levetiracetam (Rx)

>10%

Asthenia (11-15%)

Headache (14-19%)

Infection (11-15%)

Increased blood pressure (17% in children < 4 years)

Somnolence (11-15%)

Drowsiness (2-23%)

Fatigue (10-11%)

Anorexia (3-13%)

Weakness (9-15%)

Nasopharyngitis (7-15%)

Cough (2-11%)

1-10%

Viral infection (2%)

Asthma (2%)

Dizziness (5-9%)

Nervousness (2-10%)

Amnesia (2%)

Anxiety (2-3%)

Ataxia (3%)

Depression (2-5%)

Hostility (10%)

Paresthesia (2%)

Sinusitis (2%)

Diplopia (2%)

Amblyopia (2%)

Conjunctivitis (2-3%)

Albuminuria (4%)

<1%

Abnormal hepatic function tests

Dyskinesia

Eczema

Neutropenia

Decreased hematocrit

Leukopenia

Suicidal tendencies

Hepatitis

Pancreatitis

Bone marrow suppression

Epidermal necrolysis

Postmarketing Reports

Hepatic: Abnormal liver function tests, hepatic failure, hepatitis, pancreatitis

Skin: Alopecia, erythema multiforme; drug rash with eosinophilia and systemic syndrome (DRESS)

Neurologic: Choreoathetosis, dyskinesia, worsening of seizures

Hematology: Leukopenia, neutropenia, pancytopenia, thrombocytopenia, agranulocytosis

Skeletomuscular: Muscle weakness

Psychological: Panic attack

General: Weight loss

Hyponatremia

Acute kidney injury

Anaphylaxis and angioedema

Contraindications

Hypersensitivity

Cautions

Somnolence and asthenia occurred most frequently within first 4 weeks of treatment; patients should be monitored for 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 ability to drive or operate machinery

As with most antiepileptic drugs, drug should generally be withdrawn gradually because of risk of increased seizure frequency and status epilepticus; if withdrawal needed because of serious adverse reaction, rapid discontinuation can be considered

Psychiatric reactions: 13.3% of adults and 37.6% of children treated with levetiracetam reported nonpsychotic behavioral symptoms (eg, aggression, agitation, anger, anxiety, apathy, depersonalization, lability, hostility, hyperkinesis, irritability, nervousness, neurosis, and personality disorder) compared to 6.2% and 18.6% of adult and pediatric placebo patients respectively; dose reduction or discontinuation may be required

Monitor patients for behavioral abnormalities including psychotic symptoms, suicidal ideation, irritability, aggressive behavior, and for new or worsening depression, suicidal thoughts/behavior, and/or unusual changes in mood or behavior

Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) reported; median time of onset is reported to be 14-17 days; if signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered

Drug rash with eosinophilia and systemic syndrome (DRESS) reported

May impair ability to operate heavy machinery

Therapy can cause hematologic abnormalities, including decreases in white blood cell (WBC), neutrophil, and red blood cell (RBC) counts; decreases in hemoglobin and hematocrit; and increases in eosinophil counts; cases of agranulocytosis, pancytopenia, and thrombocytopenia reported in postmarketing setting; a complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders

Increases in eosinophil counts observed

Monitor patients 1 month to <4 years of age for increases in diastolic blood pressure

Seizure control during pregnancy: Physiological changes during pregnancy may gradually decrease therapeutic plasma concentrations, this is particularly pronounced during the 3rd trimester; closely monitor serum levels during pregnancy and through the postpartum period

Agranulocytosis reported; in pediatric patients (4 to <16 years of age), statistically significant decreases in WBC and neutrophil counts were seen in patients treated with immediate-release levetiracetam; no patient was discontinued secondary to low WBC or neutrophil counts

One percent of adult patients and 2% of pediatric patients (4 to 16 years of age) treated with immediate-release levetiracetam experienced psychotic symptoms (paranoia)

Use caution in renal impairment; adjust dose; use immediate release formulation, instead of the extended release formulation, in patients with ESRD requiring hemodialysis

Can cause anaphylaxis or angioedema after the first dose or at any time during treatment; if patient develops signs or symptoms of anaphylaxis or angioedema, therapy should be discontinued and patient should seek immediate medical attention; therapy should be discontinued permanently if clear alternative etiology for reaction cannot be established

Pregnancy

There are no adequate and well-controlled studies in pregnant women; prolonged experience in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy registries, and reflects experience over two decades

In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus

Drug blood levels may decrease during pregnancy; physiological changes during pregnancy may affect drug concentration; decrease in drug plasma concentrations has been observed during pregnancy; this decrease is more pronounced during third trimester; dose adjustments may be necessary to maintain clinical response

Enroll patients in the North American Antiepileptic Drug pregnancy registry; 1-888-233-2334 or visit http://www.aedpregnancyregistry.org

Lactation

Drug is excreted in human milk; there are no data on effects of drug on breastfed infant, or on milk production

Unknown if distributed in human breast milk

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal conditio

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Antiepileptic mechanism unknown; may inhibit voltage-depedent N-type calcium channels; may bind to synaptic proteins that modulate neurotransmitter release; through displacement of negative modulators may facilitate GABA-ergic inhibitory transmission

Pyrrolidone derivative

Absorption

Bioavailability: 100%

Peak plasma time: 1 hr (immediate release); 4 hr (extended release)

Distribution

Protein bound: <10%

Metabolism

Metabolism: Hepatic enzymatic hydrolysis

Metabolites: Inactive

Elimination

Half-life: 6-8 hr (increased in elderly or renal disease)

Total body clearance: 0.96 mL/min/kg

Renal clearance: 0.6 mL/min/kg; 4 mL/min/kg (metabolite)

Clearance ~40% higher in children

Dialyzable: Yes

Excretion: Urine (66%)

IV Use

IV preparation: Dilute IV solution in 100 mL compatible solution

IV administration: Infuse IV over 15 minutes

Compatabilities

• Solutions: NS, LR, D5W
• Additive/syringe: lorazepam, diazepam, valproate sodium

Oral Administration

May take with or without food

Use oral solution for children who weigh ≤20 kg

Elepsia XR, Keppra XR: Swallow tablet whole; do not chew, split, crush, or cut tablets

Spritam

• Developed with ZipDose technology, which uses 3-dimensional printing to create a porous formulation of the antiepileptic that disintegrates rapidly with a sip of liquid, even at a high dose of up to 1000 mg
• May take with or without food
• Place the whole tablet on the tongue with a dry hand and follow with a sip of liquid
• Swallow only after tablet disintegrates in mouth (mean disintegration time 11 seconds [range 2-27 seconds])
• Tablet should not be swallowed intact
• Instruct patients not to push the tablet through the foil; the foil should be peeled from the blister by bending and lifting the peel tab around the blister seal so the table does not break

Storage

Unused vials: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)

May store diluted IV solution in PVC bags at 15-30°C (59-86°F) for up to 24 hr

Extended-release or immediate release tablets: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)

Solution: Store at 20-25°C (68-77°F)