SUBVENITE

Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing products, including oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.

Valproate inhibits glucuronidation. For dosing considerations for SUBVENITE in patients on estrogen-containing products, including contraceptives, and atazanavir/ritonavir, see below and Table 13 . For dosing considerations for SUBVENITE in patients on other drugs known to induce or inhibit glucuronidation, see Tables 1 , 2 , 5 to 6 , and 13 .

Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder A therapeutic plasma concentration range has not been established for lamotrigine. 3 )] . 3 )] . Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with SUBVENITE based on the concomitant AED or other concomitant medications (see Tables 1 , 5 , and 7 ).

See below for adjustments to maintenance doses of SUBVENITE in women taking estrogen-containing oral contraceptives. 3 )] . 3 )] . The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week.

Dose increases should not exceed the recommended rate (see Tables 1 and 5 ) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation.

Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to SUBVENITE consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary.

Dose adjustments limited to the pill-free week are not recommended. 3 )] . 3 )] . 3 )] . 3 )] . Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy The effect of other hormonal contraceptive preparations or hormone replacement therapy (HRT) on the pharmacokinetics of lamotrigine has not been systematically evaluated.

Other estrogen‑containing therapies, such as HRT, may interfere with lamotrigine. 9 )]. 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 SUBVENITE in the presence of progestogens alone will likely not be needed. Patients Taking Atazanavir/Ritonavir While atazanavir/ritonavir does reduce the lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for SUBVENITE should be necessary solely based on the use of atazanavir/ritonavir.

Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with SUBVENITE based on concomitant AED or other concomitant medications (see Tables 1, 2, and 5). 3 )] . Patients with Hepatic Impairment Experience in patients with hepatic impairment is limited.

3 )] . No dosage adjustment is needed in patients with mild liver 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. 3 )] . Few patients with severe renal impairment have been evaluated during chronic treatment with lamotrigine. Because there is inadequate experience in this population, SUBVENITE should be used with caution in these patients.

Discontinuation Strategy Epilepsy:

For patients receiving SUBVENITE in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed. 10 )]. Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine.

Bipolar Disorder:

In the controlled clinical trials, there was no increase in the incidence, type, or severity of adverse reactions following abrupt termination of lamotrigine. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine.

10 )] . 2 Epilepsy—Adjunctive Therapy This section provides specific dosing recommendations for patients older than 12 years and patients aged 2 to 12 years. Within each of these age-groups, specific dosing recommendations are provided depending upon concomitant AEDs or other concomitant medications (see Table 1 for patients older than 12 years and Table 2 for patients aged 2 to 12 years).

Patients Older than 12 Years Recommended dosing guidelines are summarized in Table 1 . Table 1. 3 )] . b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.

1 )] . 3 )]. Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg/day Weeks 3 and 4 25 mg every day 50 mg/day 100 mg/day (in 2 divided doses) Week 5 onward to maintenance Increase by 25 to 50 mg/day every 1 to 2 weeks. Increase by 50 mg/day every 1 to 2 weeks.

Increase by 100 mg/day every 1 to 2 weeks. Usual maintenance dose 100 to 200 mg/day with valproate alone 100 to 400 mg/day with valproate and other drugs that induce glucuronidation (in 1 or 2 divided doses) 225 to 375 mg/day (in 2 divided doses) 300 to 500 mg/day (in 2 divided doses) Patients Aged 2 to 12 Years Recommended dosing guidelines are summarized in Table 2 .

Lower starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by lower starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials.

It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing <30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.

Table 2. 3 )] . b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.

1 )] . 3 )] . 3 mg/kg/day, add this amount to the previously administered daily dose. 6 mg/kg/day, add this amount to the previously administered daily dose. 2 mg/kg/day, add this amount to the previously administered daily dose. 5 mg/kg/day (maximum 300 mg/day in 2 divided doses) 5 to 15 mg/kg/day (maximum 400 mg/day in 2 divided doses) Maintenance dose in patients <30 kg May need to be increased by as much as 50%, based on clinical response.

May need to be increased by as much as 50%, based on clinical response. May need to be increased by as much as 50%, based on clinical response. Usual Adjunctive Maintenance Dose for Epilepsy The usual maintenance doses identified in Tables 1 and 2 are derived from dosing regimens employed in the placebo-controlled adjunctive trials in which the efficacy of lamotrigine was established.

