CENOBAMATE: 5,643 Adverse Event Reports & Safety Profile

The chemical name of XCOPRI (cenobamate) is [(1 R )-1-(2-Chlorophenyl)-2-(tetrazol-2-yl) ethyl] carbamate. Its molecular formula is C 10 H 10 ClN 5 O 2 and its molecular weight is 267.67 g/mol. The chemical structure is: Cenobamate is a white to off-white crystalline powder. It is slightly soluble in aqueous solutions (water 1.7 mg/mL) and has higher solubility in organic solvents like ethanol (209.4 mg/mL). XCOPRI tablets are for oral administration and contain the following inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate and film coating agents specified below: 12.5 mg tablets: Not applicable, since 12.5 mg tablets are uncoated. 25 mg and 100 mg tablets: FD&C Blue# 2/indigo carmine aluminum lake, iron oxide red, iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide. 50 mg tablets: iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide. 150 mg and 200 mg tablets: iron oxide red, iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.

Chemical

Structure

AND USAGE XCOPRI is indicated for the treatment of partial-onset seizures in adult patients. XCOPRI is indicated for the treatment of partial-onset seizures in adult patients. ( 1 )

AND ADMINISTRATION Prior to initiating XCOPRI, obtain serum transaminases (ALT and AST) and total bilirubin, if not recently available (i.e., within 3 months), to establish baseline liver function. ( 2.1 , 5.4 ) The recommended initial dosage of XCOPRI is 12.5 mg once daily, titrated to the recommended maintenance dosage of 200 mg once daily. The recommended titration schedule should not be exceeded. The maximum dosage is 400 mg once daily. ( 2.2 ) Hepatic impairment: For patients with mild or moderate hepatic impairment, the maximum recommended dosage is 200 mg once daily. ( 2.3 , 8.7 , 12.3 ) XCOPRI can be taken whole or the tablets can be crushed. The crushed tablet can be mixed with water and either administered by mouth as an oral suspension or administered via a nasogastric tube. ( 2.4 )

2.1 Assessments Prior to Initiating XCOPRI Liver Function Tests Prior to initiating XCOPRI, obtain serum transaminases (ALT and AST) and total bilirubin, if not recently available (i.e., within 3 months), to establish baseline liver function <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 )]</span> . For patients with baseline hepatic impairment, dosage modifications are recommended <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> .

2.2 Recommended Dosage Monotherapy and Adjunctive Therapy XCOPRI is administered orally once daily with or without food. The recommended dosage and titration, which should not be exceeded because of the potential for serious adverse reactions <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> , is included in Table 1 .

Table

1: Recommended Dosage for Partial-Onset Seizures in Adults Initial Dosage Week 1 and 2 12.5 mg once daily Titration Regimen Week 3 and 4 25 mg once daily Week 5 and 6 50 mg once daily Week 7 and 8 100 mg once daily Week 9 and 10 150 mg once daily Maintenance Dosage Week 11 and thereafter 200 mg once daily Maximum Dosage If needed based on clinical response and tolerability, dose may be increased above 200 mg by increments of 50 mg once daily every two weeks to 400 mg. 400 mg once daily

2.3 Recommended Dosage in Patients with Hepatic Impairment For patients with mild to moderate (Child-Pugh Class A to B) hepatic impairment, the maximum recommended dosage is 200 mg once daily <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.7 )]</span> . XCOPRI is not recommended for use in patients with severe (Child-Pugh Class C) hepatic impairment <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 ) and see Clinical Pharmacology ( 12.3 )]</span> .

