Levetiracetam 750 MG Oral Tablet
Generic Name: LEVETIRACETAM
Brand Name: Levetiracetam
- Substance Name(s):
- LEVETIRACETAM
OVERDOSAGE
10 10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans The highest known dose of Levetiracetam received in the clinical development program was 6000 mg/day.
Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials.
Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with Levetiracetam overdoses in postmarketing use.
10.2 Management of Overdose There is no specific antidote for overdose with Levetiracetam.
If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway.
General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient’s clinical status.
A Certified Poison Control Center should be contacted for up to date information on the management of overdose with Levetiracetam.
10.3 Hemodialysis Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose.
Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.
DESCRIPTION
11 Levetiracetam is an antiepileptic drug available as 250 mg (pink), 500 mg (pink), 750 mg (pink), and 1000 mg (white) tablets for oral administration.
The chemical name of levetiracetam, USP, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C 8H 14N 2O 2 and its molecular weight is 170.21.
Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs).
It has the following structural formula: Levetiracetam is a white to off-white crystalline powder with a faint odor and a bitter taste.
It is very soluble in water (104.0 g/100 mL).
It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane.
(Solubility limits are expressed as g/100 mL solvent.) Levetiracetam tablets contain the labeled amount of levetiracetam, USP.
Inactive ingredients: colloidal silicon dioxide, corn starch, magnesium stearate, povidone, talc, and additional agents listed below: 250 mg, 500 mg, and 750 mg tablets: Opadry II Pink 40L94198, which contains D&C Red No.27; FD&C Blue No.2; FD&C Red No.
40; FD&C Yellow No.
6; hypromellose 2910 3cP, 6cP, and 50cP; polydextrose FCC; polyethylene glycol 800; titanium dioxide; and triacetin.
1000 mg tablets: Opadry II white Y-22-7719, which contains hypromellose 2910 3cP, 6cP, and 50cP; polydextrose FCC; polyethylene glycol 800; titanium dioxide; and triacetin.
USP dissolution test is pending.
Levetiracetam Structural Formula
CLINICAL STUDIES
14 14.1 Partial Onset Seizures Effectiveness in Partial Onset Seizures in Adults with Epilepsy The effectiveness of Levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in adults was established in three multicenter, randomized, double-blind, placebo-controlled clinical studies in patients who had refractory partial onset seizures with or without secondary generalization.
The tablet formulation was used in all these studies.
In these studies, 904 patients were randomized to placebo, 1000 mg, 2000 mg, or 3000 mg/day.
Patients enrolled in Study 1 or Study 2 had refractory partial onset seizures for at least two years and had taken two or more classical AEDs.
Patients enrolled in Study 3 had refractory partial onset seizures for at least 1 year and had taken one classical AED.
At the time of the study, patients were taking a stable dose regimen of at least one and could take a maximum of two AEDs.
During the baseline period, patients had to have experienced at least two partial onset seizures during each 4-week period.
Study 1 Study 1 was a double-blind, placebo-controlled, parallel-group study conducted at 41 sites in the United States comparing Levetiracetam 1000 mg/day (N=97), Levetiracetam 3000 mg/day (N=101), and placebo (N=95) given in equally divided doses twice daily.
After a prospective baseline period of 12 weeks, patients were randomized to one of the three treatment groups described above.
The 18-week treatment period consisted of a 6-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant.
The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period).
Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency).
The results of the analysis of Study 1 are displayed in Table 10.
Table 10: Reduction in Mean Over Placebo in Weekly Frequency of Partial Onset Seizures in Study 1 Placebo (N=95) Levetiracetam 1000 mg/day (N=97) Levetiracetam 3000 mg/day (N=101) Percent reduction in partial seizure frequency over placebo – 26.1% Statistically significant versus placebo 30.1% The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) is presented in Figure 1.
Figure 1: Responder Rate (greater than or equal to 50% Reduction from Baseline) in Study 1 Study 2 Study 2 was a double-blind, placebo-controlled, crossover study conducted at 62 centers in Europe comparing Levetiracetam 1000 mg/day (N=106), Levetiracetam 2000 mg/day (N=105), and placebo (N=111) given in equally divided doses twice daily.
The first period of the study (Period A) was designed to be analyzed as a parallel-group study.
After a prospective baseline period of up to 12 weeks, patients were randomized to one of the three treatment groups described above.
The 16-week treatment period consisted of the 4-week titration period followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant.
The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period).
Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency).
The results of the analysis of Period A are displayed in Table 11.
