Levetiracetam Tablets

SPRITAM (levetiracetam) is an antiepileptic drug available as 250 mg, 500 mg, 750 mg, and 1000 mg round, white to off-white, spearmint-flavored tablets for oral suspension.

The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C8H14N2O2 and its molecular weight is 170.21. Levetiracetam is chemically unrelated to existing AEDs. It has the following structural formula:

Levetiracetam is a white to off-white crystalline powder with a faint odor and a bitter taste. It is very soluble in water (104.0 g/100 mL). It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane. (Solubility limits are expressed as g/100 mL solvent).

SPRITAM tablets for oral suspension contain 250 mg, 500 mg, 750 mg, or 1000 mg levetiracetam. Each tablet also contains the following inactive ingredients: colloidal silicon dioxide, glycerin, mannitol, microcrystalline cellulose, polysorbate 20, povidone, sucralose, butylated hydroxyanisole, and natural and artificial spearmint flavor.

SPRITAM tablets for oral suspension are unitary porous structures produced by a three-dimensional printing process that binds the powders without compression.

SPRITAM tablets for oral suspension disintegrate in a mean time of 11 seconds (ranging from 2 to 27 seconds) in the mouth, when taken with a sip of liquid, to produce small particles that may be swallowed.

The following serious adverse reactions are described below and elsewhere in the labeling:

• Behavioral Abnormalities and Psychotic Symptoms [see WARNINGS AND PRECAUTIONS]
• Suicidal Behavior and Ideation [see WARNINGS AND PRECAUTIONS]
• Somnolence and Fatigue [see WARNINGS AND PRECAUTIONS]
• Serious Dermatological Reactions [see WARNINGS AND PRECAUTIONS]
• Coordination Difficulties [see WARNINGS AND PRECAUTIONS]
• Hematologic Abnormalities [see WARNINGS AND PRECAUTIONS]
• Increase in Blood Pressure [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Partial Onset Seizures

In controlled clinical studies in adults with partial onset seizures, the most common adverse reactions in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, asthenia, infection, and dizziness. Of the most common adverse reactions in adults experiencing partial onset seizures, asthenia, somnolence, and dizziness occurred predominantly during the first 4 weeks of treatment with levetiracetam.

Table 3 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving levetiracetam in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy.

Table 3: Adverse Reactions in Pooled Placebo-Controlled, Add-On Studies in Adults with Partial Onset Seizures

In controlled adult clinical studies, 15% of patients receiving levetiracetam and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. Table 4 lists the most common ( > 1%) adverse reactions that resulted in discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients.

Table 4: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in Pooled Placebo-Controlled Studies in Adults with Partial Onset Seizures

The adverse reaction data presented below was obtained from a pooled analysis of two controlled clinical studies in pediatric patients 4 to less than 16 years of age with partial onset seizures. The most common adverse reactions in pediatric patients 4 to less than 16 years of age receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability.

Table 5 lists adverse reactions from the pooled pediatric controlled studies (4 to less than 16 years of age) that occurred in at least 2% of pediatric levetiracetam-treated patients and were numerically more common than in pediatric patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy.

Table 5: Adverse Reactions in Pooled Placebo-Controlled, Add-On Studies in Pediatric Patients 4 to 16 Years of Age with Partial Onset Seizures

In the controlled pooled pediatric clinical studies in patients 4 years to 16 years of age, 7% of patients receiving levetiracetam and 9% receiving placebo discontinued as a result of an adverse reaction.

Myoclonic Seizures

Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with JME is expected to be essentially the same as for patients with partial seizures.

In the controlled clinical study in patients 12 years of age and older with myoclonic seizures, the most common adverse reactions in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, neck pain, and pharyngitis.

Table 6 lists adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy.

Table 6: Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients 12 Years of Age and Older with Myoclonic Seizures

In the placebo-controlled study, 8% of patients receiving levetiracetam and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. The adverse reactions that led to discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients are presented in Table 7.

