左乙拉西坦缓释片_FDA_英文说明书

_______________________________________________________________________________________________________________________________________ NDA 22285 / S-013 & S-015 Keppra XR FDA Approved Labeling text dated Jul 2013 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use KEPPRA XR® safely and effectively. See full prescribing information for KEPPRA XR. KEPPRA XR (levetiracetam) extended-release tablets Initial U.S. Approval: 1999 ----------------------------RECENT MAJOR CHANGES-------------------------- Dosage and Administration, Partial Onset Seizures (2.1) [07/2013] Warnings and Precautions (5.1, 5.3, 5.4, 5.5, 5.8) [07/2013] ----------------------------INDICATIONS AND USAGE--------------------------- KEPPRA XR is an antiepileptic drug indicated for adjunctive therapy in the treatment of partial onset seizures in patients ≥16 years of age with epilepsy (1) ----------------------DOSAGE AND ADMINISTRATION----------------------- Treatment should be initiated with a dose of 1000 mg once daily. The daily dosage may be adjusted in increments of 1000 mg every 2 weeks to a maximum recommended daily dose of 3000 mg (2). See full prescribing information for use in patients with impaired renal function (2.1). ---------------------DOSAGE FORMS AND STRENGTHS----------------------  500 mg white, film-coated extended-release tablet (3)  750 mg white, film-coated extended-release tablet (3) -------------------------------CONTRAINDICATIONS------------------------------  None (4) -----------------------WARNINGS AND PRECAUTIONS------------------------  Psychiatric Reactions: Behavioral abnormalities including psychotic symptoms, suicidal ideation, irritability, and aggressive behavior have been observed. Monitor patients for psychiatric signs and symptoms (5.1)  Suicidal Behavior and Ideation: Monitor patients for new or worsening depression, suicidal thoughts/behavior, and/or unusual changes in mood or behavior (5.2)  Somnolence and Fatigue: Monitor patients for these symptoms and advise patients not to drive or operate machinery until they have gained sufficient experience on KEPPRA XR (5.3)  Withdrawal Seizures: KEPPRA XR must be gradually withdrawn (5.6) ------------------------------ADVERSE REACTIONS-------------------------------  Most common adverse reactions (incidence in KEPPRA XR-treated patients is ≥5% more than in placebo-treated patients) include: somnolence and irritability (6.1). To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 866-822-0068 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------USE IN SPECIFIC POPULATIONS------------------------  Pregnancy: Plasma levels of levetiracetam may be decreased and therefore need to be monitored closely during pregnancy. Based on animal data, may cause fetal harm (5.8, 8.1) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: [07/2013] FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Adult Patients with Impaired Renal Function 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Psychiatric Reactions 5.2 Suicidal Behavior and Ideation 5.3 Somnolence and Fatigue 5.4 Serious Dermatological Reactions 5.5 Coordination Difficulties 5.6 Withdrawal Seizures 5.7 Hematologic Abnormalities 5.8 Seizure Control During Pregnancy 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Use in Patients with Impaired Renal Function 10 OVERDOSAGE 10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans 10.2 Management of Overdose 10.3 Hemodialysis 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the Full Prescribing Information are not listed. Reference ID: 3343504 NDA 22285 / S-013 & S-015 Keppra XR FDA Approved Labeling text dated Jul 2013 1 INDICATIONS AND USAGE KEPPRA XR® is indicated as adjunctive therapy in the treatment of partial onset seizures in patients ≥16 years of age with epilepsy. 2 DOSAGE AND ADMINISTRATION Treatment should be initiated with a dose of 1000 mg once daily. The daily dosage may be adjusted in increments of 1000 mg every 2 weeks to a maximum recommended daily dose of 3000 mg. 2.1 Adult Patients with Impaired Renal Function KEPPRA XR dosing must be individualized according to the patient's renal function status. Recommended doses and adjustment for dose for adults are shown in Table 1. In order to calculate the dose recommended for patients with renal impairment, creatine clearance adjusted for body surface area must be calculated. To do this, an estimate of the patient's creatinine clearance (CLcr) in mL/min must first be calculated using the following formula: [140-age (years)] x weight (kg) (x 0.85 for ----------------------------------------- female CLcr= 72 x serum creatinine (mg/dL) patients) Then CLcr is adjusted for body surface area (BSA) as follows: CLcr (mL/min) CLcr (mL/min/1.73m2)= ---------------------------- x 1.73 BSA subject (m2) Table 1: Dosing Adjustment Regimen For Adult Patients With Impaired Renal Function Group Creatinine Clearance (mL/min/1.73m2) Dosage (mg) Frequency Normal > 80 1000 to 3000 Every 24 hours Mild 50 – 80 1000 to 2000 Every 24 hours Moderate 30 – 50 500 to 1500 Every 24 hours Severe < 30 500 to 1000 Every 24 hours 3 DOSAGE FORMS AND STRENGTHS KEPPRA XR tablets are white, oblong-shaped, film-coated extended-release tablets imprinted in red with “UCB 500XR” on one side and contain 500 mg levetiracetam. KEPPRA XR tablets are white, oblong-shaped, film-coated extended-release tablets imprinted in red with “UCB 750XR” on one side and contain 750 mg levetiracetam. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Psychiatric Reactions KEPPRA XR Tablets Reference ID: 3343504 NDA 22285 / S-013 & S-015 Keppra XR FDA Approved Labeling text dated Jul 2013 In some patients KEPPRA XR causes behavioral abnormalities. A total of 6.5% of KEPPRA XR-treated patients experienced non-psychotic behavioral disorders (reported as irritability and aggression) compared to 0% of placebo-treated patients. Irritability was reported in 6.5% of KEPPRA XR-treated patients. Aggression was reported in 1.3% of KEPPRA XR-treated patients. No patient discontinued treatment or had a dose reduction as a result of these adverse reactions. The number of patients exposed to KEPPRA XR was considerably smaller than the number of patients exposed to immediate- release KEPPRA tablets in controlled trials. Therefore, certain adverse reactions observed in the immediate-release KEPPRA controlled trials will likely occur in patients receiving KEPPRA XR. Immediate-Release KEPPRA Tablets A total of 13.3% of adult KEPPRA-treated patients compared to 6.2% of placebo patients experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, and nervousness). A total of 1.7% of adult KEPPRA-treated patients discontinued treatment due to behavioral adverse events compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of adult KEPPRA-treated patients and in 0.5% of placebo patients. One percent of adult KEPPRA-treated patients experienced psychotic symptoms compared to 0.2% of placebo patients. Two (0.3%) adult KEPPRA-treated patients were hospitalized and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. The above psychiatric signs and symptoms should be monitored. 