Torrent Lamotrigine Er 200 Mg Reviews for Epilepsy

Ther Clin Take a chance Manag. 2008 Oct; iv(5): 1035–1046.

Pharmacotherapeutics of epilepsy: use of lamotrigine and expectations for lamotrigine extended release

Abstruse

The goal in managing patients with epilepsy is complete seizure liberty. Pharmacotherapeutic management of epilepsy is complicated by multiple syndromes, inter-individual differences in drug sensitivities, inter-individual differences in drug disposition, and drug interactions. Most anti-epileptic drugs (AEDs) accept a therapeutic window with only a 2- to 3-fold concentration range. Extended release formulations offering advantages over their immediate release counter parts with less fluctuation in the serum concentration vs time curve and improved compliance. However, missed doses are more than likely to result in prolonged "sub-therapeutic serum concentrations". Best clinical consequence may sometimes require twice daily dosing of extended release formulations even though approved for once daily dosing, as this optimally balances pharmacokinetics against compliance. Lamotrigine (LTG) is a wide spectrum AED with efficacy in partial and generalized epilepsy syndromes and good tolerability. Its metabolism is afflicted by co-medications which may be inducing, neutral or inhibiting of hepatic glucuronidation. Furthermore, though the boilerplate half-life in monotherapy is about 24 hours, at that place is a large inter-individual variation that may, including the extremes, arroyo a range of x-fold. LTG-XR is expected to decrease fluctuation of serum concentration in the presence of hepatic inducing or neutral drugs. Yet, optimal clinical do good in some patients may require twice daily dosing when metabolism is rapid.

Keywords: lamotrigine, antiepileptic drugs, extended release, epilepsy, pharmacokinetics

Introduction to management issues in epilepsy

Epilepsy is a common neurologic disorder affecting well-nigh 1% of the population (Hauser et al 1993). Pharmacotherapy with anti-epileptic drugs (AEDs) remains the major treatment modality for epilepsy. Direction of epilepsy differs from the treatment of other chronic diseases in that a single breakthrough event has a major negative consequence on quality of life (Gilliam 2002). Complete control of seizures is necessary as a unmarried seizure impacts negatively on patient quality of life and independence. As an case, a single seizure usually limits driving privileges for a minimum of 3 months. Management of epilepsy is farther complicated by variables such as: multiple epilepsy syndromes with varied pharmacosensitivities, inter-individual differences within a syndrome, and inter-and intra-individual differences in AED disposition.

This review will sequentially overview: therapeutic management problems in epilepsy, role of extended release formulations, clinical outcomes with currently available extended release formulations, lamotrigine (LTG) and LTG extended release (-XR) pharmacokinetics, LTG efficacy in epilepsy syndromes, LTG safety and tolerability, LTG touch on quality of life, and a summary of the place of LTG- XR in epilepsy management.

Management issues in epilepsy

Epilepsy syndromes

Epilepsy is actually a group of disorders sharing the occurrence of unprovoked seizures. Over 30 epilepsy syndromes were described by the Committee on Classification and Terminology of The International League Against Epilepsy (1989) with varied seizure expression, historic period of onset, pharmacologic sensitivity, and prognosis. The initial categorization usually begins with determination of fractional (focal) or generalized (simultaneous bihemispheric) onset. Generalized epilepsies may be idiopathic with a proficient prognosis and include the syndromes of childhood absence, juvenile absence, and juvenile myoclonic epilepsy (Valentin et al 2007). These syndromes are genetically based and to date underlying alterations of ion channels and neurotransmitter receptors that modulate synaptic transmission accept been identified every bit the underlying cause (Helbig et al 2008). Generalized epilepsies may be symptomatic due to a broad range of genetic or catastrophic cerebral insults with a poor overall prognosis and include syndromes such equally infantile spasms, Lennox-Gastaut, and progressive myoclonic epilepsies (Duchowny and Harvey 1996). Fractional epilepsies have focal onset of seizures usually from the temporal or frontal lobes and less commonly from the parietal or occipital lobes. Etiologies of partial epilepsies are varied including mesial temporal sclerosis, cortical dysgenesis, vascular malformations, tumors, and in a minority primary genetic defects.

AEDs may be effective in select syndromes or may even worsen sure epilepsy syndromes and then are termed "narrow spectrum" (Genton 2000). Others are probable to be constructive in many epilepsy syndromes and are often referred to as "broad spectrum". Direction is farther complicated in that our knowledge of syndromes remains quite superficial and in therapeutics for a unmarried epilepsy syndrome a drug might work for 1 individual only another drug may exist required for seizure freedom in another. To appointment, there is no mode to pre-identify an private's AED sensitivity. Serum concentrations needed for seizure command too vary significantly across individuals (Schmidt and Haenel 1984) which has led to the term "private therapeutic reference concentration" (Johannessen and Tomson 2006).

