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Onfi(Clobazam Tablets and Oral Suspension)

2012-03-01 06:05:29  作者:新特药房  来源:中国新特药网天津分站  浏览次数:286  文字大小:【】【】【
简介:2011年10月24日,Lundbeck宣布,美国食品药品管理局(FDA)已批准Onfi(氯巴占)用于年龄≥2岁的Lennox-Gastaut综合征(LGS)患者痫性发作的辅助治疗。Onfi是一种苯二氮类药物,并且被列在联邦政府管制物质名单-4 上。 ...

新型癫痫药物Onfi(clobazam)片和口服混悬液是一种苯二氮卓类治疗有Lennox-Gastaut综合征(LGS)患者的新药
2011年10月21日,美国食品药品监督管理局批准Onfi片(clobazam)用作辅助(添加)治疗在成年和2岁和以上儿童中伴随Lennox-Gastaut综合征癫痫。As Onfi is 意向治疗某种疾病和情况在美国影响少于200,000人,它被FDA授予孤儿药物指定。
FDA的药品评价和研究中心神经学产品部主任Russell Katz, M.D说“Lennox-Gastaut综合征是is a severe癫痫导致衰弱癫痫的严重形式,”“是一种困难治疗的情况,和它将有助于有一种另外治疗选择”。
Lennox-Gastaut综合征寻常在4岁前开始,和可被一些情况引起,包括脑畸形,严重头损伤,中枢神经系统感染,和遗传退行性或代谢情况。在30至35百分率患者中,不能发现致病原因。患者常有广泛各种各样频繁癫痫,包括强直性(身体僵硬,眼向上偏移,瞳孔扩大,和互相模式改变),非强直性(肌张力和意识简要丧失,造成突然跌倒),不典型缺乏(神志恍惚),和肌阵挛(肌肉突然抽搐)。
大多数有Lennox-Gastaut综合征儿童经受一定程度智力功能或信息处理损伤,以及发育延迟和行为紊乱。
在2岁和以上患者的两项多中心对照研究当添加至正在试验癫痫药物中Onfi的有效性。在每个研究中,来自4周基线期至维持期药物被测试对每周癫痫(非强制性,强直性,或肌阵挛导致跌倒或丧失姿势)癫痫频数的减低的量。在两项研究中,服用Onfi患者当与服用对照治疗(一项研究安慰剂和另一项研究低剂量Onfi)癫痫控制改善。
服用Onfi患者与服用无活性片(安慰剂比较)报道的常见不良反应包括嗜睡,镇静,发热,流口水,便秘,咳嗽,泌尿道感染,失眠,进攻性,疲乏,上呼吸道感染,易怒,呕吐,吞咽困难,共济失调,支气管炎,和肺炎。
像其它抗癫痫药物,在非常小数服用药物人们中Onfi可能增加自杀念头和行为的风险。应监视服用抗癫痫药物患者抑郁,自杀念头或行为,和情绪或行为中不寻常变化.
Onfi可能思维迟缓和损害运动技能;所以,重要的是服用药物人们不要驾驶,操作重型机械,或参加其它危险活动直至他们知道药物如何影响他们。Onfi可能引起滥用和依赖。曾被分类为受控物质法下的附表IV类药物。Onfi不应突然终止。用药应与卫生保健专业人员谈话关于缓慢停止药物避免撤药症状。
剂型
片剂


口服混悬液


HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ONFI safely and effectively. See full prescribing information for ONFI.
ONFI® (clobazam) tablets, for oral use, CIV
ONFI® (clobazam) oral suspension, CIV
Initial U.S. Approval: 2011
RECENT MAJOR CHANGES
Contraindications (4)                                    12/2014
INDICATIONS AND USAGE
ONFI is a benzodiazepine indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older (1)
DOSAGE AND ADMINISTRATION
For doses above 5 mg/day administer in two divided doses (2.1)
Patients ≤30 kg body weight: Initiate at 5 mg daily and titrate as tolerated up to 20 mg daily (2.1)
Patients >30 kg body weight: Initiate at 10 mg daily and titrate as tolerated up to 40 mg daily (2.1)
Dosage adjustment needed in following groups:
Geriatric patients (2.4, 8.5)
Known CYP2C19 poor metabolizers (2.5)
Mild or moderate hepatic impairment; no information for severe hepatic impairment (2.7, 8.8)
Reduce dose, or discontinue drug gradually (2.2)
Tablets: Administer whole, broken in half along the score, or crush and mix in applesauce. (2.3)
Measure prescribed amount of oral suspension using provided adapter and dosing syringe (2.3)
Tablets and Oral suspension: Can be taken with or without food. (2.3)
DOSAGE FORMS AND STRENGTHS
Tablet: 10 mg and 20 mg with a functional score (3)
Oral Suspension: 2.5 mg/mL in 120 mL bottles (3)
CONTRAINDICATIONS
History of hypersensitivity to the drug or its ingredients (4)
WARNINGS AND PRECAUTIONS
Somnolence or Sedation: Monitor for central nervous system (CNS) depression. Risk may be increased with concomitant use of other CNS depressants. (5.1, 5.2)
Withdrawal: Symptoms may occur with rapid dose reduction or discontinuation. Discontinue ONFI gradually. (5.3)
Serious Dermatological Reactions(including Stevens-Johnson syndrome and toxic epidermal necrolysis):Discontinue ONFI at first sign of rash unless the rash is clearly not drug-related. (5.4)
Physical and Psychological Dependence: Monitor patients with a history of substance abuse for signs of habituation and dependence (5.5, 9)
Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behaviors (5.6)
ADVERSE REACTIONS
Adverse reactions that occurred at least 10% more frequently than placebo in any ONFI dose included constipation, somnolence or sedation, pyrexia, lethargy, and drooling (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck at 1-800-455-1141 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
Drugs metabolized by CYP2D6: Lower doses of these drugs may be required when used concomitantly with ONFI (7.1)
Strong or Moderate CYP2C19 Inhibitors: Dosage adjustment of ONFI may be necessary (7.2)
Alcohol: Increases blood levels of clobazam by about 50% (7.3)
USE IN SPECIFIC POPULATIONS
Pregnancy:  Based on animal data, may cause fetal harm (8.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 12/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
ONFI® (clobazam) is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Information