5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including KEPPRA XR, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2: Risk By Indication For Antiepileptic Drugs In The Pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Risk Difference: Additional Drug Patients with Events Per 1000 Patients Reference ID: 3343504 NDA 22285 / S-013 & S-015 Keppra XR FDA Approved Labeling text dated Jul 2013 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing KEPPRA XR or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 5.3 Somnolence and Fatigue KEPPRA XR Tablets In the KEPPRA XR double-blind, controlled trial in patients experiencing partial onset seizures, 7.8% of KEPPRA XR-treated patients experienced somnolence compared to 2.5% of placebo-treated patients. No patient discontinued treatment or had a dose reduction as a result of these adverse reactions. The number of patients exposed to KEPPRA XR was considerably smaller than the number of patients exposed to immediate- release KEPPRA tablets in controlled trials. Therefore, certain adverse reactions observed in the immediate-release KEPPRA controlled trials will likely occur in patients receiving KEPPRA XR. Immediate-Release KEPPRA Tablets In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of KEPPRA-treated patients reported somnolence, compared to 8.4% of placebo patients. There was no clear dose response up to 3000 mg/day. In a study where there was no titration, about 45% of patients receiving 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of the treated patients, compared to 0% in the placebo group. About 3% of KEPPRA-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo patients. In 1.4% of treated patients and in 0.9% of placebo patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence. In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of KEPPRA-treated patients reported asthenia, compared to 9.1% of placebo patients. Treatment was discontinued due to asthenia in 0.8% of treated patients as compared to 0.5% of placebo patients. In 0.5% of treated patients and in 0.2% of placebo patients the dose was reduced due to asthenia. Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment. Patients should be monitored for these signs and symptoms and advised 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. 5.4 Serious Dermatological Reactions Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients treated with levetiracetam. The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. Recurrence of the serious skin reactions following rechallenge with levetiracetam has also been reported. KEPPRA XR should be discontinued at the first sign of a rash, unless the rash is clearly not Reference ID: 3343504 6 NDA 22285 / S-013 & S-015 Keppra XR FDA Approved Labeling text dated Jul 2013 drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. 5.5 Coordination Difficulties Coordination difficulties were not observed in the KEPPRA XR controlled trial, however, the number of patients exposed to KEPPRA XR was considerably smaller than the number of patients exposed to immediate-release KEPPRA tablets in controlled trials. However, adverse reactions observed in the immediate-release KEPPRA controlled trials may also occur in patients receiving KEPPRA XR. Immediate-Release KEPPRA Tablets A total of 3.4% of adult KEPPRA-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients. A total of 0.4% of patients in controlled trials discontinued KEPPRA treatment due to ataxia, compared to 0% of placebo patients. In 0.7% of treated patients and in 0.2% of placebo patients the dose was reduced due to coordination difficulties, while one of the treated patients was hospitalized due to worsening of pre-existing ataxia. These events occurred most frequently within the first 4 weeks of treatment. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on KEPPRA to gauge whether it could adversely affect their ability to drive or operate machinery. 5.6 Withdrawal Seizures Antiepileptic drugs, including KEPPRA XR, should be withdrawn gradually to minimize the potential of increased seizure frequency. 5.7 Hematologic Abnormalities Although there were no obvious hematologic abnormalities observed in treated patients in the KEPPRA XR controlled study, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients in the immediate-release KEPPRA controlled studies should be considered to be relevant for KEPPRA XR-treated patients. In controlled trials of immediate-release KEPPRA tablets in patients experiencing partial onset seizures, minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in immediate-release KEPPRA-treated patients. A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (2.8 x 109/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (1.0 x 109/L) decreased neutrophil count. Of the treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts. 5.8 Seizure Control During Pregnancy Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy. ADVERSE REACTIONS The following adverse reactions are discussed in more details in other sections of labeling:  Psychiatric Reactions [see Warnings and Precautions (5.1)]  Suicidal Behavior And Ideation [see Warnings and Precautions (5.2)]  Somnolence And Fatigue [see Warnings and Precautions (5.3)]  Serious Dermatological Reactions [see Warnings and Precautions (5.4)]  Coordination Difficulties [see Warnings and Precautions (5.5)]  Withdrawal Seizures [see Warnings and Precautions (5.6)]  Hematologic Abnormalities [see Warnings and Precautions (5.7)]  Seizure Control During Pregnancy [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction r