5. A) To prepare an application for IND submission for Clobazam Tablet in US. B) To prepare IND checklist in us for Clobazam Tablet.

1. Drug Regulation & Regulatory Authorities
Dept. Of Quality Assurance & Regulatory Affairs
L. J. Institute of Pharmacy, Ahmedabad.
EXPERIMENT NO: DATE:
AIM: A) To prepare an application for IND submission for Clobazam Tablet in US.
B) To prepare IND checklist in us for Clobazam Tablet.
REFERENCES:
1.) http://en.wikipedia.org/wiki/Clobazam
2.) http://www.lundbeck.com/upload/us/files/pdf/Products/Onfi_MG_US_EN.pdf
3.) http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=de03bd69-2dca-459c-93b4-
541fd3e9571c
4.) http://www.drugs.com/nda/Clobazam_100611.html#c6VaF1QCPxM99P8T.99
5.)https://www.harvardpilgrim.org/pls/portal/docs/PAGE/PROVIDERS/PHARMACY/3_
TIER_PHARMACY/MRFS/ONFI_GLS_41613.PDF
Investigational New Drug Application
1. FDA Forms.
2. Table of contents
3. Introductory statements & General investigational plan
3.1 Product Information
3.1.1 Product Name
3.1.2 Brand Name
3.1.3 Active & Inactive Ingredient
3.1.4 Pharmacological Information
3.1.4.1 Mechanism Of Action
3.1.5 Structural Formula
3.1.6 Route of Administration
3.1.7 Indication
3.2 Brief summary of previous human experiments
3.3 General investigational plan
3.3.1 Rationale for Clobazam
3.3.2 Indication
3.3.3 Clinical study & no. of patient to be given Clobazam drug for study
3.3.4 Toxicological Data
4. Investigator’s Brochure
4.1 Brief description of Clobazam
4.2 A summary of Pharmacological and toxicological effects of Clobazam
4.3 A summary of pharmacokinetics and biological disposition of Clobazam in
animal
4.4 Description of possible risk and side effects to be anticipated on the basis of prior
experiment with Clobazam under investigation.
5. Protocol
5.1 Study protocol
5.2 Clinical trial investigator information
5.3 Overall clinical trial official and content
6. Chemistry Manufacturing and Control data
6.1 Product data
7. Pharmacological and Toxicological data
8. Previous human experience

2. Drug Regulation & Regulatory Authorities
Dept. Of Quality Assurance & Regulatory Affairs
L. J. Institute of Pharmacy, Ahmedabad.
9. Additional information
Content
3. Introductory statement and general investigational plan
3.1Product Information:
3.1.1. Product name: Clobazam
3.1.2. Brand name: FRISIUM, URBANOL, ONFI
3.1.3. Active and inactive ingredient:
Active ingredient: Clobazam
Inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, silicon
dioxide, and talc.
3.1.4. Pharmacological information:
Pharmacological Class of Drug: Antiepileptic drug of the benzodiazepine class
3.1.4.1 Mode of action: Clobazam binds at distinct binding sites associated with the
chloride ionopore at the post-synaptic GABA receptor. These GABA receptors are in
various locations in the CNS (limbic, reticular formation) and Clobazam increases the
duration of time for which the chloride ionopore is open. As a result, hyper polarization
and stabilization of the membrane occur as the post-synaptic inhibitory effect of GABA is
enhanced.
3.1.5 Structural formula:
Chemical Name: 7-Chloro-1-methyl-5-phenyl-1H-1,5 benzodiazepine-2,4(3H,5H)-dione
Molecular Formula: C16H13O2N2Cl
Molecular Weight: 300.7
3.1.6 Route of administration: Oral

3. Drug Regulation & Regulatory Authorities
Dept. Of Quality Assurance & Regulatory Affairs
L. J. Institute of Pharmacy, Ahmedabad.
3.1.7 Indication: Clobazam is approved as adjunctive treatment of seizures associated
with Lennox-Gastaut syndrome (LGS) in patients 2 year and older.
3.2 Brief summary of previous human experiments: Not Applicable.
3.3 General investigational plan
3.3.1 The Rational for Clobazam
To ensure that Clobazam is being used appropriately, as adjunctive treatment agents in
patients with Lennox-Gastaut syndrome (LGS). Clobazam belongs to a class of
medications called benzodiazepines which have anxiolytic and antiepileptic properties.
Outside of the United states, Clobazam has been approved for adjunctive treatment of
epilepsy including treatment of the following types of seizure: tonic-clonic, myoclonic,
myoclonic-absent, simple-partial, and partial-complex; and short term relief of severe,
disabling or distressing anxiety. It is not recommended for use in patients with mild
anxiety symptoms.
Additionally, during pivotal phase 3 clinical trials leading to the United States approval of
Clobazam in LGS, study subjects were receiving at least one other anticonvulsant
medication in addition to ONFI.
3.3.2 Indication: As per 3.1.7
3.3.3 Clinical Studies & No. of patients to be given CLOBAZAM drug for study:
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.

