Oxtellar Xr

Oxtellar XR is indicated for the treatment of partial-onset seizures in patients 6 years of age and older.

• Adult Patients: The recommended initial dosage is 600 mg once per day. Increase the dosage in weekly increments of 600 mg once per day, based on clinical response and tolerability, to a recommended maintenance dosage of 1200 mg to 2400 mg once per day. (
  
  
  2.2 General Dosing Recommendations

  Monotherapy or Adjunctive Therapy

  Adult Patients

  Initiate treatment at a dosage of 600 mg/day given orally once daily for one week. Subsequent dosage increases can be made at weekly intervals in 600 mg/day increments to achieve the recommended daily dosage.

  The recommended daily dosage of Oxtellar XR is 1200 mg to 2400 mg/day, given once daily. The dosage of 2400 mg/day showed slightly greater efficacy than 1200 mg/day, but was associated with an increase in adverse reactions

  [see Adverse Reactions (6.1)and Clinical Studies (14.1)].

  Dosage adjustment is recommended with concomitant use of strong CYP3A4 enzyme inducers or UGT inducers, which include certain antiepileptic drugs (AEDs)

  [see Drug Interactions (7.1, 7.2)].

  Pediatric Patients (6 to Less than 17 Years of Age)

  In pediatric patients 6 to less than 17 years of age, initiate treatment at a daily dosage of 8 mg/kg to 10 mg/kg orally once daily, not to exceed 600 mg per day in the first week.

  Subsequent dosage increases can be made at weekly intervals in 8 mg/kg to 10 mg/kg increments once daily, not to exceed 600 mg, to achieve the target daily dosage. The target maintenance dosage, achieved over two to three weeks, is displayed in Table 1.

  Table 1: Target Daily Dosage in Pediatric Patients (6 to Less Than 17 Years of Age)

  Weight	Target Daily Dosage
  20 kg to 29 kg	900 mg/day
  29.1 kg to 39 kg	1200 mg/day
  Greater than 39 kg	1800 mg/day

  Dosage adjustment is recommended with concomitant use of strong CYP3A4 enzyme inducers or UGT inducers, which include certain antiepileptic drugs (AEDs)

  [see Drug Interactions (7.1, 7.2))].
  )
  
• In adult patients with a creatinine clearance <30 mL/min, initiate at one-half the usual starting dosage and increase slowly. (
  
  
  2.3 Dosage Modifications in Adult Patients with Renal Impairment

  In adult patients with severe renal impairment (creatinine clearance less than 30 mL/minute), initiate Oxtellar XR at one-half the usual starting dosage (300 mg/day). Subsequent dosage increases can be made at weekly intervals in increments of 300 mg to 450 mg/day to achieve the desired clinical response

  [see Use in Specific Populations (8.6)].
  )
  
• Pediatric Patients: The recommended dosage is based on body weight and is administered orally once per day. Increase the dosage in weekly intervals based on clinical response and tolerability, to the recommended dosage. (
  
  
  2.2 General Dosing Recommendations

  Monotherapy or Adjunctive Therapy

  Adult Patients

  Initiate treatment at a dosage of 600 mg/day given orally once daily for one week. Subsequent dosage increases can be made at weekly intervals in 600 mg/day increments to achieve the recommended daily dosage.

  The recommended daily dosage of Oxtellar XR is 1200 mg to 2400 mg/day, given once daily. The dosage of 2400 mg/day showed slightly greater efficacy than 1200 mg/day, but was associated with an increase in adverse reactions

  [see Adverse Reactions (6.1)and Clinical Studies (14.1)].

  Dosage adjustment is recommended with concomitant use of strong CYP3A4 enzyme inducers or UGT inducers, which include certain antiepileptic drugs (AEDs)

  [see Drug Interactions (7.1, 7.2)].

  Pediatric Patients (6 to Less than 17 Years of Age)

  In pediatric patients 6 to less than 17 years of age, initiate treatment at a daily dosage of 8 mg/kg to 10 mg/kg orally once daily, not to exceed 600 mg per day in the first week.

  Subsequent dosage increases can be made at weekly intervals in 8 mg/kg to 10 mg/kg increments once daily, not to exceed 600 mg, to achieve the target daily dosage. The target maintenance dosage, achieved over two to three weeks, is displayed in Table 1.