A daily dose of ONFI greater than 5 mg should be administered in divided doses twice daily; a 5 mg daily dose can be administered as a single dose. Dose patients according to body weight. Individualize dosing within each body weight group, based on clinical efficacy and tolerability. Each dose in Table 1 (e.g. 5 to 20 mg in ≤30 kg weight group) has been shown to be effective, although effectiveness increases with increasing dose [see Clinical Studies (14)]. Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state.
Table 1. Recommended Total Daily Dosing by Weight Group

≤30 kg Body Weight  >30 kg Body Weight
  Starting Dose   5 mg   10 mg
  Starting Day 7   10 mg   20 mg
  Starting Day 14   20 mg   40 mg
2.2 Gradual Withdrawal
As with all antiepileptic drugs and benzodiazepines, withdraw ONFI gradually. Taper by decreasing the total daily dose by 5-10 mg/day on a weekly basis until discontinued [see Warnings and Precautions (5.3)].
2.3 Important Administration Instructions
Instruct patients to read the "Instructions for Use" carefully for complete directions on how to properly dose and administer ONFI oral suspension.
ONFI Tablet Oral Administration
ONFI tablets can be taken with or without food.
ONFI tablets can be administered whole, broken in half along the score, or crushed and mixed in applesauce.
ONFI Oral Suspension Oral Administration
ONFI oral suspension can be taken with or without food [see Clinical Pharmacology (12.3)].
Shake ONFI Oral Suspension well before every administration. When administering the oral suspension, use only the oral dosing syringe provided with the product. Each carton includes two syringes, but only one syringe should be used for dosing. The second oral syringe is reserved as a replacement in case the first syringe is damaged or lost. Insert the provided adapter firmly into the neck of the bottle before first use and keep the adapter in place for the duration of the usage of the bottle. To withdraw the dose, insert the dosing syringe into the adapter and invert the bottle then slowly pull back the plunger to prescribed dose. After removing the syringe from the bottle adapter, slowly squirt ONFI Oral Suspension into the corner of the patient's mouth. Replace the cap after each use. The cap fits over the adapter when the adapter is properly placed. See ONFI Oral Suspension "Instructions for Use" for complete instruction on how to properly dose and administer the ONFI Oral Suspension.
2.4 Dosage Adjustments in Geriatric Patients
Plasma concentrations at any given dose are generally higher in the elderly: proceed slowly with dose escalation. The starting dose should be 5 mg/day for all elderly patients. Then titrate elderly patients according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on weight) may be started on day 21 [see Use in Specific Populations (8.5)].
2.5 Dosage Adjustments in CYP2C19 Poor Metabolizers
In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam's active metabolite, will be increased. Therefore, in patients known to be CYP2C19 poor metabolizers, the starting dose should be 5 mg/day and dose titration should proceed slowly according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group) may be started on day 21 [see Use in Specific Populations (8.6), Clinical Pharmacology (12.5)].
2.6 Patients with Renal Impairment
No dose adjustment is required for patients with mild and moderate renal impairment. There is no experience with ONFI in patients with severe renal impairment or end stage renal disease (ESRD). It is not known if clobazam or its active metabolite, N-desmethylclobazam, is dialyzable [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
2.7 Dosage Adjustments in Patients with Hepatic Impairment
ONFI is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of ONFI. For this reason, proceed slowly with dosing escalations. For patients with mild to moderate hepatic impairment (Child-Pugh score 5-9), the starting dose should be 5 mg/day in both weight groups. Then titrate patients according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, start an additional titration on day 21 to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group). There is inadequate information about metabolism of ONFI in patients with severe hepatic impairment. Therefore no dosing recommendation in those patients can be given [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)].
