Lumark™

[Levetiracetam]

Lumark

Indications

LUMARK is indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy.

LUMARK 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.

LUMARK 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.

Contraindication

This product should not be administered to patients who have previously exhibited hypersensitivity to levetiracetam or any of the inactive ingredients in LUMARK tablets or oral solution.

Drug Interactions

In vitro data on metabolic interactions indicate that LUMARK is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above Cmax levels achieved within the therapeutic dose range, are neither inhibitors of nor high affinity substrates for human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.

Levetiracetam circulates largely unbound (<10% bound) to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely.

Potential pharmacokinetic interactions were assessed in clinical pharmacokinetic studies (phenytoin, valproate, oral contraceptive, digoxin, warfarin, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients.

Drug-Drug Interactions Between LUMARK And Other Antiepileptic Drugs (AEDs)

Phenytoin
LUMARK (3000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam were also not affected by phenytoin.

Valproate
LUMARK (1500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion. There also was no effect on exposure to and the excretion of the primary metabolite, ucb L057.

Potential drug interactions between LUMARK and other AEDs (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone and valproate) were also assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo-controlled clinical studies. These data indicate that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam.

Effect Of AEDs In Pediatric Patients
There was about a 22% increase of apparent total body clearance of levetiracetam when it was co-administered with enzyme-inducing AEDs. Dose adjustment is not recommended. Levetiracetam had no effect on plasma concentrations of carbamazepine, valproate, topiramate, or lamotrigine.

Other Drug Interactions

Oral Contraceptives
LUMARK (500 mg twice daily) did not influence the pharmacokinetics of an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel, or of the luteinizing hormone and progesterone levels, indicating that impairment of contraceptive efficacy is unlikely. Coadministration of this oral contraceptive did not influence the pharmacokinetics of levetiracetam.

Digoxin
LUMARK (1000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day. Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam.

Warfarin
LUMARK (1000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin. Prothrombin time was not affected by levetiracetam. Coadministration of warfarin did not affect the pharmacokinetics of levetiracetam.

Probenecid
Probenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day, did not change the pharmacokinetics of levetiracetam 1000 mg twice daily. Cssmax of the metabolite, ucb L057, was approximately doubled in the presence of probenecid while the fraction of drug excreted unchanged in the urine remained the same. Renal clearance of ucb L057 in the presence of probenecid decreased 60%, probably related to competitive inhibition of tubular secretion of ucb L057. The effect of LUMARK on probenecid was not studied.

Side Effects

The prescriber should be aware that the adverse event incidence figures in the following tables, obtained when LUMARK was added to concurrent AED therapy, cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.

Partial Onset Seizures
In well-controlled clinical studies in adults with partial onset seizures, the most frequently reported adverse events associated with the use of LUMARK in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, asthenia, infection and dizziness. In the well-controlled pediatric clinical study in children 4 to 16 years of age with partial onset seizures, the adverse events most frequently reported with the use of LUMARK in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, accidental injury, hostility, nervousness, and asthenia.

Other events reported by at least 1% of adult LUMARK-treated patients but as or more frequent in the placebo group were the following: abdominal pain, accidental injury, amblyopia, arthralgia, back pain, bronchitis, chest pain, confusion, constipation, convulsion, diarrhea, drug level increased, dyspepsia, ecchymosis, fever, flu syndrome, fungal infection, gastroenteritis, gingivitis, grand mal convulsion, insomnia, nausea, otitis media, rash, thinking abnormal, tremor, urinary tract infection, vomiting and weight gain.

Other events occurring in at least 2% of pediatric LUMARK-treated patients but as or more frequent in the placebo group were the following: abdominal pain, allergic reaction, ataxia, convulsion, epistaxis, fever, headache, hyperkinesia, infection, insomnia, nausea, otitis media, rash, sinusitis, status epilepticus (not otherwise specified), thinking abnormal, tremor, and urinary incontinence.

Myoclonic Seizures
Although the pattern of adverse events in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse event pattern for patients with JME is expected to be essentially the same as for patients with partial seizures.

In the well-controlled clinical study that included both adolescent (12 to 16 years of age) and adult patients with myoclonic seizures, the most frequently reported adverse events associated with the use of LUMARK in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, neck pain, and pharyngitis.

Other events occurring in at least 5% of LUMARK-treated patients with myoclonic seizures but as or more frequent in the placebo group were the following: fatigue and headache.

Primary Generalized Tonic-Clonic Seizures
Although the pattern of adverse events in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse event pattern for patients with PGTC seizures is expected to be essentially the same as for patients with partial seizures.

In the well-controlled clinical study that included patients 4 years of age and older with primary generalized tonic-clonic (PGTC) seizures, the most frequently reported adverse event associated with the use of LUMARK in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, was nasopharyngitis.

