warnings and cautions
5 WARNINGS AND PRECAUTIONS Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity: Discontinue if no alternate etiology. ( 5.1 ) QT Shortening: Use caution when administering XCOPRI with other drugs that shorten the QT interval ( 5.2 ) Suicidal Behavior and Ideation: Monitor patients for suicidal behavior and ideation. ( 5.3 ) Liver Injury: Clinically significant liver injury has occurred. Obtain serum transaminases (ALT and AST) and total bilirubin before initiating XCOPRI, and during treatment if clinically indicated. Discontinue XCOPRI in patients with evidence of liver injury in the absence of an alternative etiology. ( 5.4 ) Neurological Adverse Reactions: Monitor for somnolence and fatigue and advise patients not to drive or operate machinery until they have gained sufficient experience on XCOPRI. Concomitant use with other CNS depressants or alcohol may have additive effects. ( 5.5 ) Withdrawal of Antiepileptic Drugs: XCOPRI should be gradually withdrawn to minimize the potential of increased seizure frequency. ( 5.6 ) 5.1 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking XCOPRI. DRESS has occurred, including one fatality, when XCOPRI was titrated rapidly (weekly or faster titration). No cases of DRESS were reported in an open-label safety study of 1339 partial-onset seizure patients when XCOPRI was initiated at 12.5 mg once daily and titrated every two weeks. This finding does not establish that the risk of DRESS is prevented by a slower titration; however, XCOPRI should be initiated at 12.5 mg once daily and titrated every two weeks [see Dosage and Administration ( 2.2 )] . 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. This disorder is variable in its expression, and 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. XCOPRI should be discontinued immediately and not restarted if an alternative etiology for the signs or symptoms cannot be established [see Contraindications ( 4 )] . 5.2 QT Shortening In a placebo-controlled study of the QT interval, a higher percentage of subjects who took XCOPRI (31% at 200 mg and 66% at 500 mg) had a QT shortening of greater than 20 msec compared to placebo (6-17%). Reductions of the QTc interval below 300 msec were not observed [see Clinical Pharmacology ( 12.2 )] . Familial Short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. Such events in this syndrome are believed to occur primarily when the corrected QT interval falls below 300 msec. Nonclinical data also indicate that QT shortening is associated with ventricular fibrillation. Patients with Familial Short QT syndrome should not be treated with XCOPRI [see Contraindications ( 4 )] . Caution should be used when administering XCOPRI and other drugs that shorten the QT interval as there may be a synergistic effect on the QT interval that would increase the QT shortening risk. 5.3 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including XCOPRI, 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 3 shows absolute and relative risk by indication for all evaluated AEDs. Table 3: Risk of Suicidal Thoughts or Behaviors 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 Patients Risk Differences: Additional Drug Patients with Events Per 1000 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 in patients with epilepsy than in clinical trials in patients with psychiatric or other conditions, but the absolute risk differences were similar for epilepsy and psychiatric indications. Anyone considering prescribing XCOPRI or any other AED must balance this risk 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. 5.4 Liver Injury Clinically significant liver injury has been reported in patients treated with XCOPRI in the postmarketing setting. Signs of liver injury, including markedly elevated serum hepatic transaminases with elevated total bilirubin, have been reported after administration. Acute liver failure requiring transplantation has been reported in the postmarketing setting. Elevations of serum hepatic transaminases occurred in patients receiving XCOPRI in clinical trials [see Adverse Reactions ( 6.1 )] . Obtain serum transaminases (ALT and AST) and total bilirubin, if not recently available (i.e., within 3 months), before initiation of XCOPRI to establish baseline liver function. Monitor for signs and symptoms of any hepatic injury during treatment [see Dosage and Administration ( 2.1 )] , and obtain serum ALT and AST and total bilirubin promptly in patients who develop clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, jaundice, dark urine). Interrupt or discontinue treatment with XCOPRI in patients who develop liver injury without an alternative etiology. Elevation of serum hepatic transaminases greater than three times the reference range with elevated total bilirubin greater than two times the reference range is an important predictor of severe liver injury. Early identification of elevated serum hepatic transaminases and total bilirubin and interruption or discontinuation of XCOPRI may decrease the risk of a serious outcome. 