Lamotrigine Extended Release (Page 9 of 12)

12.3 Pharmacokinetics

In comparison with immediate-release lamotrigine, the plasma lamotrigine levels following administration of lamotrigine extended-release tablets are not associated with any significant changes in trough plasma concentrations, and are characterized by lower peaks, longer time to peaks, and lower peak-to-trough fluctuation, as described in detail below.

Absorption Lamotrigine is absorbed after oral administration with negligible first-pass metabolism. The bioavailability of lamotrigine is not affected by food.

In an open-label, crossover study of 44 subjects with epilepsy receiving concomitant AEDs, the steady-state pharmacokinetics of lamotrigine were compared following administration of equivalent total doses of lamotrigine extended-release tablets given once daily with those of lamotrigine immediate-release given twice daily. In this study, the median time to peak concentration (T max ) following administration of lamotrigine extended-release tablets was 4 to 6 hours in subjects taking carbamazepine, phenytoin, phenobarbital, or primidone; 9 to 11 hours in subjects taking valproate; and 6 to 10 hours in subjects taking AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate. In comparison, the median T max following administration of immediate-release lamotrigine was between 1 and 1.5 hours.

The steady-state trough concentrations for extended-release lamotrigine were similar to or higher than those of immediate-release lamotrigine depending on concomitant AED (see Table 6). A mean reduction in the lamotrigine C max by 11% to 29% was observed for lamotrigine extended-release tablets compared with immediate-release lamotrigine, resulting in a decrease in the peak-to-trough fluctuation in serum lamotrigine concentrations. However, in some subjects receiving enzyme-inducing AEDs, a reduction in C max of 44% to 77% was observed. The degree of fluctuation was reduced by 17% in subjects taking enzyme-inducing AEDs; 34% in subjects taking valproate; and 37% in subjects taking AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate. Lamotrigine extended-release tablets and immediate-release lamotrigine regimens were similar with respect to area under the curve (AUC, a measure of the extent of bioavailability) for subjects receiving AEDs other than those known to induce the metabolism of lamotrigine. The relative bioavailability of extended-release lamotrigine was approximately 21% lower than immediate-release lamotrigine in subjects receiving enzyme-inducing AEDs. However, a reduction in exposure of up to 70% was observed in some subjects in this group when they switched to lamotrigine extended-release tablets. Therefore, doses may need to be adjusted in some patients based on therapeutic response.

Table 6. Steady-State Bioavailability of Lamotrigine extended-release tablets Relative to Immediate-Release Lamotrigine at Equivalent Daily Doses (Ratio of Extended-Release to Immediate-Release 90% CI)
a Enzyme-inducing antiepileptic drugs include carbamazepine, phenytoin, phenobarbital, and primidone.

Concomitant Antiepileptic Drug

AUC (0-24 ss )

C MAX

C MIN

Enzyme-inducing antiepileptic drugs a

0.79 (0.69, 0.90)

0.71 (0.61, 0.82)

0.99 (0.89, 1.09)

Valproate

0.94 (0.81, 1.08)

0.88 (0.75, 1.03)

0.99 (0.88, 1.10)

Antiepileptic drugs other than enzyme-inducing antiepileptic drugs a or valproate

1.00 (0.88, 1.14)

0.89 (0.78, 1.03)

1.14 (1.03, 1.25)

Dose Proportionality
In healthy volunteers not receiving any other medications and given lamotrigine extended-release tablets once daily, the systemic exposure to lamotrigine increased in direct proportion to the dose administered over the range of 50 to 200 mg. At doses between 25 and 50 mg, the increase was less than dose proportional, with a 2-fold increase in dose resulting in an approximately 1.6-fold increase in systemic exposure.

Distribution
Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers.

Protein Binding
Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely. The binding of lamotrigine to plasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein-binding sites.

Metabolism
Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg of 14C-lamotrigine (15 μCi) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucuronide (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).

Enzyme Induction
The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated.

Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in t½ and a 37% increase in CL/F at steady state compared with values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving enzyme-inducing drugs such as carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation [see Drug Interactions ( 7)] .

Elimination The elimination half-life and apparent clearance of lamotrigine following oral administration of immediate-release lamotrigine to adult subjects with epilepsy and healthy volunteers is summarized in Table 7. Half-life and apparent oral clearance vary depending on concomitant AEDs.

Since the half-life of lamotrigine following administration of single doses of immediate-release lamotrigine is comparable with that observed following administration of lamotrigine extended-release tablets, similar changes in the half-life of lamotrigine would be expected for lamotrigine extended-release tablets.

Table 7. Mean Pharmacokinetic Parameters a of Immediate-Release Lamotrigine in Healthy Volunteers and Adult Subjects with Epilepsy
a The majority of parameter means determined in each study had coefficients of variation between 20% and 40% for half-life and CL/F and between 30% and 70% for T max . The overall mean values were calculated from individual study means that were weighted based on the number of volunteers/subjects in each study. The numbers in parentheses below each parameter mean represent the range of individual volunteer/subject values across studies.
b Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives and other drugs, such as rifampin and protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir, that induce lamotrigine glucuronidation have also been shown to increase the apparent clearance of lamotrigine [ see Drug Interactions ( 7)].

Adult Study Population

Number of Subjects

t ½ : Elimination Half-life (h)

CL/F: Apparent Plasma Clearance (mL/min/kg)

Healthy volunteers taking no other medications:

Single-dose lamotrigine

Multiple-dose lamotrigine

179

36

32.8

(14.0-103.0)

25.4

(11.6-61.6)

0.44

(0.12-1.10)

0.58

(0.24-1.15)

Healthy volunteers taking valproate:

Single-dose lamotrigine

Multiple-dose lamotrigine

6

18

48.3

(31.5-88.6)

70.3

(41.9-113.5)

0.30

(0.14-0.42)

0.18

(0.12-0.33)

Subjects with epilepsy taking valproate only:

Single-dose lamotrigine

4

58.8

(30.5-88.8)

0.28

(0.16-0.40)

Subjects with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone b plus valproate:

Single-dose lamotrigine

25

27.2

(11.2-51.6)

0.53

(0.27-1.04)

Subjects with epilepsy taking carbamazepine, phenytoin, phenobarbital, or primidone: b

Single-dose lamotrigine

Multiple-dose lamotrigine

24

17

14.4

(6.4-30.4)

12.6

(7.5-23.1)

1.10

(0.51-2.22)

1.21

(0.66-1.82)

Drug Interactions The apparent clearance of lamotrigine is affected by the coadministration of certain medications [see Warnings and Precautions ( 5.8, 5.12), Drug Interactions ( 7)] .

The net effects of drug interactions with lamotrigine, based on drug interaction studies using immediate-release lamotrigine, are summarized in Tables 5 and 8, followed by details of the drug interaction studies below.

Table 8. Summary of Drug Interactions with Lamotrigine

Drug

Drug Plasma Concentration With Adjunctive Lamotrigine a

Lamotrigine Plasma Concentration With Adjunctive Drugs b

Oral contraceptives (e.g., ethinylestradiol/levonorgestrel) c

d

Aripiprazole

Not assessed

e

Atazanavir/ritonavir

f

Bupropion

Not assessed

Carbamazepine

Carbamazepine epoxide g

?