Epilepsy pharmacotherapeutics

Currently, more than 12 AEDs are available with mechanism(south) of activeness very incompletely understood. Nigh accept been approved in the last decade. Employ-dependent voltage-dependent sodium channel blockade is a common action of numerous AEDs including early drugs such as phenytoin and carbam-azepine (Rogawski and Löscher 2004; Perucca 2005a). LTG is often merely categorized equally a sodium channel blocker (Lang et al 1993). Inconsistent with this machinery of action, LTG has a broad spectrum of activity in animal models and in current clinical utilize. LTG actions on loftier voltage activated calcium currents (Hainsworth et al 2001), hyperpolarization activated inward current (I h) (Poolos et al 2002), potassium currents (Huang et al 2004), and fifty-fifty nicotinic receptor channels are reported (Valles et al 2007). Many of the AEDs marketed over the last 15 years have had multiple sites of action identified (Rogawski and Löscher 2004; Perucca 2005a).

Most patients with epilepsy, most two-thirds, answer to the first drug or second AED tried (Kwan and Brodie 2000). However, the pivotal clinical trials leading to initial approval of an AED are done in highly intractable adult patients with fractional epilepsy and a severe seizure burden (about one seizure per week) and who have failed multiple AEDs. Post-approval studies are then extended to include children with a similar spectrum of epilepsy. Monotherapy trials in Europe study the more typical patient with non-intractable epilepsy. These studies take failed to show differences in efficacy across AEDs, with most subjects becoming seizure free at low doses. Even so, AEDs have differed in terms of tolerability in this report blueprint (Kwan and Brodie 2003). Few controlled trials of AEDs for other specific epilepsy syndromes exist.

In choosing an AED for a patient the major considerations are the triad: ease of employ, efficacy, and tolerability. Ease of utilize considerations includes rapidity of titration rate, lack of serious idiosyncratic reactions, and lack of potential drug interactions. Efficacy includes consideration of the underlying epilepsy syndrome, and in situations of doubt regarding the specific syndrome, wide spectrum AEDs have advantages. Required serum concentrations of AEDs are often lower for generalized epilepsy syndromes when compared to fractional (Schmidt and Haenel 1984). Tolerability includes dose-dependent side effects common to AEDs as a therapeutic grade, such equally dizziness, fatigue, unsteadiness, decreased concentration, and visual blurring. Side effects may be specific to an AED and may be beneficial, ie, weight loss, or harmful, ie, impaired memory.

Epilepsy pharmacokinetic parameters

The pharmacokinetic parameters of an AED impact on both efficacy and tolerability. Well-nigh AEDs have a small therapeutic window and so that with a ii to three fold change in serum concentration, seizures may get controlled but adverse events appear (Johannessen et al 2003).

Trough serum concentrations (C_min) may put individuals at increased risk of seizures whereas AED peak serum concentrations (C_max) may lead to adverse events. A articulate goal of therapy would exist to maintain the AED serum concentration vs fourth dimension curve in a narrow range without fluctuations. This scenario is also described equally a flat serum concentration fourth dimension curve. Integration of the time curve gives the expanse nether the bend (AUC) that measures overall drug exposure. Of course, the AED concentration fourth dimension curve in serum may not be super imposable upon cerebrospinal fluid or extracellular encephalon concentration vs time curves and this type of information is unremarkably quite limited.

Half-life is an important pharmacokinetic variable. Drugs with short half-lives need to be taken 2, three, or fifty-fifty four times per twenty-four hour period to maintain peak and trough serum concentrations within a therapeutic window. Regimens with frequent daily dosing are very inconvenient and are associated with increased medication not-adherence. Not-adherence is inversely related to the number of daily doses. Claxton et al (2001) reviewed 76 studies and plant a mean compliance of 71% for all dosing regimens combined that declined as the number of doses per day increased: i dose = 79%, two doses = 69%, 3 doses = 65%, and four doses 51% adherence. The difference between once and twice daily did not reach statistical significance though the difference between once and three times and once and iv times per twenty-four hours did. Cramer et al (2002) showed that 72% of epilepsy patients missed doses and 45% reported having a seizure later on a missed dose.

Finally, medication non-adherence (Osterberg and Blaschke 2005) and seizures result in increased wellness care utilization and cost. Begley et al (1994) detailed a model of the price of epilepsy, including medical care and fourth dimension lost from work, based on incidence and prognosis. Cost in 1990 dollars per patient was lowest for patients with remission later diagnosis and handling, US $iv,272, and highest for persons with intractable and frequent seizures, Usa $138,602 (Begley et al 1994). Population based studies from Europe have shown average almanac health care costs of Usa $100 to US $2,000 for inactive cases, Usa $900 to US $3,000 for agile cases and a two- to 7-fold increase in toll for active cases with frequent seizures compared with agile cases with few (Begley and Beghi 2002). A contempo retrospective assay of a managed care population revealed that 39% of patients were non-adherent based on AED refills and that this was associated with increased emergency room and in-patient hospital stays costing US $260 and U.s. $ane,799, respectively, per patient per year (Davis et al 2008).