3 DOSAGE FORMS AND STRENGTHS
Tablets: 10 mg and 20 mg with a functional score for oral administration.
Each ONFI tablet is a white to off-white, oval tablet with a functional score on one side and either a "1" and "0" or a "2" and "0" debossed on the other side.
Oral Suspension: 2.5 mg/mL for oral administration. Each bottle contains 120 mL of an off-white suspension.
4 CONTRAINDICATIONS
ONFI is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients. Hypersensitivity reactions have included serious dermatological reactions [see Warnings and Precautions (5.4)]. 
5 WARNINGS AND PRECAUTIONS
5.1 Somnolence or Sedation
ONFI causes somnolence and sedation. In clinical trials, somnolence or sedation was reported at all effective doses and was dose-related.
In general, somnolence and sedation begin within the first month of treatment and may diminish with continued treatment. Prescribers should monitor patients for somnolence and sedation, particularly with concomitant use of other central nervous system depressants. Prescribers should caution patients against engaging in hazardous activities requiring mental alertness, such as operating dangerous machinery or motor vehicles, until the effect of ONFI is known.
5.2 Potentiation of Sedation from Concomitant Use with Central Nervous System Depressants
Since ONFI has a central nervous system (CNS) depressant effect, patients or their caregivers should be cautioned against simultaneous use with other CNS depressant drugs or alcohol, and cautioned that the effects of other CNS depressant drugs or alcohol may be potentiated.
5.3 Withdrawal Symptoms
Abrupt discontinuation of ONFI should be avoided. ONFI should be tapered by decreasing the dose every week by 5-10 mg/day until discontinuation [see Dosage and Administration (2.2)].
Withdrawal symptoms occurred following abrupt discontinuation of ONFI; the risk of withdrawal symptoms is greater with higher doses.
As with all antiepileptic drugs, ONFI should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus.
Withdrawal symptoms (e.g., convulsions, psychosis, hallucinations, behavioral disorder, tremor, and anxiety) have been reported following abrupt discontinuance of benzodiazepines. The more severe withdrawal symptoms have usually been limited to patients who received excessive doses over an extended period of time, followed by an abrupt discontinuation. Generally milder withdrawal symptoms (e.g., dysphoria, anxiety, and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic doses for several months.
5.4 Serious Dermatological Reactions
Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with ONFI in both children and adults during the post-marketing period.  Patients should be closely monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment initiation or when re-introducing therapy. ONFI should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered [see Contraindications (4)].
5.5 Physical and Psychological Dependence
Patients with a history of substance abuse should be under careful surveillance when receiving ONFI or other psychotropic agents because of the predisposition of such patients to habituation and dependence [see Drug Abuse and Dependence (9)].
5.6 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including ONFI, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% confidence interval [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 Drug  
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 ONFI 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 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.
6 ADVERSE REACTIONS
Clinically significant adverse reactions that appear in other sections of the labeling include the following:
Somnolence or Sedation [see Warnings and Precautions (5.1)]
Potentiation of Sedation from Concomitant Use with Central Nervous System Depressants [see Warnings and Precautions (5.2)]
Withdrawal Symptoms [see Warnings and Precautions (5.3)]
Serious Dermatological Reactions [see Contraindications (4), Warnings and Precautions (5.4)]
Physical and Psychological Dependence [see Warnings and Precautions (5.5)]
Suicidal Behavior and Ideation [see Warnings and Precautions (5.6)]
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 practice.
During its development for the adjunctive treatment of seizures associated with LGS, ONFI was administered to 333 healthy volunteers and 300 patients with a current or prior diagnosis of LGS, including 197 patients treated for 12 months or more. The conditions and duration of exposure varied greatly and included single- and multiple-dose clinical pharmacology studies in healthy volunteers and two double-blind studies in patients with LGS (Study 1 and 2) [see Clinical Studies (14)]. Only Study 1 included a placebo group, allowing comparison of adverse reaction rates on ONFI at several doses to placebo.
Adverse Reactions Leading to Discontinuation in an LGS Placebo Controlled Clinical Trial (Study 1)
The adverse reactions associated with ONFI treatment discontinuation in ≥1% of patients in decreasing order of frequency included lethargy, somnolence, ataxia, aggression, fatigue, and insomnia.
Most Common Adverse Reactions in an LGS Placebo Controlled Clinical Trial (Study 1)
Table 3 lists the adverse reactions that occurred in ≥5% of ONFI treated patients (at any dose), and at a rate greater than placebo treated patients, in the randomized, double-blind, placebo-controlled, parallel group clinical study of adjunctive AED therapy for 15 weeks (Study 1).
