美国食品和药品管理局（FDA）已经批准了一项新的每日一次的奥卡西平缓释制剂（Oxtellar XR，制药公司Supernus）用于成人和6至17岁的儿童部分性发作的辅助治疗。
该剂型前身是SPN-804，建议剂量为成人每天1200至2400年毫克，年龄在6至17岁的儿童根据体重每天900至1800毫克。该产品将提供150毫克，300毫克，600毫克缓释片。
该公司指出，他们将在2013年第一季度推出新的治疗方法。
新配方的批准基于一项多中心，随机，双盲，3组年龄在18岁至65岁的成人难治性部分性癫痫的研究结果。一共有369例患者随机分配，其中366个患者意图治疗。
与安慰剂相比，2400毫克/天剂量的SPN-804显著增加反应率（P= 0.018），并且增加治疗期间（P= 0.013）和维持期间（P= 0.008）癫痫不发作时间。
服用SPN-804 2400毫克/天，1200毫克/天，与安慰剂相比，不良反应的发生率分别为69.1％，56.6％和54.5％；严重不良事件发生分别为9.8％，6.6％和6.6％。SPN-804的最常见的不良反应是头晕，嗜睡，头痛，恶心，复视，呕吐。治疗组没有死亡病例的报道。

药理分类：
二苯并氮杂。

“活性成分”（词）：
奥卡西平150毫克，300毫克，600毫克;缓释片。

公司
Supernus制药
指示（S）：
辅助治疗部分性癫痫发作的治疗成人和儿童6-17岁。

药理作用：
确切的机制，奥卡西平与10 - 羟基代谢物（MHD）发挥其抗癫痫影响，是未知的，然而，在体外研究表明，它们产生的电压敏感的钠通道的封锁，稳定hyperexcited神经膜，抑制重复神经烧成，和缩减的突触冲动的传播。此外，增加的钾电导和调制的高电压激活的钙通道，可能有助于奥卡西平的抗惊厥作用。

临床试验：
XR的Oxtellar的安全性和有效性进行了评估在一项多中心，随机，双盲，安慰剂对照，三组平行组研究（研究1）在成人难治性部分性癫痫患者，年龄18〜65岁组（n = 366 ）。这项研究包括8周基线期，治疗期间（4周的调整期后的维护阶段为期12周的）。在治疗过程中，主要终点是从基线癫痫发作频率每28天的中位数百分比的变化相对于基准期期间的标准统计显着性为P <0.05。患者随机分为三组，并给予Oxtellar：XR 1.2g/day（N = 122），Oxtellar：XR 2.4g/day（N = 123）或安慰剂（n = 121）。主要疗效结果表明中位数百分比变化在发作频率-38.2％（P <0.078）和-42.9％（P <0.003）在的Oxtellar XR 1.2g/day， 2.4g/day治疗组，分别在安慰剂组则为-28.7％。，虽然1.2g/day与安慰剂对比没有达到统计学意义，浓度 - 效应分析表明，在1.2g/day剂量是一种有效的剂量。

法律分类：
接收

成人：
空腹燕子。带全> 17yrs：最初600毫克每日一次，1周，然后可以增加600mg/day增量在每周一班;正常范围1.2g-2.4g/day伴随抗癫痫药：考虑起始于900毫克，每天一次可能会增加由300-450mg/day每周上透析的终末期肾病的时间间隔递增。严重肾功能不全（肌酐清除率<30ml/min者）：最初300mg/day：使用奥卡西平老人立即释放：最初300毫克或450毫克，每天一次，5月奥卡西平立即释放在的每周一班转换从300-450mg/day递增。增加：可能需要更高剂量。
儿童：
<6yrs：不建议6 17yrs：最初8-10mg/kg，每日一次，最大600mg/day中的第一个星期，然后可能会增加8-10mg/kg/day增量在每周的时间间隔，通常是最大600mg/day。目标维持剂量（获得超过2-3周）：2029千克：900mg/day; 29.​​1-39千克：1.2g/day;>39公斤时1.8g/day。
警告/注意事项：
...低钠血症的风险，监控征兆/症状如果发生严重肝功能不全：......不推荐卡马西平过敏症，自杀行为和意念，监控停止，如果多器官过敏性的发生;使用替代治疗，避免突然停药高龄怀孕（目录C）。癫痫发作的风险，监察过程中和产后哺乳期的母亲：不推荐使用。
互动（补）
苯妥英钠，卡马西平，苯巴比妥，丙戊酸拮抗，监测和调整剂量，可能会降低激素避孕药（左炔诺孕酮炔雌醇），其他的口头或植入避孕药的有效性。使用额外的非激素形式，注意与其他药物降低血清钠可能会影响甲状腺（T4）测试。

不良反应（补）
头晕，嗜睡，头痛，平衡障碍，震颤，呕吐，复视，乏力，疲劳;低钠血症，严重的皮肤反应（如Stevens-Johnson综合征和中毒性表皮坏死松解症）;罕见：血管神经性水肿，过敏性反应，血液系统的反应;停止，如果发生。

如何提供：
标签-100

最后更新：
2013年2月14号

Oxtellar XR
Generic Name: oxcarbazepine
Dosage Form: tablet
Indications and Usage for Oxtellar XR
Oxtellar XR™ is indicated as adjunctive therapy of partial seizures in adults and in children 6 years to 17 years of age.
Oxtellar XR Dosage and Administration
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).
