Levetiracetam (Systemic)


VA CLASSIFICATION
Primary: CN400

Commonly used brand name(s): Keppra.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Anticonvulsant—

Indications

Accepted

Epilepsy, partial seizures (treatment adjunct)—Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures in adults with epilepsy.{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    170.21{01}

Solubility
    Very soluble in water (104 grams/100 mL); freely soluble in chloroform (65.3 grams/100 mL); freely soluble in methanol (53.6 grams/100 mL); soluble in ethanol (16.5 grams/100 mL); sparingly soluble in acetonitrile (5.7 grams/100 mL); and practically insoluble in n-hexane.{01}

Mechanism of action/Effect:

The exact mechanism of action is unknown but does not involve inhibitory and excitatory neurotransmission. Stereoselective binding of levetiracetam was confined to synaptic plasma membranes in the central nervous system with no binding occurring in peripheral tissue. Levetiracetam inhibits burst firing without affecting normal neuronal excitability, which suggests that it may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity.{01}

Absorption:

Rapid and almost complete. Oral bioavailability of levetiracetam tablets is 100%, and is not affected by food.{01}

Distribution:

Volume of distribution (Vol D) is 0.7 L/kg{02}

Protein binding:

Very low (< 10%){01}{02}

Biotransformation:

Levetiracetam is not extensively metabolized. The major metabolic pathway is the enzymatic hydrolysis of the acetamide group. Cytochrome P450 isoenzyme system is not involved in the metabolism of levetiracetam. Levetiracetam and its major metabolite are neither inhibitors of or substrates for cytochrome P450 isoforms, epoxide hydrolase, or UDP-glucuronidation enzymes.{01}

Half-life:

Elimination— 7 hours{01}

Time to peak concentration:

Oral—About 1 hour in fasted subjects.{01} Food may delay the time to peak plasma concentration by 1.5 hours, and decrease the peak concentration by 20%{01}.

Time to steady state concentration:

In patients with normal renal function, steady state is achieved after 2 days of multiple twice daily dosing{01}.

Note: The pharmacokinetics of levetiracetam are linear over the dose range of 500 to 5000 mg{01}.


Elimination:
    Renal excretion (glomerular filtration with subsequent partial tubular reabsorption) as unchanged drug represents 66% of the administered dose.{01}
    The inactive metabolite, ucb L057, is excreted by glomerular filtration and active tubular secretion.{01}


With impaired renal function——
        Levetiracetam clearance was reduced by 40% in patients with mild renal function impairment (creatinine clearance of 50-80 mL per minute per 1.73 square meters of body surface area [CLcr]), by 50% in patients with moderate renal function impairment (CLcr of 30-50 mL per minute), by 60% in patients with severe renal function impairment (CLcr less than 30 mL per minute), and by 70% in anuric (end stage renal disease) patients, as compared with the clearance in subjects with normal renal function (CLcr greater than 80 mL per minute){01}. Dosage reductions based on creatinine clearance are necessary in patients with impaired renal function{01}.
        In patients on hemodialysis, approximately 50% of the pool of levetiracetam in the body is removed during a standard 4-hour procedure.



Precautions to Consider

Carcinogenicity

There was no evidence of carcinogenicity in a study in rats receiving 50, 300 and 1800 mg of levetiracetam per kg of body weight (mg/kg) per day for 104 weeks. The 1800 mg/kg per day dose corresponds to 6 times the maximum recommended daily human dose (MRHD) of 3000 mg on a mg per square meter of body surface area (mg/m2) basis and it also provided systemic exposure (area under the time-concentration curve[AUC]) approximately 6 times that achieved in humans receiving the MRHD.{01}

Mutagenicity

Mutagenicity was not demonstrated in the Ames test or 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.{01}

Pregnancy/Reproduction
Fertility—
No adverse effects on male or female fertility or reproductive performance were observed in rats at doses up to 1800 mg/kg per day (approximately 6 times the maximum recommended human dose on a mg/m2 or exposure basis).{01}

Pregnancy—
Adequate and well–controlled studies in humans have not been done. Studies in animals have shown that levetiracetam causes developmental toxicity at doses similar to or greater than human therapeutic doses. Doses ³ 350 mg/kg per day (approximately equivalent to the maximum recommended human dose (MRHD) of 3000 mg on a mg/m 2 basis) was associated with increased incidences of minor fetal skeletal abnormalities and retarded offspring growth when administered to female rats throughout pregnancy and lactation. Doses of 1800 mg/kg per day (6 times the MRHD on a mg/m2 basis) was associated with increased pup mortality and offspring behavioral alterations. The developmental no effect dose was 70 mg/kg per day (0.2 times the MRHD on a mg/m 2 basis). {01}

