Subvenite

• Cases of life-threatening 
  serious rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, and/or rash-related death have been caused by lamotrigine. The rate of serious rash is greater in pediatric patients than in adults. Additional factors that may increase the 
  risk of rash include:
• coadministration with valproate.
• exceeding recommended initial dose of SUBVENITE.
• exceeding recommended dose escalation for SUBVENITE. (
  
  

  5.1 Serious Skin Rashes

  [see Boxed Warning]

  Pediatric Population

  The incidence of serious rash associated with hospitalization and discontinuation of SUBVENITE in a prospectively followed cohort of pediatric patients (aged 2 to 17 years) is approximately 0.3% to 0.8%. One rash-related death was reported in a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking SUBVENITE as adjunctive therapy. Additionally, there have been rare cases of toxic epidermal necrolysis (TEN) with and without permanent sequelae and/or death in U.S. and foreign postmarketing experience.

  There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used valproate concomitantly for epilepsy, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not taking valproate.

  Adult Population

  Serious rash associated with hospitalization and discontinuation of SUBVENITE occurred in 0.3% (11 of 3,348) of adult patients who received SUBVENITE in premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received SUBVENITE as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received SUBVENITE as adjunctive therapy. No fatalities occurred among these individuals. 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.

  Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and those associated with multiorgan hypersensitivity

  [see Warnings and Precautions ]

  .

  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. Specifically, of 584 patients administered SUBVENITE with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered SUBVENITE 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.

  Patients with Genetic Variant Human Leukocyte Antigen (HLA)-B*1502 Allele

  Retrospective case-control studies in patients of certain Asian ancestry (e.g., 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.

  )
  
  
• Benign rashes are also caused by lamotrigine; however, it is not possible to predict which rashes will prove to be serious or life threatening. SUBVENITE should be discontinued at the first sign of rash, unless the rash is clearly not drug related. (
  
  

  5.1 Serious Skin Rashes

  [see Boxed Warning]

  Pediatric Population

  The incidence of serious rash associated with hospitalization and discontinuation of SUBVENITE in a prospectively followed cohort of pediatric patients (aged 2 to 17 years) is approximately 0.3% to 0.8%. One rash-related death was reported in a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking SUBVENITE as adjunctive therapy. Additionally, there have been rare cases of toxic epidermal necrolysis (TEN) with and without permanent sequelae and/or death in U.S. and foreign postmarketing experience.

  There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used valproate concomitantly for epilepsy, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not taking valproate.

  Adult Population

  Serious rash associated with hospitalization and discontinuation of SUBVENITE occurred in 0.3% (11 of 3,348) of adult patients who received SUBVENITE in premarketing clinical trials of epilepsy. In the bipolar and other mood disorders clinical trials, the rate of serious rash was 0.08% (1 of 1,233) of adult patients who received SUBVENITE as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received SUBVENITE as adjunctive therapy. No fatalities occurred among these individuals. 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.

  Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and those associated with multiorgan hypersensitivity

  [see Warnings and Precautions ]

  .

  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. Specifically, of 584 patients administered SUBVENITE with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered SUBVENITE 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.

  Patients with Genetic Variant Human Leukocyte Antigen (HLA)-B*1502 Allele

  Retrospective case-control studies in patients of certain Asian ancestry (e.g., 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.

  )
  
  

Dosage and Administration (

SUBVENITE is indicated for: 

• partial-onset seizures.
• primary generalized tonic-clonic (PGTC) seizures.
• generalized seizures of Lennox-Gastaut syndrome. (
  
  
  1.1 Epilepsy

  Adjunctive Therapy

  SUBVENITE is indicated as adjunctive therapy for the following seizure types in patients aged 2 years and older:

  • partial-onset seizures.
  • primary generalized tonic-clonic (PGTC) seizures.
  • generalized seizures of Lennox-Gastaut syndrome.

  Monotherapy

  SUBVENITE is indicated for conversion to monotherapy in adults (aged 16 years and older) with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED).

  Safety and effectiveness of SUBVENITE have not been established (1) as initial monotherapy; (2) for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate; or (3) for simultaneous conversion to monotherapy from 2 or more concomitant AEDs.
  )
  

Limitations of Use: Treatment of acute manic or mixed episodes is not recommended. Effectiveness of SUBVENITE in the acute treatment of mood episodes has not been established.

• Dosing is based on concomitant medications, indication, and patient age. (
  
  
  2.1 General Dosing Considerations

  Rash

  There are suggestions that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of SUBVENITE with valproate, (2) exceeding the recommended initial dose of SUBVENITE, or (3) exceeding the recommended dose escalation for SUBVENITE. However, cases have occurred in the absence of these factors

  [see Boxed Warning].

  Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for SUBVENITE is exceeded and in patients with a history of allergy or rash to other AEDs.

  SUBVENITE Starter Kits provide SUBVENITE at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications, for patients with epilepsy (older than 12 years) and bipolar I disorder (adults) and are intended to help reduce the potential for rash. The use of SUBVENITE Starter Kits is recommended for appropriate patients who are starting or restarting SUBVENITE

  [see How Supplied/Storage and Handling ]

  .

  It is recommended that SUBVENITE not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued SUBVENITE, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications

  [see Clinical Pharmacology ].

  SUBVENITE Added to Drugs Known to Induce or Inhibit Glucuronidation

  Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. 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. Dosing of SUBVENITE should be based on therapeutic response

  [see Clinical Pharmacology ].