  Table 1: Target Daily Dosage in Pediatric Patients (6 to Less Than 17 Years of Age)

  Weight	Target Daily Dosage
  20 kg to 29 kg	900 mg/day
  29.1 kg to 39 kg	1200 mg/day
  Greater than 39 kg	1800 mg/day

  Dosage adjustment is recommended with concomitant use of strong CYP3A4 enzyme inducers or UGT inducers, which include certain antiepileptic drugs (AEDs)

  [see Drug Interactions (7.1, 7.2))].
  )
  
• Geriatric Patients: Start at lower dosage (300 mg or 450 mg/day) and increase slowly. (
  
  
  2.4 Dosage Modifications in Geriatric Patients

  In geriatric patients, consider starting at a lower dosage (300 mg or 450 mg/day). Subsequent dosage increases can be made at weekly intervals in increments of 300 mg to 450 mg/day to achieve the desired clinical effect

  [see Use in Specific Populations (8.5)].
  )
  
• In conversion of oxcarbazepine immediate-release to Oxtellar XR
  
  ^®, higher dosages of Oxtellar XR may be necessary. (
  
  
  2.7 Conversion from Immediate-Release Oxcarbazepine to Oxtellar XR

  In conversion of oxcarbazepine immediate-release to Oxtellar XR, higher dosages of Oxtellar XR may be necessary

  [see Clinical Pharmacology (12.3)].
  ,
  
  
  12.3 Pharmacokinetics

  Following oral administration, oxcarbazepine is absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD), which is responsible for most antiepileptic activity.

  In clinical studies of Oxtellar XR, the elimination half-life of oxcarbazepine was between 7 and 11 hours; the elimination half-life of MHD is between 9 and 11 hours.

  In a mass balance study in humans, only 2% of total radioactivity in plasma after administration of immediate-release oxcarbazepine was due to unchanged oxcarbazepine, with approximately 70% present as MHD, and the remainder attributable to minor metabolites.

  Absorption

  Oxtellar XR administered as a once daily dosage is not bioequivalent to the same total dosage of the immediate-release formulation given twice daily at steady state. Steady state plasma concentrations of MHD are reached within 5 days when Oxtellar XR is given once daily. At steady state, when 1200 mg Oxtellar XR was given once daily, MHD C_maxoccurred 7 hours post-dose. At steady state, Oxtellar XR given once daily produced MHD exposures (AUC and C_max) about 19% lower and MHD minimum concentrations (C_min) about 16% lower than the immediate-release oxcarbazepine given twice daily when administered at the same 1200 mg total daily dosage. When Oxtellar XR was administered at an equivalent 600 mg single dose (4 × 150 mg tablets, 2 × 300 mg tablets, or 1 × 600 mg tablet), equivalent MHD exposures (AUC) were observed.

  Following a single dose of Oxtellar XR (1 × 150 mg tablets, 1 × 300 mg tablets, or 1 × 600 mg tablet), the pharmacokinetics of MHD are not linear and show greater than dose proportional increase in AUC and less than proportional increase in C_max: AUC increases 2.4-fold and C_maxincreases 1.9-fold with a 2-fold increase in dose.

  Effect of Food:

  Single dose administration of 600 mg Oxtellar XR following a high fat meal (800 – 1000 calories) produced MHD exposure (AUC) equivalent to that produced under fasting conditions. Peak MHD concentration (C_max) was about 60% higher and occurred 2 hours earlier under fed conditions than under fasting conditions.

  The increase in C_max, even without a significant change in the overall exposure, should be considered by the prescriber especially during the titration phase, when some adverse reactions are most likely to occur coincidentally with peak levels.

  Distribution

  The apparent volume of distribution of MHD is 49 L. Approximately 40% of MHD is bound to serum proteins, predominantly to albumin. Binding is independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein.

  Elimination

  Metabolism

  Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to MHD, which is primarily responsible for the pharmacological effect of Oxtellar XR^®. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD).

  Excretion

  Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of a dose of immediate-release oxcarbazepine appears in the urine, with less than 1% as unchanged oxcarbazepine. Fecal excretion accounts for less than 4% of an administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and oxcarbazepine account for 13% of the dose.

