate the effect of dose and/or concentration on the incidence of adverse reactions because, although patients were randomized to different target doses based upon concomitant AEDs, the plasma exposure was expected to be generally similar among all patients receiving different doses. However, in a randomized, parallel trial comparing placebo with 300 and 500 mg/day of immediate-release lamotrigine, the incidence of the most common adverse reactions (≥5%) such as ataxia, blurred vision, diplopia, and dizziness were dose related. Less common adverse reactions (<5%) were not assessed for dose-response relationships.
Monotherapy in Patients With Epilepsy
Adverse reactions observed in this trial were generally similar to those observed and attributed to drug in adjunctive and monotherapy immediate-release lamotrigine and adjunctive LAMOTRIGINE EXTENDED-RELEASE TABLETS placebo-controlled trials. Only 2 adverse events, nasopharyngitis and upper respiratory tract infection, were observed at a rate of ≥3% and not reported at a similar rate in previous trials. Because this trial did not include a placebo control group, causality could not be established [see Clinical Studies (14.3)].
Other Adverse Reactions Observed During the Clinical Development of Immediate-Release Lamotrigine
All reported reactions 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.
Adjunctive Therapy in Adults With Epilepsy
In addition to the adverse reactions reported above from the development of LAMOTRIGINE EXTENDED-RELEASE TABLETS, the following adverse reactions with an uncertain relationship to lamotrigine were reported during the clinical development of immediate-release lamotrigine for treatment of epilepsy in adults. These reactions occurred in ≥2% of patients receiving immediate-release lamotrigine and more frequently than in the placebo group.
Body as a Whole: Headache, flu syndrome, fever, neck pain.
Musculoskeletal: Arthralgia.
Nervous: Insomnia, convulsion, irritability, speech disorder, concentration disturbance.
Respiratory: Pharyngitis, cough increased.
Skin and Appendages: Rash, pruritus.
Urogenital: (female patients only) Vaginitis, amenorrhea, dysmenorrhea.
Monotherapy in Adults With Epilepsy
In addition to the adverse reactions reported above from the development of LAMOTRIGINE EXTENDED-RELEASE TABLETS, the following adverse reactions with an uncertain relationship to lamotrigine were reported during the clinical development of immediate-release lamotrigine for treatment of epilepsy in adults. These reactions occurred in >2% of patients receiving immediate-release lamotrigine and more frequently than in the placebo group.
Other Clinical Trial Experience
Immediate-release lamotrigine has been administered to 6,694 individuals for whom complete adverse reaction data was captured during all clinical trials, only some of which were placebo controlled.
Adverse reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are defined as those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000 patients.
Cardiovascular System: Infrequent:Hypertension, palpitations, postural hypotension, syncope, tachycardia, vasodilation.
Dermatological: Infrequent: Acne, alopecia, hirsutism, maculopapular rash, urticaria. Rare: Leukoderma, multiforme erythema, petechial rash, pustular rash.
Digestive System: Infrequent: Dysphagia, liver function tests abnormal, mouth ulceration. Rare:Gastrointestinal hemorrhage, hemorrhagic colitis, hepatitis, melena, stomach ulcer.
Endocrine System: Rare: Goiter, hypothyroidism.
Hematologic and Lymphatic System: Infrequent: Ecchymosis, leukopenia. Rare: Anemia, eosinophilia, fibrin decrease, fibrinogen decrease, iron deficiency anemia, leukocytosis, lymphocytosis, macrocytic anemia, petechia, thrombocytopenia.
Metabolic and Nutritional Disorders: Infrequent: Aspartate transaminase increased. Rare: Alcohol intolerance, alkaline phosphatase increase, alanine transaminase increase, bilirubinemia, gamma glutamyl transpeptidase increase, hyperglycemia.
Musculoskeletal System: Rare: Muscle atrophy, pathological fracture, tendinous contracture.
Nervous System: Frequent: Confusion. Infrequent: Akathisia, apathy, aphasia, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, stupor. Rare: Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, neuralgia, paralysis, peripheral neuritis.
Respiratory System: Rare:Hiccup, hyperventilation.
Special Senses: Frequent: Amblyopia. Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, tinnitus. Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, visual field defect.