Table 11: Reduction in Mean Over Placebo in Weekly Frequency of Partial Onset Seizures in Study 2: Period A Placebo (N=111) Levetiracetam 1000 mg/day (N=106) Levetiracetam 2000 mg/day (N=105) Percent reduction in partial seizure frequency over placebo – 17.1% Statistically significant versus placebo 21.4% The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) is presented in Figure 2.
The comparison of Levetiracetam 2000 mg/day to Levetiracetam 1000 mg/day for responder rate was statistically significant ( P=0.02).
Analysis of the trial as a cross-over yielded similar results.
Figure 3: Responder Rate (≥50% Reduction From Baseline) In Study 3 Study 3 Study 3 was a double-blind, placebo-controlled, parallel-group study conducted at 47 centers in Europe comparing Levetiracetam 3000 mg/day (N=180) and placebo (N=104) in patients with refractory partial onset seizures, with or without secondary generalization, receiving only one concomitant AED.
Study drug was given in two divided doses.
After a prospective baseline period of 12 weeks, patients were randomized to one of two treatment groups described above.
The 16-week treatment period consisted of a 4-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED doses were held constant.
The primary measure of effectiveness was a between group comparison of the percent reduction in weekly seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period).
Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial onset seizure frequency).
Table 12 displays the results of the analysis of Study 3.
Table 12: Reduction in Mean Over Placebo in Weekly Frequency of Partial Onset Seizures in Study 3 Placebo (N=104) Levetiracetam 3000 mg/day (N=180) Percent reduction in partial seizure frequency over placebo – 23.0% Statistically significant versus placebo The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 3.
Figure 3: Responder Rate (greater than or equal to 50% Reduction from Baseline) in Study 3 Effectiveness in Partial Onset Seizures in Pediatric Patients 4 Years to 16 Years with Epilepsy The effectiveness of Levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in pediatric patients was established in one multicenter, randomized double-blind, placebo-controlled study (Study 4), conducted at 60 sites in North America, in pediatric patients 4 to 16 years of age with partial seizures uncontrolled by standard antiepileptic drugs (AEDs).
Eligible patients on a stable dose of 1-2 AEDs, who still experienced at least 4 partial onset seizures during the 4 weeks prior to screening, as well as at least 4 partial onset seizures in each of the two 4-week baseline periods, were randomized to receive either Levetiracetam or placebo.
The enrolled population included 198 patients (Levetiracetam N=101, placebo N=97) with refractory partial onset seizures, whether or not secondarily generalized.
The study consisted of an 8-week baseline period and 4-week titration period followed by a 10 week evaluation period.
Dosing was initiated at a dose of 20 mg/kg/day in two divided doses.
During the treatment period, Levetiracetam doses were adjusted in 20 mg/kg/day increments, at 2-week intervals to the target dose of 60 mg/kg/day.
The primary measure of effectiveness was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire 14-week randomized treatment period (titration + evaluation period).
Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial onset seizure frequency per week).
Table 13 displays the results of this study.
Table 13: Reduction in Mean Over Placebo in Weekly Frequency of Partial Onset Seizures in Study 4 Placebo (N=97) Levetiracetam (N=101) Percent reduction in partial seizure frequency over placebo – 26.8% Statistically significant versus placebo The percentage of patients (y-axis) who achieved ≥ 50% reduction in weekly seizure rates from baseline in partial onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 4.
Figure 4: Responder Rate (greater than or equal to 50% Reduction from Baseline) Effectiveness in Partial Onset Seizures in Pediatric Patients 1 Month to <4 Years with Epilepsy The effectiveness of Levetiracetam as adjunctive therapy in pediatric patients was established in one multicenter, randomized double-blind, placebo-controlled study (Study 5), conducted at 62 sites in North America, South America, and Europe in pediatric patients 1 month to less than 4 years of age with partial seizures, uncontrolled by standard epileptic drugs (AEDs).
Eligible patients on a stable dose of 1-2 AEDs, who experienced at least 2 partial onset seizures during the 48-hour baseline video EEG were randomized to receive either Levetiracetam or placebo.
The enrolled population included 116 patients (Levetiracetam N=60, placebo N=56) with refractory partial onset seizures, whether or not secondarily generalized.
Randomization was stratified by age range as follows: 1 month to less than 6 months of age (N=4 treated with Levetiracetam), 6 months to less than 1 year of age (N=8 treated with Levetiracetam), 1 year to less than 2 years of age (N=20 treated with Levetiracetam), and 2 years to less than 4 years of age (N=28 treated with Levetiracetam).
The study consisted of a 5-day evaluation period which included a 1-day titration period followed by a 4-day maintenance period.
Levetiracetam dosing was determined by age and weight as follows: children 1 month to less than 6 months old were randomized to a target dose of 40 mg/kg/day, and children 6 months to less than 4 years old were randomized to a target dose of 50 mg/kg/day.