Role of extended release formulations

The goal of extended release formulations is to take drugs with curt half-lives and develop formulations with a "pseudo-long half-life" that let once or twice daily dosing with near constant (flat) serum concentration vs fourth dimension curves compared with the rapid release formulation, thus resulting in improved direction. Firstly, the decreased peak serum concentration seen with apply of extended release formulations is expected to subtract dose-dependent side furnishings that are oft maximal several hours after an oral dose. Secondly, in theory the increased trough concentration should pb to improved seizure command. Thirdly, seizure command might be improved with extended release formulations by assuasive increase of dose, bringing the hateful steady country serum concentration closer to the peak value previously achieved with the immediate release formulation. Fourthly and finally, compliance is expected to meliorate with once or twice daily dosing every bit discussed in the preceding paragraph (Sommerville 2006; Verotti et al 2007). Patients ofttimes adopt once daily doing. Ane potential shortcoming of once daily dosing is that a missed dose may exist more likely to event in a seizure. This is because the missed dose will result in a rapid reject in serum concentration based on the unmasking of the true short half-life of the AED (Table i) (Levy 1994; Bialer 2007). For this reason, it has been argued that dosing extended release formulations, that are "approved" for one time daily dosing, twice daily in many situations offers the highest probability of long-term seizure control based on improved therapeutic coverage that outweighs the small decline of adherence (Bialer 2007). The increased compliance should exist weighed against the impact of omitted dose(s) (Levy 1994). From a (theoretical) pharmacokinetic perspective, unless magnitude of not-compliance is reduced by more than two-thirds when a medication regimen is taken from iii times a day to once a day dosing (assuming half-life of 12 hours), the increased compliance is unlikely to be advantageous and may actually exist counter-productive in minimizing the occurrence of sub-therapeutic drug concentrations (Levy 1994). Non-adherence and subthreshold AED serum concentrations do relate to the occurrence of breakthrough seizures. A recent observational written report of AED postictal serum concentration, found a level less than half of the individual baseline serum concentration of AED in 44.3% of seizures (Specht et al 2003).

Table one

Comparison of extended release to firsthand release formulations

Potential benefits

Lower maximum blood concentration → improved tolerability

Increment minimum blood concentration → improved seizure control

Increase dose → improve seizure control

Patient preference for simplified dosing

Improved medication adherence (benefit may be offset by touch on of a missed dose)

Potential harm

Bear upon of missed doses on serum concentration → seizure quantum

The development of extended release formulations is driven by the above described potential clinical do good every bit well as the potential for patent extensions and marketing advantages. AEDs are also oftentimes used for psychiatric indications where once a twenty-four hour period dosing may be especially critical for medication adherence (Rogawski and Löscher 2004; Johannessen Landmark 2008). Extended release formulations currently be for phenytoin, carbamazepine, and valproic acid. Extended release formulations of lamotrigine, oxcar-bazepine, and levetiracetam are under development. Successful development requires demonstration that the compounds are therapeutically equivalent (Sommerville 2006).

Outcomes with currently released extended formulations

Clinical consequence measures comparing extended release to firsthand release formulations have included pharmacokinetic variables to assess bioequivalence and clinical measures of seizure frequency, agin event frequency, patient preference, and quality of life measures. Two extended release formulations of carbamazepine indicated for twice daily dosing are marketed in the US: a capsule with iii dewdrop types each having a dissimilar rate of release (Carbatrol^®; Shire) and an osmotic-release delivery system (Tegretol^® XR; Novartis). Clinical development included testing in double-bullheaded crossover studies demonstrating pharmacokinetic bioequivalence and no significant differences in seizure frequency but with improvements in adverse events, 55% for immediate release vs 13% for extended release, and patient preference for decreased dosing (Canger et al 1990; Tegretol OROS Written report Group 1995). Pharmacokinetic benefit besides probably came from flattening the serum concentration fourth dimension curve of the shorter half-life carbamazepine agile metabolite, carbamazepine ten,11 epoxide (McKee et al 1993). Subsequent unblinded, open-characterization studies take besides observed decreased adverse events (Miller et al 2004, Ficker et al 2005), improved quality of life (Mirza et al 1998; Ficker et al 2005) and a statistically significant decrease in the rate of seizures (Hogan et al 2003; Ficker et al 2005). The ability to modestly increase full daily dose using the extended release formulation was also demonstrated (Canger et al 1990; Miller et al 2004).

Divalproex extended release (Depakote^® ER; Abbott), canonical for once daily doing, is a tablet of sustained release hydrophilic matrix technology with sustained release over more than eighteen hours controlled by the erosion of water soluble polymer (hydroxypropyl methyl cellulose) from the matrix. Divalproex ER was approved in 2000 for the indication of migraine. The epilepsy indication was held up for two years as divalproex ER is non bioequivalent to divalproate delayed release (DR) (Depakote^®; Abbott). A meta-anlysis of 5 multiple dose studies (Dutta and Zhang 2004) with 82 good for you volunteers and 83 epilepsy patients compared different divalproex dosing regimens (ii, 3, or 4 times per day) and meal weather (fasting, low, medium, and high calorie meals). Fasting and food with varied caloric content had a less than 10% effect on divalproex ER availability. The estimated ratio of divalproex ER to divalproex DR and 95% conviction intervals for AUC, C_max, and C_min was 0.89 (0.85–0.94), 0.79 (0.74–0.84), 0.96 (0.90–i.02), respectively. When changing from divalproex to divalproex ER the recommendation was to increase the dose past 1/0.89 or 12%, to compensate for the overall decrease in AED exposure indicated by the difference in AUC. Thus, the recommendation for an viii%–20% increase in dose when changing to the ER conception, the corporeality of increase determined by the nearest tablet size. A pooled analysis from nine non-blinded, open characterization studies (v epilepsy and 4 psychiatry) showed improved tolerability with divalproex ER with significant reductions of tremor, weight proceeds, gastrointestinal symptoms, and pilus loss. Two of the open up characterization epilepsy trials reported a significant reduction of seizures (Smith et al 2004).