  Women Taking Estrogen-Containing Oral Contraceptives

  Starting SUBVENITE in Women Taking Estrogen-Containing Oral Contraceptives:

  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine

  ,

  no adjustments to the recommended dose-escalation guidelines for SUBVENITE should be necessary solely based on the use of estrogen-containing oral contraceptives

  [see Clinical Pharmacology ]

  . 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.

  Adjustments to the Maintenance Dose of SUBVENITE in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives:

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose of SUBVENITE will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level

  [see Drug Interactions (7), Clinical Pharmacology ]

  .

  (2) Starting Estrogen-Containing Oral Contraceptives:

  In women taking a stable dose of SUBVENITE and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level

  [see Drug Interactions (7), Clinical Pharmacology ]

  . 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. For women taking SUBVENITE in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, no adjustment to the dose of SUBVENITE should be necessary

  [see Drug Interactions , Clinical Pharmacology ]

  .

  (3) Stopping Estrogen-Containing Oral Contraceptives:

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose of SUBVENITE will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level

  [see Drug Interactions (7), Clinical Pharmacology ]

  . The decrease in dose of SUBVENITE should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise

  [see Clinical Pharmacology ]

  . In women taking SUBVENITE in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, no adjustment to the dose of SUBVENITE should be necessary

  [see Drug Interactions (7), Clinical Pharmacology ]

  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. Therefore, close clinical monitoring on effectiveness of SUBVENITE with dose adjustment may be necessary

  [see Warnings and Precautions ]

  . 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). In patients already taking maintenance doses of SUBVENITE and not taking glucuronidation inducers, the dose of SUBVENITE may need to be increased if atazanavir/ritonavir is added or decreased if atazanavir/ritonavir is discontinued

  [see Clinical Pharmacology ]

  .

  Patients with Hepatic Impairment

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment

  ,

  the following general recommendations can be made

  [see Use in Specific Populations (8.6), Clinical Pharmacology ]

  . 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.

  Patients with Renal Impairment

  Initial doses of SUBVENITE should be based on patients' concomitant medications (see Tables 1 to 3 and 5); reduced maintenance doses may be effective for patients with significant renal impairment

  [see Use in Specific Populations , Clinical Pharmacology ].

  Few patients with severe renal impairment have been evaluated during chronic treatment with SUBVENITE. 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.

  If a decision is made to discontinue therapy with SUBVENITE, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal

  [see Warnings and Precautions ].

  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 SUBVENITE. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of SUBVENITE. Discontinuation of SUBVENITE should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal

  [see Warnings and Precautions ]

  .
  ,
  
  
  2.2 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). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.

  Patients Older than 12 Years

  Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for SUBVENITE in Patients Older than 12 Years with Epilepsy

  	In Patients TAKING Valproatea	In Patients NOT TAKING Carbamazepine , Phenytoin , Phenobarbital , Primidoneb , or Valproatea	In Patients TAKING Carbamazepine , Phenytoin , Phenobarbital , or Primidoneb and NOT TAKING Valproatea
  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)

  ^aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine

  [see Drug Interactions , Clinical Pharmacology ].

  
  
  ^bDrugs 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. Dosing recommendations for estrogen-containing products, including oral contraceptives, and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations

  [see Dosage and Administration ]

  . Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with AEDs that induce glucuronidation and increase clearance

  [see Dosage and Administration , Drug Interactions ( 7), Clinical Pharmacology ].

  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. Escalation Regimen for SUBVENITE in Patients Aged 2 to 12 Years with Epilepsy

  	In Patients TAKING Valproatea	In Patients NOT TAKING Carbamazepine , Phenytoin , Phenobarbital , Primidoneb , or Valproatea	In Patients TAKING Carbamazepine , Phenytoin , Phenobarbital , or Primidoneb and NOT TAKING Valproatea
  Weeks 1 and 2	0 . 15 mg / kg / day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)	0 . 3 mg / kg / day in 1 or 2 divided doses, rounded down to the nearest whole tablet	0 . 6 mg / kg / day in 2 divided doses, rounded down to the nearest whole tablet
  Weeks 3 and 4	0 . 3 mg / kg / day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)	0 . 6 mg / kg / day in 2 divided doses, rounded down to the nearest whole tablet	1 . 2 mg / kg / day in 2 divided doses, rounded down to the nearest whole tablet
  Week 5 onward to maintenance	The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.	The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.	The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.
  Usual maintenance dose	1 to 5 mg / kg / day (maximum 200 mg/day in 1 or 2 divided doses) 1 to 3 mg / kg / day with valproate alone	4 . 5 to 7 . 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.

  Note: Only whole tablets should be used for dosing.

  
  
  ^aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine

  [see Drug Interactions , Clinical Pharmacology ].

  
  
  ^bDrugs 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. Dosing recommendations for estrogen-containing products, including oral contraceptives, and the protease inhibitor atazanavir/ritonavir, can be found in General Dosing Considerations

  [see Dosage and Administration ].

  Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with AEDs that induce glucuronidation and increase clearance

  [see Dosage and Administration , Drug Interactions ( 7), Clinical Pharmacology ].

  Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) with Epilepsy

  If the patient’s weight is		Give this daily dose , using the most appropriate combination of lamotrigine 2 - and 5 - mg tablets
  Greater than	And less than	Weeks 1 and 2	Weeks 3 and 4
  6.7 kg	14 kg	2 mg every other day	2 mg every day
  14.1 kg	27 kg	2 mg every day	4 mg every day
  27.1 kg	34 kg	4 mg every day	8 mg every day
  34.1 kg	40 kg	5 mg every day	10 mg every day

  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 SUBVENITE was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone

  without valproate

  , maintenance doses of adjunctive SUBVENITE as high as 700 mg/day have been used. In patients receiving

  valproate alone

  , maintenance doses of adjunctive SUBVENITE as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 to 4 has not been established in controlled trials.
  ,
  
  
  2.3 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 SUBVENITE.