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 per 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 per day (12 times the MRHD on a mg/m2basis). The developmental no effect dose was 200 mg/kg per day (1.3 times MRHD on a mg/m2basis). Maternal toxicity was also observed at 1800 mg/kg per day.{01}

Pregnant rats fed levetiracetam doses of 3600 mg/kg per day (12 times the MRHD) during the period of organogenesis produced offspring with decreased fetal weights and an increased incidence of fetal skeletal variations. {01}

No adverse developmental or maternal effects in rats treated during the last third of gestation and throughout lactation at doses up to 1800 mg/kg per day (6 times the MRHD on a mg/m2basis).{01}

FDA Pregnancy Category C{01}

Note: Note: To facilitate monitoring of fetal outcomes of pregnant women exposed to levetiracetam, physicians are encouraged to register patients in the Antiepileptic Drug Pregnancy Registry before fetal. outcome is known{01}.


Labor and delivery—The effect of levetiracetam on labor and delivery is not known{01}.

Breast-feeding

It is not known whether levetiracetam is distributed into breast milk. However, problems in humans have not been documented. {01}

Pediatrics

Appropriate studies on the relationship of age to the effects of levetiracetam have not been performed in the pediatric population in children up to the age of 16. Safety and efficacy have not been established.{01}

One pharmacokinetic study in 24 patients 6 to 12 years of age showed that the apparent clearance of levetiracetam was approximately 40 % higher than that in adults following oral administration of a single 20 mg/kg dose{01}.


Geriatrics


Appropriate studies performed to date have not demonstrated geriatric–specific problems that would limit the usefulness of levetiracetam in the elderly. However, elderly patients are more likely to have age–related renal function impairment which may require adjustment of dosage or dosing interval in patients receiving levetiracetam.{01}


Pharmacogenetics

. Due to the lack of important racial differences in creatinine clearance and the renal excretion of levetiracetam, pharmacokinetic differences due to race are not expected. Cross study comparisons between a small number of whites and Asians showed comparable pharmacokinetics.{01}

Clearances adjusted for body weight, but not maximum concentration and area under the curve, were comparable between men and women.{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Studies to assess potential pharmacokinetic interactions with levetiracetam have shown no clinically relevant interactions with digoxin, oral contraceptives, or warfarin to date{01}. Similarly, potential interactions with existing antiepileptic agents, including phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, and primidone, have not been demonstrated{01}.

Probenecid    (no interaction between probenecid and levetiracetam was observed; however, probenecid decreased the renal clearance of ucb L057 [inactive metabolite of levetiracetam] by 60%.{01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Hemoglobin
Hematocrit
Neutrophil count
Red blood cell count
White blood cell count    (minor decrease in values.{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to levetiracetam{01}
Risk-benefit should be considered when the following medical problems exist
» Renal function impairment    (reduction in total body clearance of levetiracetam; dosage reduction is recommended.{01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Note: Adverse events were usually mild to moderate in intensity.{01}


Those indicating need for medical attention
Incidence less frequent
    
Ataxia (clumsiness or unsteadiness; problems with muscle control or coordination)
    
diplopia (double vision)
    
infection (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)
    
mood or mental changes, including agitation
amnesia
anxiety
apathy
depersonalization
depression
emotional lability
hostility
and nervousness
    
sinusitis ( pain or tenderness around eyes and cheekbones; fever; stuffy or runny nose; headache; cough; shortness of breath or troubled breathing; tightness of chest or wheezing)

Note: Four patients attempted suicide during the premarketing clinical trials, 1 successfully; these attempts occurred at 4 weeks to 6 months of therapy with levetiracetam{01}. Psychotic symptoms and hallucinations also have been reported in a small number of patients, but resolved following discontinuation of levetiracetam{01}.
One-half of all other behavioral symptoms occurred within the first 4 weeks of therapy{01}.
In premarketing clinical trials, ataxia occurred most frequently within the first four weeks of treatment{01}.