Table 7: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in a Placebo-Controlled Study in Patients with Juvenile Myoclonic Epilepsy

Primary Generalized Tonic-Clonic Seizures

Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with primary generalized tonic-clonic (PGTC) seizures is expected to be essentially the same as for patients with partial seizures.

In the controlled clinical trial in patients with PGTC seizures, the most common adverse reaction in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, was nasopharyngitis.

Table 8 lists adverse reactions that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy.

Table 8: Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients 4 Years of Age and Older with PGTC Seizures

In the placebo-controlled study, 5% of patients receiving levetiracetam and 8% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of an adverse reaction.

This study was too small to adequately characterize the adverse reactions that could be expected to result in discontinuation of treatment in this population. It is expected that the adverse reactions that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials (see Table 4 and Table 7).

In addition, the following adverse reactions were seen in other controlled adult studies of levetiracetam: balance disorder, disturbance in attention, eczema, memory impairment, myalgia, and blurred vision.

The overall adverse reaction profile of levetiracetam was similar between females and males. There are insufficient data to support a statement regarding the distribution of adverse reactions by age and race.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of levetiracetam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The listing is alphabetized: abnormal liver function test, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscle weakness, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, and weight loss. Alopecia has been reported with levetiracetam use; recovery was observed in majority of cases where levetiracetam was discontinued.

SPRITAM®
(SPREE-tam)
(levetiracetam) Tablets for Oral Suspension

What is the most important information I should know about SPRITAM?

Like other antiepileptic drugs, SPRITAM may cause suicidal thoughts or actions in a very small number of people, about 1 in 500 people taking it.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity or talking (mania)
• other unusual changes in behavior or mood

Do not stop SPRITAM without first talking to a healthcare provider.

• Stopping SPRITAM suddenly can cause you to have seizures more often.
• Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.
• Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

What is SPRITAM?

SPRITAM is a prescription medicine taken by mouth that is used with other medicines to treat:

• partial onset seizures in people 4 years of age and older weighing more than 20 kg (44 pounds) with epilepsy
• myoclonic seizures in people 12 years of age and older with juvenile myoclonic epilepsy
• primary generalized tonic-clonic seizures in people 6 years of age and older weighing more than 20 kg with certain types of generalized epilepsy.

SPRITAM tablets disintegrate in the mouth on average within 11 seconds (ranging from 2-27 seconds) when taken with a sip of liquid.

Before taking your medicine, make sure you have received the correct medicine. Compare the name above with the name on your package and the appearance of your medicine with the description of SPRITAM provided below. Tell your pharmacist immediately if you think you have been given the wrong medicine.

250 mg SPRITAM is a round tablet marked with “• ” on one side.

500 mg SPRITAM is a round tablet marked with “V” on one side.

750 mg SPRITAM is a round tablet marked with “E” on one side.

1000 mg SPRITAM is a round tablet marked with “L” on one side.

What should I tell my healthcare provider before starting SPRITAM?

Before taking SPRITAM, tell your healthcare provider about all of your medical conditions, including if you:

• have or have had depression, mood problems or suicidal thoughts or behavior
• have kidney problems
• are pregnant or planning to become pregnant. It is not known if SPRITAM will harm your unborn baby. You and your healthcare provider will have to decide if you should take SPRITAM while you are pregnant. If you become pregnant while taking SPRITAM, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of the registry is to collect information about the safety of SPRITAM and other antiepileptic medicine during pregnancy.
• are breast feeding. SPRITAM can pass into your milk and may harm your baby. You and your healthcare provider should discuss whether you should take SPRITAM or breast-feed; you should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Do not start a new medicine without first talking with your healthcare provider.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine.

How should I take SPRITAM?

