FORM DA-1/88

APPLICATION FORM FOR THE REGISTRATION OF DRUGS (WHICH ARE 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 : Aprepitant

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

inclusion
____________________________________________________________________________
PRODUCT DATA SHEET

a) Presentation and Packaging Quantities:

Box contains 1 blister stripes of 4’s Capsules. Each capsule contains Aprepitant 125mg.

b) Description:
Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1
(NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and
corticosteroid receptors, the targets of existing therapies for chemotherapy-induced
nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV).
Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic
chemotherapeutic agents, such as cisplatin, via central actions. Animal and human
Positron Emission Tomography (PET) studies with aprepitant have shown that it crosses
the blood brain barrier and occupies brain NK1 receptors. Animal and human studies
show that aprepitant augments the antiemetic activity of the 5-HT3-receptor antagonist
ondansetron and the corticosteroid dexamethasone and inhibits both the acute and
delayed phases of cisplatin-induced emesis.

c) Indications and Uses:

Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)
APREPITANT, in combination with other antiemetic agents, is indicated for the:
 prevention of acute and delayed nausea and vomiting associated with initial and
repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-
dose cisplatin
 prevention of nausea and vomiting associated with initial and repeat courses of
moderately emetogenic cancer chemotherapy (MEC).
Prevention of Postoperative Nausea and Vomiting (PONV)
APREPITANT is indicated for the prevention of postoperative nausea and vomiting.
Limitations of Use
APREPITANT has not been studied for the treatment of established nausea and
vomiting.
Chronic continuous administration is not recommended.
d) Dosage and Administration:
Prevention of Chemotherapy Induced Nausea and Vomiting (CINV)
Capsules of APREPITANT (aprepitant) are given for 3 days as part of a regimen that
includes a corticosteroid and a 5-HT3 antagonist. The recommended dose of
APREPITANT is 125 mg orally 1 hour prior to chemotherapy treatment (Day 1) and 80
mg orally once daily in the morning on Days 2 and 3.
APREPITANT may be taken with or without food.
APREPITANT (fosaprepitant dimeglumine) for Injection (115 mg) is a prodrug of
aprepitant and may be substituted for oral APREPITANT (125 mg), 30 minutes prior to
chemotherapy, on Day 1 only of the CINV regimen as an intravenous infusion
administered over 15 minutes.
In clinical studies with APREPITANT, the following regimen was used for the
prevention of nausea and vomiting associated with highly emetogenic cancer
chemotherapy:
  Day Day Day Day
1 2 3 4
APREPITANT* 125 80 80 non
mg mg mg e
orall orall orall
y y y
Dexamethasone 12 8 8 8
** mg mg mg mg
orall orall orall orall
y y y y
Ondansetront 32 non non non
mg e e e
I.V.
*APREPITANT was administered orally 1 hour prior to chemotherapy treatment
on Day 1 and in the morning on Days 2 and 3.
**Dexamethasone was administered 30 minutes prior to chemotherapy
treatment on Day 1 and in the morning on Days 2 through 4. The dose of
dexamethasone was chosen to account for drug interactions.
†Ondansetron was administered 30 minutes prior to chemotherapy treatment
on Day 1.
In a clinical study with APREPITANT , the following regimen was used for the
prevention of nausea and vomiting associated with moderately emetogenic cancer
chemotherapy:
  Day Day Day
1 2 3
APREPITANT* 125 80 80
mg mg mg
orally orally orally
Dexamethasone** 12 none none
mg
orally
Ondansetront 2x8 none none
mg
orally
*APREPITANT was administered orally 1 hour prior to
chemotherapy treatment on Day 1 and in the morning on Days 2
and 3.
**Dexamethasone was administered 30 minutes prior to
chemotherapy treatment on Day 1. The dose of dexamethasone
 was chosen to account for drug interactions.
†Ondansetron 8-mg capsule was administered 30 to 60 minutes
prior to chemotherapy treatment and one 8-mg capsule was
administered 8 hours after the first dose on Day 1.
Prevention of Postoperative Nausea and Vomiting (PONV)
The recommended oral dosage of APREPITANT is 40 mg within 3 hours prior to
induction of anesthesia.
APREPITANT may be taken with or without food.
Geriatric Patients
No dosage adjustment is necessary for the elderly.
Patients with Renal Impairment
No dosage adjustment is necessary for patients with renal impairment or for patients with
end stage renal disease (ESRD) undergoing hemodialysis.
Patients with Hepatic Impairment
No dosage adjustment is necessary for patients with mild to moderate hepatic impairment
(Child-Pugh score 5 to 9). There are no clinical data in patients with severe hepatic
impairment (Child-Pugh score > 9).
Coadministration with Other Drugs
For additional information on dose adjustment for corticosteroids when coadministered
with APREPITANT,