  The half-life of the parent was about two hours, while the half-life of MHD was about nine hours after the immediate-release formulation. A population pharmacokinetic model for Oxtellar XR was developed in healthy normal adults and applied to pharmacokinetic data in patients with epilepsy. For oxcarbazepine, systemic parameters were scaled allometrically, suggesting that steady state oxcarbazepine exposure will vary inversely with weight.

  Specific Populations

  Geriatric Patients

  No studies with Oxtellar XR in elderly patients have been completed

  [see Use in Specific Populations (8.5)].

  Following administration of single (300 mg) and multiple (600 mg/day) doses of immediate-release oxcarbazepine to elderly volunteers (60-82 years of age), the maximum plasma concentrations and AUC values of MHD were 30%-60% higher than in younger volunteers (18-32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance.

  Pediatric Patients

  A pharmacokinetic study of Oxtellar XR was performed in 18 pediatric patients with epilepsy, which included patients 6 to less than 17 years of age, after multiple doses. The population pharmacokinetic model suggested that dosing of pediatric patients with Oxtellar XR can be determined based on body weight. Weight-normalized doses in pediatric patients should produce MHD exposures (AUC) comparable to that in typical adults, with oxcarbazepine exposures ~40% higher in children than in adults

  [see Use in Specific Populations (8.4)].

  The pharmacokinetics of Oxtellar XR in pediatric patients are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures.

  Pediatric Patients with Obesity

  A population PK analysis of immediate-release oxcarbazepine was conducted that included n=54 obese and non-obese pediatric patients 6 to <18 years of age to evaluate the potential impact of obesity on plasma oxcarbazepine exposures. Obesity was defined as BMI ≥95th percentile for age and sex based on CDC 2000 growth chart recommendations. Simulated results from this analysis suggested that the target maintenance doses for oxcarbazepine, applied in pediatric patients ≥6 years of age, produced equivalent steady-state exposure of MHD between pediatric patients with and without obesity. This finding is consistent when using total body weight, or when using fat-free mass in the simulations. Dosage adjustment according to obesity status is not necessary.

  Male and Female Patients

  The effects of gender have not been studied for Oxtellar XR.

  No gender-related pharmacokinetic differences have been observed in children, adults, or the elderly with immediate-release oxcarbazepine.

  Racial or Ethnic Groups

  The effects of race have not been studied for Oxtellar XR.

  Patients with Renal or Hepatic Impairment

  The effects of renal or hepatic impairment have not been studied for Oxtellar XR

  [see Use in Specific Populations (8.6, 8.7)]

  .

  Based on investigations with immediate-release oxcarbazepine, there is a linear correlation between creatinine clearance and the renal clearance of MHD. When immediate-release oxcarbazepine is administered as a single 300 mg dose in renally-impaired patients (creatinine clearance <30 mL/min), the elimination half-life of MHD is prolonged to 19 hours, with a two-fold increase in AUC. Dosage adjustment is recommended in these patients

  [see Dosage and Administration (2.3)and Use in Special Populations (8.6)]

  .

  The pharmacokinetics and metabolism of immediate-release oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically impaired subjects after a single 900 mg oral dose. Mild-to-moderate hepatic impairment did not affect the pharmacokinetics of immediate-release oxcarbazepine and MHD. The pharmacokinetics of oxcarbazepine and MHD have not been evaluated in severe hepatic impairment, and therefore it is not recommended in these patients

  [see Use in Specific Populations (8.7)]

  .

  Pregnant Women

  Due to physiological changes during pregnancy, MHD plasma levels may gradually decrease throughout pregnancy

  [see Use in Specific Populations (8.1)].

  Drug Interaction Studies

  In Vitro:

  Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs. In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD.

  Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other drugs. Results demonstrate that oxcarbazepine and its pharmacologically active 10-monohydroxy metabolite (MHD) have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19 and CYP3A4/5.

  Although inhibition of CYP3A4/5 by oxcarbazepine and MHD did occur at high concentrations, it is not likely to be of clinical significance. The inhibition of CYP2C19 by oxcarbazepine and MHD, is clinically relevant.

