2.1 Important Administration Instructions

Administer Oxtellar XR as a single daily dose taken on an empty stomach (at least 1 hour before or at least 2 hours after meals) [see Clinical Pharmacology (12.3)] . If Oxtellar XR is taken with food, adverse reactions are more likely to occur because of increased peak levels [see Clinical Pharmacology (12.3)].

Swallow Oxtellar XR tablets whole. Do not cut, crush, or chew the tablets. For ease of swallowing in pediatric patients or patients with difficulty swallowing, achieve daily dosages with multiples of appropriate lower strength tablets (e.g., 150 mg tablets).

2.2 General Dosing Recommendations

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)].

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)].

2.5 Dosage Modification with Concomitant Use of Strong CYP3A4 Enzyme Inducers or UGT Enzyme Inducers

Strong CYP3A4 inducers, including enzyme-inducing antiepileptic drugs such as carbamazepine, phenobarbital, and phenytoin, and UGT inducers (e.g., rifampin) decrease exposure to 10-monohydroxy derivative (MHD), the active metabolite [see Drug Interactions (7.2)and Clinical Pharmacology (12.3)] . Dosage adjustment of Oxtellar XR may be required after initiation, dosage modification, or discontinuation of such inducers. Dosage increases of Oxtellar XR may be necessary with concomitant use. Consider initiating at 900 mg once daily for adults and 12 to 15 mg/kg orally once daily (not to exceed 900 mg per day in the first week) in pediatric patients.

2.6 Withdrawal of AEDs

As with most antiepileptic drugs, Oxtellar XR should be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.6)].

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)].

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).

5.2 Anaphylactic Reactions and Angioedema

Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of immediate-release oxcarbazepine. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with Oxtellar XR, discontinue the drug and initiate an alternative treatment. Do not rechallenge these patients with Oxtellar XR.

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)].

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.

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.

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.

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.

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.

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.

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.

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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety data presented below are from 384 patients with partial-onset seizures who received Oxtellar XR (366 adults and 18 pediatric patients) with concomitant AEDs.

In addition, safety data presented below are from a total of 2288 patients with seizure disorders treated with immediate-release oxcarbazepine; 1832 were adults and 456 were pediatric patients.

6.2 Postmarketing and Other Experience

The following adverse reactions have been observed in named patient programs or post-marketing experience with immediate-release oxcarbazepine or Oxtellar XR. 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.

Body as a Whole:multi-organ hypersensitivity disorders characterized by features such as rash, fever, lymphadenopathy, abnormal liver function tests, eosinophilia, and arthralgia [see Warnings and Precautions (5.7)]

Cardiovascular System:atrioventricular block

Digestive System:pancreatitis and/or lipase and/or amylase increase

Hematologic and Lymphatic Systems:aplastic anemia [see Warnings and Precautions (5.8)]

Immune System Disorders: anaphylaxis [see Warnings and Precautions (5.2)]

Metabolism and Nutrition Disorders: hypothyroidism and syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Skin and Subcutaneous Tissue Disorders:erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis [see Warnings and Precautions (5.4)] , Acute Generalized Exanthematous Pustulosis (AGEP)

Musculoskeletal, Connective Tissu,e and Bone Disorders: There have been reports of decreased bone mineral density, osteoporosis and fractures in patients on long-term therapy with immediate-release oxcarbazepine.

7.1 Effect of Oxtellar XR on Other Drugs

It is recommended that the plasma levels of phenytoin be monitored during the period of Oxtellar XR titration and dosage modification [see Clinical Pharmacology (12.3)]. A decrease in the dosage of phenytoin may be required.

7.2 Effect of Other Drugs on Oxtellar XR

If Oxtellar XR and strong CYP3A4 inducers or UGT inducers (e.g., rifampin, carbamazepine, phenytoin and phenobarbital) are administered concurrently, it is recommended that the plasma levels of MHD be monitored during the period of Oxtellar XR titration [see Clinical Pharmacology (12.3)]. Dosage adjustment of Oxtellar XR may be required after initiation, dosage modification, or discontinuation of such inducers [see Dosage and Administration (2.5)].

7.3 Hormonal Contraceptives

Concurrent use of immediate-release oxcarbazepine with hormonal contraceptives may render these contraceptives less effective [see Clinical Pharmacology (12.3)]. Studies with other oral or implant contraceptives have not been conducted.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and effectiveness of Oxtellar XR in pediatric patients 6 years of age and older for the treatment of partial-onset seizures is supported by:

• An adequate and well-controlled safety and efficacy study of Oxtellar XR in adults that included pharmacokinetic sampling [see Clinical Studies (14.1)],
• A pharmacokinetic study of Oxtellar XR in pediatric patients, which included patients 6 to less than 17 years of age [see Clinical Pharmacology (12.3)],
• Safety and efficacy studies with the immediate-release formulation in adults and pediatric patients [see Clinical Studies (14.2)and Adverse Reactions (6.1)] .