4. Drug Regulation & Regulatory Authorities
Dept. Of Quality Assurance & Regulatory Affairs
L. J. Institute of Pharmacy, Ahmedabad.
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.
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).
3.3.4 Toxicological Data
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
There are no adequate studies of the effects of Clobazam on fertility.

5. Drug Regulation & Regulatory Authorities
Dept. Of Quality Assurance & Regulatory Affairs
L. J. Institute of Pharmacy, Ahmedabad.
4. Investigator’s Brochure
4.1 Brief Introduction of Clobazam Tablet
As per Section 3.1
4.2 A summary of Pharmacological and toxicological effect of Clobazam :-
As per Section 3.3.4
4.3 Summary of pharmacokinetic and biological disposition of Clobazam in animal
:-
The metabolism of the 1,5-benzodiazepine Clobazam (CLBZ) was investigated in
the rat and in vitro by GC/MS using stable isotope techniques. Coadministration of CLBZ
and pentadeuteriophenyl CLBZ to rats facilitated the identification of 4'-hydroxy CLBZ
7,4'-hydroxy N-desmethylClobazam (4'-hydroxy DMC) 5, 3',4'-dihydroxy CLBZ 13, 4'-
hydroxy-3'-methoxy CLBZ 14, 3'-hydroxy-4'-methoxy CLBZ 15, and 4'-hydroxy-3'-
methoxy DMC 16 in bile as both glucuronide and sulfate conjugates. Metabolites 7, 13,
and 14 were present in urine as sulfate conjugates. 4'-Hydroxy CLBZ and 4'-hydroxy-3'-
methoxy CLBZ were the major conjugated metabolites in bile and urine, respectively. An
unusual in vivo disposition of CLBZ to the O-methyl catechols was discovered. In bile,
the para O-methyl catechol 15 constituted 2% of the O-methyl catechols as a glucuronide
conjugate, in contrast to constituting 30% (of the O-methyl catechols) as a sulfate. This
marks an unprecedented observation of a different catechol O-methyl isomer ratio within
the same biological fluid for different conjugate pools. The isotope effect associated with
the microsomal N-demethylation of trideuteriomethyl CLBZ was determined. The values
of kH/kD were calculated at 5.07 +/- 0.37 (N = 3) and 3.88 +/- 0.23 (N = 4) for control
and induced microsomes, respectively.
4.4 A description of possible risk and side effects and to be anticipated in the basis of
prior experiment with Clobazam under investigation:-
Blood Disorders: Anemia, eosinophilia, leukopenia, thrombocytopenia
Eye Disorders: Diplopia, vision blurred
Gastrointestinal Disorders: Abdominal distention
Investigations: Hepatic enzyme increased
Musculoskeletal: Muscle spasms
Psychiatric Disorders: Agitation, anxiety, apathy, confusional state, depression, delirium,
Respiratory Disorders: Aspiration, respiratory depression
Skin and Subcutaneous Tissue Disorders: Rash, Stevens-Johnson syndrome (SJS) and
toxic epidermal necrolysis (TEN), urticaria.

6. Drug Regulation & Regulatory Authorities
Dept. Of Quality Assurance & Regulatory Affairs
L. J. Institute of Pharmacy, Ahmedabad.
5. Protocol
5.1 Study Protocol
EudraCT Number: 2007-004350-82
Sponsor's Protocol Code
Number:
OV-1004
National Competent
Authority:
Lithuania - SMCA
Clinical Trial Type: EEA CTA
Trial Status: Completed
Date on which this record
was first entered in the
EudraCT database 2008-01-21
Objective of the trial
Main objective of the trial :To determine the long-term safety and effectiveness of
open-label Clobazam in the treatment of seizures in subjects with Lennox-Gastaut
Syndrome (LGS).
Principal inclusion criteria :
1) The subject or subject’s LAR must sign and date the IRB/IEC approved Informed
Consent Form/HIPAA Authorization (if required) prior to study participation.
2) Previous participation in Ovation-sponsored LGS study.
3) Subject must weigh greater or equal 12.5 kilograms.
4) Male or female subjects must have been between 2 and 60 years of age at the time
of the enrollment in the Phase 3 double-blind study (protocol number OV-1012)
or between 2 and 30 years of age at the time of the enrollment in the Phase 2
double-blind study (protocol number OV-1002) study.
5) If female:
a. Subject is either not of childbearing potential, defined as premenarchal,
postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation,
bilateral oophorectomy or hysterectomy), or if of childbearing potential, must
comply with a method of birth control acceptable to the investigator during the
study, for at least 4 weeks prior to study entry and for 4 weeks following
completion of the study.
b. Subject is not breastfeeding.
c. Subjects of childbearing potential must have a negative serum pregnancy test at
Study Day 1.