Table 3. Adverse Reactions Reported for ≥5% of Patients and More Frequently than Placebo in Any Treatment Group

Placebo
N=59
%
 ONFI Dose Level  All ONFI
N=179
%
 Lowa
N=58
%
 Mediumb
N=62
%
 Highc
N=59
%
 Gastrointestinal Disorders
      Vomiting   5   9   5   7   7
      Constipation   0   2   2   10   5
      Dysphagia   0   0   0   5   2
 General Disorders and Administration Site Conditions
      Pyrexia   3   17   10   12   13
      Irritability   5   3   11   5   7
      Fatigue   2   5   5   3   5
 Infections and Infestations
      Upper respiratory tract infection   10   10   13   14   12
      Pneumonia   2   3   3   7   4
      Urinary tract infection   0   2   5   5   4
      Bronchitis   0   2   0   5   2
 Metabolism and Nutrition Disorders
      Decreased appetite   3   3   0   7   3
      Increased appetite   0   2   3   5   3
 Nervous System Disorders
      Somnolence or Sedation   15   17   27   32   26
          Somnolence   12   16   24   25   22
          Sedation   3   2   3   9   5
      Lethargy   5   10   5   15   10
      Drooling   3   0   13   14   9
      Ataxia   3   3   2   10   5
      Psychomotor hyperactivity   3   3   3   5   4
      Dysarthria   0   2   2   5   3
 Psychiatric Disorders
      Aggression   5   3   8   14   8
      Insomnia   2   2   5   7   5
 Respiratory Disorders
      Cough   0   3   5   7   5
aMaximum daily dose of 5 mg for ≤30 kg body weight; 10 mg for >30 kg body weight
bMaximum daily dose of 10 mg for ≤30 kg body weight; 20 mg for >30 kg body weight
cMaximum daily dose of 20 mg for ≤30 kg body weight; 40 mg for >30 kg body weight
6.2 Post Marketing Experience
These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are categorized by system organ class.
Blood Disorders: Anemia, eosinophilia, leukopenia, thrombocytopenia
Eye Disorders: Diplopia, vision blurred
Gastrointestinal Disorders: Abdominal distention
General Disorders and Administration Site Conditions: Hypothermia
Investigations: Hepatic enzyme increased
Musculoskeletal: Muscle spasms
Psychiatric Disorders: Agitation, anxiety, apathy, confusional state, depression, delirium, delusion, hallucination
Renal and Urinary Disorders: Urinary retention
Respiratory Disorders: Aspiration, respiratory depression
Skin and Subcutaneous Tissue Disorders: Rash, urticaria, angioedema, and facial and lip edema
7 DRUG INTERACTIONS
7.1 Effect of ONFI on Other Drugs
Hormonal Contraceptives
ONFI is a weak CYP3A4 inducer. As some hormonal contraceptives are metabolized by CYP3A4, their effectiveness may be diminished when given with ONFI. Additional non-hormonal forms of contraception are recommended when using ONFI [see Clinical Pharmacology (12.3), Patient Counseling Information (17)].
Drugs Metabolized by CYP2D6
ONFI inhibits CYP2D6. Dose adjustment of drugs metabolized by CYP2D6 may be necessary [see Clinical Pharmacology (12.3)].
7.2 Effect of Other Drugs on ONFI
Strong and moderate inhibitors of CYP2C19
Strong and moderate inhibitors of CYP2C19 may result in increased exposure to N-desmethylclobazam, the active metabolite of clobazam. This may increase the risk of dose-related adverse reactions. Dosage adjustment of ONFI may be necessary when co-administered with strong CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole) [see Clinical Pharmacology (12.3)].
7.3 CNS Depressants and Alcohol
Concomitant use of ONFI with other CNS depressants may increase the risk of sedation and somnolence [see Warnings and Precautions (5.2)].
Alcohol, as a CNS depressant, will interact with ONFI in a similar way and also increases clobazam's maximum plasma exposure by approximately 50%. Therefore, caution patients or their caregivers against simultaneous use with other CNS depressant drugs or alcohol, and caution that the effects of other CNS depressant drugs or alcohol may be potentiated [see Warnings and Precautions (5.2)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C.
Risk Summary
There are no adequate and well-controlled studies of ONFI in pregnant women. In animal studies, administration of clobazam during pregnancy resulted in developmental toxicity, including increased incidences of fetal malformations, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients. ONFI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Available human data on the risk of teratogenicity associated with benzodiazepines are inconclusive. There is insufficient evidence in humans to assess the effect of benzodiazepine exposure during pregnancy on neurodevelopment. Administration of benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia, hypotonia, respiratory depression, and difficulty feeding. In addition, infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period.
Data for other benzodiazepines suggest the possibility of adverse developmental effects (including long-term effects on neurobehavioral and immunological function) in animals following prenatal exposure to benzodiazepines at clinically relevant doses.
Data
Animal
In a study in which clobazam (150, 450, or 750 mg/kg/day) was orally administered to pregnant rats throughout the period of organogenesis, embryofetal mortality and incidences of fetal skeletal variations were increased at all doses. The low effect dose for embryofetal developmental toxicity in rats (150 mg/kg/day) was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, lower than those in humans at the maximum recommended human dose (MRHD) of 40 mg/day.