• Take SPRITAM exactly as prescribed.
• Your healthcare provider will tell you how much SPRITAM to take and when to take it. SPRITAM is usually taken 2 times each day. Take SPRITAM at the same times each day.
• Your healthcare provider may change your dose. Do not change your dose without talking to your healthcare provider.
• As a primary method of administration, SPRITAM is intended to disintegrate in your mouth when taken with a sip of liquid.
• Alternately, SPRITAM may be taken by adding the whole tablet to a small volume of liquid in a cup.
  • How to take SPRITAM with a sip of liquid:
    • Take SPRITAM as shown on the SPRITAM carton (box).
    • Make sure your hands are dry before you remove the SPRITAM tablet(s).
    • Peel the foil away from the blister. Do not push the tablet(s) through the foil packaging.
    • Peel the foil away from the blister by bending up and lifting the peel tab around the blister seal.
    • Empty the tablet into your dry hand.
    • Place the SPRITAM tablet on your tongue and follow with a sip of liquid. Let the tablet disintegrate all the way on your tongue before swallowing.
    • SPRITAM disintegrates in an average time of 11 seconds (ranging from 2 to 27 seconds) in the mouth when taken with a sip of liquid.
  • How to take SPRITAM with a small volume of liquid in a cup:
    • Make sure your hands are dry before you remove the SPRITAM tablet(s).
    • Peel the foil away from the blister. Do not push the tablet through the foil packaging.
    • Peel the foil away from the blister by bending up and lifting the peel tab around the blister seal.
    • Add whole SPRITAM tablet(s) to a small volume of liquid in a cup (1 tablespoon or enough to cover the medicine), and swirl gently.
    • Swallow right after the tablet(s) disintegrates.
    • If there is any medicine left in the cup, add a small volume of liquid to the cup, swirl gently, and swallow the liquid.
• SPRITAM can be taken with or without food.
• If you take too much SPRITAM, call your Poison Control Center at 1-800-222-1222 or go to the nearest emergency room right away.
• As shown on the SPRITAM carton (box), do not push the tablet through foil. The foil should be peeled away from the blister. Bend up and lift the peel tab, pulling open the seal around the blister.

What should I avoid while taking SPRITAM?

Do not drive, operate machinery or do other dangerous activities until you know how SPRITAM affects you. SPRITAM may make you dizzy or sleepy.

What are the possible side effects of SPRITAM?

• See “What is the most important information I should know about SPRITAM?” SPRITAM can cause serious side effects. Call your healthcare provider right away if you have any of these symptoms:
• mood and behavior changes such as aggression, agitation, anger, anxiety, apathy, mood swings, depression, hostility, and irritability. A few people may get psychotic symptoms such as hallucinations (seeing or hearing things that are really not there), delusions (false or strange thoughts or beliefs), and unusual behavior.
• extreme sleepiness, tiredness, and weakness
• a skin rash. Serious skin rashes can happen after you start taking SPRITAM. There is no way to tell if a mild rash will become a serious reaction. Call your healthcare provider right away if you get a rash while taking SPRITAM.
• problems with muscle coordination (problems walking and moving)

The most common side effects seen in adults who take SPRITAM include sleepiness, infection, weakness, or dizziness.

The most common side effects seen in children who take SPRITAM include the side effects above and tiredness, decreased appetite, acting aggressive, irritability, and nasal congestion.

These side effects can happen at any time but happen more often within the first 4 weeks of treatment except for infection.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of SPRITAM. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to Aprecia Pharmaceuticals Company at 1-844-882-7732 or FDA at 1-800-FDA-1088.

How should I store SPRITAM?

• Store SPRITAM at room temperature, 59°F to 86°F (15°C to 30°C).
• Keep SPRITAM and all medicines out of the reach of children.

General information about the safe and effective use of SPRITAM.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SPRITAM for a condition for which it was not prescribed. Do not give SPRITAM to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about SPRITAM. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about SPRITAM that is written for health professionals. You can also get information about SPRITAM at 1-844-882-7732.

What are the ingredients of SPRITAM?

Active ingredient: levetiracetam

Inactive ingredients: colloidal silicon dioxide, glycerin, mannitol, microcrystalline cellulose, polysorbate 20, povidone, sucralose, butylated hydroxyanisole, and natural and artificial spearmint flavor.

• It is used to treat seizures.
• It may be given to you for other reasons. Talk with the doctor.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.