Urogenital System: Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria, urinary incontinence. Rare: Acute kidney failure, breast neoplasm, creatinine increase, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency.
Postmarketing Experience with Immediate-Release Lamotrigine
The following adverse events (not listed above in clinical trials or other sections of the prescribing information) have been identified during postapproval use of immediate-release lamotrigine. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic
Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with hypersensitivity disorder.
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.
Nervous System
Aggression, exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson’s disease, tics.
Non-site Specific
Progressive immunosuppression.
Overdosage
Human Overdose Experience
Overdoses involving quantities up to 15 g have been reported for immediate-release lamotrigine, some of which have been fatal. Overdose has resulted in ataxia, nystagmus, seizures (including tonic-clonic seizures), decreased level of consciousness, coma, and intraventricular conduction delay.
Management of Overdose
There are no specific antidotes for lamotrigine. Following a suspected overdose, hospitalization of the patient is advised. General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient. If indicated, emesis should be induced; usual precautions should be taken to protect the airway. It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A Poison Control Center should be contacted for information on the management of overdosage of LAMOTRIGINE EXTENDED-RELEASE TABLETS.
Lamotrigine Extended Release Tablet - Clinical Pharmacology
Mechanism of Action
The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state. The relevance of these models to human epilepsy, however, is not known.
One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).
Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity
Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced currents (in the presence of 3 μM of glycine) in cultured hippocampal neurons exceeded 100 μM.
Pharmacodynamics
Folate Metabolism
In vitro, lamotrigine inhibited dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal folate concentrations were reduced. Significantly reduced concentrations of folate are associated with teratogenesis [see Use in Specific Populations (8.1)]. Folate concentrations were also reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were partially returned to normal when supplemented with folinic acid.
Cardiovascular
In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongation of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose) have been found in human urine [see Clinical Pharmacology (12.3)]. However, it is conceivable that plasma concentrations of this metabolite could be increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease, patients taking concomitant medications that inhibit glucuronidation).
Pharmacokinetics
In comparison with immediate-release lamotrigine, the plasma lamotrigine levels following administration of LAMOTRIGINE EXTENDED-RELEASE TABLETS are not associated with any significant changes in trough plasma concentrations, and are characterized by lower peaks, longer time to peaks, and lower peak-to-trough fluctuation, as described in detail below.
Absorption
Lamotrigine is absorbed after oral administration with negligible first-pass metabolism. The bioavailability of lamotrigine is not affected by food.
In an open-label, crossover study of 44 subjects with epilepsy receiving concomitant AEDs, the steady-state pharmacokinetics of lamotrigine were compared following administration of equivalent total doses of LAMOTRIGINE EXTENDED-RELEASE TABLETS given once daily with those of lamotrigine immediate-release given twice daily. In this study, the median time to peak concentration (Tmax) following administration of LAMOTRIGINE EXTENDED-RELEASE TABLETS was 4 to 6 hours in subjects taking carbamazepine, phenytoin, phenobarbital, or primidone; 9 to 11 hours in subjects taking valproate; and 6 to 10 hours in subjects taking AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate. In comparison, the median Tmax following administration of immediate-release lamotrigine was between 1 and 1.5 hours.
The steady-state trough concentrations for extended-release lamotrigine were similar to or higher than those of immediate-release lamotrigine depending on concomitant AED (see Table 6). A mean reduction in the lamotrigine C max by 11% to 29% was observed for LAMOTRIGINE EXTENDED-RELEASE TABLETS compared with immediate-release lamotrigine, resulting in a decrease in the peak-to-trough fluctuation in serum lamotrigine concentrations. However, in some subjects receiving enzyme-inducing AEDs, a reduction in Cmax of 44% to 77% was observed. The degree of fluctuation was reduced by 17% in subjects taking enzyme-inducing AEDs; 34% in subjects taking valproate; and 37% in subjects taking AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate. LAMOTRIGINE EXTENDED-RELEASE TABLETS and immediate-release lamotrigine regimens were similar with respect to area under the curve (AUC, a measure of the extent of bioavailability) for subjects receiving AEDs other than those known to induce the metabolism of lamotrigine. The relative bioavailability of extended-release lamotrigine was approximately 21% lower than immediate-release lamotrigine in subjects receiving enzyme-inducing AEDs. However, a reduction in exposure of up to 70% was observed in some subjects in this group when they switched to LAMOTRIGINE EXTENDED-RELEASE TABLETS. Therefore, doses may need to be adjusted in some patients based on therapeutic response.