  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 4.

  Table 4. 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.
  ,
  
  
  2.4 Bipolar Disorder

  The goal of maintenance treatment with SUBVENITE is to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy

  [see Indications and Usage ]

  .

  Patients taking SUBVENITE 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). In the clinical trials, doses up to 400 mg/day as monotherapy were evaluated; however, no additional benefit was seen at 400 mg/day compared with 200 mg/day

  [see Clinical Studies ]

  . 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 5. 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 6). 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 6). 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. In particular, the introduction of valproate requires reduction in the dose of SUBVENITE

  [see Drug Interactions , Clinical Pharmacology ].

  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 5. Escalation Regimen for SUBVENITE in Adults with Bipolar Disorder

  	In Patients TAKING Valproatea	In Patients NOT TAKING Carbamazepine , Phenytoin , Phenobarbital , Primidoneb , or Valproatea	In Patients TAKING Carbamazepine , Phenytoin , Phenobarbital , or Primidoneb and NOT TAKING Valproatea
  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

  ^aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine

  [see Drug Interactions , Clinical Pharmacology ].

  
  
  ^bDrugs 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. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations

  [see Dosage and Administration ]

  .

  Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with AEDs that induce glucuronidation and increase clearance

  [see Dosage and Administration , Drug Interactions (7), Clinical Pharmacology ]

  Table 6. Dosage Adjustments to SUBVENITE in Adults with Bipolar Disorder following Discontinuation of Psychotropic Medications

  	Discontinuation of Psychotropic Drugs ( excluding Valproatea , Carbamazepine , Phenytoin , Phenobarbital , or Primidoneb )	After Discontinuation of Valproatea	After Discontinuation of Carbamazepine , Phenytoin , Phenobarbital , or Primidoneb
  		Current Dose of SUBVENITE ( mg / day ) 100	Current Dose of SUBVENITE ( mg / day ) 400
  Week 1	Maintain current dose of SUBVENITE	150	400
  Week 2	Maintain current dose of SUBVENITE	200	300
  Week 3 onward	Maintain current dose of SUBVENITE	200	200

  ^aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine

  [see Drug Interactions , Clinical Pharmacology ].

  
  
  ^bDrugs 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. Dosing recommendations for oral contraceptives and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations

  [see Dosage and Administration ]

  .

  Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with AEDs that induce glucuronidation and increase clearance

  [see Dosage and Administration , Drug Interactions (7), Clinical Pharmacology ]
  )
  
• To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded. SUBVENITE Starter Kits are available for the first 5 weeks of treatment. (
  
  
  2.1 General Dosing Considerations

  Rash

  There are suggestions that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of SUBVENITE with valproate, (2) exceeding the recommended initial dose of SUBVENITE, or (3) exceeding the recommended dose escalation for SUBVENITE. However, cases have occurred in the absence of these factors

  [see Boxed Warning].

  Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for SUBVENITE is exceeded and in patients with a history of allergy or rash to other AEDs.

  SUBVENITE Starter Kits provide SUBVENITE at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications, for patients with epilepsy (older than 12 years) and bipolar I disorder (adults) and are intended to help reduce the potential for rash. The use of SUBVENITE Starter Kits is recommended for appropriate patients who are starting or restarting SUBVENITE

  [see How Supplied/Storage and Handling ]

  .

  It is recommended that SUBVENITE not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued SUBVENITE, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications

  [see Clinical Pharmacology ].

  SUBVENITE Added to Drugs Known to Induce or Inhibit Glucuronidation

  Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. 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. Dosing of SUBVENITE should be based on therapeutic response

  [see Clinical Pharmacology ].

  Women Taking Estrogen-Containing Oral Contraceptives

  Starting SUBVENITE in Women Taking Estrogen-Containing Oral Contraceptives:

  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine

  ,

  no adjustments to the recommended dose-escalation guidelines for SUBVENITE should be necessary solely based on the use of estrogen-containing oral contraceptives

  [see Clinical Pharmacology ]

  . 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.

  Adjustments to the Maintenance Dose of SUBVENITE in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives:

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose of SUBVENITE will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level

  [see Drug Interactions (7), Clinical Pharmacology ]

  .

  (2) Starting Estrogen-Containing Oral Contraceptives:

  In women taking a stable dose of SUBVENITE and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level

  [see Drug Interactions (7), Clinical Pharmacology ]

  . 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. For women taking SUBVENITE in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, no adjustment to the dose of SUBVENITE should be necessary

  [see Drug Interactions , Clinical Pharmacology ]

  .

  (3) Stopping Estrogen-Containing Oral Contraceptives:

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose of SUBVENITE will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level

  [see Drug Interactions (7), Clinical Pharmacology ]

  . The decrease in dose of SUBVENITE should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise

  [see Clinical Pharmacology ]

  . In women taking SUBVENITE in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, no adjustment to the dose of SUBVENITE should be necessary

  [see Drug Interactions (7), Clinical Pharmacology ]

  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. Therefore, close clinical monitoring on effectiveness of SUBVENITE with dose adjustment may be necessary

  [see Warnings and Precautions ]

  . 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). In patients already taking maintenance doses of SUBVENITE and not taking glucuronidation inducers, the dose of SUBVENITE may need to be increased if atazanavir/ritonavir is added or decreased if atazanavir/ritonavir is discontinued

  [see Clinical Pharmacology ]

  .