The primary measure of effectiveness was the responder rate (percent of patients with ≥ 50% reduction from baseline in average daily partial onset seizure frequency) assessed by a blinded central reader using a 48-hour video EEG performed during the last two days of the 4-day maintenance period.
A total of 109 patients were included in the efficacy analysis.
A statistically significant difference between Levetiracetam and placebo was observed (see Figure 5).
The treatment effect associated with Levetiracetam was consistent across age groups. Figure 5: Responder Rate for All Patients Ages 1 Month to < 4 Years (≥ 50% Reduction from Baseline) in Study 5 figure 5 14.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Effectiveness of Myoclonic Seizures in Patients ≥12 Years of Age with Juvenile Myoclonic Epilepsy (JME) The effectiveness of Levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in patients 12 years of age and older with juvenile myoclonic epilepsy (JME) experiencing myoclonic seizures was established in one multicenter, randomized, double-blind, placebo-controlled study (Study 6), conducted at 37 sites in 14 countries.
Of the 120 patients enrolled, 113 had a diagnosis of confirmed or suspected JME.
Eligible patients on a stable dose of 1 antiepileptic drug (AED) experiencing one or more myoclonic seizures per day for at least 8 days during the prospective 8-week baseline period were randomized to either Levetiracetam or placebo (Levetiracetam N=60, placebo N=60).
Patients were titrated over 4 weeks to a target dose of 3000 mg/day and treated at a stable dose of 3000 mg/day over 12 weeks (evaluation period).
Study drug was given in 2 divided doses.
The primary measure of effectiveness was the proportion of patients with at least 50% reduction in the number of days per week with one or more myoclonic seizures during the treatment period (titration + evaluation periods) as compared to baseline.
Table 14 displays the results for the 113 patients with JME in this study.
Table 14: Responder Rate (≥50% Reduction from Baseline) in Myoclonic Seizure Days per Week for Patients with JME in Study 6 Placebo (N=59) Levetiracetam (N=54) Percentage of responders 23.7% 60.4% Statistically significant versus placebo 14.3 Primary Generalized Tonic-Clonic Seizures Effectiveness in Primary Generalized Tonic-Clonic Seizures in Patients ≥6 Years of Age The effectiveness of Levetiracetam as adjunctive therapy (added to other antiepileptic drugs) in patients 6 years of age and older with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic (PGTC) seizures was established in one multicenter, randomized, double-blind, placebo-controlled study (Study 7), conducted at 50 sites in 8 countries.
Eligible patients on a stable dose of 1 or 2 antiepileptic drugs (AEDs) experiencing at least 3 PGTC seizures during the 8-week combined baseline period (at least one PGTC seizure during the 4 weeks prior to the prospective baseline period and at least one PGTC seizure during the 4-week prospective baseline period) were randomized to either Levetiracetam or placebo.
The 8-week combined baseline period is referred to as “baseline” in the remainder of this section.
Patients were titrated over 4 weeks to a target dose of 3000 mg/day for adults or a pediatric target dose of 60 mg/kg/day and treated at a stable dose of 3000 mg/day (or 60 mg/kg/day for children) over 20 weeks (evaluation period).
Study drug was given in 2 equally divided doses per day.
The primary measure of effectiveness was the percent reduction from baseline in weekly PGTC seizure frequency for Levetiracetam and placebo treatment groups over the treatment period (titration + evaluation periods).
The population included 164 patients (Levetiracetam N=80, placebo N=84) with idiopathic generalized epilepsy (predominately juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy, or epilepsy with Grand Mal seizures on awakening) experiencing primary generalized tonic-clonic seizures.
Each of these syndromes of idiopathic generalized epilepsy was well represented in this patient population.
There was a statistically significant decrease from baseline in PGTC frequency in the Levetiracetam-treated patients compared to the placebo-treated patients.
Table 15: Median Percent Reduction From Baseline In PGTC Seizure Frequency Per Week in Study 7 Placebo (N=84) Levetiracetam (N=78) Percent reduction in PGTC seizure frequency 44.6% 77.6% Statistically significant versus placebo The percentage of patients (y-axis) who achieved ≥50% reduction in weekly seizure rates from baseline in PGTC seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) is presented in Figure 6.
Figure 6: Responder Rate (greater than or equal to 50% Reduction from Baseline) in PGTC Seizure Frequency per Week
HOW SUPPLIED
16 /STORAGE AND HANDLING 16.1 How Supplied Levetiracetam tablets, USP, 250 mg are pink, oblong-shaped, bi-convex, scored film coated tablets, debossed “SLC” and “221” on either side of the score and plain on the other side.
They are supplied in containers of 120 tablets (NDC 43547-221-15).