| a Enzyme-inducing antiepileptic drugs include carbamazepine, phenytoin, phenobarbital, and primidone. | |||
| Concomitant Antiepileptic Drug | AUC(0-24ss) | CMAX | CMIN |
| Enzyme-inducing antiepileptic drugsa | 0.79 (0.69, 0.90) | 0.71 (0.61, 0.82) | 0.99 (0.89, 1.09) |
| Valproate | 0.94 (0.81, 1.08) | 0.88 (0.75, 1.03) | 0.99 (0.88, 1.10) |
| Antiepileptic drugs other than enzyme-inducing antiepileptic drugsa or valproate | 1.00 (0.88, 1.14) | 0.89 (0.78, 1.03) | 1.14 (1.03, 1.25) |
Dose Proportionality
In healthy volunteers not receiving any other medications and given LAMOTRIGINE EXTENDED-RELEASE TABLETS once daily, the systemic exposure to lamotrigine increased in direct proportion to the dose administered over the range of 50 to 200 mg. At doses between 25 and 50 mg, the increase was less than dose proportional, with a 2-fold increase in dose resulting in an approximately 1.6-fold increase in systemic exposure.
Distribution
Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers.
Protein Binding
Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to plasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein-binding sites.
Metabolism
Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14C-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).
Enzyme Induction
The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated.
Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and a 37% increase in CL/F at steady state compared with values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions (7)].
Elimination
The elimination half-life and apparent clearance of lamotrigine following oral administration of immediate-release lamotrigine to adult subjects with epilepsy and healthy volunteers is summarized in Table 7. Half-life and apparent oral clearance vary depending on concomitant AEDs.
Since the half-life of lamotrigine following administration of single doses of immediate-release lamotrigine is comparable with that observed following administration of LAMOTRIGINE EXTENDED-RELEASE TABLETS, similar changes in the half-life of lamotrigine would be expected for LAMOTRIGINE EXTENDED-RELEASE TABLETS.
| a The majority of parameter means determined in each study had coefficients of variation between 20% and 40% for half-life and CL/F and between 30% and 70% for Tmax. The overall mean values were calculated from individual study means that were weighted based on the number of volunteers/subjects in each study. The numbers in parentheses below each parameter mean represent the range of individual volunteer/subject values across studies. | |||||||
| b Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs, such as rifampin and protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir, that induce lamotrigine glucuronidation have also been shown to increase the apparent clearance of lamotrigine [see Drug Interactions (7)]. | |||||||
| Adult Study Population | Number of Subjects | t½: Elimination Half-life (h) | CL/F: Apparent Plasma Clearance (mL/min/kg) | ||||
| Healthy volunteers taking no other medications: Single-dose lamotrigine Multiple-dose lamotrigine | 179
| 32.8 (14.0-103.0) 25.4 (11.6-61.6) | 0.44 (0.12-1.10) 0.58 (0.24-1.15) | ||||
| Healthy volunteers taking valproate: Single-dose lamotrigine Multiple-dose lamotrigine | 6
| 48.3 (31.5-88.6) 70.3 (41.9-113.5) | 0.30 (0.14-0.42) 0.18 (0.12-0.33) | ||||
| Subjects with epilepsy taking valproate only: Single-dose lamotrigine | 4 | 58.8 (30.5-88.8) | 0.28 (0.16-0.40) | ||||
| Subjects with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidoneb plus valproate: Single-dose lamotrigine | 25 | 27.2 (11.2-51.6) | 0.53 (0.27-1.04) | ||||
| Subjects with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone:b Single-dose lamotrigine Multiple-dose lamotrigine | 24
| 14.4 (6.4-30.4) 12.6 (7.5-23.1) | 1.10 (0.51-2.22) 1.21 (0.66-1.82) | ||||
Drug Interactions
The apparent clearance of lamotrigine is affected by the coadministration of certain medications [see Warnings and Precautions (5.7, 5.11), Drug Interactions (7)].