Oral administration of clobazam (10, 30, or 75 mg/kg/day) to pregnant rabbits throughout the period of organogenesis resulted in decreased fetal body weights, and increased incidences of fetal malformations (visceral and skeletal) at the mid and high doses, and an increase in embryofetal mortality at the high dose. Incidences of fetal variations were increased at all doses. The highest dose tested was associated with maternal toxicity (ataxia and decreased activity). The low effect dose for embryofetal developmental toxicity in rabbits (10 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD.
Oral administration of clobazam (50, 350, or 750 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased embryofetal mortality at the high dose, decreased pup survival at the mid and high doses and alterations in offspring behavior (locomotor activity) at all doses. The low effect dose for adverse effects on pre- and postnatal development in rats (50 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD.
Pregnancy Registry
To provide information regarding the effects of in utero exposure to ONFI, physicians are advised to recommend that pregnant patients taking ONFI enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.  This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves or their caregiver.  Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/
8.3 Nursing Mothers
ONFI is excreted in human milk.  Because of the potential for serious adverse reactions in nursing infants from ONFI, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Safety and effectiveness in patients less than 2 years of age have not been established.
In a study in which clobazam (4, 36, or 120 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 14 to 48), adverse effects on growth (decreased bone density and bone length) and behavior (altered motor activity and auditory startle response; learning deficit) were observed at the high dose. The effect on bone density, but not on behavior, was reversible when drug was discontinued. The no-effect level for juvenile toxicity (36 mg/kg/day) was associated with plasma exposures (AUC) to clobazam and its major active metabolite, N-desmethylclobazam, less than those expected at therapeutic doses in pediatric patients.
8.5 Geriatric Use
Clinical studies of ONFI did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, elderly subjects appear to eliminate clobazam more slowly than younger subjects based on population pharmacokinetic analysis. For these reasons, the initial dose in elderly patients should be 5 mg/day. Patients should be titrated initially to 10-20 mg/day. Patients may be titrated further to a maximum daily dose of 40 mg if tolerated [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
8.6 CYP2C19 Poor Metabolizers
Concentrations of clobazam's active metabolite, N-desmethylclobazam, are higher in CYP2C19 poor metabolizers than in extensive metabolizers. For this reason, dosage modification is recommended [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].
8.7 Renal Impairment
The pharmacokinetics of ONFI were evaluated in patients with mild and moderate renal impairment. There were no significant differences in systemic exposure (AUC and Cmax) between patients with mild or moderate renal impairment and healthy subjects. No dose adjustment is required for patients with mild and moderate renal impairment. There is essentially no experience with ONFI in patients with severe renal impairment or ESRD. It is not known if clobazam or its active metabolite, N-desmethylclobazam, is dialyzable [see Dosage and Administration (2.6), Clinical Pharmacology (12.3)].
8.8 Hepatic Impairment
ONFI is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of ONFI. For this reason, dosage adjustment is recommended in patients with mild to moderate hepatic impairment (Child-Pugh score 5-9). There is inadequate information about metabolism of ONFI in patients with severe hepatic impairment [see Dosage and Administration (2.7), Clinical Pharmacology (12.3)].
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
ONFI contains clobazam which is a Schedule IV controlled substance.
9.2 Abuse
ONFI can be abused in a similar manner as other benzodiazepines, such as diazepam.
The pharmacological profile of ONFI is similar to that of other benzodiazepines listed in Schedule IV of the Controlled Substance Act, particularly in its potentiation of GABAergic transmission through its action on GABAA receptors, which leads to sedation and somnolence.
The World Health Organization epidemiology database contains reports of drug abuse, misuse, and overdoses associated with clobazam.
Drug abuse is the intentional non-therapeutic use of a drug, repeatedly or even sporadically, for its rewarding psychological or physiological effects.
9.3 Dependence
Dependence
Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood levels of the drug, and/or administration of an antagonist. In clinical trials, cases of dependency were reported following abrupt discontinuation of ONFI.
The risk of dependence is present even with use of ONFI at the recommended dose range over periods of only a few weeks. The risk of dependence increases with increasing dose and duration of treatment. The risk of dependence is increased in patients with a history of alcohol or drug abuse.
Withdrawal
Abrupt discontinuation of ONFI causes withdrawal symptoms. As with other benzodiazepines, ONFI should be withdrawn gradually [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].
In ONFI clinical pharmacology trials in healthy volunteers, the most common withdrawal symptoms after abrupt discontinuation were headache, tremor, insomnia, anxiety, irritability, drug withdrawal syndrome, palpitations, and diarrhea [see Warnings and Precautions (5.3)].
Other withdrawal reactions to clobazam reported in the literature include restlessness, panic attacks, profuse sweating, difficulty in concentrating, nausea and dry retching, weight loss, blurred vision, photophobia, and muscle pain and stiffness. In general, benzodiazepine withdrawal may cause seizures, psychosis, and hallucinations [see Warnings and Precautions (5.3)].
10 OVERDOSAGE
10.1 Signs and Symptoms of Overdosage
Overdose and intoxication with benzodiazepines, including ONFI, may lead to CNS depression, associated with drowsiness, confusion and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and, rarely, coma or death. The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol.