In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate , maintenance doses of adjunctive lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone , maintenance doses of adjunctive lamotrigine as high as 200 mg/day have been used.

The advantage of using doses above those recommended in Tables 1 to 3 has not been established in controlled trials. 3 Epilepsy-Conversion from Adjunctive Therapy to Monotherapy The goal of the transition regimen is to attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of lamotrigine.

The recommended maintenance dose of SUBVENITE as monotherapy is 500 mg/day given in 2 divided doses. To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations for SUBVENITE should not be exceeded [see Boxed Warning ] .

Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with SUBVENITE After achieving a dose of 500 mg/day of SUBVENITE using the guidelines in Table 1, the concomitant enzyme-inducing AED should be withdrawn by 20% decrements each week over a 4-week period.

The regimen for the withdrawal of the concomitant AED is based on experience gained in the controlled monotherapy clinical trial. Conversion from Adjunctive Therapy with Valproate to Monotherapy with SUBVENITE The conversion regimen involves the 4 steps outlined in Table 3 .

Table 3. Conversion from Adjunctive Therapy with Valproate to Monotherapy with SUBVENITE in Patients Aged 16 Years and Older with Epilepsy SUBVENITE Valproate Step 1 Achieve a dose of 200 mg/day according to guidelines in Table 1. Maintain established stable dose.

Step 2 Maintain at 200 mg/day. Decrease dose by decrements no greater than 500 mg/day/week to 500 mg/day and then maintain for 1 week. Step 3 Increase to 300 mg/day and maintain for 1 week. Simultaneously decrease to 250 mg/day and maintain for 1 week.

Step 4 Increase by 100 mg/day every week to achieve maintenance dose of 500 mg/day. Discontinue. Conversion from Adjunctive Therapy with Antiepileptic Drugs other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with SUBVENITE No specific dosing guidelines can be provided for conversion to monotherapy with SUBVENITE with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.

2 )] . Patients taking lamotrigine for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment. Adults The target dose of SUBVENITE is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of lamotrigine, and 400 mg/day in patients not taking valproate and taking either carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that increase the apparent clearance of lamotrigine).

2 )] . Accordingly, doses above 200 mg/day are not recommended. Treatment with SUBVENITE is introduced, based on concurrent medications, according to the regimen outlined in Table 4 . If other psychotropic medications are withdrawn following stabilization, the dose of SUBVENITE should be adjusted.

In patients discontinuing valproate, the dose of SUBVENITE should be doubled over a 2-week period in equal weekly increments (see Table 5 ). In patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the dose of SUBVENITE should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements (see Table 5 ).

The dose of SUBVENITE may then be further adjusted to the target dose (200 mg) as clinically indicated. If other drugs are subsequently introduced, the dose of SUBVENITE may need to be adjusted. 3 )]. To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of SUBVENITE should not be exceeded [see Boxed Warning ] .

Table 4. 3 )]. b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing products, including oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.

1 )] . 3 )]. In Patients TAKING Valproate a In Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidone b , or Valproate a In Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidone b and NOT TAKING Valproate a Weeks 1 and 2 25 mg every other day 25 mg daily 50 mg daily Weeks 3 and 4 25 mg daily 50 mg daily 100 mg daily, in divided doses Week 5 50 mg daily 100 mg daily 200 mg daily, in divided doses Week 6 100 mg daily 200 mg daily 300 mg daily, in divided doses Week 7 100 mg daily 200 mg daily up to 400 mg daily, in divided doses Table 5.

3 )]. b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified AEDs, include estrogen-containing products, including oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir.

1 )] . 3 )] . 5 Administration Instructions SUBVENITE can be administered with or without food. Use a calibrated measuring device, such as an oral dosing syringe or oral dosing cup, to measure and deliver the prescribed dose accurately.

A household teaspoon or tablespoon is not an adequate measuring device. Shake well before each use. Discard any unused portion 90 days after first opening.

1 )]. Approximately 11% of the 3,378 adult patients who received lamotrigine as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. 5%). In a dose-response trial in adults, the rate of discontinuation of lamotrigine for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related.

Monotherapy in Adults with Epilepsy:

The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with the use of lamotrigine 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 (≥5% for lamotrigine and more common on drug than placebo) adverse reactions associated with the use of lamotrigine 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 lamotrigine as monotherapy in premarketing clinical trials discontinued treatment because of an adverse reaction. 4%).