  Patients with Hepatic Impairment

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment

  ,

  the following general recommendations can be made

  [see Use in Specific Populations (8.6), Clinical Pharmacology ]

  . 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.

  Patients with Renal Impairment

  Initial doses of SUBVENITE should be based on patients' concomitant medications (see Tables 1 to 3 and 5); reduced maintenance doses may be effective for patients with significant renal impairment

  [see Use in Specific Populations , Clinical Pharmacology ].

  Few patients with severe renal impairment have been evaluated during chronic treatment with SUBVENITE. 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.

  If a decision is made to discontinue therapy with SUBVENITE, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal

  [see Warnings and Precautions ].

  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 SUBVENITE. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of SUBVENITE. Discontinuation of SUBVENITE should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal

  [see Warnings and Precautions ]

  .
  ,
  
  
  16 HOW SUPPLIED/STORAGE AND HANDLING

  SUBVENITE (lamotrigine) tablets, USP 25 mg

  
  
  White to off white, round shape, flat face beveled edge, uncoated tablets debossed with “2L” on one side and break line on other side.
  
  Bottle of 100                NDC-69102-301-01
  
  Bottle of 6600              NDC-69102-301-02

  SUBVENITE (lamotrigine) tablets, USP 100 mg

  
  
  White to off white, round shape, flat face beveled edge, uncoated tablets debossed with “10LA” on one side and break line on other side.
  
  Bottle of 100                NDC-69102-319-01
  
  Bottle of 2500              NDC-69102-319-02

  SUBVENITE (lamotrigine) tablets, USP 150 mg

  
  
  White to off white, round shape, flat face beveled edge, uncoated tablets debossed with “15LA” on one side and break line on other side.
  
  Bottle of 100                NDC-69102-150-06

  SUBVENITE (lamotrigine) tablets, USP 200 mg

  
  
  White to off white, round shape, flat face beveled edge, uncoated tablets debossed with “20LA” on one side and break line on other side.
  
  Bottle of 100                NDC-69102-320-01

  SUBVENITE (lamotrigine) tablets, USP Starter Kit for Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate (Orange Kit).

  25-mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with “2L” on one side and break line on other side.

  100-mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with “10LA” on one side and break line on other side.

  Blister pack of 42, 25 mg tablets
  
  and 7, 100 mg tablets         NDC-69102-300-01

  SUBVENITE (lamotrigine) tablets, USP Starter Kit for Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone and Not Taking Valproate (Green Kit).

  25-mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with “2L” on one side and break line on other side.

  100-mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with “10LA” on one side and break line on other side.
  
  Blister pack of 84, 25 mg tablets

  and 14, 100 mg tablets       NDC-69102-312-01

  SUBVENITE (lamotrigine) tablets, USP Starter Kit for Patients Taking Valproate (Blue Kit).

  25-mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with “2L” on one side and break line on other side.

  Blister pack of 35 tablets     NDC-69102-306-01

  Storage

  Store at 20° to 25° C (68°  to 77° F); excursions permitted to 15° to 30° C (59° to 86° F) [See USP Controlled Room Temperature].
  )
  
• Do not restart SUBVENITE in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. (
  
  
  2.1 General Dosing Considerations

  Rash

  There are suggestions that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of SUBVENITE with valproate, (2) exceeding the recommended initial dose of SUBVENITE, or (3) exceeding the recommended dose escalation for SUBVENITE. However, cases have occurred in the absence of these factors

  [see Boxed Warning].

  Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for SUBVENITE is exceeded and in patients with a history of allergy or rash to other AEDs.

  SUBVENITE Starter Kits provide SUBVENITE at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications, for patients with epilepsy (older than 12 years) and bipolar I disorder (adults) and are intended to help reduce the potential for rash. The use of SUBVENITE Starter Kits is recommended for appropriate patients who are starting or restarting SUBVENITE

  [see How Supplied/Storage and Handling ]

  .

  It is recommended that SUBVENITE not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued SUBVENITE, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications

  [see Clinical Pharmacology ].

  SUBVENITE Added to Drugs Known to Induce or Inhibit Glucuronidation

  Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. 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. Dosing of SUBVENITE should be based on therapeutic response

  [see Clinical Pharmacology ].

  Women Taking Estrogen-Containing Oral Contraceptives

  Starting SUBVENITE in Women Taking Estrogen-Containing Oral Contraceptives:

  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine

  ,

  no adjustments to the recommended dose-escalation guidelines for SUBVENITE should be necessary solely based on the use of estrogen-containing oral contraceptives

  [see Clinical Pharmacology ]

  . 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.

  Adjustments to the Maintenance Dose of SUBVENITE in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives:

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose of SUBVENITE will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level

  [see Drug Interactions (7), Clinical Pharmacology ]

  .

  (2) Starting Estrogen-Containing Oral Contraceptives:

  In women taking a stable dose of SUBVENITE and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level

  [see Drug Interactions (7), Clinical Pharmacology ]

  . 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. For women taking SUBVENITE in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, no adjustment to the dose of SUBVENITE should be necessary

  [see Drug Interactions , Clinical Pharmacology ]

  .