The net effects of drug interactions with lamotrigine, based on drug interaction studies using immediate-release lamotrigine, are summarized in Tables 5 and 8, followed by details of the drug interaction studies below.
| Drug | Drug Plasma Concentration With Adjunctive Lamotriginea | Lamotrigine Plasma Concentration With Adjunctive Drugsb |
| Oral contraceptives (e.g., ethinylestradiol/levonorgestrel)c | ↔d | ↓ |
| Aripiprazole | Not assessed | ↔e |
| Atazanavir/ritonavir | ↔f | ↓ |
| Bupropion | Not assessed | ↔ |
| Carbamazepine | ↔ | ↓ |
| Carbamazepine epoxideg | ? | |
| Felbamate | Not assessed | ↔ |
| Gabapentin | Not assessed | ↔ |
| Levetiracetam | ↔ | ↔ |
| Lithium | ↔ | Not assessed |
| Lopinavir/ritonavir | ↔e | ↓ |
| Olanzapine | ↔ | ↔g |
| Oxcarbazepine | ↔ | ↔ |
| 10-Monohydroxy oxcarbazepine metaboliteh | ↔ | |
| Phenobarbital/primidone | ↔ | ↓ |
| Phenytoin | ↔ | ↓ |
| Pregabalin | ↔ | ↔ |
| Rifampin | Not assessed | ↓ |
| Risperidone | ↔ | Not assessed |
| 9-Hydroxyrisperidonei | ↔ | |
| Topiramate | ↔h | ↔ |
| Valproate | ↓ | ↑ |
| Valproate + phenytoin and/or carbamazepine | Not assessed | ↔ |
| Zonisamide | Not assessed | ↔ |
Estrogen-Containing Oral Contraceptives
In 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-fold with mean decreases in AUC of 52% and in Cmax of 39%. In this study, trough serum lamotrigine concentrations gradually increased and were approximately 2-fold higher on average at the end of the week of the inactive hormone preparation compared with trough lamotrigine concentrations at the end of the active hormone cycle.
Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase) occurred during the week of inactive hormone preparation (pill-free week) for women not also taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation) [see Drug Interactions (7)]. The increase in lamotrigine plasma levels will be greater if the dose of LAMOTRIGINE EXTENDED-RELEASE TABLETS is increased in the few days before or during the pill-free week. Increases in lamotrigine plasma levels could result in dose-dependent adverse reactions.
In the same study, coadministration of lamotrigine (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive preparation. There were mean decreases in the AUC and Cmax of the levonorgestrel component of 19% and 12%, respectively. Measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-pituitary-ovarian axis.
The effects of doses of lamotrigine other than 300 mg/day have not been systematically evaluated in controlled clinical trials.
The clinical significance of the observed hormonal changes on ovulatory activity is unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot be excluded. Therefore, patients should be instructed to promptly report changes in their menstrual pattern (e.g., break-through bleeding).
Dosage adjustments may be necessary for women receiving estrogen-containing oral contraceptive preparations [see Dosage and Administration (2.1)].
Other Hormonal Contraceptives or Hormone Replacement Therapy
The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of LAMOTRIGINE EXTENDED-RELEASE TABLETS in the presence of progestogens alone will likely not be needed.
Aripiprazole
In 18 patients with bipolar disorder on a stable regimen of 100 to 400 mg/day of lamotrigine, the lamotrigine AUC and Cmaxwere reduced by approximately 10% in patients who received aripiprazole 10 to 30 mg/day for 7 days, followed by 30 mg/day for an additional 7 days. This reduction in lamotrigine exposure is not considered clinically meaningful.
Atazanavir/Ritonavir
In a study in healthy volunteers, daily doses of atazanavir/ritonavir (300 mg/100 mg) reduced the plasma AUC and Cmax of lamotrigine (single 100-mg dose) by an average of 32% and 6%, respectively, and shortened the elimination half-lives by 27%. In the presence of atazanavir/ritonavir (300 mg/100 mg), the metabolite-to-lamotrigine ratio was increased from 0.45 to 0.71 consistent with induction of glucuronidation. The pharmacokinetics of atazanavir/ritonavir were similar in the presence of concomitant lamotrigine to the historical data of the pharmacokinetics in the absence of lamotrigine.