Adjunctive Therapy in Pediatric Patients with Epilepsy:

The most commonly observed (≥5% for lamotrigine and more common on drug than placebo) adverse reactions seen in association with the use of lamotrigine as adjunctive treatment in pediatric patients aged 2 to 16 years 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.

9% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reaction that led to discontinuation of lamotrigine was rash. 5% of the 1,081 pediatric patients aged 2 to 16 years who received lamotrigine as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction.

6%).

Controlled Adjunctive Clinical Trials in Adults with Epilepsy:

Table 7 lists adverse reactions that occurred in adult patients with epilepsy treated with lamotrigine in placebo-controlled trials. In these trials, either lamotrigine or placebo was added to the patient’s current AED therapy. Table 7.

Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Adult Patients with Epilepsy a , b a Adverse reactions that occurred in at least 2% of patients treated with lamotrigine and at a greater incidence than placebo. b Patients in these adjunctive trials were receiving 1 to 3 of the concomitant AEDs carbamazepine, phenytoin, phenobarbital, or primidone in addition to lamotrigine or placebo.

Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than 1 category. Body System / Adverse Reaction Percent of Patients Receiving Adjunctive Lamotrigine ( n = 711 ) Percent of Patients Receiving Adjunctive Placebo ( n = 419 ) Body as a whole Headache Flu syndrome Fever Abdominal pain Neck pain Reaction aggravated (seizure exacerbation) 29 7 6 5 2 2 19 6 4 4 1 1 Digestive Nausea Vomiting Diarrhea Dyspepsia Constipation Anorexia 19 9 6 5 4 2 10 4 4 2 3 1 Musculoskeletal Arthralgia 2 0 Nervous Dizziness Ataxia Somnolence Incoordination Insomnia Tremor Depression Anxiety Convulsion Irritability Speech disorder Concentration disturbance 38 22 14 6 6 4 4 4 3 3 3 2 13 6 7 2 2 1 3 3 1 2 0 1 Respiratory Rhinitis Pharyngitis Cough increased 14 10 8 9 9 6 Skin and appendages Rash Pruritus 10 3 5 2 Special senses Diplopia Blurred vision Vision abnormality 28 16 3 7 5 1 Urogenital Female patients only Dysmenorrhea Vaginitis Amenorrhea (n = 365) 7 4 2 (n = 207) 6 1 1 In a randomized, parallel trial comparing placebo with 300 and 500 mg/day of lamotrigine, some of the more common drug-related adverse reactions were dose related (see Table 8 ).

Table 8. 05). 05). Percent of Patients Experiencing Adverse Reactions Adverse Reaction Placebo ( n = 73 ) Lamotrigine 300 mg ( n = 71 ) Lamotrigine 500 mg ( n = 72 ) Ataxia Blurred vision Diplopia Dizziness Nausea Vomiting 10 10 8 27 11 4 10 11 24 a 31 18 11 28 a , b 25 a , b 49 a , b 54 a , b 25 a 18 a The overall adverse reaction profile for lamotrigine 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 lamotrigine in placebo-controlled trials, there are insufficient data to support a statement regarding the distribution of adverse reaction reports by race.

Generally, females receiving either lamotrigine as adjunctive therapy or placebo were more likely to report adverse reactions than males. 5%). There was little difference between females and males in the rates of discontinuation of lamotrigine for individual adverse reactions.

Controlled Monotherapy Trial in Adults with Partial-Onset Seizures:

Table 9 lists adverse reactions that occurred in patients with epilepsy treated with monotherapy with lamotrigine in a double-blind trial following discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent frequency in the control group.

Table 9. Adverse Reactions in a Controlled Monotherapy Trial in Adult Patients with Partial-Onset Seizures a , b a Adverse reactions that occurred in at least 5% of patients treated with lamotrigine and at a greater incidence than valproate-treated patients.

b Patients in this trial were converted to lamotrigine or valproate monotherapy from adjunctive therapy with carbamazepine or phenytoin. Patients may have reported multiple adverse reactions during the trial; thus, patients may be included in more than 1 category.