The half-life of the routine divalproex conception is about xiv hours in the absence of inducing drugs and decreases to well-nigh 9 hours in the presence of hepatic inducing drugs. The effects of concomitant enzyme-inducing AEDs on bio-availability was investigated comparison divalproex DR dosed tid vs divalproex ER dosed 8%–20% higher as a single daily dose with the following effect on AUC, C_max, C_min: 1539 vs 1551 mg/L, 92.six vs 83.3 mg L, and 44.eight vs 45.8 mg/50. The difference in height serum concentration was meaning. Thus, while the overall bioavailability of once daily divalproex ER is comparable with that achieved with thrice daily dosing of divalproex, the peak concentration achieved is less and in that location was a 64% acme to trough fluctuation (Sommerville et al 2003). The setting of concomitant inducing drugs may be where twice daily dosing of divalproex ER results in a flatter serum concentration fourth dimension bend with amend tolerability and potential seizure control (Dutta and Reed 2006a, b). This is further supported by derivation of the "functional half-life" of divalproex ER which was 40 hours in the absence of hepatic inducers only decreased to 27 hours with concomitant inducers, resulting in an approximate l% reduction (absenteeism of inducer) and 75% reduction (presence of inducer) from baseline trough serum concentration if one dose is missed and the adjacent dose occurs 48 hours later on the last dose (Dutta and Reed 2006a, b).

To summarize current feel with AED XR formulations, they offering ameliorate tolerability. Improvement of seizure control has been demonstrated only in not-controlled, open-label clinical trials. Choosing to dose a sustained release formulation canonical for in one case daily dosing twice daily, may be more "forgiving" if a medication dose is missed and meliorate tolerated in terms of adverse events, particularly in the presence of concomitant enzyme inducers.

Lamotrigine and lamotrigine XR pharmacokinetics

LTG, with a chemical name of iii, v-diamino-6-(2, 3-dichlo-rophenyl)-one,2,4-triazine, is a broad spectrum AED first approved in Ireland in 1990 and the Us in 1994 and now having over 5 million worldwide patient exposures. The firsthand release conception typically achieves a tiptop concentration 1.four–4.viii hours after oral dose. Information technology has virtually complete bioavailability (98%). Protein binding is weak at almost 55%. Drug interactions are substantially unidirectional with other drugs affecting the charge per unit of LTG metabolism but non vice versa. In adult healthy volunteers and patients on LTG monotherapy mean half-life is about 24 hours after some autoinduction. Metabolism is affected past concomitant drugs. Half-life is shortened to a mean of 12.6 hours in the presence of hepatic inducing drugs, such every bit phenytoin, carbamazepine, phenobarbital, and primidone, and less and then by oxcarbazepine, and lengthened to a hateful of almost 60 hours in the presence valproic acid. Other drugs inducing LTG metabolism include synthetic estrogens and progestins, HIV protease inhibitors such as lopinavir and rotinavir, rifampin, sertraline, escitaloprim, risperidone, and gingko. Oral contraceptives have been shown to decrease LTG serum concentrations about 50% in a controlled study (Sabers et al 2003; Christensen et al 2007). Concomitant assistants of hepatic inducers and inhibitors produces a "pseudo-monotherapy" state, again a half-life of about 24 hours. Clearance is age-dependent, upwardly to 2-fold faster in children compared with adults and slower in infants.

Metabolism is predominantly hepatic via glucuronidation with 75%–xc% recovered in urine equally a 2-N-glucuronide derivative and small additional metabolites, a 5-N-glucuronide, an North-ii methylated derivative, unidentified metabolites, and unchanged drug (Doig and Clare 1991; Sinz and Remmel 1991). Glucuronidation reactions are catalyzed by UDP-glucouryltransferase (UGT).

The UGTs exist as a super family unit of 117 enzymes divided into 4 families (UGT1, UGT2, UGT3, and UGT8) (Mackenzie et al 2005). UGTs cohabit a multifariousness of substrates of endogenous, ie, bilirubin, steroid hormones, thyroid hormones, bile acids and fatty soluble vitamins, and exogenous, drugs. UGT1A4 and UGT2B7 have major roles in N2-glucuronidation of LTG (Rowland et al 2006). Inter-individual variability of glucuronidation would be expected to be at least 10-fold (Burchell et al 2001). Data from healthy volunteers and epilepsy patients supports a 5- to x-fold inter-individual variability in lamotrigine clearance based on concentration to dose ratio (Armijo et al 1999; Hirsch et al 2004; Bootsma et al 2008; Tompson et al 2008).

LTG-IR is normally dosed twice daily except in the presence of valproic acid where dosing may be in one case a day. In the absence of inducing agents the trough to meridian ratio for immediate release LTG would on average be 0.75 (t1/2~24 hours) and in the presence of inducing agents 0.5 (t1/ii~12 hours). Minimal fluctuation would be expected in the presence of the inhibitor valproic acrid.

An extended release formulation of LTG has been developed and is currently being studied. LTG-XR tablets incorporate a modified release eroding matrix formulation (Dif-fCORE) designed to produce a steady dissolution rate over 12–xv hours (Tompson et al 2008).