5.5 Neurological Adverse Reactions Somnolence and Fatigue XCOPRI causes dose-dependent increases in somnolence and fatigue-related adverse reactions (somnolence, fatigue, asthenia, malaise, hypersomnia, sedation, and lethargy) [see Adverse Reactions ( 6.1 )] . In Study 1 and Study 2, 31% of patients randomized to receive XCOPRI at 100 mg/day, 36% of patients randomized to receive XCOPRI at 200 mg/day, and 57% of patients randomized to receive XCOPRI at 400 mg/day reported at least one of these adverse reactions, compared to 19% of patients who received placebo. Somnolence and fatigue-related adverse reactions were serious in 0.4% of XCOPRI-treated patients compared to no patients who received placebo and led to discontinuation in 2% of XCOPRI-treated patients compared to 1% of patients who received placebo. Dizziness and Disturbance in Gait and Coordination XCOPRI causes dose-dependent adverse reactions related to dizziness and disturbance in gait and coordination (dizziness, vertigo, balance disorder, ataxia, nystagmus, gait disturbance, and abnormal coordination) [see Adverse Reactions ( 6.1 )] . In Study 1 and Study 2, 21% of patients randomized to receive XCOPRI at 100 mg/day, 31% of patients randomized to receive XCOPRI at 200 mg/day, and 52% of patients randomized to receive XCOPRI at 400 mg/day reported at least one of these adverse reactions, compared to 18% of patients who received placebo. Dizziness and disturbance in gait and coordination adverse reactions were serious in 2% of XCOPRI-treated patients compared to no patients who received placebo and led to discontinuation in 5% of XCOPRI-treated patients compared to 1% of patients who received placebo. Cognitive Dysfunction XCOPRI causes adverse reactions related to cognitive dysfunction related-events (i.e., memory impairment, disturbance in attention, amnesia, confusional state, aphasia, speech disorder, slowness of thought, disorientation, and psychomotor retardation) [see Adverse Reactions ( 6.1 )] . In Study 1 and Study 2, 6% of patients randomized to receive XCOPRI at 100 mg/day, 6% of patients randomized to receive XCOPRI at 200 mg/day, and 9% of patients randomized to receive XCOPRI at 400 mg/day reported at least one of these adverse reactions, compared to 2% of patients who received placebo. No cognitive dysfunction-related events were serious in XCOPRI-treated patients or in patients who received placebo. Cognitive dysfunction related adverse reactions led to discontinuation in 0.4% of XCOPRI-treated patients compared to no patients who received placebo. Visual Changes XCOPRI causes adverse reactions related to visual changes including diplopia, blurred vision, and impaired vision [see Adverse Reactions ( 6.1 )] . In Study 1 and Study 2, 9% of patients randomized to receive XCOPRI at 100 mg/day, 9% of patients randomized to receive XCOPRI at 200 mg/day, and 18% of patients randomized to receive XCOPRI at 400 mg/day reported at least one of these adverse reactions, compared to 2% of patients who received placebo. No visual change-related events were serious in XCOPRI-treated patients or in patients who received placebo. Visual change led to discontinuation in 0.5% of XCOPRI-treated patients compared to no patients who received placebo. Risk Amelioration Prescribers should advise patients against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of XCOPRI is known. Patients should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence and sedation, when XCOPRI is used with other drugs with sedative properties because of potential additive effects. 5.6 Withdrawal of Antiepileptic Drugs As with most antiepileptic drugs, XCOPRI should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus [see Dosage and Administration ( 2.4 ) and Clinical Studies ( 14 )] . But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.