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 : Lisdexamfetamine Dimesylate INN

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

inclusion
____________________________________________________________________________
PRODUCT DATA SHEET

a) Presentation and Packaging Quantities:

Box contains 3 blister strips of 10’s capsule. Each capsule contains Lisdexamfetamine
dimesylate 20mg.

b) Description:
Lisdexamfetamine is a prodrug of dextroamphetamine. Amphetamines are non-
catecholamine sympathomimetic amines with CNS stimulant activity. Amphetamines
block the reuptake of norepinephrine and dopamine into the presynaptic neuron and
increase the release of these monoamines into the extraneuronal space. The parent
drug, lisdexamfetamine, does not bind to the sites responsible for the reuptake of
norepinephrine and dopamine in vitro.
c) Indications and Uses:

Lisdexamfetamine dimesylate is indicated for the treatment of Attention Deficit

Hyperactivity Disorder (ADHD).

d) Dosage and Administration:

General Instructions For Use

Lisdexamfetamine should be taken by mouth in the morning with or without food; should
avoid afternoon doses because of the potential for insomnia. Lisdexamfetamine may be
administered in one of the following ways:

 Swallow Lisdexamfetamine capsules whole, or

 Open capsules, empty and mix the entire contents with yogurt, water, or orange juice.
If the contents of the capsule include any compacted powder, a spoon may be used
to break apart the powder. The contents should be mixed until completely dispersed.
Consume the entire mixture immediately. It should not be stored. The active
ingredient dissolves completely once dispersed; however, a film containing the
inactive ingredients may remain in the glass or container once the mixture is
consumed. Should not take anything less than one capsule per day, and a single
capsule should not be divided.
 Dosing Information
The recommended starting dose is 30 mg once daily in the morning in patients ages 6
and above. Dosage may be adjusted in increments of 10 mg or 20 mg at approximately
weekly intervals up to maximum dose of 70 mg/day. Patients may be maintained on their
optimal dose.

Important Information Prior To Dosing

Prior to treating children, adolescents, and adults with CNS stimulants, assess for the
presence of cardiac disease (e.g., a careful history, family history of sudden death or
ventricular arrhythmia, and physical exam).

To reduce the abuse of CNS stimulants including Lisdexamfetamine, the risk of abuse
should be assessed, prior to prescribing. After prescribing, prescription records should be
kept careful, educated patients about abuse, monitored for signs of abuse and overdose,
and re-evaluated the need for Lisdexamfetamine use.

Dosage Modifications Due To Drug Interactions

Agents that alter urinary pH can impact urinary excretion and alter blood levels of
amphetamine. Acidifying agents (e.g., ascorbic acid) decrease blood levels, while
alkalinizing agents (e.g., sodium bicarbonate) increase blood levels. Lisdexamfetamine
dosage should be adjusted accordingly.

e) Contraindications:

Lisdexamfetamine is contraindicated in patients with:

 Known hypersensitivity to amphetamine products or other ingredients of
Lisdexamfetamine . Anaphylactic reactions, Stevens-Johnson Syndrome,
angioedema, and urticaria have been observed in postmarketing reports.
 Concurrent administration of monoamine oxidase inhibitors (MAOI) or
administration of Lisdexamfetamine within 14 days of the last MAOI dose.
Hypertensive crisis can occur.

f) Side-effects:

The following adverse reactions are discussed in greater detail in other sections of the
labeling

 Serious Cardiovascular Reactions

 Blood Pressure and Heart Rate Increases
 Psychiatric Adverse Reactions
 Suppression of Growth
 Peripheral Vasculopathy, including Raynaud's phenomenon

g) Use in pregnancy and lactation:

Pregnancy
 If patients become pregnant or intend to become pregnant during Lisdexamfetamine
treatment they should tell their healthcare provider.

Lactation

Patients should notify their healthcare provider if they are breastfeeding or intend to
breastfeed an infant.

h) Precautions:

Potential For Abuse And Dependence

CNS stimulants (amphetamines and methylphenidate-containing products) have a high
potential for abuse and dependence. The risk of abuse should be assessed prior to
prescribing, and monitored for signs of abuse and dependence while on therapy.

Serious Cardiovascular Reactions

Sudden death, stroke and myocardial infarction have been reported in adults with CNS
stimulant treatment at recommended doses. Sudden death has been reported in children
and adolescents with structural cardiac abnormalities and other serious heart problems
taking CNS stimulants at recommended doses for ADHD. Use should be avoided in
patients with known structural cardiac abnormalities, cardiomyopathy, serious heart
arrhythmia, coronary artery disease, and other serious heart problems. Patients should
be evaluated who develop exertional chest pain, unexplained syncope, or arrhythmias
during Lisdexamfetamine treatment.

Blood Pressure And Heart Rate Increases

CNS stimulants cause an increase in blood pressure (mean increase about 2-4 mm Hg)
and heart rate (mean increase about 3-6 bpm). Monitor all patients for potential
tachycardia and hypertension.

Psychiatric Adverse Reactions

Exacerbation of Pre-existing Psychosis

CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder
in patients with a pre-existing psychotic disorder.

Induction of a Manic Episode in Patients with Bipolar Disorder

CNS stimulants may induce a mixed/manic episode in patients with bipolar disorder. Prior
to initiating treatment, screen patients for risk factors for developing a manic episode.