Other events occurring in at least 5% of LUMARK-treated patients with PGTC seizures but as or more frequent in the placebo group were the following: dizziness, headache, influenza, and somnolence.

Time Course Of Onset Of Adverse Events For Partial Onset Seizures
Of the most frequently reported adverse events in adults experiencing partial onset seizures, asthenia, somnolence and dizziness appeared to occur predominantly during the first 4 weeks of treatment with LUMARK.

Discontinuation Or Dose Reduction In Well-Controlled Clinical Studies

Partial Onset Seizures
In well-controlled adult clinical studies, 15.0% of patients receiving LUMARK and 11.6% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. Table 11 lists the most common (>1%) adverse events that resulted in discontinuation or dose reduction.

In the well-controlled pediatric clinical study, 16.8% of patients receiving LUMARK and 20.6% receiving placebo either discontinued or had a dose reduction as a result of an adverse event.

Myoclonic Seizures
In the placebo-controlled study, 8.3% of patients receiving LUMARK and 1.7% receiving placebo either discontinued or had a dose reduction as a result of an adverse event.

Primary Generalized Tonic-Clonic Seizures
In the placebo-controlled study, 5.1% of patients receiving LUMARK and 8.3% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of a treatment- emergent adverse event.

This study was too small to adequately characterize the adverse events leading to discontinuation. It is expected that the adverse events that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials

Comparison Of Gender, Age And Race
The overall adverse experience profile of LUMARK was similar between females and males. There are insufficient data to support a statement regarding the distribution of adverse experience reports by age and race.

Postmarketing Experience
In addition to the adverse experiences listed above, the following have been reported in patients receiving marketed LUMARK worldwide. The listing is alphabetized: abnormal liver function test, hepatic failure, hepatitis, leukopenia, neutropenia, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), thrombocytopenia, and weight loss. Alopecia has been reported with LUMARK use; recovery was observed in majority of cases where LUMARK was discontinued. There have been reports of suicidal behavior (including completed suicide) with marketed LUMARK. These adverse experiences have not been listed above, and data are insufficient to support an estimate of their incidence or to establish causation.

Drug Abuse and Dependence
The abuse and dependence potential of LUMARK has not been evaluated in human studies.

Warning and Precautions

Neuropsychiatric Adverse Events

Partial Onset Seizures

Adults
In adults experiencing partial onset seizures, LUMARK use is associated with the occurrence of central nervous system adverse events that can be classified into the following categories: 1) somnolence and fatigue, 2) coordination difficulties, and 3) behavioral abnormalities.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of LUMARK-treated patients reported somnolence, compared to 8.4% of placebo 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 the treated patients, compared to 0% in the placebo group. About 3% of LUMARK-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo patients. In 1.4% of treated patients and in 0.9% of placebo patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of treated patients reported asthenia, compared to 9.1% of placebo patients. Treatment was discontinued in 0.8% of treated patients as compared to 0.5% of placebo patients. In 0.5% of treated patients and in 0.2% of placebo patients the dose was reduced.

A total of 3.4% of LUMARK-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients. A total of 0.4% of patients in controlled trials discontinued LUMARK treatment due to ataxia, compared to 0% of placebo patients. In 0.7% of treated patients and in 0.2% of placebo patients the dose was reduced due to coordination difficulties, while one of the treated patients was hospitalized due to worsening of pre-existing ataxia.

Somnolence, asthenia and coordination difficulties occurred most frequently within the first 4 weeks of treatment.

In controlled trials of patients with epilepsy experiencing partial onset seizures, 5 (0.7%) of LUMARK-treated patients experienced psychotic symptoms compared to 1 (0.2%) placebo patient. Two (0.3%) LUMARK-treated patients were hospitalized and their treatment was discontinued. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation.

Two other events, reported as hallucinations, occurred after 1-5 months and resolved within 2-7 days while the patients remained on treatment. In one patient experiencing psychotic depression occurring within a month, symptoms resolved within 45 days while the patient continued treatment. A total of 13.3% of LUMARK patients experienced other behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.) compared to 6.2% of placebo patients. Approximately half of these patients reported these events within the first 4 weeks. A total of 1.7% of treated patients discontinued treatment due to these events, compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of treated patients and in 0.5% of placebo patients. A total of 0.8% of treated patients had a serious behavioral event (compared to 0.2% of placebo patients) and were hospitalized.

In addition, 4 (0.5%) of treated patients attempted suicide compared to 0% of placebo patients. One of these patients completed suicide. In the other 3 patients, the events did not lead to discontinuation or dose reduction. The events occurred after patients had been treated for between 4 weeks and 6 months.

Pediatric Patients
In pediatric patients experiencing partial onset seizures, LUMARK is associated with somnolence, fatigue, and behavioral abnormalities.

