Drug Safety-related Labeling Changes (SrLC)

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KEPPRA (NDA-021872)

(LEVETIRACETAM)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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10/23/2019 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Withdrawal Seizures

(additions and/or revisions are underlined)

As with most antiepileptic drugs, KEPPRA should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. But if withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.

6 Adverse Reactions

6.1 Clinical Trials Experience

(minor additions and/or revisions throughout subsection; please refer to labeling for complete information)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including KEPPRA, during pregnancy. Encourage women who are taking KEPPRA during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting   http://www.aedpregnancyregistry.org/.

Risk Summary

Prolonged experience with KEPPRA 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 developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Clinical Considerations

Levetiracetam blood levels may decrease during pregnancy.

Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester. Dose adjustments may be necessary to maintain clinical response.

Data

Human Data

While available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage.

Animal Data

When levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested. There was no evidence of maternal toxicity. The no-effect dose for adverse effects on embryofetal developmental in rats (1200 mg/kg/day) is approximately 4 times the maximum recommended human dose (MRHD) of 3000 mg on a body surface area (mg/m^2) basis.

Oral administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidence of fetal skeletal variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which was associated with maternal toxicity. The no-effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the MRHD on a mg/m^2 basis.

Oral administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested. There was no evidence of maternal toxicity. The no-effect dose for adverse effects on pre- and postnatal development in rats (70 mg/kg/day) is less than the MRHD on a mg/m^2 basis.

Oral administration of levetiracetam to rats during the latter part 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/m^2 basis).

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion)

Risk Summary

Levetiracetam is excreted in human milk. There are no data on the effects of KEPPRA on the breastfed infant, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KEPPRA and any potential adverse effects on the breastfed infant from KEPPRA or from the underlying maternal condition.

8.4 Pediatric Use

(additions and/or revisions are underlined)

The safety and effectiveness of KEPPRA for the treatment of partial-onset seizures in patients 1 month to 16 years of age have been established. The dosing recommendation in these pediatric patients varies according to age group and is weight-based.

The safety and effectiveness of KEPPRA as adjunctive therapy for the treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established.

The safety and effectiveness of KEPPRA as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established.

Safety and effectiveness for the treatment of partial-onset seizures in pediatric patients below the age of 1 month; adjunctive therapy for the treatment of myoclonic seizures in pediatric patients below the age of 12 years; and adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients below the age of 6 years have not been established.

A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of KEPPRA as adjunctive therapy in 98 (KEPPRA N=64, placebo N=34) pediatric patients, ages 4 years to 16 years, with partial seizures that were inadequately controlled. The target dose was 60 mg/kg/day.

Neurocognitive effects were measured by the Leiter-R Attention and Memory (AM) Battery, which measures various aspects of a child's memory and attention. Although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority of the drug and placebo. The Achenbach Child Behavior Checklist (CBCL/6-18), a standardized validated tool used to assess a child’s competencies and behavioral/emotional problems, was also assessed in this study. An analysis of the CBCL/6-18 indicated, on average, a worsening in KEPPRA-treated patients in aggressive behavior, one of the eight syndrome scores.

Juvenile Animal Toxicity Data

Studies of levetiracetam in juvenile rats (dosed on postnatal days 4 through 52) and dogs (dosed from postnatal weeks 3 through 7) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m^2 basis) did not demonstrate adverse effects on postnatal development.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions and/or revisions are underlined)

Psychiatric Reactions and Changes in Behavior

Advise patients and their caregivers that KEPPRA may cause changes in behavior (e.g., aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and psychotic symptoms.

Effects on Driving or Operating Machinery

Inform patients that KEPPRA may cause dizziness and somnolence. Inform patients not to drive or operate machinery until they have gained sufficient experience on KEPPRA to gauge whether it adversely affects their ability to drive or operate machinery.

Anaphylaxis and Angioedema

Advise patients to discontinue KEPPRA and seek medical care if they develop signs and symptoms of anaphylaxis or angioedema.

Dermatological Adverse Reactions

Advise patients that serious dermatological adverse reactions have occurred in patients treated with KEPPRA and instruct them to call their physician immediately if a rash develops.

Withdrawal of KEPPRA

Advise patients and caregivers not to discontinue use of KEPPRA without consulting with their healthcare provider. KEPPRA should normally be gradually withdrawn to reduce the potential of increased seizure frequency and status epilepticus.

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during KEPPRA therapy. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant.

10/24/2017 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Hematologic Abnormalities

(Additions and/or revisions are underlined)

KEPPRA can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials and included 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 have been reported in the postmarketing setting. A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

The following adverse reactions have been reported in patients receiving marketed KEPPRA worldwide. The listing is alphabetized: abnormal liver function test, acute kidney injury, anaphylaxis, angioedema, agranulocytosis, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS)…

04/24/2017 (SUPPL-23)

Approved Drug Label (PDF)

4 Contraindications

Addition of the following:

KEPPRA is contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema.

5 Warnings and Precautions

5.4 Anaphylaxis and Angioedema

Addition of the following:

KEPPRA can cause anaphylaxis or angioedema after the first dose or at any time during treatment. Signs and symptoms in cases reported in the postmarketing setting have included hypotension, hives, rash, respiratory distress, and swelling of the face, lip, mouth, eye, tongue, throat, and feet. In some reported cases, reactions were life- threatening and required emergency treatment. If a patient develops signs or symptoms of anaphylaxis or angioedema, KEPPRA should be discontinued and the patient should seek immediate medical attention. KEPPRA should be discontinued permanently if a clear alternative etiology for the reaction cannot be established.

6 Adverse Reactions

Additions and/or revisions underlined:

The following adverse reactions are discussed in more details in other sections of labeling:

  • Anaphylaxis and Angioedema

    6.2 Postmarketing Experience

    The following adverse reactions have been reported in patients receiving marketed KEPPRA worldwide. The listing is alphabetized: abnormal liver function test, acute kidney injury, anaphylaxis, angioedema, choreoathetosis …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Addition of the following:

Who should not take KEPPRA?

Do not take KEPPRA if you are allergic to levetiracetam.

What are the possible side effects of KEPPRA?

Call your healthcare provider right away if you have any of these symptoms:

    • allergic reactions such as swelling of the face, lips, eyes, tongue, and throat, trouble swallowing or breathing, and hives.

PATIENT COUNSELING INFORMATION

Addition of the following:

Anaphylaxis and Angioedema

Advise patients to discontinue KEPPRA and seek medical care if they develop signs and symptoms of anaphylaxis or angioedema.

10/26/2016 (SUPPL-22)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience (addition underlined)

…, acute kidney injury, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, and weight loss. Alopecia has been reported with KEPPRA use; recovery was observed in majority of cases where KEPPRA was discontinued.

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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