GenRx Lamotrigine

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GenRx Lamotrigine uses


1 INDICATIONS AND USAGE

GenRx Lamotrigine is indicated for:

Epilepsy-adjunctive therapy in patients aged 2 years and older:

  • Partial-onset seizures.
  • primary generalized tonic-clonic seizures.
  • generalized seizures of Lennox-Gastaut syndrome.
Epilepsy-monotherapy in patients aged 16 years and older:

Conversion to monotherapy in patients with partial-onset seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single AED. (1.1)

Bipolar disorder:

Maintenance treatment of bipolar I disorder to delay the time to occurrence of mood episodes in patients treated for acute mood episodes with standard therapy. (1.2)

Limitations of Use:

Treatment of acute manic or mixed episodes is not recommended. Effectiveness of GenRx Lamotrigine in the acute treatment of mood episodes has not been established.

1.1 Epilepsy

Adjunctive Therapy

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

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

GenRx Lamotrigine 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 GenRx Lamotrigine 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.

1.2 Bipolar Disorder

GenRx Lamotrigine is indicated for the maintenance treatment of bipolar I disorder 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 CLINICAL STUDIES (14.1)].

Limitations of Use

Treatment of acute manic or mixed episodes is not recommended. Effectiveness of GenRx Lamotrigine in the acute treatment of mood episodes has not been established.

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2 DOSAGE AND ADMINISTRATION

  • Dosing is based on concomitant medications, indication, and patient age.
  • To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations should not be exceeded.
  • Do not restart GenRx Lamotrigine in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. (2.1, 5.1)
  • Adjustments to maintenance doses will be necessary in most patients starting or stopping estrogen-containing oral contraceptives. (2.1, 5.7)
  • Discontinuation: Taper over a period of at least 2 weeks (approximately 50% dose reduction per week). (2.1,5.8)
Epilepsy:

  • 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)
  • Conversion to monotherapy-See Table 4. (2.3)
Bipolar disorder: See Tables 5 and 6. (2.4)

2.1 General Dosing Considerations

Rash

There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of GenRx Lamotrigine with valproate, (2) exceeding the recommended initial dose of GenRx Lamotrigine, or (3) exceeding the recommended dose escalation for GenRx Lamotrigine. 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 GenRx Lamotrigine is exceeded and in patients with a history of allergy or rash to other AEDs.

It is recommended that GenRx Lamotrigine not be restarted in patients who discontinued due to rash associated with prior treatment with GenRx Lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued GenRx Lamotrigine, 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 GenRx 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 GenRx Lamotrigine is affected by other concomitant medications [see CLINICAL PHARMACOLOGY (12.3)].

GenRx Lamotrigine Added to Drugs Known to Induce or Inhibit Glucuronidation

Because GenRx Lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of GenRx Lamotrigine. Drugs that induce glucuronidation include carbamazepine, phenytoin, phenobarbital, primidone, rifampin, estrogen-containing oral contraceptives, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir. Valproate inhibits glucuronidation. For dosing considerations for GenRx Lamotrigine in patients on estrogen-containing contraceptives and atazanavir/ritonavir, see below and Table 13. For dosing considerations for GenRx Lamotrigine in patients on other drugs known to induce or inhibit glucuronidation, see Tables 1, 2, 5-6, and 13.

Target Plasma Levels for Patients with Epilepsy or Bipolar Disorder

A therapeutic plasma concentration range has not been established for GenRx Lamotrigine. Dosing of GenRx Lamotrigine should be based on therapeutic response [see CLINICAL PHARMACOLOGY (12.3)].

Women Taking Estrogen-Containing Oral Contraceptives

Starting GenRx Lamotrigine in Women Taking Estrogen-Containing Oral Contraceptives

Although estrogen-containing oral contraceptives have been shown to increase the clearance of GenRx Lamotrigine [see CLINICAL PHARMACOLOGY (12.3)], no adjustments to the recommended dose-escalation guidelines for GenRx Lamotrigine should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with GenRx Lamotrigine based on the concomitant AED or other concomitant medications. See below for adjustments to maintenance doses of GenRx Lamotrigine in women taking estrogen-containing oral contraceptives.

Adjustments to the Maintenance Dose of GenRx Lamotrigine 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 GenRx Lamotrigine glucuronidation [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)], the maintenance dose of GenRx Lamotrigine will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose to maintain a consistent GenRx Lamotrigine plasma level.

(2) Starting Estrogen-Containing Oral Contraceptives

In women taking a stable dose of GenRx Lamotrigine and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce GenRx Lamotrigine glucuronidation [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold to maintain a consistent GenRx Lamotrigine plasma level. 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 unless GenRx Lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in GenRx 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 GenRx Lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to GenRx Lamotrigine 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 GenRx Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce GenRx Lamotrigine glucuronidation [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)], no adjustment to the dose of GenRx Lamotrigine should be necessary.

(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 GenRx Lamotrigine glucuronidation [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)], the maintenance dose of GenRx Lamotrigine will in most cases need to be decreased by as much as 50% in order to maintain a consistent GenRx Lamotrigine plasma level. The decrease in dose of GenRx Lamotrigine should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or GenRx Lamotrigine plasma levels indicate otherwise [see CLINICAL PHARMACOLOGY (12.3)]. In women taking GenRx Lamotrigine in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce GenRx Lamotrigine glucuronidation [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)], no adjustment to the dose of GenRx Lamotrigine should be necessary.

Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy

The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of GenRx Lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of GenRx Lamotrigine up to 2-fold, and the progestin-only pills had no effect on GenRx Lamotrigine plasma levels. Therefore, adjustments to the dosage of GenRx Lamotrigine in the presence of progestogens alone will likely not be needed.

Patients Taking Atazanavir/Ritonavir

While atazanavir/ritonavir does reduce the GenRx Lamotrigine plasma concentration, no adjustments to the recommended dose-escalation guidelines for GenRx Lamotrigine should be necessary solely based on the use of atazanavir/ritonavir. Dose escalation should follow the recommended guidelines for initiating adjunctive therapy with GenRx Lamotrigine based on concomitant AED or other concomitant medications. In patients already taking maintenance doses of GenRx Lamotrigine and not taking glucuronidation inducers, the dose of GenRx Lamotrigine may need to be increased if atazanavir/ritonavir is added, or decreased if atazanavir/ritonavir is discontinued [see CLINICAL PHARMACOLOGY (12.3)].