Bupropion
The pharmacokinetics of a 100-mg single dose of lamotrigine in healthy volunteers (n = 12) were not changed by coadministration of bupropion sustained-release formulation (150 mg twice daily) starting 11 days before lamotrigine.
Carbamazepine
Lamotrigine 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 lamotrigine than in patients receiving other AEDs with lamotrigine [see Adverse Reactions (6.1)]. 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 increased.
The addition of carbamazepine decreases lamotrigine steady-state concentrations by approximately 40%.
Esomeprazole
In a study of 30 subjects, coadministration of LAMOTRIGINE EXTENDED-RELEASE TABLETS with esomeprazole resulted in no significant change in lamotrigine levels and a small decrease in Tmax. The levels of gastric pH were not altered compared with pre-lamotrigine dosing.
Felbamate
In a trial in 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine.
Folate Inhibitors
Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism.
Gabapentin
Based on a retrospective analysis of plasma levels in 34 subjects who received lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.
Levetiracetam
Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.
Lithium
The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by coadministration of lamotrigine (100 mg/day) for 6 days.
Lopinavir/Ritonavir
The addition of lopinavir (400 mg twice daily)/ritonavir (100 mg twice daily) decreased the AUC, Cmax, and elimination half-life of lamotrigine by approximately 50% to 55.4% in 18 healthy subjects. The pharmacokinetics of lopinavir/ritonavir were similar with concomitant lamotrigine, compared with that in historical controls.
Olanzapine
The AUC and Cmax of olanzapine were similar following the addition of olanzapine (15 mg once daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) compared with the AUC and Cmax in healthy male volunteers receiving olanzapine alone (n = 16).
In the same trial, the AUC and Cmax of lamotrigine were reduced on average by 24% and 20%, respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers compared with those receiving lamotrigine alone. This reduction in lamotrigine plasma concentrations is not expected to be clinically meaningful.
Oxcarbazepine
The AUC and Cmax of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 13) compared with healthy male volunteers receiving oxcarbazepine alone (n = 13).
In the same trial, the AUC and Cmax of lamotrigine were similar following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine in healthy male volunteers compared with those receiving lamotrigine alone. Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine compared with lamotrigine alone or oxcarbazepine alone.
Phenobarbital, Primidone
The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by approximately 40%.
Phenytoin
Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-state concentrations by approximately 40%.
Pregabalin
Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine and pregabalin.
Rifampin
In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance of a single 25-mg dose of lamotrigine by approximately 2-fold (AUC decreased by approximately 40%).
Risperidone
In a 14 healthy volunteers study, multiple oral doses of lamotrigine 400 mg daily had no clinically significant effect on the single-dose pharmacokinetics of risperidone 2 mg and its active metabolite 9-OH risperidone. Following the coadministration of risperidone 2 mg with lamotrigine, 12 of the 14 volunteers reported somnolence compared with 1 out of 20 when risperidone was given alone, and none when lamotrigine was administered alone.
Topiramate
Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.
Valproate
When lamotrigine was administered to healthy volunteers (n = 18) receiving valproate, the trough steady-state valproate plasma concentrations decreased by an average of 25% over a 3-week period, and then stabilized. However, adding lamotrigine to the existing therapy did not cause a change in valproate plasma concentrations in either adult or pediatric patients in controlled clinical trials.
The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers by slightly more than 2-fold. In 1 trial, maximal inhibition of lamotrigine clearance was reached at valproate doses between 250 and 500 mg/day and did not increase as the valproate dose was further increased.
Zonisamide
In a study in 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with lamotrigine (150 to 500 mg/day for 35 days) had no significant effect on the pharmacokinetics of lamotrigine.
Known Inducers or Inhibitors of Glucuronidation
Drugs other than those listed above have not been systematically evaluated in combination with lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of LAMOTRIGINE EXTENDED-RELEASE TABLETS may require adjustment based on clinical response.
Other
In vitro assessment of the inhibitory effect of lamotrigine at OCT2 demonstrate that lamotrigine, but not the N(2)-glucuronide metabolite, is an inhibitor of OCT2 at potentially clinically relevant concentrations, with IC50 value of 53.8 μM [see Drug Interactions(7)].
