FORM DA-2/88

APPLICATION FORM FOR THE REGISTRATION OF DRUGS (WHICH ARE NOT INCLUDED AS
MONOGRAPH IN BP/BPC/USP-NF/INT.PH. OR ALREADY INTRODUCED IN BANGLADESH)

1. NAME OF THE MANUFACTURER : Incepta Pharmaceuticals Ltd.

AND PLACE OF MANUFACTURING : Savar, Dhaka.

2. MANUFACTURING LICENCE NO. : a) Biological 108

b) Non-Biological 193

3. NAME OF THE PREPARATION

a) Generic Name : Esketamine

b) Trade/Brand Name : To be submitted at the time of inclusion

4. PRODUCT DATA SHEET

a) Presentation and Packaging Quantities:

Each box contains a bottle. Each bottle of nasal spray contains esketamine 84 mg.

b) Description:
Esketamine acts primarily as a non-competitive N-methyl-D-aspartate (NMDA) receptor
antagonist.It also acts to some extent as a dopamine reuptake inhibitor. Esketamine inhibits
dopamine transporters. This increases dopamine activity in the brain.
Esketamine has an affinity for the PCP binding site of the NMDA receptor.

c) Indications and Uses:

 Esketamine as a novel treatment for patients with major depressive disorder who are at
imminent risk for suicide.
 Esketamine would be one of the new approaches to treat major depressive disorder
available to patients.

d) Dosage and Administration:

Esketamine nasal spray appeared to sustain improvement in depressive symptoms for up to 52
week in patients with treatment-resistant depression.

e) Contraindications:
No data found.

f) Precautions:

Esketamine should be used with precaution in the following situations:

 Decompensated cardiac failure and untreated hypertension

 Unstable angina pectoris
  Elevated intracranial pressure and damages or diseases of the central nervous
system, as elevation of cerebrospinal pressure has been described in connection
with ketamine anaesthesia
 In connection with eye examination or eye surgery in which intraocular pressure
should not increase
 Patients under chronic or acute influence of alcohol
 Patients who have or have had severe psychiatric disturbances
 Insufficiently treated hyperthyroidism
 Situations which require relaxed uterus myometrium (e.g. threatening uterus
rupture, prolapsed umbilical cord)

g) Side-effects:
The most common treatment-emergent adverse events during the treatment were dizziness
dissociation, nausea, headache , drowsiness, metallic taste and oral hypoesthesia, vertigo,
vomiting and viral upper respiratory tract infection .

h) Drug interactions:
No data found.

i) Pregnancy and Lactation:

No data found.

j) Over dosage:

The clinical symptoms of overdose are convulsion, cardiac arrhythmia and respiratory arrest.

Respiratory arrest must be treated by assisted or controlled ventilation until sufficient

spontaneous respiration is achieved.

Convulsions should be treated with intravenous administration of diazepam. If treatment with

diazepam does not result in sufficient response, administration of phenytoin or thiopental is
recommended.

No specific antidote is presently known.

5. TECHNICAL DATA

a) Composition/Formula

I. Name of the Substance Specifi- Qty/Tablet

Active Substance cation (in mg)

Voriconazole INN 200

II. Excipient

Microcrystalline Cellulose BP 91.32

(Avicel PH 101)
Hydroxypropyl Methylcellulose USP 100.00
(Methocel K15M CR)
Ethylcellulose BP 25.00
Povidone K-30 BP 30.00
Magnesium Stearate BP 3.00
Purified Talc BP 5.00

Coating Materials

Opadry II 85G92147 Yellow Ph. Grade 12.00

Purified water BP 80.00

b) Manufacturing Instructions:

1. Place the following materials into a planetary mixer by passing through #16 mesh screen and mix
for 15(fifteen) minutes.
Avicel PH 101, Folic Acid, Zinc Sulphate Monohydrate, Methocel K15M, Ethylcellulose
2. Add Povidone solution to step 1 and mix until a proper granular mass is obtained.
3. Dry the granules into a FBD at 50°C to 55°C for 30(thirty) minutes.
4. Pass the semi-dried granules through a Multi-mill fitted with # 20 mesh screen and again dry into
a FBD at 55°C – 60°C to LOD 2.5% - 3.0%.
5. Place the dried granules into a Double Cone Blender.
6. Add Magnesium Stearate & Purified Talc and blend for 2(two) minutes.
7. Send blend sample to QC for analysis.
8. Remove the completed blend into a suitable tared airtight container.
9. Compress the blend into tablet according to specification.
Film Coating Instruction

1. Place Methanol and Methylene Chloride in a SS container and stir to make vortex. Add the
following materials to the vortex under continuous stirring:
a. Hydroxypropyl Methylcellulose 15cps and Hydroxypropyl Methylcellulose 5cps
b. Polyethylene Glycol 6000

Stir continuously until a clear solution is obtained.