{01}

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Asthenia ( loss of strength or energy; muscle pain or weakness; unusual weak feeling)—predominantly occur during the first four weeks of treatment
    
dizziness —predominantly occur during the first four weeks of treatment
    
headache
    
pain
    
pharyngitis (cough; dryness or soreness of throat; fever; hoarseness; runny nose; tender, swollen glands in neck; trouble in swallowing; voice changes)
    
somnolence (sleepiness or unusual drowsiness)—predominantly occur during the first four weeks of treatment
{01}
Incidence less frequent
    
Anorexia (loss of appetite; weight loss )
    
cough increased
    
paresthesia (burning, crawling, itching, numbness, prickling, pins and needles, or tingling feelings)
    
rhinitis (sneezing; stuffy nose; runny nose )
    
vertigo ( dizziness or light-headedness; feeling of constant movement of self or surroundings; sensation of spinning)

{01}



Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Experience with levetiracetam overdose is very limited. The highest known ingested dose was 6000 mg, and drowsiness was the only symptom reported in the few known cases of overdose.{01}


Treatment of overdose

Note: There is no specific antidote for levetiracetam overdose.{01}



To decrease absorption:
Emesis or gastric lavage should be attempted if indicated.{01}



To enhance elimination :
Standard hemodialysis should be considered, particularly, in select patients based on clinical state or renal impairment. Approximately 50% is removed in 4 hours.{01}



Monitoring:
Monitor vital signs and clinical status.{01}



Supportive care:
General supportive care.{01}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Levetiracetam in Volume II .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to levetiracetam.{01}
Other medical problems, especially renal function impairment.{01}

Proper use of this medication

» Compliance with therapy; not taking more or less medicine than prescribed; not missing any doses.{01}
Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses

» Proper storage

Precautions while using this medication
» Importance of regular visits to physician to check progress of therapy.

» Possible dizziness and somnolence; caution when driving or doing jobs requiring alertness.{01}

» Not discontinuing levetiracetam abruptly; consulting a physician about gradually reducing dosage.{01}


Side/adverse effects
Signs of potential side effects, especially depression.


General Dosing Information
May be taken with or without food.{01}

If discontinuation of levetiracetam is necessary, dosage should be reduced gradually to minimize the potential of increased seizure frequency.{01}


Oral Dosage Forms

LEVETIRACETAM TABLETS

Usual Adult Dose
Anticonvulsant, adjunctive treatment of partial seizures
Oral, initially 500 mg twice daily as an adjunct. Increase dose, as necessary, every 2 weeks in 1000 mg a day increments. {01}


Note: Dosage adjustment required for patients with impaired renal function.{01}

Creatinine Clearance (mL/min)  Dosage (mg)  Frequency 
> 80  500 to 1500   Every 12 hours 
50 to 80  500 to 1000  Every 12 hours 
30 to 50   250 to 750  Every 12 hours  
< 30  250 to 500  Every 12 hours 

End-stage renal disease patients using dialysis–500 to 1000 mg every 24 hours with a supplemental dose of 250 to 500 mg following dialysis.{01}


Usual adult prescribing limits
Up to 3000 mg a day.{01}

Usual Pediatric Dose
Safety and efficacy have not been established.{01}

Usual Geriatric Dose
See Usual adult dose.

Usual geriatric prescribing limits
See Usual adult prescribing limits.

Strength(s) usually available
U.S.—


250 mg (Rx) [Keppra ( colloidal silicon dioxide) ( corn starch) (hydroxypropyl methylcellulose) (magnesium stearate) (polyethylene glycol 4000) (povidone) (talc) ( titanium dioxide) (FD&C Blue No. 2)]


500 mg (Rx) [Keppra (colloidal silicon dioxide ) ( corn starch) (hydroxypropyl methylcellulose) (magnesium stearate) (polyethylene glycol 4000) (povidone ) (talc) (titanium dioxide ) ( FD&C Blue No. 2) ( yellow iron oxide)]


750 mg (Rx) [Keppra (colloidal silicon dioxide ) ( corn starch) (hydroxypropyl methylcellulose) (magnesium stearate) (polyethylene glycol 4000) (povidone ) (talc) (titanium dioxide ) (FD&C Blue No. 2) ( FD&C Yellow No. 6) (red iron oxide)]

Packaging and storage:
Store at 25 °C (77 °F); excursions permitted between 15 and 30 °C (59 and 86 °F). {01}

Auxiliary labeling:
   • May cause drowsiness.
   • May cause dizziness.



Developed: 04/14/2000



References
  1. Product Information: Keppra(TM) levetiracetam. UCB Pharma, Inc., Smyrna, Ga (PI revised 12/1/99) reviewed 3/2000.
  1. Kasteleijn-Nolst Trenite DGA & Edelbroek PM: Antiepileptic drug treatment in the nineties in The Netherlands. Pharm World Sci 1997; 19(2):60-69.
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