c Up to 500 mg/day. d 1,000 mg/day. Body System / Adverse Reaction Percent of Patients Receiving Lamotrigine c as Monotherapyv ( n = 43 ) Percent of Patients Receiving Low - Dose Valproate d Monotherapy ( n = 44 ) Body as a whole Pain Infection Chest pain 5 5 5 0 2 2 Digestive Vomiting Dyspepsia Nausea 9 7 7 0 2 2 Metabolic and nutritional Weight decrease 5 2 Nervous Coordination abnormality Dizziness Anxiety Insomnia 7 7 5 5 0 0 0 2 Respiratory Rhinitis 7 2 Urogenital (female patients only) Dysmenorrhea (n = 21) 5 (n = 28) 0 Adverse reactions that occurred with a frequency of <5% and >2% of patients receiving lamotrigine 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 10 lists adverse reactions that occurred in 339 pediatric patients with partial-onset seizures or generalized seizures of Lennox-Gastaut syndrome who received lamotrigine up to 15 mg/kg/day or a maximum of 750 mg/day. Table 10.

Adverse Reactions in Pooled, Placebo-Controlled Adjunctive Trials in Pediatric Patients with Epilepsy a a Adverse reactions that occurred in at least 2% of patients treated with lamotrigine and at a greater incidence than placebo. Body System / Adverse Reaction Percent of Patients Receiving Lamotrigine ( n = 168 ) Percent of Patients Receiving Placebo ( n = 171 ) Body as a whole Infection Fever Accidental injury Abdominal pain Asthenia Flu syndrome Pain Facial edema Photosensitivity 20 15 14 10 8 7 5 2 2 17 14 12 5 4 6 4 1 0 Cardiovascular Hemorrhage 2 1 Digestive Vomiting Diarrhea Nausea Constipation Dyspepsia 20 11 10 4 2 16 9 2 2 1 Hemic and lymphatic Lymphadenopathy 2 1 Metabolic and nutritional Edema 2 0 Nervous system Somnolence Dizziness Ataxia Tremor Emotional lability Gait abnormality Thinking abnormality Convulsions Nervousness Vertigo 17 14 11 10 4 4 3 2 2 2 15 4 3 1 2 2 2 1 1 1 Respiratory Pharyngitis Bronchitis Increased cough Sinusitis Bronchospasm 14 7 7 2 2 11 5 6 1 1 Skin Rash Eczema Pruritus 14 2 2 12 1 1 Special senses Diplopia Blurred vision Visual abnormality 5 4 2 1 1 0 Urogenital Male and female patients Urinary tract infection 3 0 Bipolar Disorder in Adults The most common adverse reactions seen in association with the use of lamotrigine as monotherapy (100 to 400 mg/day) in adult patients (aged 18 to 82 years) with bipolar disorder in the 2 double-blind, placebo-controlled trials of 18 months’ duration are included in Table 11 .

Adverse reactions that occurred in at least 5% of patients and were numerically more frequent during the dose-escalation phase of lamotrigine in these trials (when patients may have been receiving concomitant medications) compared with the monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%).

During the monotherapy phase of the double-blind, placebo-controlled trials of 18 months’ duration, 13% of 227 patients who received lamotrigine (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 reaction.

The adverse reactions that most commonly led to discontinuation of lamotrigine were rash (3%) and mania/hypomania/mixed mood adverse reactions (2%). Approximately 16% of 2,401 patients who received lamotrigine (50 to 500 mg/day) for bipolar disorder in premarketing trials discontinued therapy because of an adverse reaction, most commonly due to rash (5%) and mania/hypomania/mixed mood adverse reactions (2%).

The overall adverse reaction profile for lamotrigine was similar between females and males, between elderly and nonelderly patients, and among racial groups. Table 11. Adverse Reactions in 2 Placebo-Controlled Trials in Adult Patients with Bipolar I Disorder a , b Body System / Adverse Reaction Percent of Patients Receiving Lamotrigine ( n = 227 ) Percent of Patients Receiving Placebo ( n = 190 ) General Back pain Fatigue Abdominal pain 8 8 6 6 5 3 Digestive Nausea Constipation Vomiting 14 5 5 11 2 2 Nervous System Insomnia Somnolence Xerostomia (dry mouth) 10 9 6 6 7 4 Respiratory Rhinitis Exacerbation of cough Pharyngitis 7 5 5 4 3 4 Skin Rash (nonserious) c 7 5 a Adverse reactions that occurred in at least 5% of patients treated with lamotrigine and at a greater incidence than placebo.

b Patients in these trials were converted to lamotrigine (100 to 400 mg/day) or placebo monotherapy from add-on therapy with other psychotropic medications. Patients may have reported multiple adverse reactions during the trial; thus, patients may be included in more than 1 category.