Oxtellar XR ®is not approved for pediatric patients less than 6 years of age because the size of the tablets are inappropriate for younger children.

8.5 Geriatric Use

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. Consider starting at a lower dosage and lower titration [see Dosage and Administration (2.4)] . Close monitoring of sodium levels is required in elderly patients at risk for hyponatremia [see Warnings and Precautions (5.1)].

8.6 Renal Impairment

There is a linear correlation between creatinine clearance and the renal clearance of MHD [see Clinical Pharmacology (12.3)and Dosage and Administration (2.3)].

The pharmacokinetics of Oxtellar XR has not been evaluated in patients with renal impairment. In patients with severe renal impairment (creatinine clearance <30 mL/min) given immediate-release oxcarbazepine, the elimination half-life of MHD was prolonged with a corresponding two-fold increase in AUC [see Clinical Pharmacology (12.3)]. In these patients initiate Oxtellar XR at a lower starting dosage and increase, if necessary, at a slower than usual rate until the desired clinical response is achieved [see Dosage and Administration (2.3)] .

In patients with end-stage renal disease on dialysis, it is recommended that immediate-release oxcarbazepine be used instead of Oxtellar XR.

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)].

9.2 Abuse

The abuse potential of Oxtellar XR has not been evaluated in human studies. Oxtellar XR is not habit forming, and is not expected to encourage abuse.

9.3 Dependence

Intragastric injections of oxcarbazepine to four cynomolgus monkeys demonstrated no signs of physical dependence as measured by the desire to self-administer oxcarbazepine by lever pressing activity.

10.1 Human Overdose Experience

Isolated cases of overdose with immediate-release oxcarbazepine have been reported. The maximum dose taken was approximately 48,000 mg. All patients recovered with symptomatic treatment. Nausea, vomiting, somnolence, aggression, agitation, hypotension, and tremor each occurred in more than one patient. Coma, confusional state, convulsion, dyscoordination, depressed level of consciousness, diplopia, dizziness, dyskinesia, dyspnea, QT prolongation, headache, miosis, nystagmus, overdose, decreased urine output, and blurred vision also occurred.

10.2 Treatment and Management

There is no specific antidote for Oxtellar XR overdose. Administer symptomatic and supportive treatment as appropriate. Options include removal of the drug by gastric lavage and/or inactivation by administering activated charcoal.

12.1 Mechanism of Action

The pharmacological activity of Oxtellar XR is primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine [see Clinical Pharmacology (12.3)]. The precise mechanism by which oxcarbazepine and MHD exert their antiseizure effect is unknown; however, in vitro electrophysiological studies indicate that they produce blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses. These actions are thought to be important in the prevention of seizure spread in the intact brain. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may contribute to the anticonvulsant effects of the drug. No significant interactions of oxcarbazepine or MHD with brain neurotransmitter or modulator receptor sites have been demonstrated.

12.2 Pharmacodynamics

Oxcarbazepine and its active metabolite (MHD) exhibit anticonvulsant properties in animal seizure models. They protected rodents against electrically induced tonic extension seizures and, to a lesser degree, chemically induced clonic seizures, and abolished or reduced the frequency of chronically recurring focal seizures in Rhesus monkeys with aluminum implants. No development of tolerance (i.e., attenuation of anticonvulsive activity) was observed in the maximal electroshock test when mice and rats were treated daily for five days and four weeks, respectively, with oxcarbazepine or MHD.

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Oxtellar XR Primary Trial

A multicenter, randomized, double-blind, placebo-controlled, three-arm, parallel-group study (Study 1) in male and female adults with refractory partial-onset seizures (18 to 65 years of age, inclusive) was performed to examine the safety and efficacy of Oxtellar XR.

Patients had at least three partial-onset seizures per 28 days during an 8 week Baseline Period. Subjects were receiving treatment with at least one to three antiepileptic drugs and were on stable treatment for a minimum of 4 weeks. Subjects with a diagnosis other than partial-onset seizures were excluded.

