A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Keppra Side Effects, and Drug Interactions - Levetiracetam
Keppra Side Effects, and Drug Interactions - Levetiracetam
SIDE EFFECTS
In well-controlled clinical studies, the most frequently reported
adverse events associated with the use of Keppra in combination with other AEDs,
not seen at an equivalent frequency among placebo-treated patients, were somnolence,
asthenia, infection and dizziness.
Table 4 lists treatment-emergent adverse events that occurred
in at least 1% of patients with epilepsy treated with Keppra participating in
placebo-controlled studies and were numerically more common in patients treated
with Keppra than placebo. In these studies, either Keppra or placebo was added
to concurrent AED therapy. Adverse events were usually mild to moderate in intensity.
The prescriber should be aware that these figures, obtained
when Keppra 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.
Table 4: Incidence (%) Of Treatment-Emergent Adverse Events
In Placebo-Controlled, Add-On Studies by Body System. (Adverse Events Occurred
In At Least 1% Of Keppra -Treated Patients And Occurred More Frequently Than
Placebo-Treated Patients.)
|
Body System/ Adverse Event
|
Keppra (N = 769) %
|
Placebo (N=439) %
|
|
Body as a Whole
|
|
Asthenia
|
15
|
9
|
|
Headache
|
14
|
13
|
|
Infection
|
13
|
8
|
|
Pain
|
7
|
6
|
|
Digestive System
|
|
Anorexia
|
3
|
2
|
|
Nervous System
|
|
Amnesia
|
2
|
1
|
|
Anxiety
|
2
|
1
|
|
Ataxia
|
3
|
1
|
|
Depression
|
4
|
2
|
|
Dizziness
|
9
|
4
|
|
Emotional Lability
|
2
|
0
|
|
Hostility
|
2
|
1
|
|
Nervousness
|
4
|
2
|
|
Paresthesia
|
2
|
1
|
|
Somnolence
|
15
|
8
|
|
Vertigo
|
3
|
1
|
|
Respiratory System
|
|
Cough Increased
|
2
|
1
|
|
Pharyngitis
|
6
|
4
|
|
Rhinitis
|
4
|
3
|
|
Sinusitis
|
2
|
1
|
|
Special Senses
|
|
Diplopia
|
2
|
1
|
Other events reported by 1% or more of patients treated with
Keppra but as or more frequent in the placebo group were: abdominal pain, accidental
injury, amblyopia, arthralgia, back pain, bronchitis, chest pain, confusion,
constipation, convulsion, diarrhea, drug level increased, dyspepsia, ecchymosis,
fever, flu syndrome, gastroenteritis, gingivitis, grand mal convulsion, infection
fungal, insomnia, nausea, otitis media, rash, thinking abnormal, tremor, urinary
tract infection, vomiting and weight gain.
Time Course Of Onset Of Adverse Events
Of the most frequently reported adverse events, asthenia, somnolence
and dizziness appeared to occur predominantly during the first four weeks of
treatment with Keppra.
Discontinuation Or Dose Reduction In Well-Controlled Clinical
Studies
In well-controlled clinical studies, 15.0% of patients receiving
Keppra and 11.6% receiving placebo either discontinued or had a dose reduction
as a result of an adverse event. The adverse events most commonly associated
(>1%) with discontinuation or dose reduction in either treatment group are
presented in Table 5.
Table 5: Adverse Events Most Commonly Associated With Discontinuation
Or Dose Reduction In Placebo-Controlled Studies In Patients With Epilepsy
| |
Number (%)
|
|
|
Keppra (N= 769)
|
Placebo (N = 439)
|
|
Asthenia
|
10 (1.3%)
|
3 (0.7%)
|
|
Convulsion
|
23 (3.0%)
|
15 (3.4%)
|
|
Dizziness
|
11 (1.4%)
|
0
|
|
Somnolence
|
34 (4.4%)
|
7 (1.6%)
|
|
Rash
|
0
|
5 (1.1%)
|
Comparison Of Gender, Age And Race
The overall adverse experience profile of Keppra 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.
DRUG ABUSE AND DEPENDENCE
The abuse and dependence potential of Keppra has not been evaluated
in human studies.
DRUG INTERACTIONS
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, warfarin, digoxin, oral contraceptive) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients.
Drug-Drug Interactions between Keppra and Existing Antiepileptic Drugs (AEDs)
Potential drug interactions between Keppra and existing AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) were 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 existing AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam.
Other Drug Interactions
Oral Contraceptives
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.
Digoxin
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.
Warfarin
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
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
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 (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
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 ³ 350 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 ³ 600 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.
Pregnancy Exposure Registry
To facilitate monitoring fetal outcomes of pregnant women exposed to Keppra physicians are encouraged to register patients, before fetal outcome is known (e.g., ultrasound, results of amniocentesis, etc.), in the Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334 (toll free).
Labor And Delivery
The effect of Keppra on labor and delivery in humans is unknown.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Keppra is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in patients below the age of 16 have not been established.
Geriatric Use
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. The dosage should be
reduced in patients with impaired renal function receiving Keppra and supplemental
doses should be given to patients after dialysis (see DOSAGE
AND ADMINISTRATION, Patients with Impaired Renal Function).
top