The pharmacokinetic profile of LTG-XR in patients with epilepsy was recently published (Tompson et al 2008). Patients had a diagnosis of epilepsy, complex partial or generalized seizures) and were already on a stable dose of LTG-IR (immediate release) prior to enrollment. The study had an open up-characterization crossover blueprint beginning with a 2-week baseline on LTG-IR, followed by 2 weeks on LTG-XR, and then ane calendar week follow-upwardly dorsum on LTG-IR. Forty-four subjects were enrolled with 3 equal groups of patients based on concomitant AED effects on hepatic metabolism: neutral (n = 15), inducing (n = 15) or inhibiting (n = fourteen) LTG metabolism. Pharmacokinetic measures were steady land 24 hour serum concentration vs fourth dimension curves (AUC (0–24)), C_max, C_min, T_max (time to maximal serum concentration afterward oral dose), and fluctuation index. Fluctuation index measures flatness of the concentration time curve and is defined every bit (C_max – C_min) divided by the boilerplate serum concentration (C_avg). Data are given every bit the geometric mean (individual values are multiplied and so the nth root of the product is taken). Data variation was described past coefficient of variation defined every bit the standard departure divided by the hateful and so reported as a pct by multiplying by 100. Coefficient of variation is a dimensionless number assuasive comparing between datasets with wildly different means.

LTG daily doses, mean and range, were 400 mg (200–600 mg), 600 mg (200–1200 mg), and 200 mg (50–800 mg) for the neutral, induced, and inhibited groups respectively. LTG-IR was given every 12 hours and compared with one time daily dosing of LTG-XR. Median serum LTG concentration-time profiles over 24 hours for the ii LTG formulations are shown in Figure one. For the neutral and especially for the induced groups, the LTG-XR conception produced marked flattening of the serum concentration-time curves, slower absorption charge per unit and decreased fluctuation. At that place was no decrease of C_min fifty-fifty on the first twenty-four hour period of transition to LTG-XR. The effect was minimal for the inhibited group.

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Median serum lamotrigine concentration—fourth dimension profiles for steady-land LTG-IR on offset day of switch (Day xv) and steady-state XR in one case-daily (Twenty-four hours 28 for (A) induced subjects. (B) neutral subjects, and (C) inhibited subjects. Bid, twice-daily, qd, in one case-daily.

Reproduced with permission from Tompson DJ, Ali I, Oliver-Willwong R, et al 2008. Steady-country pharmacokinetics of lamotrigine when converting from a twice-daily firsthand-release to a once-daily extended-release conception in subjects with epilepsy (The COMPASS Study). Epilepsia, 49: 410–vii. Copyright © 2008 Blackwell Publishing.

The time to maximal serum concentration, T_max, for LTG-IR was typically 1–one.5 hours for the three groups ranging from 0.five to half dozen.thirteen. T_max was prolonged past LTG-XR for the neutral group to ten hours (range 0.00–24.00). Like T_max prolongation was noted for the inhibited group (mean nine.08, range ii.88–24.00 hours) but was somewhat shorter for the induced group (mean 6.00, range 0.00–23.85 hours). AUC (0–24) was similar for the 2 LTG formulations with the exception of the group on concomitant inducers where it was reduced on average 21% lower for the XR formulation with 90% confidence interval between x% and 31%. Steady-country C_max on LTG-XR compared with LTG-IR was on average 29% lower for the induced group compared to virtually 11% subtract for the neutral and inhibited groups. In contrast C_min for the three groups was similar for both LTG preparations. Equally would be expected, the fluctuation alphabetize during baseline on LTG-IR was lowest for the grouping on inhibitors (0.318), intermediate for the neutral grouping (0.545), and highest for the induced group (0.986). The fluctuation index at steady-land LTG-XR was 0.209 for the inhibited, 0.341 for the neutral but 0.817 for the induced group. A dose normalized statistical analysis comparing the primary pharmacokinetic parameters showed that both AUC (0–24) and C_max for the induced group was outside the 90% conviction interval relative to the neutral and inhibited groups (Tables 2, 3). The modest study did not observe a reduction of adverse events or improvement of seizure event in transitioning from LTG-IR to LTG-XR. However, over two-thirds (69%) of subjects reported a preference for LTG-XR and 17% reported no preference leaving only xiv% with a preference for twice daily dosing.

Table 2

Summary of serum lamotrigine pharmacokinetic parameters (geometric mean and % CVb)