Felbamate

Not assessed

Gabapentin

Not assessed

Lacosamide

Not assessed

Levetiracetam

Lithium

Not assessed

Lopinavir/ritonavir

e

Olanzapine

g

Oxcarbazepine

10-Monohydroxy oxcarbazepine metabolite h

Perampanel

Not assessed

e

Phenobarbital/primidone

Phenytoin

Pregabalin

Rifampin

Not assessed

Risperidone

Not assessed

9-Hydroxyrisperidone i

Topiramate

h

Valproate

Valproate + phenytoin and/or carbamazepine

Not assessed

Zonisamide

Not assessed

  • a From adjunctive clinical trials and volunteer trials.
  • b Net effects were estimated by comparing the mean clearance values obtained in adjunctive clinical trials and volunteer trials.
  • c The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated in clinical trials, although the effect may be similar to that seen with the ethinylestradiol/levonorgestrel combinations.
  • d Modest decrease in levonorgestrel.
  • e Slight decrease, not expected to be clinically meaningful.
  • f Compared with historical controls.
  • g Not administered, but an active metabolite of carbamazepine.
  • h Not administered, but an active metabolite of oxcarbazepine.
  • i Not administered, but an active metabolite of risperidone.
  • j Slight increase, not expected to be clinically meaningful.
  • ↔= No significant effect.
  • ? = Conflicting data.

Estrogen-Containing Oral Contraceptives
In 16 female volunteers, an oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel increased the apparent clearance of lamotrigine (300 mg/day) by approximately 2-fold with mean decreases in AUC of 52% and in C max of 39%. In this study, trough serum lamotrigine concentrations gradually increased and were approximately 2-fold higher on average at the end of the week of the inactive hormone preparation compared with trough lamotrigine concentrations at the end of the active hormone cycle.

Gradual transient increases in lamotrigine plasma levels (approximate 2-fold increase) occurred during the week of inactive hormone preparation (pill-free week) for women not also taking a drug that increased the clearance of lamotrigine (carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir that induce lamotrigine glucuronidation) [see Drug Interactions ( 7)] . The increase in lamotrigine plasma levels will be greater if the dose of lamotrigine extended-release tablets is increased in the few days before or during the pill-free week. Increases in lamotrigine plasma levels could result in dose-dependent adverse reactions.

In the same study, coadministration of lamotrigine (300 mg/day) in 16 female volunteers did not affect the pharmacokinetics of the ethinylestradiol component of the oral contraceptive preparation. There were mean decreases in the AUC and C max of the levonorgestrel component of 19% and 12%, respectively. Measurement of serum progesterone indicated that there was no hormonal evidence of ovulation in any of the 16 volunteers, although measurement of serum FSH, LH, and estradiol indicated that there was some loss of suppression of the hypothalamic-pituitary-ovarian axis.

The effects of doses of lamotrigine other than 300 mg/day have not been systematically evaluated in controlled clinical trials.

The clinical significance of the observed hormonal changes on ovulatory activity is unknown. However, the possibility of decreased contraceptive efficacy in some patients cannot be excluded. Therefore, patients should be instructed to promptly report changes in their menstrual pattern (e.g., break-through bleeding).

Dosage adjustments may be necessary for women receiving estrogen-containing oral contraceptive preparations [see Dosage and Administration ( 2.1)].

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

Aripiprazole
In 18 patients with bipolar disorder on a stable regimen of 100 to 400 mg/day of lamotrigine, the lamotrigine AUC and C max were reduced by approximately 10% in patients who received aripiprazole 10 to 30 mg/day for 7 days, followed by 30 mg/day for an additional 7 days. This reduction in lamotrigine exposure is not considered clinically meaningful.

Atazanavir/Ritonavir
In a study in healthy volunteers, daily doses of atazanavir/ritonavir (300 mg/100 mg) reduced the plasma AUC and C max of lamotrigine (single 100-mg dose) by an average of 32% and 6%, respectively, and shortened the elimination half-lives by 27%. In the presence of atazanavir/ritonavir (300 mg/100 mg), the metabolite-to-lamotrigine ratio was increased from 0.45 to 0.71 consistent with induction of glucuronidation. The pharmacokinetics of atazanavir/ritonavir were similar in the presence of concomitant lamotrigine to the historical data of the pharmacokinetics in the absence of lamotrigine.