  (3) Stopping Estrogen-Containing Oral Contraceptives:

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose of SUBVENITE will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level

  [see Drug Interactions (7), Clinical Pharmacology ]

  . The decrease in dose of SUBVENITE should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise

  [see Clinical Pharmacology ]

  . In women taking SUBVENITE in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, no adjustment to the dose of SUBVENITE should be necessary

  [see Drug Interactions (7), Clinical Pharmacology ]

  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. Therefore, close clinical monitoring on effectiveness of SUBVENITE with dose adjustment may be necessary

  [see Warnings and Precautions ]

  . 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). In patients already taking maintenance doses of SUBVENITE and not taking glucuronidation inducers, the dose of SUBVENITE may need to be increased if atazanavir/ritonavir is added or decreased if atazanavir/ritonavir is discontinued

  [see Clinical Pharmacology ]

  .

  Patients with Hepatic Impairment

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment

  ,

  the following general recommendations can be made

  [see Use in Specific Populations (8.6), Clinical Pharmacology ]

  . 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.

  Patients with Renal Impairment

  Initial doses of SUBVENITE should be based on patients' concomitant medications (see Tables 1 to 3 and 5); reduced maintenance doses may be effective for patients with significant renal impairment

  [see Use in Specific Populations , Clinical Pharmacology ].

  Few patients with severe renal impairment have been evaluated during chronic treatment with SUBVENITE. 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.

  If a decision is made to discontinue therapy with SUBVENITE, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal

  [see Warnings and Precautions ].

  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 SUBVENITE. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of SUBVENITE. Discontinuation of SUBVENITE should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal

  [see Warnings and Precautions ]

  .
  ,
  
  5.1)
  
• Adjustments to maintenance doses will be necessary in most patients starting or stopping estrogen-containing products, including oral contraceptives. (
  
  
  2.1 General Dosing Considerations

  Rash

  There are suggestions that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of SUBVENITE with valproate, (2) exceeding the recommended initial dose of SUBVENITE, or (3) exceeding the recommended dose escalation for SUBVENITE. However, cases have occurred in the absence of these factors

  [see Boxed Warning].

  Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for SUBVENITE is exceeded and in patients with a history of allergy or rash to other AEDs.

  SUBVENITE Starter Kits provide SUBVENITE at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications, for patients with epilepsy (older than 12 years) and bipolar I disorder (adults) and are intended to help reduce the potential for rash. The use of SUBVENITE Starter Kits is recommended for appropriate patients who are starting or restarting SUBVENITE

  [see How Supplied/Storage and Handling ]

  .

  It is recommended that SUBVENITE not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued SUBVENITE, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications

  [see Clinical Pharmacology ].

  SUBVENITE Added to Drugs Known to Induce or Inhibit Glucuronidation

  Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. 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. Dosing of SUBVENITE should be based on therapeutic response

  [see Clinical Pharmacology ].

  Women Taking Estrogen-Containing Oral Contraceptives

  Starting SUBVENITE in Women Taking Estrogen-Containing Oral Contraceptives:

  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine

  ,

  no adjustments to the recommended dose-escalation guidelines for SUBVENITE should be necessary solely based on the use of estrogen-containing oral contraceptives

  [see Clinical Pharmacology ]

  . 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.

  Adjustments to the Maintenance Dose of SUBVENITE in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives:

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose of SUBVENITE will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level

  [see Drug Interactions (7), Clinical Pharmacology ]

  .

  (2) Starting Estrogen-Containing Oral Contraceptives:

  In women taking a stable dose of SUBVENITE and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level

  [see Drug Interactions (7), Clinical Pharmacology ]

  . 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. For women taking SUBVENITE in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, no adjustment to the dose of SUBVENITE should be necessary

  [see Drug Interactions , Clinical Pharmacology ]

  .

  (3) Stopping Estrogen-Containing Oral Contraceptives:

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose of SUBVENITE will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level

  [see Drug Interactions (7), Clinical Pharmacology ]

  . The decrease in dose of SUBVENITE should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise

  [see Clinical Pharmacology ]

  . In women taking SUBVENITE in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, no adjustment to the dose of SUBVENITE should be necessary

  [see Drug Interactions (7), Clinical Pharmacology ]

  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. Therefore, close clinical monitoring on effectiveness of SUBVENITE with dose adjustment may be necessary

  [see Warnings and Precautions ]

  . 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). In patients already taking maintenance doses of SUBVENITE and not taking glucuronidation inducers, the dose of SUBVENITE may need to be increased if atazanavir/ritonavir is added or decreased if atazanavir/ritonavir is discontinued

  [see Clinical Pharmacology ]

  .

  Patients with Hepatic Impairment

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment

  ,

  the following general recommendations can be made

  [see Use in Specific Populations (8.6), Clinical Pharmacology ]

  . 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.

  Patients with Renal Impairment

  Initial doses of SUBVENITE should be based on patients' concomitant medications (see Tables 1 to 3 and 5); reduced maintenance doses may be effective for patients with significant renal impairment

  [see Use in Specific Populations , Clinical Pharmacology ].

  Few patients with severe renal impairment have been evaluated during chronic treatment with SUBVENITE. 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.

  If a decision is made to discontinue therapy with SUBVENITE, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal

  [see Warnings and Precautions ].

  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 SUBVENITE. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of SUBVENITE. Discontinuation of SUBVENITE should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal

  [see Warnings and Precautions ]

  .
  ,
  
  
  5.9 Concomitant Use with Estrogen-Containing Products, Including Oral Contraceptives

  Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine [see Clinical Pharmacology (12.3)] . Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking SUBVENITE  [see Dosage and Administration ( 2.1)] . 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.
  )
  
• Discontinuation: Taper over a period of at least 2 weeks (approximately 50% dose reduction per week). (
  
  
  2.1 General Dosing Considerations

  Rash

  There are suggestions that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of SUBVENITE with valproate, (2) exceeding the recommended initial dose of SUBVENITE, or (3) exceeding the recommended dose escalation for SUBVENITE. However, cases have occurred in the absence of these factors

  [see Boxed Warning].