Serum LTG PK parameter	Formulation
Serum LTG PK parameter	LTG-IR (day 14)	LTG-XR (day 15)	LTG-XR (solar day 28)
Induced
AUC (0–24) (μgh/ml)	100 (85.9%)	92.0 (75.nine%)	79.0 (100%)
Cmax (μg/ml)	6.71 (fourscore.v%)	5.49 (64.ane%)	4.77 (85.9%)
Cmin (μyard/ml)	2.66 (100%)	2.51 (79.1%)	2.10 (131%)
Fluctuation index	0.986 (40.1%)	0.780 (31%)	0.817 (l.0%)
Tmax (h)	1.01 (0.50–298)^a	6.00 (0.00–23.85)^a	4.00 (0.00–24.00)^a
Inhibited
AUC (0–24) (μgh/ml)	208 (59.seven%)	198 (62.8%)	167 (48.1%)
Cmax (μgrand/ml)	10.two (57.5%)	9.37 (58.3%)	7.77 (49.0%)
Cmin (μg/ml)	seven.44 (53.ix%)	7.41 (57.vi%)	six.32 (47.i%)
Fluctuation index	0.318 (27.0%)	0.240 (44.three%)	0.209 (16.4%)
Tmax (h)	1.00 (0.50–6.thirteen)^a	ix.08 (2.88–24.00)^a	xi.00 (0.00–24.00)^a
Neutral
AUC (0–24) (μgh/ml)	142 (43.iv%)	114 (44.3%)	138 (forty.viii%)
Cmax (μg/ml)	7.82 (39.3%)	five.80 (38.vii%)	six.83 (38.6%)
Cmin (μthousand/ml)	four.57 (46.half dozen%)	3.31 (66.4%)	four.87 (41.0%)
Fluctuation alphabetize	0.545 (29.5%)	0.470 (62.2%)	0.341 (40.6%)
Tmax (h)	1.l (0.50–three.02)^a	10.00 (0.00–24.00)^a	6.00 (0.00–24.00)^a

Table three

Summary of statistical analysis of dose normalized steady-country lamotrigine parameters

Serum LTG PK parameter	Geometric to the lowest degree squares hateful ratio (90% CI)
Serum LTG PK parameter	Induced	Inhibited	Neutral
AUC (0–24)	0.79 (0.688, 0.899)	0.94 (0.810, one.084)	1.00 (0.882, 1.140)
Cmax	0.71 (0.613, 0.823)	0.88 (0.750, ane.030)	0.89 (0.775, 1.026)
Cτ	0.99 (0.894, 1.094)	0.99 (0.884, 1.101)	one.xiv (i.033, 1.252)

Efficacy for LTG-XR for partial seizures was demonstrated confronting placebo in an add-on blinded study design (Naritoku et al 2007). The study included 238 patients (118 LTG-XR, 121 placebo) with a minimum of 8 partial seizures during the 8-week baseline while on ane–two baseline AEDs. Concomitant AEDs for the LTG-XR and placebo groups were carbamazepine (43% vs 42%), valproic acrid (23% vs 35%), topiramate (16% vs 14%), oxcarbazepine (9 % vs 18%), phenytoin (14% vs 13%), and levetiracam (thirteen% vs 11%). LTG-XR titration charge per unit and target dose was adjusted to the presence of valproic acid (200 mg/mean solar day), enzyme-inducing AEDs (500 mg/day), and 300 mg for metabolically neutral drugs. Eighty percent of subjects randomized to LTG-XR compared with 87% to placebo completed the study. During maintenance phase, 61.iii% of subjects on LTG-XR vs 42.2% on placebo accomplished at least a fifty% reduction in seizure frequency. Agin outcome rates were similar with 69% vs 62% reporting at least one adverse event except for dizziness (18% LTG-XR vs 5% placebo). Seventy-ane percent reporting dizziness were on carbamazepine. This association has been previously reported. At that place were no differences between LTG-XR and placebo on health outcomes questionnaires (Contour of Mood States, Epidemiologic Depression Scale, Quality of Life in Epilepsy-31-P, Liverpool Adverse Feel Contour, Seizure Severity Questionnaire, and the Epworth Sleepiness Scale).

In summary, the pharmacokinetic data show similar parameters for AUC (0–24), C_min, and C_max for LTG-XR and LTG–IR in the presence of the inhibitor valproic acrid or the absence of concomitant inducing AEDs. In the presence of inducing AEDs, the AUC and C_max were reduced 20%–xxx% and the fluctuation index, 0.817, was high compared with the absenteeism of inducers, 0.341. Therefore, in the presence of inducing drugs, LTG-XR twice daily dosing should be considered, particularly in patients more difficult to control. The achieved more than stable-serum concentration time curve may outweigh the pocket-size increment of medication adherence. The "boilerplate" patient on LTG-XR in the absence of inducing AEDs is likely to do very well. With the boilerplate 24 hour one-half-life of LTG, even missing a single dose is unlikely to exist catastrophic in most patients. However, LTG clearance rate is highly variable, and patients who are rapid metabolizers, identified by dose to concentration ratio, may also do good from the decreased fluctuation of the serum concentration time curve achieved with twice daily dosing and the "forgiveness" of a missed dose. Children with their rapid metabolism may also benefit from twice daily dosing.

In terms of benefits in seizure and tolerability, no differences were establish in a small pharmacokinetic report directly comparison LTG-XR and LTG-IR. Therefore, no straight statement can be made though extrapolation to experience with divalproex and carbamazepine XR formulations anticipates do good.

Lamotrigine indications and uses in epilepsy syndromes

LTG-IR was initially indicated as addition therapy in partial epilepsies in adults and afterward in children in a higher place the age of two. A recent report has demonstrated efficacy below two years of historic period downward to ane month of age (Piňa-Garza et al 2008). In the pivotal clinical trials in adults, daily dosages between 200 and 500 mg were studied. As most subjects were on concomitant enzyme-inducing AEDs, trough serum concentrations of only ane–4 μg/mL were accomplished (Messenheimer et al1994). More than contempo data suggest that serum concentrations of at least 15 μg/mL are generally well tolerated (Froscher et al 2002; Hirsch et al 2004; Morris et al 2004b). A pharmaco-dynamic interaction of lamotrigine with valproate to improve seizure control when combined has been reported for partial seizures (Pisani et al 1999) and generalized seizures (Ferrie and Panyiotopoulos 1994).