Levetiracetam tablets, USP, 500 mg are pink, oblong-shaped, bi-convex, scored film coated tablets, debossed “SLC” and”222″ on either side of the score and plain on the other side.
They are supplied in containers of 120 tablets (NDC 43547-222-15), and 1,000 tablets (NDC 43547-222-11).
Levetiracetam tablets, USP, 750 mg are pink, oblong-shaped, bi-convex, scored film coated tablets, debossed “SLC” and”223″ on either side of the score and plain on the other side.
They are supplied in containers of 120 tablets (NDC 43547-223-15).
Levetiracetam tablets, USP, 1000 mg are white to off-white, modified capsules shaped, bi-convex, scored film-coated tablets, debossed “SLC” and”224″ on either side of the score and plain on the other side.
They are supplied in containers of 60 tablets (NDC 43547-224-06).
16.2 Storage Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Pharmacist: Dispense in a tight, light-resistant container with a child-resistant closure.
RECENT MAJOR CHANGES
Warnings and Precautions, ( 5.1, 5.3, 5.7, 5.8) 03/2015
GERIATRIC USE
8.5 Geriatric Use There were 347 subjects in clinical studies of levetiracetam that were 65 and over.
No overall differences in safety were observed between these subjects and younger subjects.
There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of Levetiracetam in these patients.
Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)].
DOSAGE FORMS AND STRENGTHS
3 Levetiracetam tablets, USP, 250 mg are pink, oblong-shaped, bi-convex, scored film coated tablets, debossed “SLC” and “221” on either side of the score and plain on the other side.
Levetiracetam tablets, USP, 500 mg are pink, oblong-shaped, bi-convex, scored film coated tablets, debossed “SLC” and “222” on either side of the score and plain on the other side.
Levetiracetam tablets, USP, 750 mg are pink, oblong-shaped, bi-convex, scored film coated tablets, debossed “SLC” and “223” on either side of the score and plain on the other side.
Levetiracetam tablets, USP, 1000 mg are white to off-white, modified capsules shaped, bi-convex, scored film-coated tablets, debossed “SLC” and “224” on either side of the score and plain on the other side.
250 mg, 500 mg, 750 mg, and 1000 mg film-coated, scored tablets ( 3)
MECHANISM OF ACTION
12.1 Mechanism of Action The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown.
The antiepileptic activity of levetiracetam was assessed in a number of animal models of epileptic seizures.
Levetiracetam did not inhibit single seizures induced by maximal stimulation with electrical current or different chemoconvulsants and showed only minimal activity in submaximal stimulation and in threshold tests.
Protection was observed, however, against secondarily generalized activity from focal seizures induced by pilocarpine and kainic acid, two chemoconvulsants that induce seizures that mimic some features of human complex partial seizures with secondary generalization.
Levetiracetam also displayed inhibitory properties in the kindling model in rats, another model of human complex partial seizures, both during kindling development and in the fully kindled state.
The predictive value of these animal models for specific types of human epilepsy is uncertain.
In vitro and in vivo recordings of epileptiform activity from the hippocampus have shown that levetiracetam inhibits burst firing without affecting normal neuronal excitability, suggesting that levetiracetam may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity.
Levetiracetam at concentrations of up to 10 μM did not demonstrate binding affinity for a variety of known receptors, such as those associated with benzodiazepines, GABA (gamma-aminobutyric acid), glycine, NMDA (N-methyl-D-aspartate), re-uptake sites, and second messenger systems.
Furthermore, in vitro studies have failed to find an effect of levetiracetam on neuronal voltage-gated sodium or T-type calcium currents and levetiracetam does not appear to directly facilitate GABAergic neurotransmission.
However, in vitro studies have demonstrated that levetiracetam opposes the activity of negative modulators of GABA- and glycine-gated currents and partially inhibits N-type calcium currents in neuronal cells.
A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam.
Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis.
Although the molecular significance of levetiracetam binding to SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in audiogenic seizure-prone mice.
These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug.
INDICATIONS AND USAGE
1 Levetiracetam is indicated for adjunctive therapy in the treatment of: Partial onset seizures in patients one month of age and older with epilepsy ( 1.1) Myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy ( 1.2) Primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy ( 1.3) 1.1 Partial Onset Seizures Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children 1 month of age and older with epilepsy.
1.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Levetiracetam is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy.
1.3 Primary Generalized Tonic-Clonic Seizures Levetiracetam is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy.
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of Levetiracetam in the adjunctive treatment of partial onset seizures in pediatric patients age 1 month to 16 years old with epilepsy have been established [see Clinical Studies (14.1)] .
The dosing recommendation in these pediatric patients varies according to age group and is weight-based [see Dosage and Administration (2.2)].
