Levetiracetam

Medical uses

Levetiracetam has been approved in the United States as add-on treatment for partial (focal), myoclonic, and tonic-clonic seizures. Levetiracetam has been approved in the European Union as a monotherapy treatment for epilepsy in the case of partial seizures, or as an adjunctive therapy for partial, myoclonic, and tonic-clonic seizures. Levetiracetam has been shown to reduce partial (focal) seizures by 50% or more as an add-on medication. It is also used in veterinary medicine for similar purposes.

Levetiracetam is sometimes used off-label to treat status epilepticus or to prevent seizures associated with subarachnoid hemorrhages.

Levetiracetam has potential benefits for other psychiatric and neurologic conditions such as Tourette syndrome, anxiety disorder, and Alzheimer's disease. However, its most serious adverse effects are behavioral, and its benefit-risk ratio in these conditions is not well understood.

Levetiracetam has not been found to be useful for treatment of neuropathic pain, nor for treatment of essential tremors. Levetiracetam has not been found to be useful for treating autism, but is an effective treatment for partial, myoclonic, or tonic-clonic seizures associated with autism spectrum disorder.

Pregnancy

Levetiracetam is a Pregnancy Category C Drug. Studies in female pregnant rats have shown minor fetal skeletal abnormalities when given maximum recommended human doses of levetiracetam orally throughout pregnancy and lactation.^[14]

Elderly

Studies were conducted to look for increased adverse effects in the elderly population as compared to younger patients. One such study published in Epilepsy Research showed no significant increase in incidence of adverse symptoms experienced by young or elderly patients with central nervous system (CNS) disorders.^[16]

Children

Levetiracetam may be safely used with caution in children over the age of 4. However, it has not been determined whether it can be safely given to children under the age of 4.

Kidney impairment

Kidney impairment decreases the rate of elimination of levetiracetam from the body. Individuals with reduced kidney function may require dose adjustments. Kidney function can be estimated from the rate of creatinine clearance.

Liver impairment

Dose adjustment of levetiracetam is not necessary in liver impairment.

Adverse effects

The most common adverse effects of levetiracetam treatment include CNS effects such as somnolence, decreased energy, headache, dizziness, and coordination difficulties. These adverse effects are most pronounced in the first month of therapy. About 4% of patients dropped out of pre-approval clinical trials due to these side effects.

About 13% of people taking levetiracetam experience adverse neuropsychiatric symptoms, which are usually mild. These include agitation, hostility, apathy, anxiety, emotional lability, and depression. Serious psychiatric adverse side effects that are reversed by drug discontinuation occur in about 1%. These include hallucinations, suicidal thoughts, or psychosis. These occurred mostly within the first month of therapy, but they could develop at any time during treatment.

A study published in 2005 suggests that the addition of pyridoxine (vitamin B6) may reduce some of the psychiatric symptoms.

Although rare, Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which appears as a painful spreading rash with redness and blistering and/or peeling skin, have been reported in patients treated with levetiracetam. The incidence of SJS following exposure to anti-epileptics such as levetiracetam is about 1 in 3,000.

Levetiracetam should not be used in people who have previously shown hypersensitivity to levetiracetam or any of the inactive ingredients in the tablet or oral solution. Such hypersensitivity reactions include, but are not limited to, unexplained rash with redness or blistered skin, difficulty breathing, and tightness in the chest or airways.

Suicide

Levetiracetam, along with other anti-epileptic drugs, can increase the risk of suicide behavior or thoughts. People taking levetiracetam should be monitored closely for signs of worsening depression, suicidal thoughts or tendencies, or any altered emotional or behavioral states.

Drug interactions

No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications. The pharmacokinetic profile of levetiracetam is not influenced by phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, lamotrigine, gabapentin, digoxin, oral contraceptives ethinylestradiol, or warfarin.

Mechanism of action

The exact mechanism by which levetiracetam acts to treat epilepsy is unknown. However, the drug binds to a synaptic vesicle glycoprotein, SV2A, and inhibits presynaptic calcium channels reducing neurotransmitter release and acting as a neuromodulator. This is believed to impede impulse conduction across synapses.

Absorption

The absorption of levetiracetam tablets and oral solution is rapid and essentially complete. The bioavailability of levetiracetam is close to 100 percent, and the effect of food on absorption is minor.

Distribution

The volume of distribution of levetiracetam is similar to total body water. Levetiracetam modestly binds to plasma proteins (less than 10%).

Metabolism

Levetiracetam does not undergo extensive metabolism, and the metabolites formed are not active and do not exert pharmacological activity. Metabolism of levetiracetam is not by liver cytochrome P450 enzymes, but through other metabolic pathways such as hydrolysis and hydroxylation.

Excretion

Levetiracetam is eliminated from the body primarily by the kidneys with about 66 percent of the original drug passed unchanged into urine. The plasma half-life of levetiracetam in adults is about 6 to 8 hours.

Available forms

Levetiracetam is available as regular and extended release oral formulations and as intravenous formulations.

The branded version Keppra is manufactured by UCB Pharmaceuticals Inc.

In 2015 Aprecia’s 3d-printed form of the drug was approved by the FDA.