1 )]. Other reactions 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 reactions that occurred with a frequency of <5% and >1% of patients receiving lamotrigine 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 Reactions following Abrupt Discontinuation:

In the 2 controlled clinical trials, there was no increase in the incidence, severity, or type of adverse reactions in patients with bipolar disorder after abruptly terminating therapy with lamotrigine. 10 )].

Mania/Hypomania/Mixed Episodes:

During the double-blind placebo-controlled clinical trials in bipolar I disorder in which adults were converted to monotherapy with lamotrigine (100 to 400 mg/day) from other psychotropic medications and followed for up to 18 months, the rates of manic or hypomanic or mixed mood episodes reported as adverse reactions were 5% for patients treated with lamotrigine (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 reactions of mania (including hypomania and mixed mood episodes) were reported in 5% of patients treated with lamotrigine (n = 956), 3% of patients treated with lithium (n = 280), and 4% of patients treated with placebo (n = 803).

2 Other Adverse Reactions Observed in All Clinical Trials 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.

During these trials, all adverse reactions were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse reactions, similar types of adverse reactions 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 lamotrigine who experienced an event of the type cited on at least 1 occasion while receiving lamotrigine. All reported adverse 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.

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.

Body as a Whole Infrequent:

Allergic reaction, chills, malaise.

Cardiovascular System Infrequent:

Flushing, hot flashes, hypertension, palpitations, postural hypotension, syncope, tachycardia, vasodilation.

Dermatological Infrequent:

Acne, alopecia, hirsutism, maculopapular rash, skin discoloration, urticaria.

Rare:

Angioedema, erythema, exfoliative dermatitis, fungal dermatitis, herpes zoster, leukoderma, multiforme erythema, petechial rash, pustular rash, Stevens-Johnson syndrome, vesiculobullous rash.

Digestive System Infrequent:

Dysphagia, eructation, gastritis, gingivitis, increased appetite, increased salivation, liver function tests abnormal, mouth ulceration.

Rare:

Gastrointestinal hemorrhage, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hemorrhagic colitis, hepatitis, melena, stomach ulcer, stomatitis, tongue edema.

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, general edema, gamma glutamyl transpeptidase increase, hyperglycemia.

Musculoskeletal System Infrequent :

Arthritis, leg cramps, myasthenia, twitching.

Rare:

Bursitis, muscle atrophy, pathological fracture, tendinous contracture.

Nervous System Frequent:

Confusion, paresthesia.

Infrequent:

Akathisia, apathy, aphasia, central nervous system 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, suicidal ideation.

Rare:

Choreoathetosis, delirium, delusions, dysphoria, dystonia, extrapyramidal syndrome, faintness, grand mal convulsions, hemiplegia, hyperalgesia, hyperesthesia, hypokinesia, hypotonia, manic depression reaction, muscle spasm, neuralgia, neurosis, paralysis, peripheral neuritis.

Respiratory System Infrequent:

Yawn.

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, anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency. 3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of lamotrigine.

Because these reactions 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, pseudolymphoma.

Gastrointestinal Esophagitis. Hepatobiliary Tract and Pancreas Pancreatitis. Immunologic Hypogammaglobulinemia, 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. Renal and Urinary Disorders Tubulointerstitial nephritis (has been reported alone and in association with uveitis).

Skin and Subcutaneous Tissue Disorders Photosensitivity reaction.

However, in worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate. 3 )] . Risk Factors Concomitant Use of Valproate There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults.

16%) of 2,398 clinical trial patients and volunteers administered lamotrigine in the absence of valproate were hospitalized. Patients with History of Allergy or Rash to Other Antiepileptic Drugs The risk of rash may be increased in patients with a history of allergy or rash to other AEDs.

Not Adhering to the Recommended Dosage The risk of rash is increased by both exceeding the recommended initial dose of SUBVENITE and exceeding the recommended dose escalation for SUBVENITE. , Han Chinese and Thai) suggest that the HLA-B*1502 allele is associated with an increased risk (approximately 2-3 times higher) of developing Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in patients using lamotrigine.