The safety and effectiveness of Levetiracetam as adjunctive treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established [ see Clinical Studies (14.2)].
The safety and effectiveness of Levetiracetam as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established [see Clinical Studies (14.3)].
A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of Levetiracetam as adjunctive therapy in 98 (Levetiracetam N=64, placebo N=34) pediatric patients, ages 4 to 16 years old, with partial seizures that were inadequately controlled.
The target dose was 60 mg/kg/day.
Neurocognitive effects were measured by the Leiter-R Attention and Memory (AM) Battery, which measures various aspects of a child’s memory and attention.
Although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority of the drug and placebo.
The Achenbach Child Behavior Checklist (CBCL/6-18), a standardized validated tool used to assess a child’s competencies and behavioral/emotional problems, was also assessed in this study.
An analysis of the CBCL/6-18 indicated on average a worsening in Levetiracetam-treated patients in aggressive behavior, one of the eight syndrome scores [see Warnings and Precautions (5.1)] .
Studies of levetiracetam in juvenile rats (dosing from day 4 through day 52 of age) and dogs (dosing from week 3 through week 7 of age) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m 2 basis) did not indicate a potential for age-specific toxicity.
PREGNANCY
8.1 Pregnancy Levetiracetam blood levels may decrease during pregnancy [see Warnings and Precautions (5.9)].
Pregnancy Category C There are no adequate and controlled studies in pregnant women.
In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses.
Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Oral administration of levetiracetam to female rats throughout pregnancy and lactation led to increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses ≥350 mg/kg/day (equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/m 2 basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/m 2 basis).
The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m 2 basis).
There was no overt maternal toxicity at the doses used in this study.
Oral administration of levetiracetam to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and increased incidences of minor fetal skeletal abnormalities at doses ≥600 mg/kg/day (4 times MRHD on a mg/m 2 basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a mg/m 2 basis).
The developmental no effect dose was 200 mg/kg/day (equivalent to the MRHD on a mg/m 2 basis).
Maternal toxicity was also observed at 1800 mg/kg/day.
When levetiracetam was administered orally to pregnant rats during the period of organogenesis, fetal weights were decreased and the incidence of fetal skeletal variations was increased at a dose of 3600 mg/kg/day (12 times the MRHD).
1200 mg/kg/day (4 times the MRHD) was a developmental no effect dose.
There was no evidence of maternal toxicity in this study.
Treatment of rats with levetiracetam during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m 2 basis).
Pregnancy Registry To provide information regarding the effects of in utero exposure to Levetiracetam, physicians are advised to recommend that pregnant patients taking Levetiracetam 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 the patients themselves.
Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
NUSRING MOTHERS
8.3 Nursing Mothers Levetiracetam is excreted in human milk.
Because of the potential for serious adverse reactions in nursing infants from Levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Behavioral abnormalities including psychotic symptoms, suicidal ideation, irritability, and aggressive behavior have been observed; monitor patients for psychiatric signs and symptoms ( 5.1) Suicidal Behavior and Ideation: Monitor patients for new or worsening depression, suicidal thoughts/behavior, and/or unusual changes in mood or behavior ( 5.2) Monitor for somnolence and fatigue and advise patients not to drive or operate machinery until they have gained sufficient experience on Levetiracetam ( 5.3) Withdrawal Seizures: Levetiracetam must be gradually withdrawn ( 5.6) 5.1 Behavioral Abnormalities and Psychotic Symptoms Levetiracetam may cause behavioral abnormalities and psychotic symptoms.
Patients treated with Levetiracetam should be monitored for psychiatric signs and symptoms.
Behavioral abnormalities In clinical studies, 13% of adult Levetiracetam-treated patients and 38% of pediatric Levetiracetam-treated patients (4 to 16 years of age) compared to 6% and 19% of adult and pediatric placebo-treated patients, experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder).
A randomized double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of Levetiracetam as adjunctive therapy in pediatric patients (4 to 16 years of age).
The results from an exploratory analysis indicated a worsening in Levetiracetam-treated patients on aggressive behavior (one of eight behavior dimensions) as measured in a standardized and systematic way using a validated instrument, the Achenbach Child Behavior Checklist (CBCL/6-18).
In clinical studies in pediatric patients 1 month to < 4 years of age, irritability was reported in 12% of the Levetiracetam-treated patients compared to 0% of placebo-treated patients.
In clinical studies, 1.7% of adult Levetiracetam-treated patients discontinued treatment due to behavioral adverse reactions, compared to 0.2% of placebo-treated patients.
The treatment dose was reduced in 0.8% of adult Levetiracetam-treated patients and in 0.5% of placebo-treated patients.