e) Contraindications:
Hypersensitivity to any component of this medication.
APREPITANT should not be used concurrently with pimozide, terfenadine, astemizole, or
cisapride, since inhibition of CYP3A4 by aprepitant could result in elevated plasma
concentrations of these drugs, potentially causing serious or life-threatening reactions

f) Side-effects:
Clinical adverse experiences for the CINV regimen in conjunction with highly and
moderately emetogenic chemotherapy (incidence >10%) are: alopecia, anorexia,
asthenia/fatigue, constipation, diarrhea, headache, hiccups, nausea.
Clinical adverse experiences for the PONV regimen (incidence >5%) are: constipation,
hypotension, nausea, pruritus, pyrexia.

g) Use in pregnancy and lactation:

Pregnancy

Pregnancy Category B
Reproduction studies have been performed in rats at oral doses up to 1000 mg/kg twice
daily (plasma AUC0-24hr of 31.3 mcg•hr/mL, about 1.6 times the human exposure at the
recommended dose) and in rabbits at oral doses up to 25 mg/kg/day (plasma AUC0-24hr
of 26.9 mcg•hr/mL, about 1.4 times the human exposure at the recommended dose) and
have revealed no evidence of impaired fertility or harm to the fetus due to aprepitant.
There are, however, no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response, this
drug should be used during pregnancy only if clearly needed.

Lactation
Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in
human milk. Because many drugs are excreted in human milk and because of the
potential for possible serious adverse reactions in nursing infants from aprepitant and
 because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity
studies, 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.

h) Precautions:
CYP3A4 Interactions
APREPITANT (aprepitant), a dose-dependent inhibitor of CYP3A4, should be used with
caution in patients receiving concomitant medications that are primarily metabolized
through CYP3A4. Moderate inhibition of CYP3A4 by aprepitant, 125 mg/80 mg regimen,
could result in elevated plasma concentrations of these concomitant medications.
Weak inhibition of CYP3A4 by a single 40 mg dose of aprepitant is not expected to alter
the plasma concentrations of concomitant medications that are primarily metabolized
through CYP3A4 to a clinically significant degree.
When aprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma
concentrations could be elevated. When APREPITANT is used concomitantly with
medications that induce CYP3A4 activity, aprepitant plasma concentrations could be
reduced and this may result in decreased efficacy of APREPITANT.
Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel,
paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and
vincristine. In clinical studies, APREPITANT (125 mg/80 mg regimen) was administered
commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not
adjusted to account for potential drug interactions.
In separate pharmacokinetic studies no clinically significant change in docetaxel or
vinorelbine pharmacokinetics was observed when APREPITANT (125 mg/80 mg
regimen) was co-administered.
Due to the small number of patients in clinical studies who received the CYP3A4
substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring
are advised in patients receiving these agents or other chemotherapy agents metabolized
primarily by CYP3A4 that were not studied.
Coadministration with Warfarin (a CYP2C9 substrate)
Coadministration of APREPITANT with warfarin may result in a clinically significant
decrease in International Normalized Ratio (INR) of prothrombin time. In patients on
chronic warfarin therapy, the INR should be closely monitored in the 2-week period,
particularly at 7 to 10 days, following initiation of the 3-day regimen of APREPITANT with
each chemotherapy cycle, or following administration of a single 40 mg dose of
APREPITANT for the prevention of postoperative nausea and vomiting.
Coadministration with Hormonal Contraceptives
Upon coadministration with APREPITANT, the efficacy of hormonal contraceptives during
and for 28 days following the last dose of APREPITANT may be reduced. Alternative or
back-up methods of contraception should be used during treatment with APREPITANT
and for 1 month following the last dose of APREPITANT.
Patients with Severe Hepatic Impairment
There are no clinical or pharmacokinetic data in patients with severe hepatic impairment
(Child-Pugh score > 9). Therefore, caution should be exercised when APREPITANT is
administered in these patients