2.4 Administration Instructions XCOPRI can be taken whole or the tablets can be crushed. The crushed tablet can be mixed with water and either administered by mouth as an oral suspension or administered via a nasogastric tube, as described below <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>. Administration of Crushed Tablets by Mouth as Oral Suspension Crush the appropriate number of tablet(s) for the prescribed dose. In a cup, combine the crushed tablet(s) and 25 mL of water. Swirl to suspend the crushed tablet(s). Drink the suspension immediately. Do not store the tablet-water mixture for later use. To ensure no tablet residue is left in the container, rinse the container with 25 mL of water and drink. Visually confirm that no particles are left in the container. If particles remain, repeat step 5. Administration of Crushed Tablets via Nasogastric (NG)

Tube

Crush the appropriate number of tablet(s) for the prescribed dose. In an appropriate container, combine the crushed tablet(s) and 25 mL of water. Swirl to suspend the crushed tablet(s). Ensuring no particles are left in the container, instill the suspension with a syringe into the NG tube. Refill the catheter-tip syringe again with 10 mL of water, swirl gently, and administer. Visually confirm that no particles are left in the syringe. If particles remain, repeat step 5.

2.5 Discontinuation of XCOPRI If XCOPRI is discontinued, the dosage should be gradually reduced over a period of at least 2 weeks, unless safety concerns require abrupt withdrawal <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.6 )]</span> .

XCOPRI is contraindicated in patients with: Hypersensitivity to cenobamate or any of the inactive ingredients in XCOPRI [see Warnings and Precautions ( 5.1 ) and Description ( 11 )]

Familial

Short QT syndrome [see Warnings and Precautions ( 5.2 )] Hypersensitivity to cenobamate or any of the inactive ingredients in XCOPRI. ( 4 )

Familial

Short QT syndrome. ( 4 )

REACTIONS The following serious adverse reactions are described in more detail in the Warnings and Precautions section of the labeling: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions ( 5.1 )] QT Shortening [see Warnings and Precautions ( 5.2 )]

Suicidal

Behavior and Ideation [see Warnings and Precautions ( 5.3 )]

Liver

Injury [see Warnings and Precautions ( 5.4 )]

Neurological Adverse

Reactions [see Warnings and Precautions ( 5.5 )] Withdrawal of Antiepileptic Drugs [see Warnings and Precautions ( 5.6 )] The most common adverse reactions in patients receiving XCOPRI (at least 10% for XCOPRI and more frequently than placebo) include somnolence, dizziness, fatigue, diplopia, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact SK Life Science, Inc. at 1-866-657-5574 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions and for varying durations, adverse reaction frequencies observed in the clinical trials of a drug cannot be directly compared with frequencies in the clinical trials of another drug and may not reflect the frequencies observed in practice. In all controlled and uncontrolled trials performed in adult partial-onset seizure patients, XCOPRI was administered as adjunctive therapy to 1944 patients. Of these patients, 1575 were treated for at least 6 months, 710 for at least 12 months, 349 for at least 24 months, and 320 for at least 36 months. A total of 658 patients (442 patients treated with XCOPRI and 216 patients treated with placebo) constituted the safety population in the pooled analysis of placebo-controlled studies in patients with partial-onset seizures (Studies 1 and 2) <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . The adverse reactions presented in Table 4 are based on this safety population; the median length of treatment in these studies was 18 weeks. Of the patients in those studies, approximately 49% were male, 76% were Caucasian, and the mean age was 39 years.

In Study

1 and Study 2, adverse events occurred in 77% of patients treated with XCOPRI and 68% treated with placebo.

Table

4 gives the incidence of adverse reactions that occurred in subjects with partial-onset seizures in any XCOPRI treatment group and for which the incidence was greater than placebo during the controlled clinical trials. The most common adverse reactions that occurred in XCOPRI-treated patients (incidence at least 10% and greater than placebo) were somnolence, dizziness, fatigue, diplopia, and headache. The discontinuation rates because of adverse events were 11%, 9%, and 21% for patients randomized to receive XCOPRI at doses of 100 mg/day, 200 mg/day, and 400 mg/day, respectively, compared to 4% in patients randomized to receive placebo. The adverse reactions most commonly (1% or greater in any XCOPRI treatment group, and greater than placebo) leading to discontinuation, in descending order of frequency, were ataxia, dizziness, somnolence, diplopia, nystagmus, and vertigo.