Dosing for Adults in Adjunctive Therapy
The recommended daily dose of Oxtellar XR™ is 1,200 mg to 2,400 mg per day, given once daily. The dose of 2,400 mg per day showed slightly greater efficacy than 1,200 mg per day, but was associated with an increase in adverse reactions.
Initiate treatment at a dose of 600 mg per day given once daily for one week. Subsequent dose increases can be made at weekly intervals in 600 mg per day increments to achieve the recommended daily dose.
Dosing for Children (6 to 17 years of age) in Adjunctive Therapy
In pediatric patients 6 years to 17 years of age, initiate treatment at a daily dose of 8 mg/kg to 10 mg/kg once daily, not to exceed 600 mg per day in the first week.
Subsequent dose 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 dose. The target maintenance dose, achieved over two to three weeks, is displayed in Table 1.
Dosage Modifications in Patients with Renal Impairment
In patients with severe renal impairment (creatinine clearance less than 30 mL/minute), initiate Oxtellar XR™ at one-half the usual starting dose (300 mg per day). Subsequent dose increases can be made at weekly intervals in increments of 300 mg to 450 mg per day to achieve the desired clinical response. [see Use in Specific Populations (8.5)].
Dosage Modifications in Geriatric Patients
In geriatric patients, consider starting at a lower dose (300 mg or 450 mg per day). Subsequent dose increases can be made at weekly intervals in increments of 300 mg to 450 mg per day to achieve the desired clinical effect [see Use in Specific Populations (8.4)].
Dosage Modification for use with Concomitant Antiepileptic Drugs
Enzyme inducing antiepileptic drugs such as carbamazepine, phenobarbital, and phenytoin decrease exposure to 10-monohydroxy derivative (MHD), the active metabolite. Dosage increases may be necessary. Consider initiating dose at 900 mg once per day [see Drug Interactions (7.1)].
Withdrawal of AEDs
As with all antiepileptic drugs, Oxtellar XR™ should be withdrawn gradually to minimize the potential of increased seizure frequency [see Warnings and Precautions (5.6)].
Conversion from Immediate-Release Oxcarbazepine to Oxtellar XR™
In conversion of oxcarbazepine immediate-release to Oxtellar XR™, higher doses of Oxtellar XR™ may be necessary [see Clinical Pharmacology (12.3)].