  Therefore, it is important that the dosing recommendations be followed closely.

  The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for SUBVENITE is exceeded and in patients with a history of allergy or rash to other AEDs.

  SUBVENITE Starter Kits provide SUBVENITE at doses consistent with the recommended titration schedule for the first 5 weeks of treatment, based upon concomitant medications, for patients with epilepsy (older than 12 years) and bipolar I disorder (adults) and are intended to help reduce the potential for rash. The use of SUBVENITE Starter Kits is recommended for appropriate patients who are starting or restarting SUBVENITE

  [see How Supplied/Storage and Handling ]

  .

  It is recommended that SUBVENITE not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued SUBVENITE, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications

  [see Clinical Pharmacology ].

  SUBVENITE Added to Drugs Known to Induce or Inhibit Glucuronidation

  Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. 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. Dosing of SUBVENITE should be based on therapeutic response

  [see Clinical Pharmacology ].

  Women Taking Estrogen-Containing Oral Contraceptives

  Starting SUBVENITE in Women Taking Estrogen-Containing Oral Contraceptives:

  Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine

  ,

  no adjustments to the recommended dose-escalation guidelines for SUBVENITE should be necessary solely based on the use of estrogen-containing oral contraceptives

  [see Clinical Pharmacology ]

  . 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.

  Adjustments to the Maintenance Dose of SUBVENITE in Women Taking Estrogen-Containing Oral Contraceptives:

  (1) Taking Estrogen-Containing Oral Contraceptives:

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose of SUBVENITE will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent lamotrigine plasma level

  [see Drug Interactions (7), Clinical Pharmacology ]

  .

  (2) Starting Estrogen-Containing Oral Contraceptives:

  In women taking a stable dose of SUBVENITE and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent lamotrigine plasma level

  [see Drug Interactions (7), Clinical Pharmacology ]

  . 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. For women taking SUBVENITE in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, no adjustment to the dose of SUBVENITE should be necessary

  [see Drug Interactions , Clinical Pharmacology ]

  .

  (3) Stopping Estrogen-Containing Oral Contraceptives:

  In women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, the maintenance dose of SUBVENITE will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level

  [see Drug Interactions (7), Clinical Pharmacology ]

  . The decrease in dose of SUBVENITE should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise

  [see Clinical Pharmacology ]

  . In women taking SUBVENITE in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation, no adjustment to the dose of SUBVENITE should be necessary

  [see Drug Interactions (7), Clinical Pharmacology ]

  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. Therefore, close clinical monitoring on effectiveness of SUBVENITE with dose adjustment may be necessary

  [see Warnings and Precautions ]

  . 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). In patients already taking maintenance doses of SUBVENITE and not taking glucuronidation inducers, the dose of SUBVENITE may need to be increased if atazanavir/ritonavir is added or decreased if atazanavir/ritonavir is discontinued

  [see Clinical Pharmacology ]

  .

  Patients with Hepatic Impairment

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment

  ,

  the following general recommendations can be made

  [see Use in Specific Populations (8.6), Clinical Pharmacology ]

  . 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.

  Patients with Renal Impairment

  Initial doses of SUBVENITE should be based on patients' concomitant medications (see Tables 1 to 3 and 5); reduced maintenance doses may be effective for patients with significant renal impairment

  [see Use in Specific Populations , Clinical Pharmacology ].

  Few patients with severe renal impairment have been evaluated during chronic treatment with SUBVENITE. 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.

  If a decision is made to discontinue therapy with SUBVENITE, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal

  [see Warnings and Precautions ].

  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 SUBVENITE. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of SUBVENITE. Discontinuation of SUBVENITE should involve a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) unless safety concerns require a more rapid withdrawal

  [see Warnings and Precautions ]

  .
  ,
  
  5.10)
  

• Adjunctive therapy—See Table 1 for patients older than 12 years and Tables 2 and 3 for patients aged 2 to 12 years. (
  
  
  2.2 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). A weight-based dosing guide for patients aged 2 to 12 years on concomitant valproate is provided in Table 3.

  Patients Older than 12 Years

  Recommended dosing guidelines are summarized in Table 1.

  Table 1. Escalation Regimen for SUBVENITE in Patients Older than 12 Years with Epilepsy

  	In Patients TAKING Valproatea	In Patients NOT TAKING Carbamazepine , Phenytoin , Phenobarbital , Primidoneb , or Valproatea	In Patients TAKING Carbamazepine , Phenytoin , Phenobarbital , or Primidoneb and NOT TAKING Valproatea
  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)

  ^aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine

  [see Drug Interactions , Clinical Pharmacology ].

  
  
  ^bDrugs 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. Dosing recommendations for estrogen-containing products, including oral contraceptives, and the protease inhibitor atazanavir/ritonavir can be found in General Dosing Considerations

  [see Dosage and Administration ]

  . Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with AEDs that induce glucuronidation and increase clearance

  [see Dosage and Administration , Drug Interactions ( 7), Clinical Pharmacology ].