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, sertraline, or trazodone.
Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6.
Specific Populations
Renal Impairment: Twelve volunteers with chronic renal failure (mean creatinine clearance: 13 mL/min, range: 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100-mg dose of immediate-release lamotrigine. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared with 26.2 hours in healthy volunteers. On average, approximately 20% (range: 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour session [see Dosage and Administration (2.1)].
Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100-mg dose of immediate-release lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic impairment (Child-Pugh classification system) and compared with 12 subjects without hepatic impairment. The subjects with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearances of lamotrigine in subjects with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared with 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in subjects with mild, moderate, severe without ascites, and severe with ascites hepatic impairment were 46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in healthy controls [see Dosage and Administration (2.1)].
Elderly: The pharmacokinetics of lamotrigine following a single 150-mg dose of immediate-release lamotrigine were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance: 61 mL/min, range: 33 to 108 mL/min). The mean half-life of lamotrigine in these subjects was 31.2 hours (range: 24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range: 0.26 to 0.48 mL/min/kg).
Gender: The clearance of lamotrigine is not affected by gender. However, during dose escalation of immediate-release lamotrigine in 1 clinical trial in patients with epilepsy on a stable dose of valproate (n = 77), mean trough lamotrigine concentrations, unadjusted for weight, were 24% to 45% higher (0.3 to 1.7 mcg/mL) in females than in males.
Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than Caucasians.
Pediatric Patients: Safety and effectiveness of LAMOTRIGINE EXTENDED-RELEASE TABLETS for use in patients younger than 13 years have not been established.
Clinical Studies
Adjunctive Therapy for Primary Generalized Tonic-Clonic Seizures
The effectiveness of LAMOTRIGINE EXTENDED-RELEASE TABLETS as adjunctive therapy in subjects with PGTC seizures was established in a 19-week, international, multicenter, double-blind, randomized, placebo-controlled trial in 143 patients aged 13 years and older (n=70 on LAMOTRIGINE EXTENDED-RELEASE TABLETS, n=73 on placebo). Patients with at least 3 PGTC seizures during an 8-week baseline phase were randomized to 19 weeks of treatment with LAMOTRIGINE EXTENDED-RELEASE TABLETS or placebo added to their current AED regimen of up to 2 drugs. Patients were dosed on a fixed-dose regimen, with target doses ranging from 200 to 500 mg/day of LAMOTRIGINE EXTENDED-RELEASE TABLETS based on concomitant AEDs (target dose = 200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine levels, and 500 mg for enzyme-inducing AEDs).
The primary efficacy endpoint was percent change from baseline in PGTC seizure frequency during the double-blind treatment phase. For the intent-to-treat population, the median percent reduction in PGTC seizure frequency was 75% in patients treated with LAMOTRIGINE EXTENDED-RELEASE TABLETS and 32% in patients treated with placebo, a difference that was statistically significant, defined as a 2-sided P value ≤0.05.
Figure 1 presents the percentage of patients (X-axis) with a percent reduction in PGTC seizure frequency (responder rate) from baseline through the entire treatment period at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in PGTC seizure frequency was consistently higher for the group treated with LAMOTRIGINE EXTENDED-RELEASE TABLETS compared with the placebo group. For example, 70% of patients randomized to LAMOTRIGINE EXTENDED-RELEASE TABLETS experienced a 50% or greater reduction in PGTC seizure frequency, compared with 32% of patients randomized to placebo. Patients with an increase in seizure frequency >100% are represented on the Y-axis as equal to or greater than -100%.
Figure 1. Proportion of Patients by Responder Rate for LAMOTRIGINE EXTENDED-RELEASE TABLETS and Placebo Group (Primary Generalized Tonic-Clonic Seizures Study)
Adjunctive Therapy for Partial-Onset Seizures
The effectiveness of immediate-release lamotrigine as adjunctive therapy was initially established in 3 pivotal, multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial-onset seizures.