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 [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)], the following general recommendations can be made. 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 GenRx Lamotrigine should be based on patients' concomitant medications ; reduced maintenance doses may be effective for patients with significant renal impairment [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with GenRx Lamotrigine. Because there is inadequate experience in this population, GenRx Lamotrigine should be used with caution in these patients.

Discontinuation Strategy

Epilepsy

For patients receiving GenRx Lamotrigine 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 GenRx Lamotrigine, 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 (5.8)].

Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce GenRx Lamotrigine glucuronidation should prolong the half-life of GenRx Lamotrigine; discontinuing valproate should shorten the half-life of GenRx 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 GenRx Lamotrigine. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of GenRx Lamotrigine. Discontinuation of GenRx Lamotrigine 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 (5.8)].

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. 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.


In Patients TAKING ValproateValproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)].

In Patients NOT TAKING Carbamazepine , Phenytoin , Phenobarbital , Primidoneb , or Valproate

In Patients TAKING Carbamazepine , Phenytoin , Phenobarbital , or Primidoneb <GenRx Lamotrigine~b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing 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 (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance.~GenRx Lamotrigine> and NOT TAKING Valproate

Weeks 1 and 2

25 mg every other day

25 mg every day

50 mg / day

Weeks 3 and 4

25 mg every day

50 mg / day

100 mg / day

(in 2 divided doses)

Week 5 onward to maintenance

Increase by 25 to 50 mg/day every 1 to 2 weeks.

Increase by 50 mg/day every 1 to 2 weeks.

Increase by 100 mg/day every 1 to 2 weeks.

Usual maintenance dose

100 to 200 mg / day with valproate alone


100 to 400 mg / day with valproate and other drugs that induce glucuronidation

(in 1 or 2 divided doses)

225 to 375 mg / day

(in 2 divided doses)

300 to 500 mg / day

(in 2 divided doses)

Patients Aged 2 to 12 Years

Recommended dosing guidelines are summarized in Table 2.

Lower starting doses and slower dose escalations than those used in clinical trials are recommended because of the suggestion that the risk of rash may be decreased by lower starting doses and slower dose escalations. Therefore, maintenance doses will take longer to reach in clinical practice than in clinical trials. It may take several weeks to months to achieve an individualized maintenance dose. Maintenance doses in patients weighing less than 30 kg, regardless of age or concomitant AED, may need to be increased as much as 50%, based on clinical response.


In Patients TAKING Valproatea

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

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

Note: Only whole tablets should be used for dosing.

*Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see DRUG INTERACTIONS (7), Pharmacokinetics (12.3)].

<GenRx Lamotrigine~b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing 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 (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance.~GenRx Lamotrigine>

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 less than 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.

If the patient’s weight is

Give this daily dose, using the most appropriate combination of Lamotrigine 5 mg tablets

Greater than

And less than

Weeks 1 and 2

Weeks 3 and 4

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 GenRx Lamotrigine was established. In patients receiving multidrug regimens employing carbamazepine, phenytoin, phenobarbital, or primidone without valproate, maintenance doses of adjunctive GenRx Lamotrigine as high as 700 mg/day have been used. In patients receiving valproate alone, maintenance doses of adjunctive GenRx Lamotrigine 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 attempt to maintain seizure control while mitigating the risk of serious rash associated with the rapid titration of GenRx Lamotrigine.

The recommended maintenance dose of GenRx Lamotrigine 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 GenRx Lamotrigine should not be exceeded.

Conversion from Adjunctive Therapy with Carbamazepine, Phenytoin, Phenobarbital, or Primidone to Monotherapy with GenRx Lamotrigine

After achieving a dose of 500 mg/day of GenRx Lamotrigine 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 GenRx Lamotrigine

The conversion regimen involves the 4 steps outlined in Table 4.


GenRx Lamotrigine

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 AEDs other than Carbamazepine, Phenytoin, Phenobarbital, Primidone, or Valproate to Monotherapy with GenRx Lamotrigine

No specific dosing guidelines can be provided for conversion to monotherapy with GenRx Lamotrigine with AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate.

2.4 Bipolar Disorder

The goal of maintenance treatment with GenRx Lamotrigine is to delay the time to occurrence of mood episodes in patients treated for acute mood episodes with standard therapy [see INDICATIONS AND USAGE (1)].

Patients taking GenRx Lamotrigine for more than 16 weeks should be periodically reassessed to determine the need for maintenance treatment.

Adults

The target dose of GenRx Lamotrigine is 200 mg/day (100 mg/day in patients taking valproate, which decreases the apparent clearance of GenRx 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 that increase the apparent clearance of GenRx 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 (14.2)]. Accordingly, doses above 200 mg/day are not recommended.

Treatment with GenRx Lamotrigine 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 GenRx Lamotrigine should be adjusted. In patients discontinuing valproate, the dose of GenRx Lamotrigine should be doubled over a 2-week period in equal weekly increments. In patients discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitor lopinavir/ritonavir that induce GenRx Lamotrigine glucuronidation, the dose of GenRx Lamotrigine should remain constant for the first week and then should be decreased by half over a 2-week period in equal weekly decrements. The dose of GenRx Lamotrigine may then be further adjusted to the target dose (200 mg) as clinically indicated.


If other drugs are subsequently introduced, the dose of GenRx Lamotrigine may need to be adjusted. In particular, the introduction of valproate requires reduction in the dose of GenRx Lamotrigine [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)].


To avoid an increased risk of rash, the recommended initial dose and subsequent dose escalations of GenRx Lamotrigine should not be exceeded [see BOXED WARNING].

a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)].

<GenRx Lamotrigine~b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing 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 (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance.~GenRx Lamotrigine>


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

a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see DRUG INTERACTIONS (7), CLINICAL PHARMACOLOGY (12.3)].