10.2 Management of Overdosage
The management of ONFI overdose may include gastric lavage and/or administration of activated charcoal, intravenous fluid replenishment, early control of airway and general supportive measures, in addition to monitoring level of consciousness and vital signs. Hypotension can be treated by replenishment with plasma substitutes and, if necessary, with sympathomimetic agents.
The efficacy of supplementary administration of physostigmine (a cholinergic agent) or of flumazenil (a benzodiazepine antagonist) in ONFI overdose has not been assessed. The administration of flumazenil in cases of benzodiazepine overdose can lead to withdrawal and adverse reactions. Its use in patients with epilepsy is typically not recommended.
11 DESCRIPTION
Table 4. Description

Proprietary Name:   ONFI®
  Established Name:   Clobazam
  Dosage Forms:   Tablet and Oral Suspension
  Route of Administration:   Oral
  Established Pharmacologic Class of Drug:   Benzodiazepine
  Chemical Name:   7-Chloro-1-methyl-5-phenyl-1H-1,5 benzodiazepine-2,4(3H,5H)-dione
Structural Formula:

Clobazam is a white or almost white, crystalline powder with a slightly bitter taste; is slightly soluble in water, sparingly soluble in ethanol, and freely soluble in methylene chloride. The melting range of clobazam is from 182ºC to 185ºC. The molecular formula is C16H13O2N2Cl and the molecular weight is 300.7.
Each ONFI tablet contains 10 mg or 20 mg of clobazam. Tablets also contain as inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, silicon dioxide, and talc.
ONFI is also available for oral administration as an off-white suspension containing clobazam at a concentration of 2.5 mg/mL. Inactive ingredients include magnesium aluminum silicate, xanthan gum, citric acid monohydrate, disodium hydrogen phosphate dihydrate, simethicone emulsion, polysorbate 80, methylparaben, propylparaben, propylene glycol, sucralose, maltitol solution, berry flavor, purified water.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The exact mechanism of action for clobazam, a 1,5-benzodiazepine, is not fully understood but is thought to involve potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABAA receptor.
12.2 Pharmacodynamics
Effects on Electrocardiogram
The effect of ONFI 20 mg and 80 mg administered twice daily on QTc interval was evaluated in a randomized, evaluator blinded, placebo-, and active-controlled (moxifloxacin 400 mg) parallel thorough QT study in 280 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on the Fridericia correction method was below 10 ms, the threshold for regulatory concern. Thus, at a dose two times the maximum recommended dose, ONFI did not prolong the QTc interval to any clinically relevant extent.
12.3 Pharmacokinetics
The peak plasma levels (Cmax) and the area under the curve (AUC) of clobazam are dose-proportional over the dose range of 10-80 mg following single- or multiple-dose administration of ONFI. Based on a population pharmacokinetic analysis, the pharmacokinetics of clobazam are linear from 5-160 mg/day. Clobazam is converted to N-desmethylclobazam which has about 1/5 the activity of clobazam. The estimated mean elimination half-lives (t1/2) of clobazam and N-desmethylclobazam were 36-42 hours and 71-82 hours, respectively.
Absorption
Clobazam is rapidly and extensively absorbed following oral administration. The time to peak concentrations (Tmax) of clobazam tablets under fasted conditions ranged from 0.5 to 4 hours after single- or multiple-dose administrations. The relative bioavailability of clobazam tablets compared to an oral solution is approximately 100%. After single dose administration of the oral suspension under fasted conditions, the Tmax ranged from 0.5 to 2 hours. Based on exposure (Cmax and AUC) of clobazam, ONFI tablets and suspension were shown to have similar bioavailability under fasted conditions. The administration of ONFI tablets with food or when crushed in applesauce does not affect absorption. Although not studied, the oral bioavailability of the oral suspension is unlikely to be affected under fed conditions.
Distribution
Clobazam is lipophilic and distributes rapidly throughout the body. The apparent volume of distribution at steady state was approximately 100 L. The in vitro plasma protein binding of clobazam and N-desmethylclobazam is approximately 80-90% and 70%, respectively.
Metabolism and Excretion
Clobazam is extensively metabolized in the liver, with approximately 2% of the dose recovered in urine and 1% in feces as unchanged drug. The major metabolic pathway of clobazam involves N-demethylation, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. N-desmethylclobazam, an active metabolite, is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations are 3-5 times higher than those of the parent compound. Based on animal and in vitro receptor binding data, estimates of the relative potency of N-desmethylclobazam compared to parent compound range from 1/5 to equal potency. N-desmethylclobazam is extensively metabolized, mainly by CYP2C19. N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine. Following a single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine.
The polymorphic CYP2C19 is the major contributor to the metabolism of the pharmacologically active N-desmethylclobazam [see Clinical Pharmacology (12.5)]. In CYP2C19 poor metabolizers, levels of N-desmethylclobazam were 5-fold higher in plasma and 2- to 3-fold higher in the urine than in CYP2C19 extensive metabolizers.