  In vitro, the UDP-glucuronyl transferase level was increased, indicating induction of this enzyme. Increases of 22% with MHD and 47% with oxcarbazepine were observed. As MHD, the predominant plasma substrate, is only a weak inducer of UDP-glucuronyl transferase, it is unlikely to have an effect on drugs that are mainly eliminated by conjugation through UDP-glucuronyl transferase (e.g., valproic acid, lamotrigine).

  In addition, oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives and cyclosporine resulting in a lower plasma concentration of these drugs.

  Several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD. No autoinduction has been observed with immediate-release oxcarbazepine.

  As binding of MHD to plasma proteins is low (40%), clinically significant interactions with other drugs through competition for protein binding sites are unlikely.

  In Vivo:

  Other Antiepileptic Drugs

  Potential interactions between immediate-release oxcarbazepine and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and Cmin are summarized in Table 5

  [see Drug Interactions (7.1, 7.2)].

  Table 5: AED Drug Interactions with Immediate-Release (IR) Oxcarbazepine

  AED Coadministered (daily dosage)	IR-Oxcarbazepine (daily dosage)	Influence of IR-Oxcarbazepine on AED Concentration Mean Change [90% Confidence Interval]	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
  Carbamazepine (400 – 2000 mg)	900 mg	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
  Phenobarbital (100 – 150 mg)	600 – 1800 mg	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
  Phenytoin (250 – 500 mg)	600 – 1800 >1200-2400	nc ,Pediatrics up to 40% increaseMean increase in adults at high doses of immediate-release oxcarbazepine [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
  Valproic Acid (400 – 2800 mg)	600-1800	nc	18% decrease [CI: 13% decrease, 40% decrease]
  Lamotrigine (200 mg)	1200	nc	nc

  Hormonal Contraceptives

  Coadministration of immediate-release oxcarbazepine with an oral contraceptive has been shown to influence the plasma concentrations of two components of hormonal contraceptives, ethinylestradiol (EE) and levonorgestrel (LNG). The mean AUC values of EE were decreased by 48% [90% CI: 22-65] in one study and 52% [90% CI: 38-52] in another study. The mean AUC values of LNG were decreased by 32% [90% CI: 20-45] in one study and 52% [90% CI: 42-52] in another study.

  Other Drug Interactions

  Calcium Antagonists: After repeated coadministration of immediate-release oxcarbazepine, the AUC of felodipine was lowered by 28% [90% CI: 20-33]. Verapamil produced a decrease of 20% [90% CI: 18-27] of the plasma levels of MHD after coadministration with immediate-release oxcarbazepine

  Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD after coadministration with immediate-release oxcarbazepine. Results with warfarin show no evidence of interaction with either single or repeated doses of immediate-release oxcarbazepine.
  )
  

• 150 mg: yellow modified-oval shaped with "150" printed on one side
• 300 mg: brown modified-oval shaped with "300" printed on one side
• 600 mg: brownish red modified-oval shaped with "600" printed on one side

• Pregnancy:
  May cause fetal harm. (
  
  
  5.9 Risk of Seizures in the Pregnant Patient

  Due to physiological changes during pregnancy, plasma concentrations of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. Monitor patients carefully during pregnancy and through the postpartum period because MHD concentrations may increase after delivery.
  ,
  
  
  8.1 Pregnancy

  Pregnancy Exposure Registry

  There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as Oxtellar XR, during pregnancy. Encourage women who are taking Oxtellar XR 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

  There are no adequate data on the developmental risks associated with the use of Oxtellar XR in pregnant women; however, Oxtellar XR is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Data on a limited number of pregnancies from pregnancy registries suggest that oxcarbazepine monotherapy use is associated with congenital malformations (e.g., craniofacial defects such as oral clefts, and cardiac malformations such as ventricular septal defects). Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity (embryolethality, growth retardation) were observed in the offspring of animals treated with either oxcarbazepine or its active 10-hydroxy metabolite (MHD) during pregnancy at doses similar to the maximum recommended human dose (MRHD).

  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

  An increase in seizure frequency may occur during pregnancy because of altered levels of the active metabolite of oxcarbazepine. Monitor patients carefully during pregnancy and through the postpartum period

  [see Warnings and Precautions (5.9)]

  Data

  Human Data

  Data from published registries have reported craniofacial defects such as oral clefts and cardiac malformations such as ventricular septal defects in children with prenatal oxcarbazepine exposure.