<GenRx Lamotrigine~b Drugs that induce lamotrigine glucuronidation and increase clearance, other than the specified antiepileptic drugs, include estrogen-containing 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 (2.1)]. Patients on rifampin and the protease inhibitor lopinavir/ritonavir should follow the same dosing titration/maintenance regimen used with antiepileptic drugs that induce glucuronidation and increase clearance.~GenRx Lamotrigine>


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 Lamotrigine (mg/day)

100

Current Dose of Lamotrigine (mg/day)

400

Week 1

Maintain current dose of Lamotrigine

150

400

Week 2

Maintain current dose of Lamotrigine

200

300

Week 3 onward

Maintain current dose of Lamotrigine

200

200

2.5 Administration of GenRx Lamotrigine Tablets (Chewable, Dispersible)

GenRx Lamotrigine Tablets (Chewable, Dispersible)may be swallowed whole, chewed, or dispersed in water or diluted fruit juice. If the tablets are chewed, consume a small amount of water or diluted fruit juice to aid in swallowing.

To disperse GenRx Lamotrigine Tablets (Chewable, Dispersible), add the tablets to a small amount of liquid (1 teaspoon, or enough to cover the medication). Approximately 1 minute later, when the tablets are completely dispersed, swirl the solution and consume the entire quantity immediately. No attempt should be made to administer partial quantities of the dispersed tablets.

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3 DOSAGE FORMS AND STRENGTHS

  • Tablets: 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg
  • Tablets (Chewable, Dispersible): 5 mg, and 25 mg. (3.2, 16)

3.1 Tablets

25 mg, white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of bisect is debossed with logo of "ZC" and other side is debossed with "79" and other side is plain.

50 mg, white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of bisect is debossed with logo of "ZC" and other side is debossed with "90" and other side is plain.

100 mg, white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of bisect is debossed with logo of "ZC" and other side is debossed with "80"and other side is plain.

150 mg, white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of bisect is debossed with logo of "ZC" and other side is debossed with "81" and other side is plain.

200 mg, white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of bisect is debossed with logo of "ZC" and other side is debossed with "82" and other side is plain.

250 mg, white to off-white, round, flat, beveled-edged tablets with bisect on one side; one side of bisect is debossed with logo of "ZC" and other side is debossed with "91"and other side is plain.

3.2 Tablets

5 mg, white to off-white, round, flat- faced, radial-edged tablets with bisect on one side and plain on other side; one side of the bisect is debossed with "Z" and other side is debossed with "13".

25 mg, white to off-white, round, flat- faced, radial-edged tablets debossed with logo of "Z" and "12" on one side and plain on the other side.

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4 CONTRAINDICATIONS

Hypersensitivity to the drug or its ingredients. ( Boxed Warning, 4 )

GenRx Lamotrigine is contraindicated in patients who have demonstrated hypersensitivity (e.g., rash, angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to the drug or its ingredients [see Boxed Warning, Warnings and Precautions (5.1), (5.2)].

5 WARNINGS AND PRECAUTIONS

  • Life-threatening serious rash and/or rash-related death: Discontinue at the first sign of rash, unless the rash is clearly not drug related.
  • Fatal or life-threatening hypersensitivity reaction: Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms, may be fatal or life threatening. Early signs may include rash, fever, and lymphadenopathy. These reactions may be associated with other organ involvement, such as hepatitis, hepatic failure, blood dyscrasias, or acute multiorgan failure. GenRx Lamotrigine should be discontinued if alternate etiology for this reaction is not found. (5.2)
  • Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia): May occur, either with or without an associated hypersensitivity syndrome. Monitor for signs of anemia, unexpected infection, or bleeding. (5.3)
  • Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors. (5.4)
  • Aseptic meningitis: Monitor for signs of meningitis. (5.5)
  • Medication errors due to product name confusion: Strongly advise patients to visually inspect tablets to verify the received drug is correct. (5.6,16, 17)

5.1 Serious Skin Rashes

The incidence of serious rash associated with hospitalization and discontinuation of GenRx Lamotrigine 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 GenRx Lamotrigine as adjunctive therapy. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in US 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 GenRx Lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received GenRx Lamotrigine 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 GenRx Lamotrigine as initial monotherapy and 0.13% (2 of 1,538) of adult patients who received GenRx Lamotrigine 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 a rash associated with a variable number of the following systemic manifestations: fever, lymphadenopathy, facial swelling, and hematologic and hepatologic abnormalities.

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 GenRx Lamotrigine 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 GenRx Lamotrigine in the absence of valproate were hospitalized.

Patients with History of Allergy or Rash to Other AEDs

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

5.2 Multiorgan Hypersensitivity Reactions and Organ Failure

Multiorgan hypersensitivity reactions, also known as drug reaction with eosinophilia and systemic symptoms, have occurred with GenRx Lamotrigine. Some have been fatal or life threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved.

Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received GenRx Lamotrigine in epilepsy clinical trials. Rare fatalities from multiorgan failure have also been reported in postmarketing use.

Isolated liver failure without rash or involvement of other organs has also been reported with GenRx Lamotrigine.

It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. GenRx Lamotrigine should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Prior to initiation of treatment with GenRx Lamotrigine, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g.,

fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a healthcare provider immediately.

5.3 Blood Dyscrasias

There have been reports of blood dyscrasias that may or may not be associated with the hypersensitivity syndrome. These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia.

5.4 Suicidal Behavior and Ideation

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

Pooled analyses of 199 placebo-controlled clinical trials of 11 different AEDs showed that patients randomized to 1 of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared with patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared with 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

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

Table 7 shows absolute and relative risk by indication for all evaluated AEDs.

Indication

Placebo Patients with Events

per 1,000 Patients

Drug Patients with Events

per 1,000 Patients

Relative Risk: Incidence of Events

in Drug Patients/Incidence in Placebo Patients

Risk Difference: Additional Drug Patients

with Events per 1,000 Patients

Epilepsy

1

3.4

3.5

2.4

Psychiatric

5.7

8.5

1.5

2.9

Other

1

1.8

1.9

0.9

Total

2.4

4.3

1.8

1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing GenRx Lamotrigine or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, the emergence of suicidal thoughts or suicidal behavior or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

5.5 Aseptic Meningitis

Therapy with GenRx Lamotrigine increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate.

Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking GenRx Lamotrigine for various indications. Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment. In most cases, symptoms were reported to resolve after discontinuation of GenRx Lamotrigine. Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of treatment) that were frequently more severe. Some of the patients treated with GenRx Lamotrigine who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases.

Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases. Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction [see WARNINGS AND PRECAUTIONS (5.2)].

5.6 Potential Medication Errors

Medication errors involving GenRx Lamotrigine have occurred. In particular, the name GenRx Lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of GenRx Lamotrigine. To reduce the potential of medication errors, write and say GenRx Lamotrigine clearly. Depictions of the GenRx Lamotrigine tablets and GenRx Lamotrigine tablets can be found in the Medication Guide that accompanies the product to highlight the distinctive markings, colors, and shapes that serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. To avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are GenRx Lamotrigine, as well as the correct formulation of GenRx Lamotrigine, each time they fill their prescription.

5.7 Concomitant Use with Oral Contraceptives

Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of GenRx Lamotrigine [see CLINICAL PHARMACOLOGY (12.3)]. Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking GenRx Lamotrigine [see DOSAGE AND ADMINISTRATION (2.1)]. During the week of inactive hormone preparation (pill-free week) of oral contraceptive therapy, plasma GenRx Lamotrigine levels are expected to rise, as much as doubling at the end of the week. Adverse reactions consistent with elevated levels of GenRx Lamotrigine, such as dizziness, ataxia, and diplopia, could occur.

5.8 Withdrawal Seizures

As with other AEDs, GenRx Lamotrigine should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. In clinical trials in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of GenRx Lamotrigine. Unless safety concerns require a more rapid withdrawal, the dose of GenRx Lamotrigine should be tapered over a period of at least 2 weeks [see DOSAGE AND ADMINISTRATION (2.1)].

5.9 Status Epilepticus

Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with GenRx Lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries, etc.) were made.

5.10 Sudden Unexplained Death in Epilepsy

During the premarketing development of GenRx Lamotrigine, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure).

Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained death in epilepsy (SUDEP) in patients not receiving GenRx Lamotrigine (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for GenRx Lamotrigine, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon with the cohort receiving GenRx Lamotrigine and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated SUDEP rates in patients receiving GenRx Lamotrigine and those receiving other AEDs, chemically unrelated to each other, that underwent clinical testing in similar populations. Importantly, that drug is chemically unrelated to GenRx Lamotrigine. This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect.

5.11 Addition of GenRx Lamotrigine to a Multidrug Regimen that Includes Valproate

Because valproate reduces the clearance of GenRx Lamotrigine, the dosage of GenRx Lamotrigine in the presence of valproate is less than half of that required in its absence [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS (7)].

5.12 Binding in the Eye and Other Melanin-Containing Tissues

Because GenRx Lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that GenRx Lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in 1 controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine's binding to melanin is unknown [see CLINICAL PHARMACOLOGY (12.2)].

Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects.

5.13 Laboratory Tests

False-Positive Drug Test Results

GenRx Lamotrigine has been reported to interfere with the assay used in some rapid urine drug screens, which can result in false-positive readings, particularly for phencyclidine (PCP). A more specific analytical method should be used to confirm a positive result.

Plasma Concentrations of GenRx Lamotrigine

The value of monitoring plasma concentrations of GenRx Lamotrigine in patients treated with GenRx Lamotrigine has not been established. Because of the possible pharmacokinetic interactions between GenRx Lamotrigine and other drugs, including AEDs, monitoring of the plasma levels of GenRx Lamotrigine and concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of GenRx Lamotrigine and other drugs and whether or not dosage adjustments are necessary.

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6 ADVERSE REACTIONS

  • Epilepsy: Most common adverse reactions in adults were dizziness, headache, diplopia, ataxia, nausea, blurred vision, somnolence, rhinitis, pharyngitis, and rash. Additional adverse reactions (incidence ≥10%) reported in children included vomiting, infection, fever, accidental injury, diarrhea, abdominal pain, and tremor. (6.1)
  • Bipolar disorder: Most common adverse reactions (incidence >5%) in adults were nausea, insomnia, somnolence, back pain, fatigue, rash, rhinitis, abdominal pain, and xerostomia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals USA Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

The following adverse reactions are described in more detail in the WARNINGS AND PRECAUTIONS section of the label:

  • Serious skin rashes [see WARNINGS AND PRECAUTIONS (5.1) ]
  • Multiorgan hypersensitivity reactions and organ failure [see WARNINGS AND PRECAUTIONS (5.2)]
  • Blood dyscrasias [see WARNINGS AND PRECAUTIONS (5.3)]
  • Suicidal behavior and ideation [see WARNINGS AND PRECAUTIONS (5.4)]
  • Aseptic meningitis [see WARNINGS AND PRECAUTIONS (5.5)]
  • Withdrawal seizures [see WARNINGS AND PRECAUTIONS (5.8)]
  • Status epilepticus [see WARNINGS AND PRECAUTIONS (5.9)]
  • Sudden unexplained death in epilepsy [see WARNINGS AND PRECAUTIONS (5.10)]

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Epilepsy

Most Common Adverse Reactions in All Clinical Trials

Adjunctive Therapy in Adults with Epilepsy

The most commonly observed (≥5% for GenRx Lamotrigine and more common on drug than placebo) adverse reactions seen in association with GenRx Lamotrigine during adjunctive therapy in adults and not seen at an equivalent frequency among placebo-treated patients were: dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, and rash. Dizziness, diplopia, ataxia, blurred vision, nausea, and vomiting were dose related. Dizziness, diplopia, ataxia, and blurred vision occurred more commonly in patients receiving carbamazepine with GenRx Lamotrigine than in patients receiving other AEDs with GenRx Lamotrigine. Clinical data suggest a higher incidence of rash, including serious rash, in patients receiving concomitant valproate than in patients not receiving valproate [see WARNINGS AND PRECAUTIONS (5.1)].