Overall, 11% of Levetiracetam-treated pediatric patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6% of placebo-treated patients.
Psychotic symptoms In clinical studies, 1% of Levetiracetam-treated adult patients, 2% of Levetiracetam-treated pediatric patients 4 to 16 years of age, and 17% of Levetiracetam-treated pediatric patients 1 month to <4 years of age experienced psychotic symptoms, compared to 0.2%, 2%, and 5% in the corresponding age groups treated with placebo.
In a controlled study that assessed the neurocognitive and behavioral effects of Levetiracetam in pediatric patients 4 to 16 years of age, 1.6% of Levetiracetam-treated patients experienced paranoia, compared to 0% of placebo-treated patients.
In the same study, 3.1% of Levetiracetam-treated patients experienced confusional state, compared to 0% of placebo-treated patients [see Use in Specific Populations (8.4)] .
In clinical studies, two (0.3%) Levetiracetam-treated adult patients were hospitalized and their treatment was discontinued due to psychosis.
Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation.
There was no difference between drug and placebo-treated patients in the incidence of the pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions.
5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including Levetiracetam, 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 (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one 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 to patients randomized to placebo.
In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.
There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number 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 one week after starting drug 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 mechanisms 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 (5-100 years) in the clinical trials analyzed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Tabel 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 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 Levetiracetam or any other AED must balance the risk of suicidal thoughts or behaviors 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, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.
5.3 Somnolence and Fatigue Levetiracetam may cause somnolence and fatigue.
Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on Levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.
Somnolence In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 15% of Levetiracetam-treated patients reported somnolence, compared to 8% of placebo-treated patients.
There was no clear dose response up to 3000 mg/day.
In a study where there was no titration, about 45% of patients receiving 4000 mg/day reported somnolence.
The somnolence was considered serious in 0.3% of Levetiracetam-treated patients, compared to 0% in the placebo group.
About 3% of Levetiracetam-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo-treated patients.
In 1.4% of Levetiracetam-treated patients and 0.9% of placebo-treated patients, the dose was reduced, while 0.3% of the Levetiracetam-treated patients were hospitalized due to somnolence.
Asthenia In controlled clinical studies of adult patients with epilepsy experiencing partial onset seizures, 15% of Levetiracetam-treated patients reported asthenia, compared to 9% of placebo-treated patients.
Treatment was discontinued due to asthenia in 0.8% of Levetiracetam-treated patients as compared to 0.5% of placebo-treated patients.
In 0.5% of Levetiracetam-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to asthenia.
Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment.
In general, the incidences of somnolence and fatigue in the pediatric partial onset seizure studies, and in pediatric and adult myoclonic and primary generalized tonic-clonic seizure studies were comparable to those of the adult partial onset seizure studies.
5.4 Serious Dermatological Reactions Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both pediatric and adult patients treated with Levetiracetam.
The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment.
Recurrence of the serious skin reactions following rechallenge with Levetiracetam has also been reported.
Levetiracetam should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related.
If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.
5.5 Coordination Difficulties Levetiracetam may cause coordination difficulties.
In controlled clinical studies in adult patients with partial onset seizure studies, 3.4% of adult Levetiracetam-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo-treated patients.
A total of 0.4% of patients in controlled clinical studies discontinued Levetiracetam treatment due to ataxia, compared to 0% of placebo-treated patients.
In 0.7% of Levetiracetam-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to coordination difficulties, while one of the Levetiracetam-treated patients was hospitalized due to worsening of pre-existing ataxia.
These events occurred most frequently within the first 4 weeks of treatment.
Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on Levetiracetam to gauge whether it could adversely affect their ability to drive or operate machinery.
5.6 Withdrawal Seizures Antiepileptic drugs, including Levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.
5.7 Hematologic Abnormalities Levetiracetam can cause hematologic abnormalities.
Hematologic abnormalities occurred in clinical trials and included decreases in red blood cell (RBC) counts, hemoglobin, and hematocrit, and increases in eosinophil counts.
Decreased white blood cell (WBC) and neutrophil counts also occurred in clinical trials.
Cases of agranulocytosis have been reported in the postmarketing setting.
Partial Onset Seizures Adults Minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 10 6/mm 3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in Levetiracetam-treated patients in controlled trials.
A total of 3.2% of Levetiracetam-treated and 1.8% of placebo-treated patients had at least one possibly significant (≤2.8 x 10 9/L) decreased WBC, and 2.4% of Levetiracetam-treated and 1.4% of placebo-treated patients had at least one possibly significant (≤1.0 x 10 9/L) decreased neutrophil count.
Of the Levetiracetam-treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment.