Pharmacokinetics in Specific Populations
Age
Population pharmacokinetic analyses showed that the clearance of clobazam is lower in elderly subjects compared to other age groups (ages 2 to 64). Dosing should be adjusted in the elderly [see Dosage and Administration (2.4)].
Sex
Population pharmacokinetic analyses showed no difference in the clearance of clobazam between women and men.
Race
Population pharmacokinetic analyses including Caucasian (75%), African American (15%), and Asian (9%) subjects showed that there is no evidence of clinically significant effect of race on the clearance of clobazam.
Renal Impairment
The effect of renal impairment on the pharmacokinetics of clobazam was evaluated in patients with mild (creatinine clearance [CLCR] >50 to 80 mL/min; N=6) and moderate (CLCR=30 to 50 mL/min; N=6) renal dysfunction, with matching healthy controls (N=6), following administration of multiple doses of ONFI 20 mg/day. There were insignificant changes in Cmax (3-24%) and AUC (≤13%) for clobazam or N-desmethylclobazam in patients with mild or moderate renal impairment compared to patients with normal renal function. Patients with severe renal impairment or ESRD were not included in this study.
Hepatic Impairment
There are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of clobazam. In a small study, the pharmacokinetics of a 20 mg single oral dose of ONFI in 9 patients with liver impairment were compared to healthy controls (N=6). The Cmax and the mean plasma clearance of clobazam, as well as the Cmax of N-desmethylclobazam, showed no significant change compared to the healthy controls. The AUC values of N-desmethylclobazam in these patients were not available. Adjust dosage in patients with hepatic impairment [see Dosage and Administration (2.7)].
Drug Interaction Studies
In vitro studies:
Clobazam did not inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A4, UGT1A6, or UGT2B4 in vitro. N-desmethylclobazam showed weak inhibition of CYP2C9, UGT1A4, UGT1A6 and UGT2B4.
Clobazam and N-desmethylclobazam did not significantly increase CYP1A2 or CYP2C19 activities, but did induce CYP3A4 activity in a concentration-dependent manner. Clobazam and N-desmethylclobazam also increased UGT1A1 mRNA but at concentrations much higher than therapeutic levels. The potential for clobazam or N-desmethylclobazam to induce CYP2B6 and CYP2C8 has not been evaluated.
Clobazam and N-desmethylclobazam do not inhibit P-glycoprotein (P-gp), but are P-gp substrates.
In vivo studies:
Potential for ONFI to Affect Other Drugs
The effect of repeated 40 mg once-daily doses of ONFI on the pharmacokinetic profiles of single-dose dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), caffeine (CYP1A2 substrate), and tolbutamide (CYP2C9 substrate), was studied when these probe substrates were given as a drug cocktail (N=18).
Clobazam increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively, reflecting its inhibition of CYP2D6 in vivo. Drugs metabolized by CYP2D6 may require dose adjustment when used with ONFI.
Clobazam decreased the AUC and Cmax of midazolam by 27% and 24%, respectively, and increased the AUC and Cmax of the metabolite 1-hydroxymidazolam by 4-fold and 2-fold, respectively. This level of induction does not call for dosage adjustment of drugs that are primarily metabolized by CYP3A4 when used concomitantly with ONFI. Some hormonal contraceptives are metabolized by CYP3A4 and their effectiveness may be diminished when given with ONFI [see Drug Interactions (7.1)]. Repeated ONFI doses had no effect on caffeine and tolbutamide.
A population pharmacokinetic analysis indicated clobazam did not affect the exposure of valproic acid (a CYP2C9/2C19 substrate) or lamotrigine (a UGT substrate).
Potential for Other Drugs to Affect ONFI
Co-administration of ketoconazole (a strong CYP3A4 inhibitor) 400 mg once-daily for 5 days increased clobazam AUC by 54%, with an insignificant effect on clobazam Cmax. There was no significant change in AUC and Cmax of N-desmethylclobazam (N=18).
Strong (e.g., fluconazole, fluvoxamine, ticlopidine) and moderate (e.g., omeprazole) inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam, the active metabolite of clobazam, based on extrapolation from pharmacogenomic data [see Clinical Pharmacology (12.5)]. Dosage adjustment of ONFI may be necessary when co-administered with strong or moderate CYP2C19 inhibitors [see Drug Interactions (7.2)].
The effects of concomitant antiepileptic drugs that are CYP3A4 inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C9 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), and CYP2C9 inhibitors (felbamate and oxcarbazepine) were evaluated using data from clinical trials. Results of population pharmacokinetic analysis show that these concomitant antiepileptic drugs did not significantly alter the pharmacokinetics of clobazam or N-desmethylclobazam at steady-state.
Alcohol has been reported to increase the maximum plasma exposure of clobazam by approximately 50%. Alcohol may have additive CNS depressant effects when taken with ONFI [see Warnings and Precautions (5.2), Drug Interactions (7.3)].