Bupropion
The pharmacokinetics of a 100-mg single dose of lamotrigine in healthy volunteers (n = 12) were not changed by coadministration of bupropion sustained-release formulation (150 mg twice daily) starting 11 days before lamotrigine.

Carbamazepine
Lamotrigine has no appreciable effect on steady-state carbamazepine plasma concentration. Limited clinical data suggest there is a higher incidence of dizziness, diplopia, ataxia, and blurred vision in patients receiving carbamazepine with lamotrigine than in patients receiving other AEDs with lamotrigine [see Adverse Reactions ( 6.1)] . The mechanism of this interaction is unclear. The effect of lamotrigine on plasma concentrations of carbamazepine-epoxide is unclear. In a small subset of patients (n = 7) studied in a placebo-controlled trial, lamotrigine had no effect on carbamazepine-epoxide plasma concentrations, but in a small, uncontrolled study (n = 9), carbamazepine-epoxide levels increased.
The addition of carbamazepine decreases lamotrigine steady-state concentrations by approximately 40%.

Esomeprazole
In a study of 30 subjects, coadministration of lamotrigine extended-release tablets with esomeprazole resulted in no significant change in lamotrigine levels and a small decrease in T max . The levels of gastric pH were not altered compared with pre-lamotrigine dosing.

Felbamate
In a trial in 21 healthy volunteers, coadministration of felbamate (1,200 mg twice daily) with lamotrigine (100 mg twice daily for 10 days) appeared to have no clinically relevant effects on the pharmacokinetics of lamotrigine.

Folate Inhibitors
Lamotrigine is a weak inhibitor of dihydrofolate reductase. Prescribers should be aware of this action when prescribing other medications that inhibit folate metabolism.

Gabapentin
Based on a retrospective analysis of plasma levels in 34 subjects who received lamotrigine both with and without gabapentin, gabapentin does not appear to change the apparent clearance of lamotrigine.

Lacosamide
Plasma concentrations of lamotrigine were not affected by concomitant lacosamide (200, 400, or 600 mg/day) in placebo-controlled clinical trials in patients with partial-onset seizures.

Levetiracetam
Potential drug interactions between levetiracetam and lamotrigine were assessed by evaluating serum concentrations of both agents during placebo-controlled clinical trials. These data indicate that lamotrigine does not influence the pharmacokinetics of levetiracetam and that levetiracetam does not influence the pharmacokinetics of lamotrigine.

Lithium
The pharmacokinetics of lithium were not altered in healthy subjects (n = 20) by coadministration of lamotrigine (100 mg/day) for 6 days.

Lopinavir/Ritonavir
The addition of lopinavir (400 mg twice daily)/ritonavir (100 mg twice daily) decreased the AUC, C max , and elimination half-life of lamotrigine by approximately 50% to 55.4% in 18 healthy subjects. The pharmacokinetics of lopinavir/ritonavir were similar with concomitant lamotrigine, compared with that in historical controls.

Olanzapine
The AUC and C max of olanzapine were similar following the addition of olanzapine (15 mg once daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 16) compared with the AUC and C max in healthy male volunteers receiving olanzapine alone (n = 16).

In the same trial, the AUC and C max of lamotrigine were reduced on average by 24% and 20%, respectively, following the addition of olanzapine to lamotrigine in healthy male volunteers compared with those receiving lamotrigine alone. This reduction in lamotrigine plasma concentrations is not expected to be clinically meaningful.

Oxcarbazepine
The AUC and C max of oxcarbazepine and its active 10-monohydroxy oxcarbazepine metabolite were not significantly different following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine (200 mg once daily) in healthy male volunteers (n = 13) compared with healthy male volunteers receiving oxcarbazepine alone (n = 13).

In the same trial, the AUC and C max of lamotrigine were similar following the addition of oxcarbazepine (600 mg twice daily) to lamotrigine in healthy male volunteers compared with those receiving lamotrigine alone. Limited clinical data suggest a higher incidence of headache, dizziness, nausea, and somnolence with coadministration of lamotrigine and oxcarbazepine compared with lamotrigine alone or oxcarbazepine alone.