Dosage Forms and Strengths
Extended-release tablets:
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
Contraindications
Oxtellar XR™ is contraindicated in patients with a known hypersensitivity to oxcarbazepine or to any of its components [see Warnings and Precautions (5.2, 5.3)].
Warnings and Precautions
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 dose 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). Post-marketing cases of symptomatic hyponatremia 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).
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™.
Hypersensitivity Reactions in Patients with Hypersensitivity to Carbamazepine
Inform patients who have had hypersensitivity reactions to carbamazepine that approximately 25%-30% of them will experience hypersensitivity reactions with Oxtellar XR™. Question patients about any prior adverse reactions with carbamazepine. 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 (5.8)].
Serious Dermatological Reactions
Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have occurred in both children and adults in 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.
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.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Withdrawal of AEDs
As with all AEDs, Oxtellar XR™ should be withdrawn gradually to minimize the potential of increased seizure frequency.
Multi-Organ Hypersensitivity
Multi-organ hypersensitivity reactions have occurred in close temporal association (median time to detection 13 days: range 4-60) to the initiation of immediate-release oxcarbazepine therapy in adult and pediatric patients. Although there have been a limited number of reports, many of these cases resulted in hospitalization and some were life-threatening. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. These included the following: hematologic and lymphatic (e.g., eosinophilia, thrombocytopenia, lymphadenopathy, leukopenia, neutropenia, splenomegaly), hepatobiliary (e.g., hepatitis, liver function test abnormalities), renal (e.g., proteinuria, nephritis, oliguria, renal failure), muscles and joints (e.g., joint swelling, myalgia, arthralgia, asthenia), nervous system (e.g., hepatic encephalopathy), respiratory (e.g., dyspnea, pulmonary edema, asthma, bronchospasm, interstitial lung disease), hepatorenal syndrome, pruritus, and angioedema. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, discontinue Oxtellar XR™ and initiate an alternative treatment.
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 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.
Laboratory Tests
Laboratory data from clinical trials suggest that immediate-release oxcarbazepine may be associated with decreases in T4, without changes in T3 or TSH.
Adverse Reactions
The following adverse reactions are described in other sections of the labeling:
•Hyponatremia [see Warnings and Precautions (5.1)]
•Anaphylactic Reactions and Angioedema [see Warnings and Precautions (5.2)]
•Hypersensitivity Reactions in Patients with Hypersensitivity to Carbamazepine [see Warnings and Precautions (5.3)]
•Serious Dermatological Reactions [see Warnings and Precautions (5.4)]
•Suicidal Behavior and Ideation [see Warnings and Precautions (5.5)]
•Withdrawal of AEDs [see Warnings and Precautions (5.6)]
•Multi-Organ Hypersensitivity [see Warnings and Precautions (5.7)]
•Hematologic Reactions [see Warnings and Precautions (5.8)]
•Risk of Seizures in the Pregnant Patient [see Warnings and Precautions (5.9)]
•Laboratory Tests [see Warnings and Precautions (5.10)]
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 epilepsy who received Oxtellar XR™ (366 adults and 18 children) with concomitant AEDs.
In addition, safety data presented below are from a total of 2,288 patients with seizure disorders treated with immediate-release oxcarbazepine; 1,832 were adults and 456 were children.
Most Common Adverse Reactions Reported by Adult Patients Receiving Concomitant AEDs in Oxtellar XR™ Clinical Studies
Table 3 lists adverse reactions that occurred in at least 2% of adult patients with epilepsy treated with Oxtellar XR™ or placebo and concomitant AEDs and that were numerically more common in the patients treated with any dose of Oxtellar XR™ than in patients receiving placebo.
The overall incidence of adverse reactions appeared to be dose related, particularly during the Titration Period. The most commonly observed (≥ 5%) adverse reactions seen in association with Oxtellar XR™ and more frequent than in placebo-treated patients were: dizziness, somnolence, headache, balance disorder, tremor, vomiting, diplopia, and asthenia.