i) Drug interaction:
Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer
of CYP3A4. Aprepitant is also an inducer of CYP2C9.
Effect of Aprepitant on the Pharmacokinetics of Other Agents
CYP3A4 Substrates
Weak inhibition of CYP3A4 by a single 40 mg dose of aprepitant is not expected to alter
the plasma concentrations of concomitant medications that are primarily metabolized
through CYP3A4 to a clinically significant degree. However, higher aprepitant doses or
repeated dosing at any aprepitant dose may have a clinically significant effect.
As a moderate inhibitor of CYP3A4 at a dose of 125 mg/80 mg, aprepitant can increase
plasma concentrations of concomitantly administered oral medications that are
metabolized through CYP3A4. The use of fosaprepitant may increase CYP3A4 substrate
plasma concentrations to a lesser degree than the use of oral aprepitant (125 mg).
5-HT3 antagonists
In clinical drug interaction studies, aprepitant did not have clinically important effects on
the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active
metabolite of dolasetron).
Corticosteroids
Dexamethasone: APREPITANT, when given as a regimen of 125 mg with
dexamethasone coadministered orally as 20 mg on Day 1, and APREPITANT when
given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2
through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, by 2.2-fold on
Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50%
when coadministered with APREPITANT (125 mg/80 mg regimen), to achieve exposures
of dexamethasone similar to those obtained when it is given without APREPITANT. The
daily dose of dexamethasone administered in clinical chemotherapy induced nausea and
vomiting studies with APREPITANT reflects an approximate 50% reduction of the dose of
dexamethasone . A single dose of APREPITANT (40 mg) when coadministered with a
single oral dose of dexamethasone 20 mg, increased the AUC of dexamethasone by
1.45-fold. Therefore, no dose adjustment is recommended.
Methylprednisolone: APREPITANT, when given as a regimen of 125 mg on Day 1 and 80
mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4
substrate, by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was
coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3.
The IV methylprednisolone dose should be reduced by approximately 25%, and the oral
methylprednisolone dose should be reduced by approximately 50% when coadministered
with APREPITANT (125 mg/80 mg regimen) to achieve exposures of methylprednisolone
similar to those obtained when it is given without APREPITANT. Although the
concomitant administration of methylprednisolone with the single 40 mg dose of
aprepitant has not been studied, a single 40 mg dose of APREPITANT produces a weak
inhibition of CYP3A4 (based on midazolam interaction study) and it is not expected to
alter the plasma concentrations of methylprednisolone to a clinically significant degree.
Therefore, no dose adjustment is recommended.
Chemotherapeutic agents
Docetaxel: In a pharmacokinetic study, APREPITANT (125 mg/80 mg regimen) did not
influence the pharmacokinetics of docetaxel.
Vinorelbine: In a pharmacokinetic study, APREPITANT (125 mg/80 mg regimen) did not
influence the pharmacokinetics of vinorelbine to a clinically significant degree.
CYP2C9 Substrates (Warfarin, Tolbutamide)
Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide,
which are metabolized through CYP2C9. Coadministration of APREPITANT with these
drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin,
may result in lower plasma concentrations of these drugs.
Warfarin: A single 125-mg dose of APREPITANT was administered on Day 1 and 80
mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin
therapy. Although there was no effect of APREPITANT on the plasma AUC of R(+) or
S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin (a
CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the
prothrombin time (reported as International Normalized Ratio or INR) 5 days after
completion of dosing with APREPITANT. In patients on chronic warfarin therapy, the
prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7
to 10 days, following initiation of the 3-day regimen of APREPITANT with each
chemotherapy cycle, or following administration of a single 40 mg dose of APREPITANT
for the prevention of postoperative nausea and vomiting.
Tolbutamide: APREPITANT, when given as 125 mg on Day 1 and 80 mg/day on Days 2
and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28%
on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was
administered orally prior to the administration of the 3-day regimen of APREPITANT and
on Days 4, 8, and 15. APREPITANT, when given as a 40-mg single oral dose on Day 1,
decreased the AUC of tolbutamide (a CYP2C9 substrate) by 8% on Day 2, 16% on Day
4, 15% on Day 8, and 10% on Day 15, when a single dose of tolbutamide 500 mg was
administered orally prior to the administration of APREPITANT 40 mg and on Days 2, 4,
8, and 15. This effect was not considered clinically important.
Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule
with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of
norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC
of norethindrone by 8%.
In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and
norethindrone was administered on Days 1 through 21, and APREPITANT was given as
a 3-day regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron
32 mg IV on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on
Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day
10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations
during Days 9 through 21. While there was no effect of APREPITANT on the AUC of
norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough
concentrations during Days 9 through 21.
In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and
norgestimate (which is converted to norelgestromin) was administered on Days 1 through
21, and APREPITANT 40 mg was given on Day 8. In the study, the AUC of ethinyl
estradiol decreased by 4% and 29% on Day 8 and Day 12, respectively, while the AUC of
norelgestromin increased by 18% on Day 8 and decreased by 10% on Day 12. In
addition, the trough concentrations of ethinyl estradiol and norelgestromin on Days 8
through 21 were generally lower following coadministration of the oral contraceptive with
APREPITANT 40 mg on Day 8 compared to the trough levels following administration of
the oral contraceptive alone.
The coadministration of APREPITANT may reduce the efficacy of hormonal
contraceptives (these can include birth control pills, skin patches, implants, and certain
IUDs) during and for 28 days after administration of the last dose of APREPITANT.
Alternative or back-up methods of contraception should be used during treatment with
APREPITANT and for 1 month following the last dose of APREPITANT.
Midazolam: APREPITANT increased the AUC of midazolam, a sensitive CYP3A4
substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of
midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of APREPITANT
125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased
plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4
(alprazolam, triazolam) should be considered when coadministering these agents with
APREPITANT (125 mg/80 mg). A single dose of APREPITANT (40 mg) increased the
AUC of midazolam by 1.2-fold on Day 1, when a single oral dose of midazolam 2 mg was
coadministered on Day 1 with APREPITANT 40 mg; this effect was not considered
clinically important.
In another study with intravenous administration of midazolam, APREPITANT was given
as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given
prior to the administration of the 3-day regimen of APREPITANT and on Days 4, 8, and
15. APREPITANT increased the AUC of midazolam by 25% on Day 4 and decreased the
AUC of midazolam by 19% on Day 8 relative to the dosing of APREPITANT on Days 1
through 3. These effects were not considered clinically important. The AUC of midazolam
on Day 15 was similar to that observed at baseline.
 An additional study was completed with intravenous administration of midazolam and
APREPITANT. Intravenous midazolam 2 mg was given 1 hour after oral administration of
a single dose of APREPITANT 125 mg. The plasma AUC of midazolam was increased by
1.5-fold. Depending on clinical situations (e.g., elderly patients) and degree of monitoring
available, dosage adjustment for intravenous midazolam may be necessary when it is
coadministered with APREPITANT for the chemotherapy induced nausea and vomiting
indication (125 mg on Day 1 followed by 80 mg on Days 2 and 3).