  Animal Data

  When pregnant rats were given oxcarbazepine (30, 300, or 1000 mg/kg/day) orally throughout the period of organogenesis, increased incidences of fetal malformations (craniofacial, cardiovascular, and skeletal) and variations were observed at the intermediate and high doses (approximately 1.2 and 4 times, respectively, the MRHD on a mg/m²basis). Increased embryofetal death and decreased fetal body weights were seen at the high dose. Doses ≥ 300 mg/kg were also maternally toxic (decreased body weight gain, clinical signs), but there is no evidence to suggest that teratogenicity was secondary to the maternal effects.

  In a study in which pregnant rabbits were orally administered MHD (20, 100, or 200 mg/kg/day) during organogenesis, embryofetal mortality was increased at the highest dose (1.5 times the MRHD on a mg/m²basis). This dose produced only minimal maternal toxicity.

  In a study in which female rats were dosed orally with oxcarbazepine (25, 50, or 150 mg/kg/day) during the latter part of gestation and throughout the lactation period, a persistent reduction in body weights and altered behavior (decreased activity) were observed in offspring exposed to the highest dose (0.6 times the MRHD on a mg/m²basis). Oral administration of MHD (25, 75, or 250 mg/kg/day) to rats during gestation and lactation resulted in a persistent reduction in offspring weights at the highest dose (equivalent to the MRHD on a mg/m²basis).
  )
  
• Severe Hepatic Impairment:
  Not recommended. (
  
  
  8.7 Hepatic Impairment

  The pharmacokinetics of oxcarbazepine and MHD has not been evaluated in severe hepatic impairment, and therefore is not recommended in these patients

  [see Clinical Pharmacology (12.3)].
  )
  

• Hyponatremia:
  Monitor sodium as recommended. (
  
  
  5.1 Hyponatremia

  Clinically significant hyponatremia (sodium <125 mmol/L) may develop during Oxtellar XR use. Serum sodium levels less than 125 mmol/L have occurred in immediate-release oxcarbazepine-treated patients generally in the first three months of treatment. However, clinically significant hyponatremia may develop more than a year after initiating therapy.

  Most immediate-release oxcarbazepine-treated patients who developed hyponatremia were asymptomatic in clinical trials. However, some of these patients had their dosage reduced, discontinued, or had their fluid intake restricted for hyponatremia. Serum sodium levels returned toward normal when the dosage was reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction). Cases of symptomatic hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported during post-marketing use of immediate-release oxcarbazepine.

  Among treated patients in a controlled trial of adjunctive therapy with Oxtellar XR in 366 adults with complex partial seizures, 1 patient receiving 2400 mg experienced a severe reduction in serum sodium (117 mEq/L) requiring discontinuation from treatment, while 2 other patients receiving 1200 mg experienced serum sodium concentrations low enough (125 and 126 mEq/L) to require discontinuation from treatment. The overall incidence of clinically significant hyponatremia in patients treated with Oxtellar XR was 1.2%, although slight shifts in serum sodium concentrations from Normal to Low (<135 mEq/L) were observed for the 2400 mg (6.5%) and 1200 mg (9.8%) groups compared to placebo (1.7%).

  Measure serum sodium concentrations if patients develop symptoms of hyponatremia (e.g., nausea, malaise, headache, lethargy, confusion, obtunded consciousness, or increase in seizure frequency or severity). Consider measurement of serum sodium concentrations during treatment with Oxtellar XR, particularly if the patient receives concomitant medications known to decrease serum sodium levels (for example, drugs associated with inappropriate ADH secretion).
  )
  
• Cross Hypersensitivity Reaction to Carbamazepine:
  Discontinue immediately if hypersensitivity occurs. (
  
  
  5.3 Cross Hypersensitivity Reaction to Carbamazepine

  Approximately 25% to 30% of patients who have had hypersensitivity reactions to carbamazepine will experience hypersensitivity reactions with Oxtellar XR. For this reason, patients should be specifically questioned about any prior experience with carbamazepine, and patients with a history of hypersensitivity reactions to carbamazepine should ordinarily be treated with Oxtellar XR only if the potential benefit justifies the potential risk. Discontinue Oxtellar XR immediately if signs or symptoms of hypersensitivity develop [see