Adverse Reactions Associated with Discontinuation of Oxtellar XR™ Treatment: Approximately 23.3% of the 366 adult patients receiving Oxtellar XR™ in clinical studies discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation of Oxtellar XR™ (reported by ≥2%) were: dizziness (9.8%), vomiting (5.3%), nausea (3.7%), diplopia (3.2%), and somnolence (2.4%).
Adjunctive Therapy with Oxtellar XR™ in Pediatric Patients 4 to 16 Years Old Previously Treated with other AEDs
In a pharmacokinetic study in 18 children (age 4-16 years) with partial seizures treated with different doses of Oxtellar XR™, the observed adverse reactions seen in association with Oxtellar XR™ were similar to those seen in adults.
Most Common Adverse Reactions in Immediate-Release Oxcarbazepine Controlled Clinical Studies
Controlled Clinical Studies of Adjunctive Therapy with Immediate-Release Oxcarbazepine in Adults Previously Treated with other AEDs: Table 4 lists adverse reactions that occurred in at least 2% of adult patients with epilepsy treated with immediate-release oxcarbazepine or placebo with concomitant AEDs and that were numerically more common in the patients treated with any dose of immediate-release oxcarbazepine than in placebo. As immediate-release oxcarbazepine and Oxtellar XR™ were not examined in the same trial, adverse event frequencies cannot be directly compared between the two formulations.
Other Reactions Observed in Association with the Administration of Immediate-Release Oxcarbazepine
In the paragraphs that follow, the adverse reactions, other than those in the preceding tables or text, that occurred in a total of 565 children and 1,574 adults exposed to immediate-release oxcarbazepine and that are reasonably likely to be related to drug use are presented. Events common in the population, events reflecting chronic illness and events likely to reflect concomitant illness are omitted particularly if minor. They are listed in order of decreasing frequency. Because the reports cite reactions observed in open label and uncontrolled trials, the role of immediate-release oxcarbazepine in their causation cannot be reliably determined.
Body as a Whole: fever, malaise, pain chest precordial, rigors, weight decrease.
Cardiovascular System: bradycardia, cardiac failure, cerebral hemorrhage, hypertension, hypotension postural, palpitation, syncope, tachycardia.
Digestive System: appetite increased, blood in stool, cholelithiasis, colitis, duodenal ulcer, dysphagia, enteritis, eructation, esophagitis, flatulence, gastric ulcer, gingival bleeding, gum hyperplasia, hematemesis, hemorrhage rectum, hemorrhoids, hiccup, mouth dry, pain biliary, pain right hypochondrium, retching, sialoadenitis, stomatitis, stomatitis ulcerative.
Hematologic and Lymphatic System: thrombocytopenia.
Laboratory Abnormality: gamma-GT increased, hyperglycemia, hypocalcemia, hypoglycemia, hypokalemia, liver enzymes elevated, serum transaminase increased.
Musculoskeletal System: hypertonia muscle.
Nervous System: aggressive reaction, amnesia, anguish, anxiety, apathy, aphasia, aura, convulsions aggravated, delirium, delusion, depressed level of consciousness, dysphonia, dystonia, emotional lability, euphoria, extrapyramidal disorder, feeling drunk, hemiplegia, hyperkinesia, hyperreflexia, hypoesthesia, hypokinesia, hyporeflexia, hypotonia, hysteria, libido decreased, libido increased, manic reaction, migraine, muscle contractions involuntary, nervousness, neuralgia, oculogyric crisis, panic disorder, paralysis, paroniria, personality disorder, psychosis, ptosis, stupor, tetany.
Respiratory System: asthma, bronchitis, coughing, dyspnea, epistaxis, laryngismus, pleurisy.
Skin and Appendages: acne, alopecia, angioedema, bruising, dermatitis contact, eczema, facial rash, flushing, folliculitis, heat rash, hot flushes, photosensitivity reaction, pruritus genital, psoriasis, purpura, rash erythematous, rash maculopapular, vitiligo, urticaria.