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

In a dose-response trial in adults, the rate of discontinuation of GenRx Lamotrigine for dizziness, ataxia, diplopia, blurred vision, nausea, and vomiting was dose related.

Monotherapy in Adults with Epilepsy

The most commonly observed (≥5% for GenRx Lamotrigine and more common on drug than placebo) adverse reactions seen in association with the use of GenRx Lamotrigine during the monotherapy phase of the controlled trial in adults not seen at an equivalent rate in the control group were vomiting, coordination abnormality, dyspepsia, nausea, dizziness, rhinitis, anxiety, insomnia, infection, pain, weight decrease, chest pain, and dysmenorrhea. The most commonly observed (≥5% for GenRx Lamotrigine and more common on drug than placebo) adverse reactions associated with the use of GenRx Lamotrigine during the conversion to monotherapy (add-on) period, not seen at an equivalent frequency among low-dose valproate-treated patients, were dizziness, headache, nausea, asthenia, coordination abnormality, vomiting, rash, somnolence, diplopia, ataxia, accidental injury, tremor, blurred vision, insomnia, nystagmus, diarrhea, lymphadenopathy, pruritus, and sinusitis.

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

Adjunctive Therapy in Pediatric Patients with Epilepsy

The most commonly observed (≥5% for GenRx Lamotrigine and more common on drug than placebo) adverse reactions seen in association with the use of GenRx Lamotrigine as adjunctive treatment in pediatric patients aged 2 to 16 years and not seen at an equivalent rate in the control group were infection, vomiting, rash, fever, somnolence, accidental injury, dizziness, diarrhea, abdominal pain, nausea, ataxia, tremor, asthenia, bronchitis, flu syndrome, and diplopia.

In 339 patients aged 2 to 16 years with partial-onset seizures or generalized seizures of Lennox-Gastaut syndrome, 4.2% of patients on GenRx Lamotrigine and 2.9% of patients on placebo discontinued due to adverse reactions. The most commonly reported adverse reaction that led to discontinuation of GenRx Lamotrigine was rash.

Approximately 11.5% of the 1,081 pediatric patients aged 2 to 16 years who received GenRx Lamotrigine as adjunctive therapy in premarketing clinical trials discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were rash (4.4%), reaction aggravated (1.7%), and ataxia (0.6%).

Controlled Adjunctive Clinical Trials in Adults with Epilepsy

Table 8 lists adverse reactions that occurred in adult patients with epilepsy treated with GenRx Lamotrigine in placebo-controlled trials. In these trials, either GenRx Lamotrigine or placebo was added to the patient's current AED therapy.

Body System /

Adverse Reaction

Percent of Patients

Receiving Adjunctive GenRx Lamotrigine ( n = 711 )

Percent of Patients

Receiving Adjunctive Placebo ( n = 419 )

Body as a whole



Headache

29

19

Flu syndrome

7

6

Fever

6

4

Abdominal pain

5

4

Neck pain

2

1

Reaction aggravated

(seizure exacerbation)

2

1

Digestive



Nausea

19

10

Vomiting

9

4

Diarrhea

6

4

Dyspepsia

5

2

Constipation

4

3

Anorexia

2

1

Musculoskeletal



Arthralgia

2

0

Nervous



Dizziness

38

13

Ataxia

22

6

Somnolence

14

7

Incoordination

6

2

Insomnia

6

2

Tremor

4

1

Depression

4

3

Anxiety

4

3

Convulsion

3

1

Irritability

3

2

Speech disorder

3

0

Concentration disturbance

2

1

Respiratory



Rhinitis

14

9

Pharyngitis

10

9

Cough increased

8

6

Skin and appendages



Rash

10

5

Pruritus

3

2

Special senses



Diplopia

28

7

Blurred vision

16

5

Vision abnormality

3

1

Urogenital



Female patients only

(n=365)

(n=207)

Dysmenorrhea

7

6

Vaginitis

4

1

Amenorrhea

2

1

In a randomized, parallel trial comparing placebo with 300 and 500 mg/day of GenRx Lamotrigine, some of the more common drug-related adverse reactions were dose related.


Percent of Patients Experiencing Adverse Reactions

Adverse Reaction

Placebo

( n = 73 )

GenRx Lamotrigine

300 mg

( n = 71 )

GenRx Lamotrigine

500 mg

( n = 72 )

Ataxia

10

10

28Significantly greater than placebo group (p<0.05). , Significantly greater than group receiving GenRx Lamotrigine 300 mg (p<0.05).

Blurred vision

10

11

25 ,

Diplopia

8

24

49 ,

Dizziness

27

31

54 ,

Nausea

11

18

25

Vomiting

4

11

18

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

Controlled Monotherapy Trial in Adults with Partial-Onset Seizures

Table 10 lists adverse reactions that occurred in patients with epilepsy treated with monotherapy with GenRx Lamotrigine in a double-blind trial following discontinuation of either concomitant carbamazepine or phenytoin not seen at an equivalent frequency in the control group.

Body System /

Adverse Reaction

Percent of Patients Receiving GenRx LamotrigineUp to 500 mg/day. as Monotherapy

( n = 43 )

Percent of Patients Receiving Low - Dose Valproate1,000 mg/day. Monotherapy

( n = 44 )

Body as a whole



Pain

5

0

Infection

5

2

Chest pain

5

2

Digestive



Vomiting

9

0

Dyspepsia

7

2

Nausea

7

2

Metabolic and nutritional



Weight decrease

5

2

Nervous



Coordination abnormality

7

0

Dizziness

7

0

Anxiety

5

0

Insomnia

5

2

Respiratory



Rhinitis

7

2

Urogenital ( female patients only )

(n=21)

(n=28)

Dysmenorrhea

5

0

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

Body as a Whole: Asthenia, fever.

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

Metabolic and Nutritional: Peripheral edema.

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

Respiratory: Epistaxis, bronchitis, dyspnea.

Skin and Appendages: Contact dermatitis, dry skin, sweating.

Special Senses: Vision abnormality.