2. Place a small quantity of Methanol in a S.S. container and add the following :
 Titanium Dioxide
 Purified Talc
 Iron Oxide Yellow
 Polysorbate 80 (Tween 80)

Homogenize the mix well.

3. Transfer step 2 to step 1 by passing through #100 mesh screen and stir for 30-45 minutes.
4. Keep coating solution in a solution tank with continuous stirring
5. Coat the core tablet with this solution using a film coating machine.

c) Control Data for the Active material:

As per In-house specification

d) Pharmacopoeia References for other constituents:

As that mentioned in the composition/formula

e) Control Data for finished product:

Appearance : Yellow colored round shaped film coated tablet

Color : Yellow
Hardness : 70N-120N
Av. tablet wt.(core) : 300mg
DT : NMT 30 minutes
Label claim : Each box contains 4’s or 8’s or 10’s tablets of blister strip packs. Each
film-coated tablet contains 50 mg of Sildenafil INN (as citrate).

f) Stability Data : To be submitted at the time of inclusion

g) Proposed Shelf Life : To be submitted at the time of inclusion.

7. Pharmacological Data: No Data found.

8. Toxicological Data:

The first study focused on adults with treatment-resistant depression where patients were
randomized to flexibly dosed esketamine nasal spray (56 mg or 84 mg twice weekly) added to a
newly initiated oral antidepressant or placebo nasal spray added to a newly initiated oral
antidepressant.
Most common treatment-emergent adverse effects >10% reported in the esketamine group were
metallic taste, nausea, vertigo, dizziness, headache, drowsiness, dissociation, blurred vision,
paranesthesia and anxiety, while in the placebo group metallic taste and headache were
reported.

9. Clinical Data:

The data found that continuing treatment with esketamine nasal spray plus an oral antidepressant
in patients beyond 16 weeks showed clinically meaningful and statistically significant superiority
to treatment with an oral antidepressant plus placebo nasal spray in delaying time to relapse of
symptoms of depression. Furthermore, the data indicated that patients in stable remission treated
with esketamine nasal spray plus an oral antidepressant reduced the risk of relapse by 51%
(estimated Hazard Ratio =
0.49; 95% CI: 0.29, 0.84) compared to patients in the oral antidepressant plusplacebo nasal
spray group. The five most frequently reported adverse events in the esketamine treated patients
(≥5%) during the maintenance phase weretemporary impaired sense of taste vertigo,
dissociation, drowsiness, anddizziness.

A longterm safety study of esketamine nasal spray showed that in adults with treatment resistant
depression, esketamine nasal spray plus an oral antidepressant was generally well tolerated with
no new safety signals identified after repeated longterm dosing for up to oneyear (52 weeks). The
safety profile of esketamine was similar to that observed in previous short term Phase 2 and 3
studies in patients with treatment resistant depression. The data from this open label study also
indicated that treatment with esketamine nasal spray plus an oral antidepressant appeared to be
associated with sustained improvement in depressive symptoms for up to 52 weeks.

Johnson & Johnson subsidiary Janssen has presented its Phase 3 data for its esketamine nasal
spray for treatment-resistant depression for the first time in Europe at the International College of
Neuropsychopharmacology in Vienna, Austria.

The study was a randomised, double-blind, multi-centre study with 705 adult participants. The
data showed that continuing treatment beyond 16 weeks with esketamine in combination with an
oral antidepressant was statistically significant and clinically meaningful compared with oral
antidepressant treatment with a placebo nasal spray in reducing the time to relapse to the
symptoms of depression.

10. a) Number of manufacturers already manufacturing the product in Bangladesh: None

b) Estimated market size of the product in Bangladesh: Tk. 10 million (approx.)

11. a) Proposed maximum retail price ( MRP) : To be submitted at the time of inclusion.

b) Estimated price – per dose; per day treatment, cost for the recommended course of
treatment: To be submitted at the time of inclusion
12. Particulars:

Signature: Signature:

MAHBUBUL KARIM A.K.M. ZAKARIA

Director, Technical Operations Sr. Manager, R & D Formulation

Qualification: Qualification:
B. Pharm. (Hons.) B. Pharm (Hons.)
M. Pharm M. Pharm

Registration No. A – 811 Registration No. A – 1617

Date of joining in this company: Date of joining in this company :

1st April. 2004 1st May 2001

Total experience in Pharmaceutical Total experience in Pharmaceutical

Industry: Twenty Five Years Industry: Ten Years

9) In case of imported drugs : Not applicable

10) Date of Submission :

11) Additional Information (if any) : Not applicable