The effectiveness of LAMOTRIGINE EXTENDED-RELEASE TABLETS as adjunctive therapy in partial-onset seizures, with or without secondary generalization, was established in a 19-week, multicenter, double-blind, placebo-controlled trial in 236 patients aged 13 years and older (approximately 93% of patients were aged 16 to 65 years). Approximately 36% were from the U.S. and approximately 64% were from other countries including Argentina, Brazil, Chile, Germany, India, Korea, Russian Federation, and Ukraine. Patients with at least 8 partial-onset seizures during an 8-week prospective baseline phase (or 4-week prospective baseline coupled with a 4-week historical baseline documented with seizure diary data) were randomized to treatment with LAMOTRIGINE EXTENDED-RELEASE TABLETS (n = 116) or placebo (n = 120) added to their current regimen of 1 or 2 AEDs. Approximately half of the patients were taking 2 concomitant AEDs at baseline. Target doses ranged from 200 to 500 mg/day of LAMOTRIGINE EXTENDED-RELEASE TABLETS based on concomitant AED (target dose = 200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine, and 500 mg for enzyme-inducing AEDs). The median partial seizure frequency per week at baseline was 2.3 for LAMOTRIGINE EXTENDED-RELEASE TABLETS and 2.1 for placebo.
The primary endpoint was the median percent change from baseline in partial-onset seizure frequency during the entire double-blind treatment phase. The median percent reductions in weekly partial-onset seizures were 47% in patients treated with LAMOTRIGINE EXTENDED-RELEASE TABLETS and 25% on placebo, a difference that was statistically significant, defined as a 2-sided P value <0.05.
Figure 2 presents the percentage of patients (X-axis) with a percent reduction in partial-onset seizure frequency (responder rate) from baseline through the entire treatment period at least as great as that represented on the Y-axis. The proportion of patients achieving any particular level of reduction in partial-onset seizure frequency was consistently higher for the group treated with LAMOTRIGINE EXTENDED-RELEASE TABLETS compared with the placebo group. For example, 44% of patients randomized to LAMOTRIGINE EXTENDED-RELEASE TABLETS experienced a 50% or greater reduction in partial-onset seizure frequency compared with 21% of patients randomized to placebo.
Figure 2. Proportion of Patients by Responder Rate for LAMOTRIGINE EXTENDED-RELEASE TABLETS and Placebo Group (Partial-Onset Seizure Study)
Conversion to Monotherapy for Partial-Onset Seizures
The effectiveness of LAMOTRIGINE EXTENDED-RELEASE TABLETS as monotherapy for partial-onset seizures was established in a historical control trial in 223 adults with partial-onset seizures. The historical control methodology is described in a publication by French, et al. [see References 15)]. Briefly, in this study, patients were randomized to ultimately receive either LAMOTRIGINE EXTENDED-RELEASE TABLETS 300 or 250 mg once a day, and their responses were compared with those of a historical control group. The historical control consisted of a pooled analysis of the control groups from 8 studies of similar design, which utilized a subtherapeutic dose of an AED as a comparator. Statistical superiority to the historical control was considered to be demonstrated if the upper 95% confidence interval for the proportion of patients meeting escape criteria in patients receiving LAMOTRIGINE EXTENDED-RELEASE TABLETS remained below the lower 95% prediction interval of 65.3% derived from the historical control data.
In this study, patients aged 13 years and older experienced at least 4 partial-onset seizures during an 8-week baseline period with at least 1 seizure occurring during each of 2 consecutive 4-week periods while receiving valproate or a non-enzyme-inducing AED. LAMOTRIGINE EXTENDED-RELEASE TABLETS was added to either valproate or a non-enzyme-inducing AED over a 6- to 7-week period followed by the gradual withdrawal of the background AED. Patients were then continued on monotherapy with LAMOTRIGINE EXTENDED-RELEASE TABLETS for 12 weeks. The escape criteria were 1 or more of the following:
(1) doubling of average monthly seizure count during any 28 consecutive days, (2) doubling of highest consecutive 2-day seizure frequency during the entire treatment phase, (3) emergence of a new seizure type compared with baseline (4) clinically significant prolongation of generalized tonic-clonic seizures or worsening of seizure considered by the investigator to require intervention. These criteria were similar to those in the 8 controlled trials from which the historical control group was constituted.
The upper 95% confidence limits of the proportion of subjects meeting escape criteria (40.2% at 300 mg/day and 44.5% at 250 mg/day) were below the threshold of 65.3% derived from the historical control data.