Incidence in Controlled Adjunctive Trials in Pediatric Patients with Epilepsy:

Table 11 lists adverse reactions that occurred in 339 pediatric patients with partial-onset seizures or generalized seizures of Lennox-Gastaut syndrome who received GenRx Lamotrigine up to 15 mg/kg/day or a maximum of 750 mg/day.

Body System / Adverse Reaction

Percent of Patients Receiving GenRx Lamotrigine ( n = 168 )

Percent of Patients Receiving Placebo ( n = 171 )

Body as whole



Infection

20

17

Fever

15

14

Accidental injury

14

12

Abdominal pain

10

5

Asthenia

8

4

Flu syndrome

7

6

Pain

5

4

Facial edema

2

1

Photosensitivity

2

0

Cardiovascular



Hemorrhage

2

1

Digestive



Vomiting

20

16

Diarrhea

11

9

Nausea

10

2

Constipation

4

2

Dyspepsia

2

1

Hemic and lymphatic



Lymphadenopathy

2

1

Metabolic and nutritional



Edema

2

0

Nervous system



Somnolence

17

15

Dizziness

14

4

Ataxia

11

3

Tremor

10

1

Emotional lability

4

2

Gait abnormality

4

2

Thinking abnormality

3

2

Convulsions

2

1

Nervousness

2

1

Vertigo

2

1

Respiratory



Pharyngitis

14

11

Bronchitis

7

5

Increased cough

7

6

Sinusitis

2

1

Bronchospasm

2

1

Skin



Rash

14

12

Eczema

2

1

Pruritus

2

1

Special senses



Diplopia

5

1

Blurred vision

4

1

Visual abnormality

2

0

Urogenital



Male and female patients



Urinary tract infection

3

0

Bipolar Disorder in Adults

The most common adverse reactions seen in association with the use of GenRx Lamotrigine as monotherapy (100 to 400 mg/day) in adult patients (aged 18 to 82 years) with bipolar disorder in the 2 double-blind placebo-controlled trials of 18 months' duration are included in Table 12. Adverse reactions that occurred in at least 5% of patients and were numerically more frequent during the dose-escalation phase of GenRx Lamotrigine in these trials (when patients may have been receiving concomitant medications) compared with the monotherapy phase were: headache (25%), rash (11%), dizziness (10%), diarrhea (8%), dream abnormality (6%), and pruritus (6%).

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

The overall adverse reaction profile for GenRx Lamotrigine was similar between females and males, between elderly and nonelderly patients, and among racial groups.

Body System /

Adverse Reaction

Percent of Patients Receiving GenRx Lamotrigine

( n = 227 )

Percent of Patients Receiving Placebo

( n = 190 )

General



Back pain

8

6

Fatigue

8

5

Abdominal pain

6

3

Digestive



Nausea

14

11

Constipation

5

2

Vomiting

5

2

Nervous System



Insomnia

10

6

Somnolence

9

7

Xerostomia (dry mouth)

6

4

Respiratory



Rhinitis

7

4

Exacerbation of cough

5

3

Pharyngitis

5

4

Skin



Rash (nonserious)In the overall bipolar and other mood disorders clinical trials, the rate of serious rash was

7

5

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

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

General: Fever, neck pain.

Cardiovascular: Migraine.

Digestive: Flatulence.

Metabolic and Nutritional: Weight gain, edema.

Musculoskeletal: Arthralgia, myalgia.

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

Respiratory: Sinusitis.

Urogenital: Urinary frequency.

Adverse Reactions following Abrupt Discontinuation

In the 2 controlled clinical trials, there was no increase in the incidence, severity, or type of adverse reactions in patients with bipolar disorder after abruptly terminating therapy with GenRx Lamotrigine. In the clinical development program in adults with bipolar disorder, 2 patients experienced seizures shortly after abrupt withdrawal of GenRx Lamotrigine [see WARNINGS AND PRECAUTIONS (5.8)].

Mania/Hypomania/Mixed Episodes

During the double-blind placebo-controlled clinical trials in bipolar I disorder in which adults were converted to monotherapy with GenRx Lamotrigine (100 to 400 mg/day) from other psychotropic medications and followed for up to 18 months, the rates of manic or hypomanic or mixed mood episodes reported as adverse reactions were 5% for patients treated with GenRx Lamotrigine (n = 227), 4% for patients treated with lithium (n = 166), and 7% for patients treated with placebo (n = 190). In all bipolar controlled trials combined, adverse reactions of mania (including hypomania and mixed mood episodes) were reported in 5% of patients treated with GenRx Lamotrigine (n = 956), 3% of patients treated with lithium (n = 280), and 4% of patients treated with placebo (n = 803).

6.2 Other Adverse Reactions Observed in All Clinical Trials

GenRx Lamotrigine has been administered to 6,694 individuals for whom complete adverse reaction data was captured during all clinical trials, only some of which were placebo controlled. During these trials, all adverse reactions were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse reactions, similar types of adverse reactions were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. The frequencies presented represent the proportion of the 6,694 individuals exposed to GenRx Lamotrigine who experienced an event of the type cited on at least 1 occasion while receiving GenRx Lamotrigine. All reported adverse reactions are included except those already listed in the previous tables or elsewhere in the labeling, those too general to be informative, and those not reasonably associated with the use of the drug.

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

Body as a Whole

Infrequent: Allergic reaction, chills, malaise.

Cardiovascular System

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

Dermatological

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

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

Digestive System

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

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

Endocrine System

Rare: Goiter, hypothyroidism.

Hematologic and Lymphatic System

Infrequent: Ecchymosis, leukopenia.

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

Metabolic and Nutritional Disorders

Infrequent: Aspartate transaminase increased.

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

Musculoskeletal System

Infrequent: Arthritis, leg cramps, myasthenia, twitching.

Rare: Bursitis, muscle atrophy, pathological fracture, tendinous contracture.

Nervous System

Frequent: Confusion, paresthesia.

Infrequent: Akathisia, apathy, aphasia, central nervous system depression, depersonalization, dysarthria, dyskinesia, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, libido decreased, memory decrease, mind racing, movement disorder, myoclonus, panic attack, paranoid reaction, personality disorder, psychosis, sleep disorder, stupor, suicidal ideation.