In the double-blind, controlled trial in children with epilepsy experiencing partial onset seizures, 22.8% of LUMARK-treated patients experienced somnolence, compared to 11.3% of placebo patients. The design of the study prevented accurately assessing dose-response effects. No patient discontinued treatment for somnolence. In about 3.0% of LUMARK-treated patients and in 3.1% of placebo patients the dose was reduced as a result of somnolence.

Asthenia was reported in 8.9% of LUMARK-treated patients, compared to 3.1% of placebo patients. No patient discontinued treatment for asthenia, but asthenia led to a dose reduction in 3.0% of LUMARK-treated patients compared to 0% of placebo patients.

A total of 37.6% of the LUMARK-treated patients experienced behavioral symptoms (reported as agitation, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesia, nervousness, neurosis, and personality disorder), compared to 18.6% of placebo patients. Hostility was reported in 11.9% of LUMARK-treated patients, compared to 6.2% of placebo patients. Nervousness was reported in 9.9% of LUMARK-treated patients, compared to 2.1% of placebo patients. Depression was reported in 3.0% of LUMARK-treated patients, compared to 1.0% of placebo patients. One LUMARK-treated patient experienced suicidal ideation.

A total of 3.0% of LUMARK-treated patients discontinued treatment due to psychotic and nonpsychotic adverse events, compared to 4.1% of placebo patients. Overall, 10.9% of LUMARK-treated patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6.2% of placebo patients.

Myoclonic Seizures
During clinical development, the number of patients with myoclonic seizures exposed to LUMARK was considerably smaller than the number with partial seizures. Therefore, underreporting of certain adverse events was more likely to occur in the myoclonic seizure population. In adult and adolescent patients experiencing myoclonic seizures, LUMARK is associated with somnolence and behavioral abnormalities. It is expected that the events seen in partial seizure patients would occur in patients with JME.

In the double-blind, controlled trial in adults and adolescents with juvenile myoclonic epilepsy experiencing myoclonic seizures, 11.7% of LUMARK-treated patients experienced somnolence compared to 1.7% of placebo patients. No patient discontinued treatment as a result of somnolence. In 1.7% of LUMARK-treated patients and in 0% of placebo patients the dose was reduced as a result of somnolence.

Non-psychotic behavioral disorders (reported as aggression and irritability) occurred in 5% of the LUMARK-treated patients compared to 0% of placebo patients. Non-psychotic mood disorders (reported as depressed mood, depression, and mood swings) occurred in 6.7% of LUMARK-treated patients compared to 3.3% of placebo patients. A total of 5.0% of LUMARK-treated patients had a reduction in dose or discontinued treatment due to behavioral or psychiatric events (reported as anxiety, depressed mood, depression, irritability, and nervousness), compared to 1.7% of placebo patients.

Primary Generalized Tonic-Clonic Seizures
During clinical development, the number of patients with primary generalized tonic-clonic epilepsy exposed to LUMARK was considerably smaller than the number with partial epilepsy, described above. As in the partial seizure patients, behavioral symptoms appeared to be associated with LUMARK treatment. Gait disorders and somnolence were also described in the study in primary generalized seizures, but with no difference between placebo and LUMARK treatment groups and no appreciable discontinuations. Although it may be expected that drug related events seen in partial seizure patients would be seen in primary generalized epilepsy patients (e.g. somnolence and gait disturbance), these events may not have been observed because of the smaller sample size.

In patients 6 years of age and older experiencing primary generalized tonic-clonic seizures, LUMARK is associated with behavioral abnormalities.

In the double-blind, controlled trial in patients with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic seizures, irritability was the most frequently reported psychiatric adverse event occurring in 6.3% of LUMARK-treated patients compared to 2.4% of placebo patients. Additionally, non-psychotic behavioral disorders (reported as abnormal behavior, aggression, conduct disorder, and irritability) occurred in 11.4% of the LUMARK-treated patients compared to 3.6% of placebo patients. Of the LUMARK-treated patients experiencing non-psychotic behavioral disorders, one patient discontinued treatment due to aggression. Non-psychotic mood disorders (reported as anger, apathy, depression, mood altered, mood swings, negativism, suicidal ideation, and tearfulness) occurred in 12.7% of LUMARK-treated patients compared to 8.3% of placebo patients. No LUMARK-treated patients discontinued or had a dose reduction as a result of these events. One LUMARK-treated patient experienced suicidal ideation. One patient experienced delusional behavior that required the lowering of the dose of LUMARK.

In a long-term open label study that examined patients with various forms of primary generalized epilepsy, along with the non-psychotic behavioral disorders, 2 of 192 patients studied exhibited psychotic-like behavior. Behavior in one case was characterized by auditory hallucinations and suicidal thoughts and led to LUMARK discontinuation. The other case was described as worsening of pre-existent schizophrenia and did not lead to drug discontinuation.