  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. Escalation Regimen for SUBVENITE in Patients Aged 2 to 12 Years with Epilepsy

  	In Patients TAKING Valproatea	In Patients NOT TAKING Carbamazepine , Phenytoin , Phenobarbital , Primidoneb , or Valproatea	In Patients TAKING Carbamazepine , Phenytoin , Phenobarbital , or Primidoneb and NOT TAKING Valproatea
  Weeks 1 and 2	0 . 15 mg / kg / day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)	0 . 3 mg / kg / day in 1 or 2 divided doses, rounded down to the nearest whole tablet	0 . 6 mg / kg / day in 2 divided doses, rounded down to the nearest whole tablet
  Weeks 3 and 4	0 . 3 mg / kg / day in 1 or 2 divided doses, rounded down to the nearest whole tablet (see Table 3 for weight-based dosing guide)	0 . 6 mg / kg / day in 2 divided doses, rounded down to the nearest whole tablet	1 . 2 mg / kg / day in 2 divided doses, rounded down to the nearest whole tablet
  Week 5 onward to maintenance	The dose should be increased every 1 to 2 weeks as follows: calculate 0.3 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.	The dose should be increased every 1 to 2 weeks as follows: calculate 0.6 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.	The dose should be increased every 1 to 2 weeks as follows: calculate 1.2 mg/kg/day, round this amount down to the nearest whole tablet, and add this amount to the previously administered daily dose.
  Usual maintenance dose	1 to 5 mg / kg / day (maximum 200 mg/day in 1 or 2 divided doses) 1 to 3 mg / kg / day with valproate alone	4 . 5 to 7 . 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.

  Note: Only whole tablets should be used for dosing.

  
  
  ^aValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine

  [see Drug Interactions , Clinical Pharmacology ].

  
  
  ^bDrugs 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. Dosing recommendations for estrogen-containing products, including oral contraceptives, and the protease inhibitor atazanavir/ritonavir, can be found in General Dosing Considerations

  [see Dosage and Administration ].

  Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with AEDs that induce glucuronidation and increase clearance

  [see Dosage and Administration , Drug Interactions ( 7), Clinical Pharmacology ].

  Table 3. The Initial Weight-Based Dosing Guide for Patients Aged 2 to 12 Years Taking Valproate (Weeks 1 to 4) with Epilepsy

  If the patient’s weight is		Give this daily dose , using the most appropriate combination of lamotrigine 2 - and 5 - mg tablets
  Greater than	And less than	Weeks 1 and 2	Weeks 3 and 4
  6.7 kg	14 kg	2 mg every other day	2 mg every day
  14.1 kg	27 kg	2 mg every day	4 mg every day
  27.1 kg	34 kg	4 mg every day	8 mg every day
  34.1 kg	40 kg	5 mg every day	10 mg every day

  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 SUBVENITE was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone

  without valproate

  , maintenance doses of adjunctive SUBVENITE as high as 700 mg/day have been used. In patients receiving

  valproate alone

  , maintenance doses of adjunctive SUBVENITE as high as 200 mg/day have been used. The advantage of using doses above those recommended in Tables 1 to 4 has not been established in controlled trials.
  )
  
• Conversion to monotherapy—See Table 4. (
  
  
  2.3 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 SUBVENITE.

  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 4.

  Table 4. 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.
  )
  

• Tablets: 25 mg, 100 mg, 150 mg, and 200 mg; scored. (
  
  
  3.1 Tablets

  25 mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with "2L" on one side and break line on other side.

  100 mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with "10LA" on one side and break line on other side.

  150 mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with "15LA" on one side and break line on other side.

  200 mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with "20LA" on one side and break line on other side.
  ,
  
  
  16 HOW SUPPLIED/STORAGE AND HANDLING

  SUBVENITE (lamotrigine) tablets, USP 25 mg

  
  
  White to off white, round shape, flat face beveled edge, uncoated tablets debossed with “2L” on one side and break line on other side.
  
  Bottle of 100                NDC-69102-301-01
  
  Bottle of 6600              NDC-69102-301-02

  SUBVENITE (lamotrigine) tablets, USP 100 mg

  
  
  White to off white, round shape, flat face beveled edge, uncoated tablets debossed with “10LA” on one side and break line on other side.
  
  Bottle of 100                NDC-69102-319-01
  
  Bottle of 2500              NDC-69102-319-02

  SUBVENITE (lamotrigine) tablets, USP 150 mg

  
  
  White to off white, round shape, flat face beveled edge, uncoated tablets debossed with “15LA” on one side and break line on other side.
  
  Bottle of 100                NDC-69102-150-06

  SUBVENITE (lamotrigine) tablets, USP 200 mg

  
  
  White to off white, round shape, flat face beveled edge, uncoated tablets debossed with “20LA” on one side and break line on other side.
  
  Bottle of 100                NDC-69102-320-01

  SUBVENITE (lamotrigine) tablets, USP Starter Kit for Patients Not Taking Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate (Orange Kit).

  25-mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with “2L” on one side and break line on other side.

  100-mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with “10LA” on one side and break line on other side.

  Blister pack of 42, 25 mg tablets
  
  and 7, 100 mg tablets         NDC-69102-300-01

  SUBVENITE (lamotrigine) tablets, USP Starter Kit for Patients Taking Carbamazepine, Phenytoin, Phenobarbital, or Primidone and Not Taking Valproate (Green Kit).

  25-mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with “2L” on one side and break line on other side.

  100-mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with “10LA” on one side and break line on other side.
  
  Blister pack of 84, 25 mg tablets

  and 14, 100 mg tablets       NDC-69102-312-01

  SUBVENITE (lamotrigine) tablets, USP Starter Kit for Patients Taking Valproate (Blue Kit).

  25-mg, white to off white, round shape, flat face beveled edge, uncoated tablets debossed with “2L” on one side and break line on other side.