No patient was discontinued secondary to low neutrophil counts.
Pediatric Patients 4 Years to < 16 Years Statistically significant decreases in WBC and neutrophil counts were seen in Levetiracetam-treated patients as compared to placebo.
The mean decreases from baseline in the Levetiracetam-treated group were -0.4 × 10 9/L and -0.3 × 10 9/L, respectively, whereas there were small increases in the placebo group.
Mean relative lymphocyte counts increased by 1.7% in Levetiracetam-treated patients, compared to a decrease of 4% in placebo patients (statistically significant).
In the controlled trial, more Levetiracetam-treated patients had a possibly clinically significant abnormally low WBC value (3% of Levetiracetam-treated patients versus 0% of placebo-treated patients), however, there was no apparent difference between treatment groups with respect to neutrophil count (5% of Levetiracetam-treated patients versus 4.2% of placebo-treated patients).
No patient was discontinued secondary to low WBC or neutrophil counts.
In the controlled cognitive and neuropsychological safety study, 5 patients (8.6%) in the Levetiracetam-treated group and two patients (6.1%) in the placebo-treated group and 5 subjects (8.6%) in the Levetiracetam-Treated group had high eosinophil count values that were possibly clinically significant (≥10% or ≥ 0.7 x 10 9/L).
5.8 Increase in Blood Pressure In a randomized, placebo-controlled study in patients 1 month to <4 years of age, a significantly higher risk of increased diastolic blood pressure was observed in the Levetiracetam-treated patients (17%), compared to the placebo-treated patients (2%).
There was no overall difference in mean diastolic blood pressure between the treatment groups.
This disparity between the Levetiracetam and placebo treatment groups was not observed in the studies of older children or in adults.
Monitor patients 1 month to <4 years of age for increases in diastolic blood pressure.
5.9 Seizure Control During Pregnancy Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy.
This decrease is more pronounced during the third trimester.
It is recommended that patients be monitored carefully during pregnancy.
Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Suicidal Behavior and Ideation Counsel patients, their caregivers, and/or families that antiepileptic drugs (AEDs), including Levetiracetam , may increase the risk of suicidal thoughts and behavior and advise patients to be alert for the emergence or worsening of symptoms of depression; unusual changes in mood or behavior; or suicidal thoughts, behavior, or thoughts about self-harm.
Advise patients, their caregivers, and/or families to immediately report behaviors of concern to a healthcare provider.
Psychiatric Reactions and Changes in Behavior Advise patients that Levetiracetam may cause changes in behavior (e.g.
aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and psychotic symptoms.
Effects on Driving or Operating Machinery Inform patients that Levetiracetam may cause dizziness and somnolence.
Inform patients not to drive or operate machinery until they have gained sufficient experience on Levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.
Dermatological Adverse Reactions Advise patients that serious dermatological adverse reactions have occurred in patients treated with Levetiracetam and instruct them to call their physician immediately if a rash develops.
Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during Levetiracetam therapy.
Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant.
This registry is collecting information about the safety of antiepileptic drugs during pregnancy.
To enroll, patients can call the toll free number 1-888-233-2334.
[see Use In Specific Populations (8.1)].
Manufactured by: Zhejiang Huahai Pharmaceutical Co., Ltd.
Xunqiao, Linhai, Zhejiang 317024, China Distributed by: Solco Healthcare US, LLC Cranbury, NJ 08512, USA Revised: 12/2015 07347-06
DOSAGE AND ADMINISTRATION
2 Use the oral solution for pediatric patients with body weight ≤ 20 kg ( 2.1).
For pediatric patients, use weight-based dosing for the oral solution with a calibrated measuring device (not a household teaspoon or tablespoon) ( 2.1) Partial Onset Seizures 1 Month to < 6 Months: 7 mg/kg twice daily; increase by 7 mg/kg twice daily every 2 weeks to recommended dose of 21 mg/kg twice daily ( 2.2) 6 Months to < 4 Years: 10 mg/kg twice daily; increase by 10 mg/kg twice daily every 2 weeks to recommended dose of 25 mg/kg twice daily ( 2.2) 4 Years to < 16 Years: 10 mg/kg twice daily; increase by 10 mg/kg twice daily every 2 weeks to recommended dose of 30 mg/kg twice daily ( 2.2) Adults 16 Years and Older: 500 mg twice daily; increase by 500 mg twice daily every 2 weeks to a recommended dose of 1500 mg twice daily ( 2.2) Myoclonic Seizures in Adults and Pediatric Patients 12 Years and Older 500 mg twice daily; increase by 500 mg twice daily every 2 weeks to recommended dose of 1500 mg twice daily ( 2.3) Primary Generalized Tonic-Clonic Seizures 6 Years to < 16 Years: 10 mg/kg twice daily, increase in increments of 10 mg/kg twice daily every 2 weeks to recommended dose of 30 mg/kg twice daily ( 2.4) Adults 16 Years and Older: 500 mg twice daily, increase by 500 mg twice daily every 2 weeks to recommended dose of 1500 mg twice daily ( 2.4) Adult Patients with Impaired Renal Function Dose adjustment is recommended, based on the patient’s estimated creatinine clearance ( 2.5, 8.6) 2.1 Important Administration Instructions Levetiracetam is given orally with or without food.