Withdrawal Seizures
Antiepileptic drugs, including LUMARK, should be withdrawn gradually to minimize the potential of increased seizure frequency.

Hematologic Abnormalities
Partial Onset Seizures

Adults
Minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in LUMARK-treated patients in controlled trials.

A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (<2.8 x 109/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (<1.0 x 109/L) decreased neutrophil count. Of the 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
Minor, but statistically significant, decreases in WBC and neutrophil counts were seen in LUMARK-treated patients as compared to placebo. The mean decreases from baseline in the LUMARK-treated group were -0.4 x 109/L and -0.3 x 109/L, respectively, whereas there were small increases in the placebo group. Mean relative lymphocyte counts increased by 1.7% in LUMARK-treated patients, compared to a decrease of 4% in placebo patients (statistically significant).

In the well-controlled trial, more LUMARK-treated patients had a possibly clinically significant abnormally low WBC value (3.0% LUMARK-treated versus 0% placebo), however, there was no apparent difference between treatment groups with respect to neutrophil count (5.0% LUMARK-treated versus 4.2% placebo). No patient was discontinued secondary to low WBC or neutrophil counts.

Juvenile Myoclonic Epilepsy
Although there were no obvious hematologic abnormalities observed in patients with JME, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients should be considered to be relevant for JME patients.

Hepatic Abnormalities
There were no meaningful changes in mean liver function tests (LFT) in controlled trials in adult or pediatric patients; lesser LFT abnormalities were similar in drug and placebo treated patients in controlled trials (1.4%). No adult or pediatric patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment.

Information For Patients

  • Patients should be instructed to take LUMARK only as prescribed.
  • Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
  • Patients should be advised that LUMARK may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate machinery or engage in other hazardous activities until they have gained sufficient experience on LUMARK to gauge whether it adversely affects their performance of these activities.
  • Patients should be advised that Lumark may cause changes in behavior (e.g. aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and in rare cases patients may experience psychotic symptoms and/or suicidal ideation.
  • Physicians should advise patients and caregivers to read the patient information leaflet which appears as the last section of the labeling.

    Laboratory Tests
    Although most laboratory tests are not systematically altered with LUMARK treatment, there have been relatively infrequent abnormalities seen in hematologic parameters and liver function tests.

    Carcinogenesis, Mutagenesis, Impairment Of Fertility

    Carcinogenesis
    Rats were dosed with levetiracetam in the diet for 104 weeks at doses of 50, 300 and 1800 mg/kg/day. The highest dose corresponds to 6 times the maximum recommended daily human dose (MRHD) of 3000 mg on a mg/m2 basis and it also provided systemic exposure (AUC) approximately 6 times that achieved in humans receiving the MRHD. There was no evidence of carcinogenicity. A study was conducted in which mice received levetiracetam in the diet for 80 weeks at doses of 60, 240 and 960 mg/kg/day (high dose is equivalent to 2 times the MRHD on a mg/m2 or exposure basis). Although no evidence for carcinogenicity was seen, the potential for a carcinogenic response has not been fully evaluated in that species because adequate doses have not been studied.

    Mutagenesis
    Levetiracetam was not mutagenic in the Ames test or in mammalian cells in vitro in the Chinese hamster ovary/HGPRT locus assay. It was not clastogenic in an in vitro analysis of metaphase chromosomes obtained from Chinese hamster ovary cells or in an in vivo mouse micronucleus assay. The hydrolysis product and major human metabolite of levetiracetam (ucb L057) was not mutagenic in the Ames test or the in vitro mouse lymphoma assay.

    Impairment Of Fertility
    No adverse effects on male or female fertility or reproductive performance were observed in rats at doses up to 1800 mg/kg/day (approximately 6 times the maximum recommended human dose on a mg/m2or exposure basis).

    Pregnancy

    Pregnancy Category C
    In animal studies, levetiracetam produced evidence of developmental toxicity at doses similar to or greater than human therapeutic doses.

    Administration to female rats throughout pregnancy and lactation was associated with increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses >350 mg/kg/day (approximately equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/m2 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/m2 basis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m2 basis). There was no overt maternal toxicity at the doses used in this study.

    Treatment of 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 (approximately 4 times MRHD on a mg/m2 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/m2 basis). The developmental no effect dose was 200 mg/kg/day (1.3 times the MRHD on a mg/m2 basis). Maternal toxicity was also observed at 1800 mg/kg/day.

    When pregnant rats were treated 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 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/m2 basis).

    There are no adequate and well-controlled studies in pregnant women. LUMARK should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    Labor And Delivery

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

    Nursing Mothers
    Levetiracetam is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from LUMARK, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

    Pediatric Use
    Safety and effectiveness in patients below 4 years of age have not been established.