Special Senses: accommodation abnormal, cataract, conjunctival hemorrhage, edema eye, hemianopia, mydriasis, otitis externa, photophobia, scotoma, taste perversion, tinnitus, xerophthalmia.
Urogenital and Reproductive System: dysuria, hematuria, intermenstrual bleeding, leukorrhea, menorrhagia, micturition frequency, pain renal, pain urinary tract, polyuria, priapism, renal calculus, urinary tract infection.
Other: Systemic lupus erythematosus.
Postmarketing and Other Experience
The following adverse reactions have been identified during post-approval use of immediate-release oxcarbazepine. 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)]
Anaphylaxis:[see Warnings and Precautions (5.2)]
Digestive System: pancreatitis and/or lipase and/or amylase increase
Hematologic and Lymphatic Systems: aplastic anemia [see Warnings and Precautions (5.8)]
Skin and Appendages: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis [see Warnings and Precautions (5.4)]
Drug Interactions
Oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5).
In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD.
These interactions have implications when Oxtellar XR™ is used with other AEDs or hormonal contraceptives.
Other Antiepileptic Drugs
Potential interactions between immediate-release oxcarbazepine and other AEDs were assessed in clinical studies. Oxtellar XR™ would be expected to have the same effects on coadministered AEDs as immediate-release oxcarbazepine.
Hormonal Contraceptives
Coadministration of immediate-release oxcarbazepine with an oral contraceptive decreased the plasma concentrations of two components of hormonal contraceptives, ethinylestradiol and levonorgestrel. Therefore, concurrent use of Oxtellar XR™ with these hormonal contraceptives and other oral or implant contraceptives may render these contraceptives less effective [see Clinical Pharmacology (12.3)]. Additional non-hormonal forms of contraception are recommended.
USE IN SPECIFIC POPULATIONS
Pregnancy
Oxtellar XR™ plasma concentrations may decrease during pregnancy [see Warnings and Precautions (5.9)]
Pregnancy Category C
There are no adequate and well-controlled clinical studies of Oxtellar XR™ in pregnant women; however, Oxtellar XR™ is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Given this fact, and the results of the animal studies described, it is likely that Oxtellar XR™ is a human teratogen. Oxtellar XR™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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.
When pregnant rats were given oxcarbazepine (30, 300, or 1000 mg/kg) 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 maximum recommended human dose [MRHD] on a mg/m2 basis). 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) during organogenesis, embryofetal mortality was increased at the highest dose (1.5 times the MRHD on a mg/m2 basis). 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) 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/m2 basis). Oral administration of MHD (25, 75, or 250 mg/kg) 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/m2 basis).
To provide information regarding the effects of in utero exposure to Oxtellar XR™, physicians are advised to recommend that pregnant patients taking Oxtellar XR™ enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
Nursing Mothers
Oxcarbazepine and its active metabolite (MHD) are excreted in human milk. A milk-to-plasma concentration ratio of 0.5 was found for both. Because of the potential for serious adverse reactions to Oxtellar XR™ in nursing infants, a decision should be made about whether to discontinue nursing or to discontinue the drug in nursing women, taking into account the importance of the drug to the mother.
Pediatric Use
The short term safety and effectiveness of Oxtellar XR™ in pediatric patients ages 6 to 16 years with partial onset seizures is supported by:
1)
An adequate and well-controlled short term safety and efficacy study of Oxtellar XR™ in adults that included pharmacokinetic sampling [see Clinical Studies (14.1)],
2)
A pharmacokinetic study of Oxtellar XR™ in pediatric patients ages 4 to 16 years [see Clinical Pharmacology (12.3)], and
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, and has not been studied in patients younger than 4 years of age.
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 dose and lower titration [see Dosage and Administration (2.5)].
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 (2.4)].
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 dose and increase, if necessary, at a slower than usual rate until the desired clinical response is achieved [see Dosage and Administration (2.4)].