  Blister pack of 35 tablets     NDC-69102-306-01

  Storage

  Store at 20° to 25° C (68°  to 77° F); excursions permitted to 15° to 30° C (59° to 86° F) [See USP Controlled Room Temperature].
  )
  

• Pregnancy: Based on animal data may cause fetal harm. (
  
  
  8.1 Pregnancy

  Pregnancy Exposure Registry

  There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including SUBVENITE, during pregnancy. Encourage women who are taking SUBVENITE during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.

  Risk Summary

  Data from several prospective pregnancy exposure registries and epidemiological studies of pregnant women have not detected an increased frequency of major congenital malformations or a consistent pattern of malformations among women exposed to lamotrigine compared with the general population

  (see Data)

  . The majority of SUBVENITE pregnancy exposure data are from women with epilepsy. In animal studies, administration of lamotrigine during pregnancy resulted in developmental toxicity (increased mortality, decreased body weight, increased structural variation, neurobehavioral abnormalities) at doses lower than those administered clinically.

  Lamotrigine decreased fetal folate concentrations in rats, an effect known to be associated with adverse pregnancy outcomes in animals and humans

  (see Data)

  .

  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

  Clinical Considerations

  Disease-associated Maternal and/or Embryofetal Risk

  Epilepsy, with or without exposure to antiepileptic drugs, has been associated with several adverse outcomes during pregnancy, including preeclampsia, preterm labor, antepartum and postpartum hemorrhage, placental abruption, poor fetal growth, prematurity, fetal death, and maternal mortality. The risk of maternal or fetal injury may be greatest for patients with untreated or poorly controlled convulsive seizures. Women with epilepsy who become pregnant should not abruptly discontinue antiepileptic drugs, including SUBVENITE, due to the risk of status epilepticus or severe seizures, which may be life-threatening [see Warnings and Precautions (5.10)].

  Dose Adjustments During Pregnancy and the Postpartum Period

  As with other AEDs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-pregnancy concentrations after delivery. Dose adjustments may be necessary to maintain clinical response.

  Data

  Human Data

  : Data from several international pregnancy registries have not shown an increased risk for malformations overall. The International Lamotrigine Pregnancy Registry reported major congenital malformations in 2.2% (95% CI: 1.6%, 3.1%) of 1,558 infants exposed to lamotrigine monotherapy in the first trimester of pregnancy. The NAAED Pregnancy Registry reported major congenital malformations among 2.0% of 1,562 infants exposed to lamotrigine monotherapy in the first trimester. EURAP, a large international pregnancy registry focused outside of North America, reported major birth defects in 2.9% (95% CI: 2.3%, 3.7%) of 2,514 exposures to lamotrigine monotherapy in the first trimester. The frequency of major congenital malformations was similar to estimates from the general population.

  The NAAED Pregnancy Registry observed an increased risk of isolated oral clefts: among 2,200 infants exposed to lamotrigine early in pregnancy, the risk of oral clefts was 3.2 per 1,000 (95% CI: 1.4, 6.3), a 3-fold increased risk versus unexposed healthy controls. This finding has not been observed in other large international pregnancy registries. Furthermore, a case-control study based on 21 congenital anomaly registries covering over 10 million births in Europe reported an adjusted odds ratio for isolated oral clefts with lamotrigine exposure of 1.45 (95% CI: 0.8, 2.63).

  Several meta-analyses have not reported an increased risk of major congenital malformations following lamotrigine exposure in pregnancy compared with healthy and disease-matched controls. No patterns of specific malformation types were observed.

  The same meta-analyses evaluated the risk of additional maternal and infant outcomes including fetal death, stillbirth, preterm birth, small for gestational age, and neurodevelopmental delay. Although there are no data suggesting an increased risk of these outcomes with lamotrigine monotherapy exposure, differences in outcome definition, ascertainment methods, and comparator groups limit the conclusions that can be drawn.

  Animal Data:

  When lamotrigine was administered to pregnant mice, rats, or rabbits during the period of organogenesis (oral doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal body weight and increased incidences of fetal skeletal variations were seen in mice and rats at doses that were also maternally toxic. The no-effect doses for embryofetal developmental toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and rabbits) or less than (rats) the human dose of 400 mg/day on a body surface area (mg/m²) basis.

  In a study in which pregnant rats were administered lamotrigine (oral doses of 0, 5, or 25 mg/kg) during the period of organogenesis and offspring were evaluated postnatally, neurobehavioral abnormalities were observed in exposed offspring at both doses. The lowest effect dose for developmental neurotoxicity in rats is less than the human dose of 400 mg/day on a mg/m²basis. Maternal toxicity was observed at the higher dose tested.

  When pregnant rats were administered lamotrigine (oral doses of 0, 5, 10, or 20 mg/kg) during the latter part of gestation and throughout lactation, increased offspring mortality (including stillbirths) was seen at all doses. The lowest effect dose for pre- and post-natal developmental toxicity in rats is less than the human dose of 400 mg/day on a mg/m²basis. Maternal toxicity was observed at the 2 highest doses tested.

  When administered to pregnant rats, lamotrigine decreased fetal folate concentrations at doses greater than or equal to 5 mg/kg/day, which is less than the human dose of 400 mg/day on a mg/m²basis.
  )
  
• Hepatic impairment: Dosage adjustments required in patients with moderate and severe liver impairment. (
  
  2.1,
  
  
  8.6 Hepatic Impairment

  Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 subjects with mild, moderate, and severe liver impairment, the following general recommendations can be made

  [see Clinical Pharmacology ( 12.3)]

  . 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

  [see Dosage and Administration ].
  )
  
• Renal impairment: Reduced maintenance doses may be effective for patients with significant renal impairment. (
  
  2.1,
  
  8.7)