Table

4: Adverse Reactions in Pooled Placebo-Controlled Adjunctive Therapy Studies in Patients with Partial-Onset Seizures with XCOPRI Frequency in Any Treatment Arm Greater Than 1% Over Placebo * Reported as an adverse reaction; see Laboratory Abnormalities for ALT changes from collected laboratory values Adverse Reaction XCOPRI Placebo 100mg 200mg 400mg n = 108 % n= 223 % n=111 % n=216 % Cardiac Disorders Palpitations 0 0 2 0 Ear and Labyrinth Disorders Vertigo 1 1 6 1 Eye Disorders Diplopia 6 7 15 2 Vision Blurred 2 2 4 0 Gastrointestinal Disorders Nausea 6 6 9 3 Constipation 2 4 8 0 Diarrhea 1 3 5 0 Vomiting 2 4 5 0 Dry Mouth 1 1 3 0 Abdominal Pain 2 2 1 0 Dyspepsia 2 2 0 0 Infections and Infestations Nasopharyngitis 2 4 5 3 Pharyngitis 1 2 0 0 Urinary Tract Infection 2 5 0 2 Injury, Poisoning and Procedural Complications Head Injury 1 0 2 0 Investigations Alanine Aminotransferase Increased* 1 1 4 0 Aspartate Aminotransferase Increased 1 1 3 0 Weight Decreased 2 0 1 0 Metabolism and Nutrition Disorders Decreased Appetite 3 1 5 1 Musculoskeletal and Connective Tissue Disorders Back Pain 4 2 5 3 Musculoskeletal Chest Pain 2 1 0 0 Nervous System Disorders Somnolence 19 22 37 11 Dizziness 18 22 33 15 Fatigue 12 14 24 7 Headache 10 12 10 9 Balance Disorder 3 5 9 1 Gait Disturbance 1 3 8 1 Dysarthria 2 1 7 0 Nystagmus 3 7 6 0 Ataxia 2 3 6 2 Aphasia 2 1 4 0 Asthenia 0 1 3 1 Dysgeusia 2 0 2 0 Memory Impairment 2 1 2 0 Migraine 0 0 2 0 Sedation 1 1 2 0 Tremor 0 3 1 1 Psychiatric Disorders Confusional State 2 2 3 0 Euphoric Mood 0 0 2 0 Irritability 1 0 2 0 Suicidal Ideation 2 1 0 0 Renal and Urinary Disorders Pollakiuria 0 1 0 0 Reproductive System and Breast Disorders Dysmenorrhea 1 2 1 0 Respiratory, Thoracic and Mediastinal Disorders Hiccups 0 1 1 0 Dyspnea 0 3 0 0 Skin and Subcutaneous Tissue Disorders Pruritus 2 1 0 0 Rash Papular 2 0 0 0 Laboratory Abnormalities Hepatic Transaminases [see Warnings and Precautions ( 5.4 )]

In Study

2, there was a post-baseline elevation of alanine aminotransferase (ALT) to greater than 3 times the upper limit of normal (ULN) in 1 (0.9%) patient treated with 100 mg XCOPRI, 2 (1.8%) patients treated with 200 mg, and 3 (2.7%) patients treated with 400 mg, compared to no patients who took placebo. The maximum ALT elevation was 7.6 times ULN in patients treated with 400 mg XCOPRI. Potassium In clinical studies, there was a post-baseline elevation of potassium values greater than 5 meq/L (upper reference range) in patients treated with XCOPRI.

In Study

1, there were 17 (17%) patients treated with XCOPRI 200 mg compared to 8 (7%) patients who took placebo with normal baseline potassium values who had at least one post-baseline maximum value greater than 5 meq/L.