The study included an 8 week Baseline Period, followed by a Treatment Period, which included a 4 week Titration Phase followed by a 12 week Maintenance Phase. The primary endpoint of the study was median percentage change from baseline in seizure frequency per 28 days during the treatment period relative to the baseline period. The criterion for statistical significance was p<0.05. A total of 366 patients were enrolled at 88 sites in North America and Eastern Europe. Subjects were randomized to one of three treatment groups and took Oxtellar XR (1200 or 2400 mg/day) or placebo.

Table 6 presents the primary efficacy results by treatment group.

Although the 1200 mg/day-placebo contrast did not reach statistical significance, concentration-response analyses reveal that the 1200 mg/day dosage is an effective dosage.

14.2 Immediate-Release Oxcarbazepine Adjunctive Therapy Trials

The effectiveness of immediate-release oxcarbazepine as an adjunctive therapy for partial-onset seizures in adults was demonstrated at dosages of 600mg/day, 1200mg/day, and 2400mg/day (divided twice daily) in a randomized, double-blind, placebo-controlled trial. All dosages resulted in a statistically significant reduction in seizure frequency when compared to placebo (p<0.05).

The effectiveness of immediate-release oxcarbazepine in dosages of 30-46 mg/kg/day, depending on baseline weight, as an adjunctive therapy for partial-onset seizures in pediatric patients, including patients 6 to less than 17 years of age, was studied in a randomized, double-blind, placebo-controlled trial. Oxcarbazepine in the single weight-based dosage group resulted in a statistically significant reduction in seizure frequency when compared to placebo (p<0.05).

16.1 How Supplied

150 mg (yellow modified-oval shaped tablet printed "150" on one side with edible black ink).

300 mg (brown modified-oval shaped tablet printed "300" on one side with edible black ink).

600 mg (brownish red modified-oval shaped tablet printed "600" on one side with edible black ink).

16.2 Storage and Handling

Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F to 86°F) [See USP controlled room temperature]. Protect from light and moisture. Dispense in a tight, light-resistant container.

Administration Information

Advise patients to take the tablet whole. Do not cut, chew, or crush the tablet. Advise patients to take Oxtellar XR on an empty stomach. This means they should take Oxtellar XR at least one hour before food or at least two hours after food [see Dosage and Administration (2.1)and Clinical Pharmacology (12.3)] .

Hyponatremia

Advise patients that Oxtellar XR may reduce serum sodium concentrations especially if they are taking other medications that can lower sodium. Advise patients to report symptoms of low sodium like nausea, tiredness, lack of energy, confusion, and more frequent or more severe seizures [see Warnings and Precautions (5.1)].

Anaphylactic Reactions and Angioedema

Anaphylactic reactions and angioedema may occur during treatment with Oxtellar XR. Advise patients to immediately report signs and symptoms suggesting angioedema (swelling of the face, eyes, lips, tongue, or difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician [see Warnings and Precautions (5.2)].

Cross Hypersensitivity Reaction to Carbamazepine

Inform patients who have exhibited hypersensitivity reactions to carbamazepine that approximately 25%-30% of these patients may also experience hypersensitivity reactions with Oxtellar XR. If patients experience a hypersensitivity reaction while taking Oxtellar XR, advise them to consult with their physician immediately [see Warnings and Precautions (5.3)].

Serious Dermatological Reactions

Advise patients that serious skin reactions have been reported in association with immediate-release oxcarbazepine. If patients experience a skin reaction while taking Oxtellar XR, advise patients to consult with their physician immediately [see Warnings and Precautions (5.4)].

Suicidal Behavior and Ideation

Counsel patients, their caregivers, and families that AEDs, including Oxtellar XR, may increase the risk of suicidal thoughts and behavior and that they need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Advise them to immediately report behaviors of concern to healthcare providers [see Warnings and Precautions (5.5)].

DRESS/Multi-Organ Hypersensitivity

Instruct patients that a fever associated with signs of other organ system involvement (e.g., rash, lymphadenopathy, hepatic dysfunction, etc.) occurring during treatment with Oxtellar XR may be drug-related, and advise them to consult their physician immediately [see Warnings and Precautions (5.7)].

Hematologic Reactions

Advise patients that there have been rare reports of blood disorders reported in patients treated with immediate-release oxcarbazepine. Instruct patients to immediately consult with their physician if they experience symptoms suggestive of blood disorders during treatment with Oxtellar XR  [see Warnings and Precautions (5.8)].

Drug Interactions

Warn female patients of childbearing age that the concurrent use of Oxtellar XR with hormonal contraceptives may render this method of contraception less effective [see Drug Interactions (7.3)and Use in Specific Populations (8.1)]. Additional non-hormonal forms of contraception are recommended when using Oxtellar XR.

Pregnancy Registry

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during OXTELLAR XR therapy. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].