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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
KEPPRA (NDA-021872)
(LEVETIRACETAM)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
03/12/2024 (SUPPL-35)
5 Warnings and Precautions
5.6 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Multiorgan HypersensitivityNewly added subsection:
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including KEPPRA. These events can be fatal or life- threatening, particularly if diagnosis and treatment do not occur as early as possible. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. KEPPRA should be discontinued if an alternative etiology for the signs or symptoms cannot be established [see Contraindications (4)].
6 Adverse Reactions
Addition of the following to the bulleted line listing:
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.6)]
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEAdditions and/or revisions underlined:
…
What are the possible side effects of KEPPRA? KEPPRA can cause serious side effects including:
…
a serious allergic reaction that may affect your skin or other parts of your body such as your liver, kidneys, heart, or blood cells. This allergic reaction can be life-threatening and can cause death, particularly if it is not treated as early as possible. Call your healthcare provider right away if you have:
a skin rash
fever or swollen glands that do not go away
swelling of your face
shortness of breath
dark urine
yellowing of the skin or whites of the eyes
…
Additions and/or revisions underlined:
…
DRESS/Multiorgan Hypersensitivity
Instruct patients and caregivers that a fever or rash associated with signs of other organ system involvement (e.g., lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider immediately. KEPPRA should be discontinued immediately if a serious hypersensitivity reaction is suspected [see Warnings and Precautions (5.6)].
…
08/17/2023 (SUPPL-34)
6 Adverse Reactions
6.2 Postmarketing Experience
Additions and/or revisions underlined:
The following adverse reactions have been reported in patients receiving 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), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, obsessive-compulsive disorders (OCD), pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, weight loss, and worsening of seizures including in patients with SCN8A mutations. Alopecia has been reported with KEPPRA use; recovery was observed in majority of cases where KEPPRA was discontinued.
09/30/2020 (SUPPL-29)
6 Adverse Reactions
6.2 Postmarketing Experience(Additions and/or revisions 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), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, weight loss, and worsening of seizures.
10/23/2019 (SUPPL-28)
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).
(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.
(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)
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)
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 AngioedemaAddition 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 GUIDEAddition 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.
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)
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.