In patients with end-stage renal disease on dialysis, it is recommended that immediate release oxcarbazepine be used instead of Oxtellar XR™.
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)].
Drug Abuse and Dependence
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.
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.
Overdosage
Human Overdose Experience
Isolated cases of overdose with immediate-release oxcarbazepine have been reported. The maximum dose taken was approximately 24,000 mg. All patients recovered with symptomatic treatment.
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.
Oxtellar XR Description
Oxtellar XR™ is an antiepileptic drug (AED). Oxtellar XR™ extended-release tablets contain oxcarbazepine for once-a-day oral administration.
Oxcarbazepine is 10,11-Dihydro-10-oxo-5H-dibenz[b,f]-azepine-5-carboxamide, and its structural formula is
Oxcarbazepine is off-white to yellow crystalline powder.
Oxcarbazepine is sparingly soluble in chloroform (30-100 g/L). In aqueous media over pH range 1 to 8, oxcarbazepine is practically insoluble and its solubility is 40 mg/L (0.04 g/L) at pH 7.0, 25°C. The molecular formula is C15H12N2O2 and its molecular weight is 252.27.
Oxtellar XR™ tablets contain the following inactive ingredients: colloidal silicon dioxide, hypromellose, yellow iron oxide (150 mg, 300 mg tablets only), red iron oxide (300 mg, 600 mg tablets only), black iron oxide (300 mg tablet only), magnesium stearate, methacrylic acid copolymer, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, sodium lauryl sulfate, talc, and titanium dioxide. Each tablet is printed on one side with edible black ink.
Oxtellar XR - Clinical Pharmacology
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.
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.
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 human, 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 dose is not bioequivalent to the same total dose 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 Cmax occurred 7 hours post-dose. At steady state, Oxtellar XR™ given once daily produced MHD exposures (AUC and Cmax) about 19% lower and MHD minimum concentrations (Cmin) about 16% lower than the immediate-release oxcarbazepine given twice daily when administered at the same 1200 mg total daily dose. When Oxtellar XR™ was administered at an equivalent 600 mg single dose (4 x 150 mg tablets, 2 x 300 mg tablets, or 1 x 600 mg tablet), equivalent MHD exposures (AUC) were observed.
Following a single dose of Oxtellar XR™ (1 x 150 mg tablets, 1 x 300 mg tablets, or 1 x 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 Cmax: AUC increases 2.4-fold and Cmax increases 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 (Cmax) was about 60% higher and occurred 2 hours earlier under fed conditions than under fasting conditions.
The increase in Cmax, 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.
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).
Elimination
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.
Special Populations
Elderly
No studies with Oxtellar XR™ in elderly patients have been completed [see Use in Specific Populations (8.4)].
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
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, and has not been studied in patients younger than 4 years of age. A pharmacokinetic study of Oxtellar XR™ was performed in 18 pediatric patients with epilepsy, 4 to 16 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 (8.3)].
Gender
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.
Race
The effects of race have not been studied for Oxtellar XR™.
Renal or Hepatic Impairment
The effects of renal or hepatic impairment have not been studied for Oxtellar XR™ [see Use in Specific Populations (8.5, 8.6)].
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. Dose adjustment is recommended in these patients [see Dosage and Administration (2.4) and Use in Special Populations (8.5)].
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 (8.6)].
Pregnancy
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 UDPglucuronyl 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:
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. Therefore, concurrent use of oxcarbazepine with hormonal contraceptives may render these contraceptives less effective.
Calcium Channel 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.
Other Interactions
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.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
In two-year carcinogenicity studies, oxcarbazepine was administered in the diet at doses of up to 100 mg/kg/day to mice and by gavage at doses of up to 250 mg/kg/day to rats, and the pharmacologically active 10-hydroxy metabolite (MHD) was administered orally at doses of up to 600 mg/kg/day to rats.