LTG is besides canonical in the treatment of generalized seizures in Lennox-Gastaut (Motte et al 1997). It is also approved for conversion to monotherapy (Gilliam et al 1998). With initiation of therapy, the ho-hum upward titration has prohibited blessing as initial therapy for epilepsy.

AEDs often have uses outside of epilepsy (Rogawski and Löscher 2004; Johannessen Landmark 2008). LTG has psychiatric indication with controlled studies showing efficacy in the handling of bipolar disorder (Calabrese et al 2008).

LTG-XR has been shown to take efficacy, compared with placebo, in fractional epilepsies in adults to date. This is the initial indication submitted to the FDA. Ongoing studies are evaluating efficacy in primary generalized tonic-clonic seizures (Biton et al 2008) and conversion to monotherapy. There is no reason to expect a different spectrum of activeness than for the immediate release formulation.

Virtually AEDs have rarely been formally studied in controlled, blinded designs of most specific epilepsy syndromes. LTG-IR has been described as having efficacy in a number of generalized epilepsy syndromes in non-controlled designs (Gericke et al 1999). Open-label studies have reported efficacy in childhood absence (Frank et al1999) and juvenile myoclonic epilepsy (Morris et al 2004a). LTG may worsen myoclonus in a subset of juvenile myoclonic epilepsy (Biraben et al 2000; Carrazana et al 2001). LTG has been reported to potentially worsen severe myoclonic epilepsy of infancy (Guerrini et al 1998).

Lamotrigine rubber and tolerability

General tolerability

Overall LTG-IR was well tolerated compared to placebo in a meta-analysis of clinical trials with the odds ratio for withdrawal of 1.19 (CI 95%: 0.79, 1.79). Review of data from placebo-controlled add-on studies showed the post-obit adverse events occurring a minimum of 3% more on LTG than on placebo: dizziness (35–5 = twenty), diplopia (25–6 = 19), ataxia (20–six = 14), nausea (xix–9 = 10), blurred vision (13–4 = 9), somnolence (xiii–vii = 6), airsickness (x–5 = five), abnormal coordination (half dozen–two = 4), tremor (v–ane = iv), indisposition (half dozen–3 = 3), and rhinitis, (xi–8 = iii). (Messenheimer et al 1998). Ataxia, diplopia, dizziness, and nausea occurred statistically more commonly with LTG treatment. Rash was noted in x% on LTG and 5% in controls.

Rash

Rash was the nigh common serious adverse consequence observed in both the add together-on and monotherapy clinical trials occurring in 42 of 3071 subjects (ane.4%) and ii of 443 (0.5%). Nigh rashes were simple morbiliform. Rash leading to hospitalization occurred in 11 (0.3%) and iv were Stevens-Johnson Syndrome (0.ane%). Toxic-epidermal necrolysis and hypersensitivity syndrome take been reported.

Rash almost ever occurs in the kickoff eight weeks later on the offset of LTG therapy. In the epilepsy trials, rash incidence was related to the effects of the concomitant AEDs on LTG metabolism: highest in the presence of the inhibitor valproic acrid (12.2%), lowest in the presence of inducing AEDs (2%) and with metabolically neutral AEDs (3%). These data suggest a concentration dependent effect. This was confirmed by review of rash incidence in trials of all indications with initial LTG dose and rash charge per unit as follows: 25 mg (~i%), fifty mg (~nine%), 100 mg (~12%), and 200 mg (38%). The rate of upward titration also affects rash rate: at calendar week 5, LTG dose 62.5 had a i.five% incidence compared with 12% at 375 mg/twenty-four hour period. These results led to the manufacturer's recommendation as to starting dose and upward titration rates for LTG in the presence of valproic acid, inducing AEDs, and neutral AEDs (Lamotrigine package insert 2007).

Decreasing the rate of initial titration was recommended by the manufacturer in 1993 and has dramatically decreased the incidence of rash, both benign (Hirsch et al 2006; Arif et al 2007) and serious (Kanner 2005; Mockenhaupt et al 2005). A German population-based study, using an academically run registry to ascertain all hospitalized cases of Stevens-Johnson Syndrome and toxic epidermal necrolysis combined with identified total and new users of lamotrigine via review of prescriptions claimed through the general health insurance plan covering 85% of the population, showed an incidence 5 cases per 4,450 exposures in 1993, 2 of 7,610 exposures in 1994, and three of 17,648 exposures in 1999. The rates of both beneficial and serious rash rate with initiation of LTG is now comparable to phenytoin, carbamazepine, phenobarbital, and zonisamide (Zonisamide packet insert 2008).