The risks and benefits of therapy should be weighed when considering use of SUBVENITE in patients known to be positive for HLA-B*1502. Application of HLA genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management.

Many HLA B*1502 positive patients treated with SUBVENITE will not develop SJS/TEN or other hypersensitivity reactions, and these reactions can still occur in HLA B*1502 negative patients of any ethnicity. 2 Hemophagocytic Lymphohistiocytosis Hemophagocytic lymphohistiocytosis (HLH) has occurred in pediatric and adult patients taking lamotrigine, the active ingredient in SUBVENITE, for various indications.

HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation. It is associated with high mortality rates if not recognized early and treated. Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high serum ferritin, hypertriglyceridemia, and liver function and coagulation abnormalities.

In cases of HLH reported with lamotrigine, patients have presented with signs of systemic inflammation (fever, rash, hepatosplenomegaly, and organ system dysfunction) and blood dyscrasias. Symptoms have been reported to occur within 8 to 24 days following the initiation of treatment.

Patients who develop early manifestations of pathologic immune activation should be evaluated immediately, and a diagnosis of HLH should be considered. SUBVENITE should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

3 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with patients taking antiepileptic drugs, including lamotrigine, the active ingredient in SUBVENITE.

These events can be fatal or life threatening, particularly if diagnosis and treatment do not occur as early as possible. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, 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. Because this disorder is variable in its expression, other organ systems not noted here may be involved. Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received lamotrigine in epilepsy clinical trials.

Rare fatalities from multiorgan failure have also been reported in postmarketing use. Isolated liver failure without rash or involvement of other organs has also been reported with lamotrigine. , fever, lymphadenopathy) may be present even though a rash is not evident.

If such signs or symptoms are present, the patient should be evaluated immediately. SUBVENITE should be discontinued if an alternative etiology for the signs or symptoms cannot be established. 2 )] . , Brugada syndrome], clinically important ischemic heart disease, or multiple risk factors for coronary artery disease).

Elevated heart rates could also increase the risk of ventricular conduction slowing with SUBVENITE. Any expected or observed benefit of SUBVENITE in an individual patient with clinically important structural or functional heart disease must be carefully weighed against the risks for serious arrhythmias and/or death for that patient.

Concomitant use of other sodium channel blockers may further increase the risk of proarrhythmia. 3 )] . These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.

6 Suicidal Behavior and Ideation AEDs, including SUBVENITE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

7) of suicidal thinking or behavior compared with patients randomized to placebo. 24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated.

There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed.

Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 6 shows absolute and relative risk by indication for all evaluated AEDs. Table 6. 9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing SUBVENITE or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, the emergence of suicidal thoughts or suicidal behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers. 7 Aseptic Meningitis Therapy with SUBVENITE increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate.

Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking lamotrigine for various indications. Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal rigidity.

Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment. In most cases, symptoms were reported to resolve after discontinuation of lamotrigine.

Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of treatment) that were frequently more severe. Some of the patients treated with SUBVENITE who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.

Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases.

3) ]. 8 Potential Medication Errors Medication errors involving lamotrigine have occurred. In particular, the name lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of lamotrigine.

To reduce the potential for medication errors, write and say SUBVENITE clearly. SUBVENITE is a pink oral suspension. To avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect the product to verify that it is SUBVENITE oral suspension, each time they fill their prescription.

3 )] . 1 )] . During the week of inactive hormone preparation (pill-free week) of oral contraceptive therapy, plasma lamotrigine levels are expected to rise, as much as doubling at the end of the week. Adverse reactions consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur.

Other oral contraceptive and other estrogen-containing therapies (such as HRT) have not been studied, though they may similarly affect lamotrigine pharmacokinetic parameters. 10 Withdrawal Seizures As with most AEDs, SUBVENITE should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus.

In clinical trials in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of lamotrigine. 1 )] . If withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.

11 Status Epilepticus Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases.

At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus. , seizure clusters, seizure flurries) were made. 4 ), Drug Interactions ( 7 )] . 13 Binding in the Eye and Other Melanin-Containing Tissues Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time.

This raises the possibility that SUBVENITE may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in one controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure.

2 )]. Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects. 14 Laboratory Tests False-Positive Drug Test Results Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens, which can result in false-positive readings, particularly for phencyclidine (PCP).

A more specific analytical method should be used to confirm a positive result.