  Warnings and Precautions (5.2, 5.7)

  ].
  )
  
• Serious Dermatological Reactions:
  Discontinue if observed. (
  
  
  5.4 Serious Dermatological Reactions

  Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have occurred in both children and adults treated with immediate-release oxcarbazepine use. The median time of onset for reported cases was 19 days. Such serious skin reactions may be life threatening, and some patients have required hospitalization with very rare reports of fatal outcome. Recurrence of the serious skin reactions following rechallenge with immediate-release oxcarbazepine has also been reported.

  The reporting rate of TEN and SJS associated with immediate-release oxcarbazepine use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate estimates by a factor of 3- to 10-fold. Estimates of the background incidence rate for these serious skin reactions in the general population range between 0.5 to 6 cases per million-person years. Therefore, if a patient develops a skin reaction while taking Oxtellar XR, consider discontinuing Oxtellar XR use and prescribing another AED.

  Association with HLA-B*1502

  Patients carrying the HLA-B*1502 allele may be at increased risk for SJS/TEN with Oxtellar XR treatment.

  Human Leukocyte Antigen (HLA) allele B*1502 increases the risk for developing SJS/TEN in patients treated with carbamazepine. The chemical structures of immediate-release oxcarbazepine and Oxtellar XR are similar to that of carbamazepine. Available clinical evidence, and data from nonclinical studies showing a direct interaction between immediate-release oxcarbazepine and HLA-B*1502 protein, suggest that the HLA-B*1502 allele may also increase the risk for SJS/TEN with Oxtellar XR.

  The frequency of HLA-B*1502 allele ranges from 2 to 12% in Han Chinese populations, is about 8% in Thai populations, and above 15% in the Philippines and in some Malaysian populations. Allele frequencies up to about 2% and 6% have been reported in Korea and India, respectively. The frequency of the HLA-B*1502 allele is negligible in people from European descent, several African populations, indigenous peoples of the Americas, Hispanic populations, and in Japanese (<1%).

  Testing for the presence of the HLA-B*1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with Oxtellar XR. The use of Oxtellar XR should be avoided in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Consideration should also be given to avoid the use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not generally recommended in patients from populations in which the prevalence of HLA-B*1502 is low, or in current Oxtellar XR users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLA-B*1502 status.

  The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dosage, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been well characterized.
  )
  
• Suicidal Behavior and Ideation:
  Monitor for symptoms. (
  
  
  5.5 Suicidal Behavior and Ideation

  Antiepileptic drugs (AEDs), including Oxtellar XR, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication 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 Patients	Risk Difference: 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 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 Oxtellar 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 Oxtellar XR treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
  )
  
• Withdrawal of
  Oxtellar XR
  
  ^®
  :
  Withdrawal gradually. (
  
  
  5.6 Withdrawal of AEDs

  As with most AEDs, Oxtellar XR should be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.
  )
  
• Drug Reaction with Eosinophilia and Systemic symptoms (DRESS)/Multi-Organ Hypersensitivity:
  Discontinue if suspected. (
  
  
  5.7 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity

  Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has occurred with immediate-release oxcarbazepine. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in associated with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocaraditis, 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 manifestatios of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. Oxtellar XR should be discontinued if an alternative etiology for the signs and symptoms cannot be established.
  )
  
• Hematologic Reactions:
  Discontinue if suspected. (
  
  
  5.8 Hematologic Reactions

  Rare reports of pancytopenia, agranulocytosis, and leukopenia have been seen in patients treated with immediate-release oxcarbazepine during post-marketing experience. Discontinuation of Oxtellar XR should be considered if any evidence of these hematologic reactions develops.
  )
  
• Risk of Seizure Aggravation:
  Discontinue if occurs. (
  
  
  5.10 Risk of Seizure Aggravation

  Exacerbation of or new onset primary generalized seizures has been reported with immediate-release oxcarbazepine. The risk of aggravation of primary generalized seizures is seen especially in children but may also occur in adults. In case of seizure aggravation, Oxtellar XR should be discontinued.
  )