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

Respiratory System

Infrequent: Yawn.

Rare: Hiccup, hyperventilation.

Special Senses

Frequent: Amblyopia.

Infrequent: Abnormality of accommodation, conjunctivitis, dry eyes, ear pain, photophobia, taste perversion, tinnitus.

Rare: Deafness, lacrimation disorder, oscillopsia, parosmia, ptosis, strabismus, taste loss, uveitis, visual field defect.

Urogenital System

Infrequent: Abnormal ejaculation, hematuria, impotence, menorrhagia, polyuria, urinary incontinence.

Rare: Acute kidney failure, anorgasmia, breast abscess, breast neoplasm, creatinine increase, cystitis, dysuria, epididymitis, female lactation, kidney failure, kidney pain, nocturia, urinary retention, urinary urgency.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of GenRx Lamotrigine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic: Agranulocytosis, hemolytic anemia, lymphadenopathy not associated with hypersensitivity disorder.

Gastrointestinal: Esophagitis.

Hepatobiliary Tract and Pancreas: Pancreatitis.

Immunologic: Lupus-like reaction, vasculitis.

Lower Respiratory: Apnea.

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

Nervous System : Aggression, exacerbation of Parkinsonian symptoms in patients with pre-existing Parkinson's disease, tics.

Non-site Specific: Progressive immunosuppression.

7 DRUG INTERACTIONS

  • Valproate increases GenRx Lamotrigine concentrations more than 2-fold. (7, 12.3)
  • Carbamazepine, phenytoin, phenobarbital, primidone, and rifampin decrease GenRx Lamotrigine concentrations by approximately 40%. (7, 12.3)
  • Estrogen-containing oral contraceptives decrease GenRx Lamotrigine concentrations by approximately 50%. (7,12.3)
  • Protease inhibitors lopinavir/ritonavir and atazanavir/lopinavir decrease GenRx Lamotrigine exposure by approximately 50% and 32%, respectively. (7,12.3)
  • Coadministration with organic cationic transporter 2 substrates with narrow therapeutic index is not recommended (7, 12.3)
Significant drug interactions with GenRx Lamotrigine are summarized in this section. Additional details of these drug interaction studies are provided in the Clinical Pharmacology section [see CLINICAL PHARMACOLOGY (12.3)].

Concomitant Drug

Effect on Concentration of Lamotrigine or Concomitant Drug

Clinical Comment

↓ = Decreased (induces GenRx Lamotrigine glucuronidation).

↑ = Increased (inhibits GenRx Lamotrigine glucuronidation).

? = Conflicting data.

Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel

↓ lamotrigine

Decreased lamotrigine concentrations approximately 50%.


↓ levonorgestrel

Decrease in levonorgestrel component by 19%.

Carbamazepine and epoxide

↓ lamotrigine

Addition of carbamazepine decreases lamotrigine concentration approximately 40%.


? Carbamazepine

epoxide

May increase

Carbamazepine epoxide levels.

Lopinavir/ritonavir

↓ lamotrigine

Decreased lamotrigine concentration approximately 50%.

Atazanavir/ritonavir

↓ lamotrigine

Decreased lamotrigine AUC approximately 32%.

Phenobarbital/Primidone

↓ lamotrigine

Decreased lamotrigine concentration approximately 40%.

Phenytoin

↓ lamotrigine

Decreased lamotrigine concentration approximately 40%.

Rifampin

↓ lamotrigine

Decreased lamotrigine AUC approximately 40%.

Valproate

↑ lamotrigine

Increased lamotrigine concentrations slightly more than 2-fold.


? valproate

There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

Effect of GenRx Lamotrigine on Organic Cationic Transporter 2 Substrates

GenRx Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins . This may result in increased plasma levels of certain drugs that are substantially excreted via this route. Coadministration of GenRx Lamotrigine with OCT2 substrates with a narrow therapeutic index (e.g., dofetilide) is not recommended.

8 USE IN SPECIFIC POPULATIONS

  • Pregnancy: Based on animal data may cause fetal harm.
  • Hepatic impairment: Dosage adjustments required in patients with moderate and severe liver impairment. (2.1, 8.6)
  • Renal impairment: Reduced maintenance doses may be effective for patients with significant renal impairment. (2.1, 8.7)

8.1 Pregnancy

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


Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. In animal studies, GenRx Lamotrigine was developmentally toxic at doses lower than those administered clinically. GenRx Lamotrigine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When GenRx 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 GenRx Lamotrigine (oral doses of 5 or 25 mg/kg) during the period of organogenesis and offspring were evaluated postnatally, behavioral 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/m2 basis. Maternal toxicity was observed at the higher dose tested.

When pregnant rats were administered GenRx Lamotrigine (oral doses of 5, 10, or 20 mg/kg) during the latter part of gestation, increased offspring mortality (including stillbirths) was seen at all doses. The lowest effect dose for peri/postnatal developmental toxicity in rats is less than the human dose of 400 mg/day on a mg/m2 basis. Maternal toxicity was observed at the 2 highest doses tested.

GenRx Lamotrigine decreases fetal folate concentrations in rat, an effect known to be associated with adverse pregnancy outcomes in animals and humans.


Pregnancy Registry

To provide information regarding the effects of in utero exposure to GenRx Lamotrigine, physicians are advised to recommend that pregnant patients taking GenRx Lamotrigine enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334 and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org.

8.2 Labor and Delivery

The effect of GenRx Lamotrigine on labor and delivery in humans is unknown.

8.3 Nursing Mothers

Preliminary data indicate that GenRx Lamotrigine passes into human milk. Because the effects on the infant exposed to GenRx Lamotrigine by this route are unknown, breastfeeding while taking GenRx Lamotrigine is not recommended.

8.4 Pediatric Use

Epilepsy

GenRx Lamotrigine is indicated as adjunctive therapy in patients aged 2 years and older for partial-onset seizures and the generalized seizures of Lennox-Gastaut syndrome, and PGTC seizures.