Perampanel
In a pooled analysis of data from 3 placebo-controlled clinical trials investigating adjunctive perampanel in patients with partial-onset and primary generalized tonic-clonic seizures, the highest perampanel dose evaluated (12 mg/day) increased lamotrigine clearance by <10%. An effect of this magnitude is not considered to be clinically relevant.

Phenobarbital, Primidone
The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by approximately 40%.

Phenytoin
Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-state concentrations by approximately 40%.

Pregabalin
Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine and pregabalin.

Rifampin
In 10 male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance of a single 25-mg dose of lamotrigine by approximately 2-fold (AUC decreased by approximately 40%).

Risperidone
In a 14 healthy volunteers study, multiple oral doses of lamotrigine 400 mg daily had no clinically significant effect on the single-dose pharmacokinetics of risperidone 2 mg and its active metabolite 9-OH risperidone. Following the coadministration of risperidone 2 mg with lamotrigine, 12 of the 14 volunteers reported somnolence compared with 1 out of 20 when risperidone was given alone, and none when lamotrigine was administered alone.

Topiramate
Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.

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

The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers by slightly more than 2-fold. In 1 trial, maximal inhibition of lamotrigine clearance was reached at valproate doses between 250 and 500 mg/day and did not increase as the valproate dose was further increased.

Zonisamide
In a study in 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with lamotrigine (150 to 500 mg/day for 35 days) had no significant effect on the pharmacokinetics of lamotrigine.

Known Inducers or Inhibitors of Glucuronidation
Drugs other than those listed above have not been systematically evaluated in combination with lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine, and doses of lamotrigine extended-release tablets may require adjustment based on clinical response.

Other In vitro assessment of the inhibitory effect of lamotrigine at OCT2 demonstrate that lamotrigine, but not the N(2)-glucuronide metabolite, is an inhibitor of OCT2 at potentially clinically relevant concentrations, with IC50 value of 53.8 μM [see Drug Interactions (7)] .

Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, sertraline, or trazodone.

Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6.

Specific Populations

Patients with Renal Impairment: Twelve volunteers with chronic renal failure (mean creatinine clearance: 13 mL/min, range: 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100-mg dose of immediate-release lamotrigine. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared with 26.2 hours in healthy volunteers. On average, approximately 20% (range: 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour session [see Dosage and Administration ( 2.1)] .

Patients with Hepatic Impairment: The pharmacokinetics of lamotrigine following a single 100-mg dose of immediate-release lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic impairment (Child-Pugh classification system) and compared with 12 subjects without hepatic impairment. The subjects with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearances of lamotrigine in subjects with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared with 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in subjects with mild, moderate, severe without ascites, and severe with ascites hepatic impairment were 46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in healthy controls [see Dosage and Administration ( 2.1)] .

Geriatric Patients: The pharmacokinetics of lamotrigine following a single 150-mg dose of immediate-release lamotrigine were evaluated in 12 elderly volunteers between the ages of 65 and 76 years (mean creatinine clearance: 61 mL/min, range: 33 to 108 mL/min). The mean half-life of lamotrigine in these subjects was 31.2 hours (range: 24.5 to 43.4 hours), and the mean clearance was 0.40 mL/min/kg (range: 0.26 to 0.48 mL/min/kg).

Male and Female Patients: The clearance of lamotrigine is not affected by gender. However, during dose escalation of immediate-release lamotrigine in 1 clinical trial in patients with epilepsy on a stable dose of valproate (n = 77), mean trough lamotrigine concentrations, unadjusted for weight, were 24% to 45% higher (0.3 to 1.7 mcg/mL) in females than in males.

Racial or Ethnic Groups: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than Caucasians.

Pediatric Patients: Safety and effectiveness of lamotrigine extended-release tablets for use in patients younger than 13 years have not been established.

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