12.5 Pharmacogenomics
The polymorphic CYP2C19 is the main enzyme that metabolizes the pharmacologically active N-desmethylclobazam. Compared to CYP2C19 extensive metabolizers, N-desmethylclobazam AUC and Cmax are approximately 3-5 times higher in poor metabolizers (e.g., subjects with *2/*2 genotype) and 2 times higher in intermediate metabolizers (e.g., subjects with *1/*2 genotype). The prevalence of CYP2C19 poor metabolism differs depending on racial/ethnic background. Dosage in patients who are known CYP2C19 poor metabolizers may need to be adjusted [see Dosage and Administration (2.5)].
The systemic exposure of clobazam is similar for both CYP2C19 poor and extensive metabolizers.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
The carcinogenic potential of clobazam has not been adequately assessed.
In a limited study in rats, oral administration of clobazam (4, 20, and 100 mg/kg/day) for 2 years resulted in an increased incidence of thyroid follicular cell adenomas in males at the high dose.
Mutagenesis
Clobazam and the major active metabolite, N-desmethylclobazam, were negative for genotoxicity, based on data from a battery of in vitro (bacteria reverse mutation, mammalian clastogenicity) and in vivo (mouse micronucleus) assays.
Impairment of Fertility
In a study in which clobazam (50, 350, or 750 mg/kg/day) was orally administered to male and female rats prior to and during mating and continuing in females to gestation day 6, increases in abnormal sperm and pre-implantation loss were observed at the highest dose tested.  The no effect level for fertility and early embryonic development in rats was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than those in humans at the maximum recommended human dose of 40 mg/day.
14 CLINICAL STUDIES
The effectiveness of ONFI for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome was established in two multicenter controlled studies (Study 1 and Study 2). Both studies were similar in terms of disease characteristics and concomitant AED treatments. The most common concomitant AED treatments at baseline included: valproate, lamotrigine, levetiracetam, and topiramate.
Study 1
Study 1 (N=238) was a randomized, double-blind, placebo-controlled study consisting of a 4-week baseline period followed by a 3-week titration period and 12-week maintenance period. Patients age 2-54 years with a current or prior diagnosis of LGS were stratified into 2 weight groups (12.5 kg to ≤30 kg or >30 kg) and then randomized to placebo or one of three target maintenance doses of ONFI according to Table 5.
Table 5. Study 1 Total Daily Dose

≤30 kg Body Weight  >30 kg Body Weight
  Low Dose   5 mg daily   10 mg daily
  Medium Dose   10 mg daily   20 mg daily
  High Dose   20 mg daily   40 mg daily
Doses above 5 mg/day were administered in two divided doses.
The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to 12-week maintenance period.
The pre-dosing baseline mean weekly drop seizure frequency was 98, 100, 61, and 105 for the placebo, low-, medium-, and high-dose groups, respectively. Figure 1 presents the mean percent reduction in weekly drop seizures from this baseline. All dose groups of ONFI were statistically superior (p≤0.05) to the placebo group. This effect appeared to be dose dependent.
Figure 1. Mean Percent Reduction from Baseline in Weekly Drop Seizure Frequency (Study 1)


Figure 2 shows changes from baseline in weekly drop seizure frequency by category for patients treated with ONFI and placebo in Study 1. Patients in whom the seizure frequency increased are shown at left as "worse." Patients in whom the seizure frequency decreased are shown in five categories.

Figure 2. Drop Seizure Response by Category for ONFI and Placebo (Study 1)


There was no evidence that tolerance to the therapeutic effect of ONFI developed during the 3-month maintenance period.
Study 2
Study 2 (N=68) was a randomized, double-blind comparison study of high- and low-dose ONFI, consisting of a 4-week baseline period followed by a 3-week titration period and 4-week maintenance period. Patients age 2-25 years with a current or prior diagnosis of LGS were stratified by weight, then randomized to either a low or high dose of ONFI, and then entered a 3-week titration period.
The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to the 4-week maintenance period.
A statistically significantly greater reduction in seizure frequency was observed in the high-dose group compared to the low-dose group (median percent reduction of 93% vs 29%; p<0.05).
16 HOW SUPPLIED/STORAGE AND HANDLING
Each ONFI tablet contains 10 mg or 20 mg of clobazam and is a white to off-white, oval tablet with a functional score on one side and either a "1" and "0" or a "2" and "0" debossed on the other side.
NDC 67386-314-01: 10 mg scored tablet, Bottles of 100
NDC 67386-315-01: 20 mg scored tablet, Bottles of 100
ONFI oral suspension is a berry flavored off-white liquid supplied in a bottle with child-resistant closure.  The oral suspension is packaged with a dispenser set which contains two calibrated oral dosing syringes and a bottle adapter. 
Store and dispense ONFI oral suspension in its original bottle in an upright position.  Use within 90 days of first opening the bottle, then discard any remainder.
NDC 67386-313-21: 2.5 mg/mL supplied in a bottle containing 120 mL of suspension.
Store tablets and oral suspension at 20°C to 25°C (68°F to 77°F). See USP controlled room temperature.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=de03bd69-2dca-459c-93b4-541fd3e9571c

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