Safety and efficacy of GenRx Lamotrigine used as adjunctive treatment for partial-onset seizures were not demonstrated in a small, randomized, double-blind, placebo-controlled withdrawal trial in very young pediatric patients. GenRx Lamotrigine was associated with an increased risk for infectious adverse reactions (lamotrigine 37%, Placebo 5%), and respiratory adverse reactions (lamotrigine 26%, Placebo 5%). Infectious adverse reactions included bronchiolitis, bronchitis, ear infection, eye infection, otitis externa, pharyngitis, urinary tract infection, and viral infection. Respiratory adverse reactions included nasal congestion, cough, and apnea.

Additional information describing a clinical study in which efficacy was not demonstrated in pediatric patients ages 10 to 17 years is approved for GlaxoSmithKline LLC's LAMICTAL® (lamotrigine) products. However, due to GlaxoSmithKline LLC's marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Juvenile Animal Data

In a juvenile animal study in which GenRx Lamotrigine (oral doses of 5, 15, or 30 mg/kg) was administered to young rats (postnatal days 7 to 62), decreased viability and growth were seen at the highest dose tested and long-term behavioral abnormalities (decreased locomotor activity, increased reactivity, and learning deficits in animals tested as adults) were observed at the 2 highest doses. The no-effect dose for adverse effects on neurobehavioral development is less than the human dose of 400 mg/day on a mg/m2 basis.

8.5 Geriatric Use

Clinical trials of GenRx Lamotrigine for epilepsy and bipolar disorder did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients or exhibit a different safety profile than that of younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

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 [see CLINICAL PHARMACOLOGY ], the following general recommendations can be made. 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 (2.1)].

8.7 Renal Impairment

GenRx Lamotrigine is metabolized mainly by glucuronic acid conjugation, with the majority of the metabolites being recovered in the urine. In a small study comparing a single dose of GenRx Lamotrigine in subjects with varying degrees of renal impairment with healthy volunteers, the plasma half-life of GenRx Lamotrigine was approximately twice as long in the subjects with chronic renal failure [see CLINICAL PHARMACOLOGY (12.3)].


Initial doses of GenRx Lamotrigine should be based on patients' AED regimens; reduced maintenance doses may be effective for patients with significant renal impairment. Few patients with severe renal impairment have been evaluated during chronic treatment with GenRx Lamotrigine. Because there is inadequate experience in this population, GenRx Lamotrigine should be used with caution in these patients [see DOSAGE AND ADMINISTRATION (2.1)].

10 OVERDOSAGE

10.1 Human Overdose Experience

Overdoses involving quantities up to 15 g have been reported for GenRx Lamotrigine, some of which have been fatal. Overdose has resulted in ataxia, nystagmus, seizures, decreased level of consciousness, coma, and intraventricular conduction delay.

10.2 Management of Overdose

There are no specific antidotes for GenRx Lamotrigine. Following a suspected overdose, hospitalization of the patient is advised. General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient. If indicated, emesis should be induced; usual precautions should be taken to protect the airway. It should be kept in mind that immediate-release GenRx Lamotrigine is rapidly absorbed [see CLINICAL PHARMACOLOGY (12.3)]. It is uncertain whether hemodialysis is an effective means of removing GenRx Lamotrigine from the blood. In 6 renal failure patients, about 20% of the amount of GenRx Lamotrigine in the body was removed by hemodialysis during a 4-hour session. A Poison Control Center should be contacted for information on the management of overdosage of GenRx Lamotrigine.

11 DESCRIPTION

GenRx Lamotrigine, an AED of the phenyltriazine class, is chemically unrelated to existing AEDs. Lamotrigine's chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. GenRx Lamotrigine, USP is a white to pale cream-colored powder and has a pKa of 5.7. GenRx Lamotrigine is very slightly soluble in water (0.17 mg/mL at 25°C) and slightly soluble in 0.1 M HCl (4.1 mg/mL at 25°C). The structural formula is:

NDC 68382-109-01 in bottle of 100 tablets

GenRx Lamotrigine Tablets (Chewable, Dispersible), 25 mg

Rx only

100 tablets

ZYDUS

NDC 68382-006-01 in bottle of 100 tablets

GenRx Lamotrigine Tablets USP, 25 mg

Rx only

100 tablets

ZYDUS

NDC 68382-007-01 in bottle of 100 tablets

GenRx Lamotrigine Tablets USP, 50 mg

Rx only

100 tablets

ZYDUS

NDC 68382-008-01 in bottle of 100 tablets

GenRx Lamotrigine Tablets USP, 100 mg

Rx only

100 tablets

ZYDUS

NDC 68382-009-14 in bottle of 60 tablets

GenRx Lamotrigine Tablets USP, 150 mg

Rx only

60 tablets

ZYDUS

NDC 68382-010-05 in bottle of 500 tablets

GenRx Lamotrigine Tablets USP, 200 mg

Rx only

500 tablets

ZYDUS

NDC 68382-011-05 in bottle of 500 tablets

GenRx Lamotrigine Tablets USP, 250 mg

Rx only

500 tablets

ZYDUS

GenRx Lamotrigine Tablets (Chewable, Dispersible), 5 mg Lamotrigine Tablets (Chewable, Dispersible), 5mg GenRx Lamotrigine Tablets (Chewable, Dispersible), 25 mg GenRx Lamotrigine Tablets USP, 25 mg GenRx Lamotrigine Tablets USP, 50 mg GenRx Lamotrigine Tablets USP, 100 mg GenRx Lamotrigine Tablets USP, 150 mg GenRx Lamotrigine Tablets USP, 200 mg GenRx Lamotrigine Tablets USP, 250 mg

GenRx Lamotrigine pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


GenRx Lamotrigine available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


GenRx Lamotrigine destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


GenRx Lamotrigine Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


GenRx Lamotrigine pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."LAMOTRIGINE TABLET LAMOTRIGINE TABLET, CHEWABLE [ZYDUS PHARMACEUTICALS (USA) INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."LAMOTRIGINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "lamotrigine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming GenRx Lamotrigine?

Depending on the reaction of the GenRx Lamotrigine after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider GenRx Lamotrigine not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is GenRx Lamotrigine addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on GenRx Lamotrigine, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of GenRx Lamotrigine consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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