Although the study population was not fully comparable with the historical control population and the study was not fully blinded, numerous sensitivity analyses supported the primary results. Efficacy was further supported by the established effectiveness of the immediate-release formulation as monotherapy.
References
1. French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of epilepsy. Epilepsia. 2010; 51(10):1936-1943.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Rash
Prior to initiation of treatment with LAMOTRIGINE EXTENDED-RELEASE TABLETS, inform patients that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and instruct them to report any such occurrence to their healthcare providers immediately.
Multiorgan Hypersensitivity Reactions, Blood Dyscrasias and Organ Failure
Inform patients that multiorgan hypersensitivity reactions and acute multiorgan failure may occur with lamotrigine. Isolated organ failure or isolated blood dyscrasias without evidence of multiorgan hypersensitivity may also occur. Instruct patients to contact their healthcare providers immediately if they experience any signs or symptoms of these conditions [see Warnings and Precautions (5.2, 5.3)].
Suicidal Thinking and Behavior
Inform patients, their caregivers, and families that AEDs, including LAMOTRIGINE EXTENDED-RELEASE TABLETS, may increase the risk of suicidal thoughts and behavior. Instruct them to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts or behavior or thoughts about self-harm. Instruct them to immediately report behaviors of concern to their healthcare providers.
Worsening of Seizures
Instruct patients to notify their healthcare providers if worsening of seizure control occurs.
Central Nervous System Adverse Effects
Inform patients that lInform patients that LAMOTRIGINE EXTENDED-RELEASE TABLETS may cause dizziness, somnolence, and other symptoms and signs of central nervous system depression. Accordingly, instruct them neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on LAMOTRIGINE EXTENDED-RELEASE TABLETS to gauge whether or not it adversely affects their mental and/or motor performance.
Pregnancy and Nursing
Instruct patients to notify their healthcare providers if they become pregnant or intend to become pregnant during therapy and if they intend to breastfeed or are breastfeeding an infant.
Encourage patients to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334 [see Use in Specific Populations (8.1)].
Inform patients who intend to breastfeed that LAMOTRIGINE EXTENDED-RELEASE TABLETS is present in breast milk and advise them to monitor their child for potential adverse effects of this drug. Discuss the benefits and risks of continuing breastfeeding.
Oral Contraceptive Use
Instruct women to notify their healthcare providers if they plan to start or stop use of oral contraceptives or other female hormonal preparations. Starting estrogen-containing oral contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen-containing oral contraceptives (including the pill-free week) may significantly increase lamotrigine plasma levels [see Warnings and Precautions (5.7), Clinical Pharmacology (12.3)]. Also instruct women to promptly notify their healthcare providers if they experience adverse reactions or changes in menstrual pattern (e.g., break-through bleeding) while receiving LAMOTRIGINE EXTENDED-RELEASE TABLETS in combination with these medications.
Discontinuing LAMOTRIGINE EXTENDED-RELEASE TABLETS
Instruct patients to notify their healthcare providers if they stop taking LAMOTRIGINE EXTENDED-RELEASE TABLETS for any reason and not to resume LAMOTRIGINE EXTENDED-RELEASE TABLETS without consulting their healthcare providers.
Aseptic Meningitis
Inform patients that LAMOTRIGINE EXTENDED-RELEASE TABLETS may cause aseptic meningitis. Instruct them to notify their healthcare providers immediately if they develop signs and symptoms of meningitis such as headache, fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, myalgia, chills, confusion, or drowsiness while taking LAMOTRIGINE EXTENDED-RELEASE TABLETS.
Potential Medication Errors
To avoid a medication error of using the wrong drug or formulation, strongly advise patients to visually inspect their tablets to verify that they are LAMOTRIGINE EXTENDED-RELEASE TABLETS each time they fill their prescription [see Dosage Forms and Strengths (3), How Supplied/Storage and Handling (16)]. Refer the patient to the Medication Guide that provides depictions of the LAMOTRIGINE EXTENDED-RELEASE TABLETS.
Manufactured For:
TruPharma, LLC
Tampa, FL 33609
Made in the U.S.A.
Rev. 02/2017