Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including KEPPRA, 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 7 shows absolute and relative risk by indication for all evaluated AEDs.
Table 7 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|
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 KEPPRA 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.
Neuropsychiatric Adverse Events
Partial Onset Seizures
In adults experiencing partial onset seizures, KEPPRA 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 KEPPRA-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 KEPPRA-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 KEPPRA-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 KEPPRA 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 KEPPRA-treated patients experienced psychotic symptoms compared to 1 (0.2%) placebo patient. Two (0.3%) KEPPRA-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 KEPPRA 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 pediatric patients experiencing partial onset seizures, KEPPRA 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 KEPPRA-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 KEPPRA-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 KEPPRA-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 KEPPRA-treated patients compared to 0% of placebo patients.
A total of 37.6% of the KEPPRA-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 KEPPRA-treated patients, compared to 6.2% of placebo patients. Nervousness was reported in 9.9% of KEPPRA-treated patients, compared to 2.1% of placebo patients. Depression was reported in 3.0% of KEPPRA-treated patients, compared to 1.0% of placebo patients.
A total of 3.0% of KEPPRA-treated patients discontinued treatment due to psychotic and nonpsychotic adverse events, compared to 4.1% of placebo patients. Overall, 10.9% of KEPPRA-treated patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6.2% of placebo patients.
During clinical development, the number of patients with myoclonic seizures exposed to KEPPRA was considerably smaller than the number with partial seizures. Therefore, under-reporting of certain adverse events was more likely to occur in the myoclonic seizure population. In adult and adolescent patients experiencing myoclonic seizures, KEPPRA 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 KEPPRA-treated patients experienced somnolence compared to 1.7% of placebo patients. No patient discontinued treatment as a result of somnolence. In 1.7% of KEPPRA-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 KEPPRA-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 KEPPRA-treated patients compared to 3.3% of placebo patients. A total of 5.0% of KEPPRA-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 KEPPRA was considerably smaller than the number with partial epilepsy, described above. As in the partial seizure patients, behavioral symptoms appeared to be associated with KEPPRA treatment. Gait disorders and somnolence were also described in the study in primary generalized seizures, but with no difference between placebo and KEPPRA 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, KEPPRA 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 KEPPRA-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 KEPPRA-treated patients compared to 3.6% of placebo patients. Of the KEPPRA-treated patients experiencing non-psychotic behavioral disorders, one patient discontinued treatment due to aggression. Non-psychotic mood disorders (including anger, apathy, depression, mood altered, mood swings, negativism, and tearfulness) occurred in 12.7% of KEPPRA-treated patients compared to 8.3% of placebo patients. No KEPPRA-treated patients discontinued or had a dose reduction as a result of these events. One patient experienced delusional behavior that required the lowering of the dose of KEPPRA.
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 KEPPRA discontinuation. The other case was described as worsening of pre-existent schizophrenia and did not lead to drug discontinuation.
Antiepileptic drugs, including KEPPRA, should be withdrawn gradually to minimize the potential of increased seizure frequency.
Partial Onset Seizures
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 KEPPRA-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.
Minor, but statistically significant, decreases in WBC and neutrophil counts were seen in KEPPRA-treated patients as compared to placebo. The mean decreases from baseline in the KEPPRA-treated group were -0.4 × 109/L and -0.3 × 109/L, respectively, whereas there were small increases in the placebo group. Mean relative lymphocyte counts increased by 1.7% in KEPPRA-treated patients, compared to a decrease of 4% in placebo patients (statistically significant).
In the well-controlled trial, more KEPPRA-treated patients had a possibly clinically significant abnormally low WBC value (3.0% KEPPRA-treated versus 0% placebo), however, there was no apparent difference between treatment groups with respect to neutrophil count (5.0% KEPPRA-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.
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 and caregivers should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking KEPPRA. The Medication Guide may also be found in the full prescribing information for KEPPRA posted on http://www.ucb-usa.com or by calling 1-866-822-0068. Patients should be instructed to take KEPPRA only as prescribed.
Patients, their caregivers, and families should be counseled that AEDs, including KEPPRA, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of 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.
Patients should be advised that KEPPRA 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.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be encouraged 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. UCB, Inc. has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes associated with pregnant women being treated with all UCB antiepileptic drugs, including KEPPRA. To ensure broad program access and reach, either a healthcare provider or the patient can initiate enrollment in the UCB AED Pregnancy Registry by calling (888) 537-7734 (toll free) (See Pregnancy Section).
Patients should be advised that KEPPRA 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 KEPPRA to gauge whether it adversely affects their performance of these activities.
Although most laboratory tests are not systematically altered with KEPPRA treatment, there have been relatively infrequent abnormalities seen in hematologic parameters and liver function tests.
In vitro data on metabolic interactions indicate that KEPPRA 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 KEPPRA And Other Antiepileptic Drugs (AEDs)
KEPPRA (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.
KEPPRA (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 KEPPRA 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
KEPPRA (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.
KEPPRA (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.
KEPPRA (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, 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 KEPPRA on probenecid was not studied.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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.
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/m2 or exposure basis).
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. KEPPRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. As with other antiepileptic drugs, physiological changes during pregnancy may affect levetiracetam concentration. There have been reports of decreased levetiracetam concentration during pregnancy. Discontinuation of antiepileptic treatments may result in disease worsening, which can be harmful to the mother and the fetus.
To provide information regarding the effects of in utero exposure to KEPPRA, physicians are advised to recommend that pregnant patients taking KEPPRA 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/.
UCB, Inc. has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes associated with pregnant women being treated with all UCB antiepileptic drugs, including KEPPRA. To ensure broad program access and reach, either a healthcare provider or the patient can initiate enrollment in the UCB AED Pregnancy Registry by calling (888) 537-7734 (toll free).
Labor And Delivery
The effect of KEPPRA on labor and delivery in humans is unknown.
Levetiracetam is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from KEPPRA, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness in patients below 4 years of age have not been established.
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/m2 basis) did not indicate a potential for age-specific toxicity.
Of the total number of subjects in clinical studies of levetiracetam, 347 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 KEPPRA in these patients.
A study in 16 elderly subjects (age 61-88 years) with oral administration of single dose and multiple twice-daily doses for 10 days showed no pharmacokinetic differences related to age alone.
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.
Use In Patients With Impaired Renal Function
Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with impaired renal function receiving KEPPRA and supplemental doses should be given to patients after dialysis (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION, Adult Patients With Impaired Renal Function).