Pregnancy: teratogenesis and management

Until recently, counseling patients regarding the furnishings of AEDs on pregnancy outcome has relied on retrospective data that indicated a 2- to 3-fold increased gamble in the incidence of major malformations with the older AEDs (Holmes et al 2001; Perucca 2005b; Battino and Tomson 2007) with increasing risk on polytherapy, especially with valproic acid. The newer AEDs released since 1990 arrived with no data available to counsel women planning pregnancies. Therefore, multiple prospective registries have been established to make full this gap in information: national registries as the Swedish Medical Birth Registry and in Finland, contained academic registries as the North American Pregnancy registry, United Kingdom Register, European and International Registry of Antiepileptic Drugs and Pregnancy (EURAP) and the Australian Register, and pharmaceutical company registries. GlaxoSmithKline (GSK) began a pregnancy registry for women on LTG in 1992. More data are currently available for LTG than for whatsoever other new AED.

The GSK Lamotrigine pregnancy registry (2008) has accumulated 1155 outcomes involving start trimester monotherapy exposure and identified 31 major malformations for a rate of 2.7% (95% CI: 1.9%–iii.8%) compared with an estimated general population hazard of 1.62% (95% CI 0.9%–2.3%) identified by the Brigham and Women'southward Surveillance program and Metropolitan Atlanta Congenital Defects Programme. The registry is currently powered to find a 1.six-fold increase in monotherapy associated hazard (The Lamotrigine Pregnancy Registry Interim Report i September 1992 through 30 September 2007). Similar malformation rates are reported in the UK registry (3.2%, north = 647, 95% CI: 2.1%–4.9%) and North American registry (2.3%, n = 684, 95% CI: 0.9%–3.viii%) (Holmes et al 2008).

The United kingdom of great britain and northern ireland pregnancy registry suggests a dose-dependent effect of LTG seen by 200 mg/day or more (Morrow et al 2008). Dose-dependence has not been confirmed by the GSK registry in daily doses up to 400 mg with insufficient data at higher doses (Cunnington et al 2007) or for the North American registry (Holmes et al 2008).

An increased occurrence of facial cleft has been reported in 2 registries. The Swedish Medical Birth Registry found a scissure palate rate in xc first trimester LTG monotherapy exposures of 9.9 per 1000 compared to an expected rate of 2 per 1000; relative rate 4.v% (95% CI: 2.seven%–7.ane%). The N American Pregnancy Registry also identified a specific increase in not-syndromic scissure palates with LTG: in 684 outcomes there were three isolated cleft palates, one scissure lip, and ane crack palate plus cleft lip for a combined rate of 7.three/1000 compared to a rate in the comparison population of 0.vii/1000 (Holmes et al 2008). The comparator group was historical and taken from the Agile Malformations and Surveillance Program at Brigham and Women's Hospital in Boston with 206,224 infants and elective pregnancy terminations accumulated between 1972–1974 and 1979 and 2000. The rates of facial fissure were 1 in 647 outcomes for a rate of ii/1000 in the UK registry (Morrow et al 2006), 2 in 707 for a charge per unit of 3/grand in the GSK International Registry, 0 in 128 outcomes in the Australian Pregnancy Registry, and 0 of 51 outcomes in the Danish Multicentre Registry (Holmes et al 2008).

Overall multiple registries have power to exclude a two- to three-fold increase in major malformations by LTG. An increase in specific defects can not be excluded and several registries have noted an increased rate of facial clefts. There are major differences in the pattern of the registries that may business relationship for differences in outcome (Tomson et al 2007; French et al 2008). House conclusions will require identification of similar outcomes across registries. Studies of the effects of neonatal AED exposure on noesis are ongoing (Meador et al 2006; Tomson and Battino 2008).

LTG has been associated with increased frequency of seizures during pregnancy. This observation has been attributed to increased clearance of LTG with failing serum concentrations during pregnancy. The increase in LTG clearance is substantial with reports ranging from about 94% to 250% (Öhman et al 2008; Pennell et al 2008).

Quality of life

About 30% of patients complain of medication side effects, most commonly tiredness and cognition (Gilliam et al 1997, Fisher et al 2000). Specific complaints in decreasing order of study were bug of noesis, energy level, schoolhouse functioning, childbearing, coordination, and sexual function (Fisher et al 2000). Mood is as well a strong predictor of wellness cess in patients with epilepsy.

LTG has been compared to phenytoin, carbamazepine, valproic acid, and topiramate in double-blind, controlled trials of intractable epilepsy, new onset epilepsy or healthy volunteers. These studies accept consistently found meliorate cognitive status based on objective measures equally well equally improved quality of life and mood on subjective inventories (Cohen et al 1985; Gillham et al 2000; Sackellares et al 2002; Meador et al 2005; Blum et al 2006; Meador 2006). Like observations are noted in open characterization trials. LTG has also been associated with improved sexual function in women and men (Gil-Nagel et al 2006).

Conclusions

LTG is a broad spectrum AED that is typically dosed twice a day with good overall tolerability. In the presence of valproic acrid which inhibits metabolism via glucuronidation, LTG may easily be dosed once per day. LTG-XR is an improved formulation that will exist approved for once daily dosing. Extrapolating to experience with other extended release formulations, this should lead to improved tolerability, patient preference, compliance, and possibly seizure control. Notwithstanding, in patients with rapid metabolism or on concomitant hepatic inducing drugs, there is significant serum concentration fluctuation plus a lack of forgiveness for a missed dose of medication. Twice daily dosing in these patients may meliorate therapeutic coverage outweighing the modest refuse of adherence. Overall, LTG XR is a welcome amanuensis to our AED armamentarium.

Footnotes

Disclosures

The author has no conflicts of involvement to disclose.

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