7. Drug Regulation & Regulatory Authorities
Dept. Of Quality Assurance & Regulatory Affairs
L. J. Institute of Pharmacy, Ahmedabad.
6) In the investigator’s opinion, parent or caregiver must be able to keep an accurate
seizure diary.
Principal exclusion criteria:
1) Greater than 14 days have elapsed since the subject received his/her last dose of
study medication in the previous Ovation-sponsored LGS study.
2) Subject had a serious or severe adverse event in the previous Ovation sponsored
LGS study that in the opinion of the investigator was probably or definitely
related to Clobazam use and precludes safe use of Clobazam.
3) Subject has had an anoxic episode requiring resuscitation within 6 months of
study entry.
4) Subject has a history of an allergic reaction or significant sensitivity to
benzodiazepines or to any of the other ingredients in Clobazam tablets.
5) Subject is taking more than 3 concurrent AEDs. NOTE: Vagal Nerve Stimulator
(VNS) or ketogenic diet is allowed and will not be counted in the three allowed
AEDs.
6) Subject is currently taking long-term systemic steroids (excluding inhaled
medication for asthma treatment) or any other daily medication known to
exacerbate epilepsy. An exception will be made of prophylactic medication, for
example, for idiopathic nephrotic syndrome or asthma.
7) If the subject is taking felbamate, has been taking it for less than 1 year prior to
study entry or previous treatment with felbamate resulted in withdrawal due to
liver or bone marrow adverse events.
8) Subject has experienced an idiosyncratic reaction to an AED, e.g., carbamazepine
with resulting aplastic anemia or agranulocytosis, topiramate with resulting
metabolic acidosis, felbamate with resulting aplastic anemia or hepatic failure, or
lamotrigine with resulting skin irritation and/or rash.
9) Subject has shown any clinically significant history of hyper-sensitivity to CNS-
active medications leading to neurobehavioral aberrations (e.g., increased biting,
scratching, kicking, or hitting).
10) Subject has taken or used any investigational drug or device in the 30 days prior to
screening, with the exception of Clobazam in an Ovation-sponsored study.
11) Subject has a clinically significant unstable hepatic, hematological, renal,
cardiovascular, gastrointestinal, or pulmonary disease or ongoing malignancy.
12) Subject has a diagnosis of sleep apnea.
13) Subject has a compromised respiratory function or severe respiratory
insufficiency.
14) Subject has a history of severe muscle weakness, including myasthenia gravis.
15) Subject has a clinically significant abnormal laboratory value or
electrocardiogram (ECG) abnormality.
16) Subject has progressive lesion confirmed by magnetic resonance imaging (MRI)
or computed tomography (CT) scan.
17) Subject has a history of drug or alcohol abuse.

8. Drug Regulation & Regulatory Authorities
Dept. Of Quality Assurance & Regulatory Affairs
L. J. Institute of Pharmacy, Ahmedabad.
18) Subject has a history of poor compliance on past antiepileptic therapy.
19) Subject has inadequate supervision by parent or guardian.
20) For any reason, the subject is considered by the investigator to be an unsuitable
candidate for the study.
End points
Percent reduction at various time intervals in number of drop seizures (average per
week in the week preceding each study visit) compared to the baseline period of the study
from which the subject rolled over (previous Ovation sponsored study)
5.2 Clinical trial investigator information:
Confidential
5.3 Overall clinical trial officials and contacts:
Confidential
6. Chemistry manufacturing and control data
6.1 Product Data
As per Section 3.1
7. Pharmacological & Toxicological Data
As per Section 3.1.4 & 3.3.4
8. Previous human experience
Not applicable
9. Additional information
Not applicable