The Levetiracetam dosing regimen depends on the indication, age group, dosage form (tablets or oral solution), and renal function.
Prescribe the oral solution for pediatric patients with body weight ≤ 20 kg.
Prescribe the oral solution or tablets for pediatric patients with body weight above 20 kg.
When using the oral solution in pediatric patients, dosing is weight-based (mg per kg) using a calibrated measuring device (not a household teaspoon or tablespoon).
2.2 Dosing for Partial Onset Seizures Adults 16 Years and Older Initiate treatment with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily).
Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg.
There is no evidence that doses greater than 3000 mg/day confer additional benefit.
Pediatric Patients 1 Month to < 6 Months:Initiate treatment with a daily dose of 14 mg/kg in 2 divided doses (7 mg/kg twice daily).
Increase the daily dose every 2 weeks by increments of 14 mg/kg to the recommended daily dose of 42 mg/kg (21 mg/kg twice daily).
In the clinical trial, the mean daily dose was 35 mg/kg in this age group.
The effectiveness of lower doses has not been studied.
6 Months to <4 Years:Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).
Increase the daily dose in 2 weeks by an increment of 20 mg/kg to the recommended daily dose of 50 mg/kg (25 mg/kg twice daily).
If a patient cannot tolerate a daily dose of 50 mg/kg, the daily dose may be reduced.
In the clinical trial, the mean daily dose was 47 mg/kg in this age group.
4 Years to < 16 Years:Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).
Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily).
If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced.
In the clinical trial, the mean daily dose was 44 mg/kg.
The maximum daily dose was 3000 mg/day.
For Levetiracetam tablet dosing in pediatric patients weighing 20 to 40 kg, initiate treatment with a daily dose of 500 mg given as twice daily dosing (250 mg twice daily).
Increase the daily dose every 2 weeks by increments of 500 mg to a maximum recommended daily dose of 1500 mg (750 mg twice daily).
For Levetiracetam tablet dosing in pediatric patients weighing more than 40 kg, initiate treatment with a daily dose of 1000 mg/day given as twice daily dosing (500 mg twice daily).
Increase the daily dose every 2 weeks by increments of 1000 mg/day to a maximum recommended daily dose of 3000 mg (1500 mg twice daily).
2.3 Dosing for Myoclonic Seizures in Patients 12 Years of Age and Older with Juvenile Myoclonic Epilepsy Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily).
Increase the dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg.
The effectiveness of doses lower than 3000 mg/day has not been studied.
2.4 Dosing for Primary Generalized Tonic-Clonic Seizures Adults 16 Years and Older Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily).
Increase dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg.
The effectiveness of doses lower than 3000 mg/day has not been adequately studied.
Pediatric Patients Ages 6 to <16 Years Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).
Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily).
The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.
Patients with body weight ≤20 kg should be dosed with oral solution.
Patients with body weight above 20 kg can be dosed with either tablets or oral solution [see Dosage and Administration (2.1)].
Only whole tablets should be administered.
2.5 Dosage Adjustments in Adult Patients with Renal Impairment Levetiracetam tablets dosing must be individualized according to the patient’s renal function status.
Recommended dosage adjustments for adults are shown in Table 1.
In order to calculate the dose recommended for patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated.
To do this an estimate of the patient’s creatinine clearance (CLcr) in mL/min must first be calculated using the following formula: Then CLcr is adjusted for body surface area (BSA) as follows: Table 1: Dosing Adjustment Regimen for Adult Patients with Renal Impairment Group Creatinine Clearance (mL/min/1.73m 2) Dosage (mg) Frequency Normal > 80 500 to 1,500 Every 12 hours Mild 50 – 80 500 to 1,000 Every 12 hours Moderate 30 – 50 250 to 750 Every 12 hours Severe < 30 250 to 500 Every 12 hours ESRD patients using dialysis ——- 500 to 1,000 Following dialysis, a 250 to 500 mg supplemental dose is recommended.
Every 24 hours Figure 2: Responder Rate (≥50% Reduction From Baseline) In Study 2: Period A Figure 3: Responder Rate (≥50% Reduction From Baseline) In Study 3