j) Overdose:
No specific information is available on the treatment of overdosage.
Drowsiness and headache were reported in one patient who ingested 1440 mg of
aprepitant.
In the event of overdose, APREPITANT should be discontinued and general supportive
treatment and monitoring should be provided. Because of the antiemetic activity of
aprepitant, drug-induced emesis may not be effective.
Aprepitant cannot be removed by hemodialysis.

5. TECHNICAL DATA

a) Composition/Formula

I. Name of the Substance Specification Qty./Tablet

Active Substance (in mg)

Aliskiren INN 300

II. Excipients
 Sodium Starch Glycolate BP 3.000
Lactose BP 10.40
Microcrystalline Cellulose BP 122.5
(Avicel PH 101)
Povidone K 30 BP 10.05

Magnesium Stearate BP 2.000

Colloidal Silicone Dioxide USPNF 2.000

b) Manufacturing Instructions:

1) Place the following materials into a Rapid Mixer Granulator (RMG) after passing through
#16 mesh screen (if necessary).
Sodium Starch Glycolate, Lactose, Micro crystalline Cellulose (Avicel PH101).
2) Add Povidone solution to step-1 and mix for 5 to 7 minutes until a granulating mass is
obtained.
3) Discharge the wet mass through to a FBD bowl at slow speed with both Agitator and
Chopper ON.
4) Dry the wet granules in fluid bed dryer at 700 C-750 C temperature. Keep the moisture
content up to 1%.
5) Pass the dried granules through #20 mesh screen and place the granules into double
cone blender.
6) Add Clomiphene Citrate to the step 4 and mix for 20 minutes.
7) Then add Magnesium Stearate and mix it for 1 minute.
8) Send some blend to QC for analysis.
9) Transfer the blend into a suitable tare container line with polybag with proper labeling and
lid.

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 : Conform
Color : White
Shape : Round
Hardness : 50N - 80N
Av. tablet wt. : 150 mg
DT : NMT 15 minutes
Label claim/Tablet : Each tablet contains Trifluoperazine Hydrochloride BP 1 mg.

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

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

6. a) Number of manufacturers already manufacturing the product in Bangladesh:

DCC-244
 b) Estimated market size of the product in Bangladesh: Tk. 10 million (approx.)

7. 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.

8. For locally manufactured drugs:

Signature: Signature:

MAHBUBUL KARIM A.K.M. ZAKARIA

Director, Technical Operations Deputy 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