In Study

2, there was a dose-related distribution where at least one post-baseline potassium value was greater than 5 meq/L, occurring in 8.3%, 9.1%, and 10.8% of the patients treated with XCOPRI 100 mg, 200 mg, and 400 mg, respectively, compared to 5.6% of patients who took placebo. Two patients had a maximum potassium value of 5.9 meq/L.

Other Adverse Reactions

Gastrointestinal disorders: There was an incidence of appendicitis in the overall clinical trial safety population of 2.9 cases of appendicitis/1000 patient-years of exposure that is in excess of the expected background rate in the general population.

Adverse Reactions

Based on Gender No significant gender differences were noted in the incidence of adverse reactions.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of XCOPRI. 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.

Psychiatric

Disorders: Psychosis (hallucinations, delusions/paranoia), hostility, aggression.

Hepatobiliary

Disorders: Hepatic failure [see Warnings and Precautions ( 5.4 )]

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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> .

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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span> , 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) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ) and Clinical Studies ( 14 )]</span> . But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.

INTERACTIONS Phenytoin: Gradually decrease phenytoin dosage by up to 50%. ( 7.1 ) Phenobarbital and Clobazam: Reduce dosage as needed when used concomitantly with XCOPRI. ( 7.1 ) Lamotrigine, Carbamazepine: Increase dosage as needed when used concomitantly with XCOPRI. ( 7.1 ) CYP2B6 and CYP3A Substrates: Increase dosage as needed when used concomitantly with XCOPRI. ( 7.1 ) CYP2C19 Substrates: Reduce dosage as needed when used concomitantly with XCOPRI. ( 7.1 )

Oral

Contraceptives: Effectiveness of hormonal oral contraceptives may be reduced when administered concomitantly with XCOPRI. Women should use additional or alternative non-hormonal birth control. ( 7.1 )

7.1 Effect of XCOPRI on Other Drugs Table 5 summarizes the effect of XCOPRI on other drugs <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

Table

5: Pharmacokinetic Drug Interactions Drug or Substrate Type Effect of XCOPRI on Drug or Substrate Clinical Recommendation Antiepileptic Drugs lamotrigine ↓ plasma concentrations Because of a potential for reduced efficacy of these drugs, increase the dosage of lamotrigine or carbamazepine, as needed, when used concomitantly with XCOPRI. carbamazepine ↓ plasma concentrations phenytoin ↑ plasma concentrations Because of a potential 2-fold increase in phenytoin levels, gradually decrease phenytoin dosage by up to 50% as XCOPRI is being titrated. phenobarbital ↑ plasma concentrations Because of a potential for an increase in the risk of adverse reactions from these drugs, consider a reduction in dosage of phenobarbital or clobazam, as clinically appropriate, when used concomitantly with XCOPRI. desmethylclobazam, the active metabolite of clobazam ↑ plasma concentrations CYP2B6 Substrates ↓ plasma concentrations Because of a potential for reduced efficacy of these drugs, increase the dosage of CYP2B6 or CYP3A4 substrates, as needed, when used concomitantly with XCOPRI. CYP3A Substrates ↓ plasma concentrations Oral contraceptives ↓ plasma concentrations Because of the potential for reduced efficacy of oral contraceptives, women should use additional or alternative non-hormonal birth control while taking XCOPRI. CYP2C19 Substrates ↑ plasma concentrations Because of a potential for an increase in the risk of adverse reactions from these drugs, consider a reduction in dosage of CYP2C19 substrates, as clinically appropriate, when used concomitantly with XCOPRI.

7.2 Drug that Shorten the QT Interval XCOPRI can shorten the QT interval; therefore, caution should be used when administering XCOPRI and other drugs that shorten the QT interval <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.2 )]</span>.

7.3 CNS Depressants and Alcohol Concomitant use of XCOPRI with other CNS depressants, including alcohol, may increase the risk of neurological adverse reactions, including sedation and somnolence <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.5 )]</span> .