In mice, a dose-related increase in the incidence of hepatocellular adenomas was observed at oxcarbazepine doses ≥ 70 mg/kg/day or approximately 0.1 times the maximum recommended human dose (MRHD) on a mg/m2 basis.
In rats, the incidence of hepatocellular carcinomas was increased in females treated with oxcarbazepine at doses≥25 mg/kg/day (0.1 times the MRHD on a mg/m2 basis), and incidences of hepatocellular adenomas and/or carcinomas were increased in males and females treated with MHD at doses of 600 mg/kg/day (2.4 times the MRHD on a mg/m2 basis) and≥250 mg/kg/day (equivalent to the MRHD on a mg/m2 basis), respectively.
There was an increase in the incidence of benign testicular interstitial cell tumors in rats at 250 mg oxcarbazepine/kg/day and at≥250mg MHD/kg/day, and an increase in the incidence of granular cell tumors in the cervix and vagina in rats at 600 mg MHD/kg/day.
Mutagenesis
Oxcarbazepine increased mutation frequencies in the Ames test in vitro in the absence of metabolic activation in one of five bacterial strains. Both oxcarbazepine and MHD produced increases in chromosomal aberrations and polyploidy in the Chinese hamster ovary assay in vitro in the absence of metabolic activation. MHD was negative in the Ames test, and no mutagenic or clastogenic activity was found with either oxcarbazepine or MHD in V79 Chinese hamster cells in vitro. Oxcarbazepine and MHD were both negative for clastogenic or aneugenic effects (micronucleus formation) in an in vivo rat bone marrow assay.
Impairment of Fertility
In a fertility study in which rats were administered MHD (50, 150, or 450 mg/kg) orally prior to and during mating and early gestation, estrous cyclicity was disrupted and numbers of corpora lutea, implantations, and live embryos were reduced in females receiving the highest dose (approximately two times the MRHD on a mg/m2 basis).
Clinical Studies
Oxtellar XR™ has been evaluated as adjunctive therapy for partial seizures in adults. The use of Oxtellar XR™ for the treatment of partial seizures in children is based on adequate and well-controlled studies of Oxtellar XR™ in adults, along with clinical trials of immediate-release oxcarbazepine in children, and on pharmacokinetic evaluations of the use of Oxtellar XR™ in children.
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 epilepsy (18 to 65 years of age, inclusive) was performed to examine the safety and efficacy of Oxtellar XR™.
Patients had at least three partial 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 epilepsy 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.
Although the 1200 mg/day-placebo contrast did not reach statistical significance, concentration-response analyses reveal that the 1200 mg/day dose is an effective dose.
Immediate-Release Oxcarbazepine Adjunctive Therapy Trials
The effectiveness of immediate-release oxcarbazepine as an adjunctive therapy for partial seizures in adults was demonstrated at doses of 600mg per day, 1200mg per day and 2400mg per day (divided twice daily) in a randomized, double-blind, placebo-controlled trial. All doses resulted in a statistically significant reduction in seizure frequency when compared to placebo (p<0.05).
The effectiveness of immediate-release oxcarbazepine in doses of 30-46 mg/kg/day, depending on baseline weight, as an adjunctive therapy for partial seizures in children 3 years to 17 years of age was studied in a randomized, double-blind, placebo-controlled trial. Oxcarbazepine in the single weight based dose group resulted in a statistically significant reduction in seizure frequency when compared to placebo (p<0.05).
How Supplied/Storage and Handling
Dosage Form Supplied
150 mg (yellow modified-oval shaped tablet printed "150" on one side with edible black ink).
Bottles of 100 tablets……………………………NDC 17772-121-01

300 mg (brown modified-oval shaped tablet printed "300" on one side with edible black ink).
Bottles of 100 tablets……………………………NDC 17772-122-01
600 mg (brownish red modified-oval shaped tablet printed "600" on one side with edible black ink).
Bottles of 100 tablets………………………… NDC 17772-123-01
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.