New Psychotic or Manic Symptoms

CNS stimulants, at recommended doses, may cause psychotic or manic symptoms, e.g.
hallucinations, delusional thinking, or mania in children and adolescents without a prior
history of psychotic illness or mania. If such symptoms occur, consider discontinuing the
CNS stimulant. In a pooled analysis of multiple short-term, placebo-controlled studies of
CNS stimulants, psychotic or manic symptoms occurred in 0.1% of CNS stimulant-treated
patients compared to 0% in placebo-treated patients.

Suppression of Growth
CNS stimulants have been associated with weight loss and slowing of growth rate in
pediatric patients. Closely monitor growth (weight and height) in pediatric patients treated
with CNS stimulants, including Lisdexamfetamine . In a 4-week, placebo-controlled trial of
Lisdexamfetamine in patients ages 6 to 12 years old, there was a dose-related decrease
in weight in the Lisdexamfetamine groups compared to weight gain in the placebo group.
Additionally, in studies of another stimulant, there was slowing of the increase in height.
 Peripheral Vasculopathy, Including Raynaud's Phenomenon
Stimulants, including Lisdexamfetamine , used to treat ADHD are associated with
peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are
usually intermittent and mild; however, very rare sequelae include digital ulceration
and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's
phenomenon, were observed in post-marketing reports at different times and at
therapeutic doses in all age groups throughout the course of treatment. Signs and
symptoms generally improve after reduction in dose or discontinuation of drug. Careful
observation for digital changes is necessary during treatment with ADHD stimulants.
Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain
patients.

i) Drug Interactions:

Acidifying and Alkalinizing Agents

Ascorbic acid and other agents that acidify urine increase urinary excretion and decrease
the half-life of amphetamine. Sodium bicarbonate and other agents that alkalinize urine
decrease urinary excretion and extend the half-life of amphetamine. The dosage should
be adjusted accordingly.

Monoamine Oxidase Inhibitors

Lisdexamfetamine should not be administered concomitantly with monoamine oxidase
inhibitors or within 14 days after discontinuing MAOI treatment. Concomitant use of
MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include
death, stroke, myocardial infarction, aortic dissection, ophthalmological complications,
eclampsia, pulmonary edema, and renal failure.

Effect of Other Drugs on Lisdexamfetamine

From a pharmacokinetic perspective, no dose adjustment of Lisdexamfetamine is
necessary when Lisdexamfetamine is coadministered with guanfacine, venlafaxine, or
omeprazole.

Effect Of Lisdexamfetamine on Other Drugs

From a pharmacokinetic perspective, no dose adjustment of CYP1A2, CYP2D6,
CYP2C19, and CYP3A4 substrates are necessary when Lisdexamfetamine is
coadministered. In addition, no dose adjustment of guanfacine or venlafaxine is needed
when Lisdexamfetamine is coadministered.

j) Over dose:

Patient should consult with a Certified Poison Control Center (1-800-222-1222) for up-to-
date guidance and advice for treatment of overdosage. Individual patient response to
amphetamines varies widely. Toxic symptoms may occur idiosyncratically at low doses.

Manifestations of amphetamine overdose include restlessness, tremor, hyperreflexia,

rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia,
and rhabdomyolysis. Fatigue and depression usually follow the central nervous system
stimulation. Other reactions include arrhythmias, hypertension or hypotension, circulatory
collapse, nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning is usually
preceded by convulsions and coma.
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. Pharmacological Data:

Pharmacokinetics

Pharmacokinetic studies of dextroamphetamine after oral administration of

lisdexamfetamine have been conducted in patients ages 6 to 12 years with ADHD and in
healthy adult volunteers.

In 18 patients ages 6 to 12 years with ADHD, the Tmax of dextroamphetamine was

approximately 3.5 hours following single-dose oral administration of lisdexamfetamine
dimesylate either 30 mg, 50 mg, or 70 mg after an 8-hour overnight fast.  The Tmax of
lisdexamfetamine was approximately 1 hour.  Linear pharmacokinetics of
dextroamphetamine after single-dose oral administration of lisdexamfetamine dimesylate
was established over the dose range of 30 mg to 70 mg in children ages 6 to 12 years
and over a range of 50 mg to 250 mg in adults. Dextroamphetamine pharmacokinetic
parameters following administration of lisdexamfetamine dimesylate in adults exhibited
low inter-subject (<25%) and intra-subject (<8%) variability. Safety and efficacy have not
been studied above the maximum recommended dose of 70mg.

There is no accumulation of dextroamphetamine AUC at steady state in healthy adults

and no accumulation of lisdexamfetamine after once-daily dosing for 7 consecutive days.

Neither food (a high fat meal or yogurt) nor orange juice, affect the observed AUC and
Cmax of dextroamphetamine in healthy adults after single-dose oral administration of 70
mg of Lisdexamfetamine capsules. Food prolongs Tmax by approximately 1 hour (from
3.8 hrs at fasted state to 4.7 hrs after a high fat meal or to 4.8 hrs with yogurt).   After an
8-hour fast, the AUCs for dextroamphetamine following oral administration of
lisdexamfetamine dimesylate in solution and as intact capsules were equivalent.

Weight/Dose normalized AUC and Cmax were 22% and 12% lower, respectively, in adult
females than in males on day 7 following a 70 mg/day dose of lisdexamfetamine
dimesylate for 7 days.  Weight/Dose normalized AUC and Cmax values were the same in
pediatric patients ages 6 to 12 years following single doses of 30-70 mg.

Metabolism and Excretion

After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal

tract.  Lisdexamfetamine is converted to dextroamphetamine and l-lysine primarily in
blood due to the hydrolytic activity of red blood cells.  In vitro data demonstrated that red
blood cells have a high capacity for metabolism of lisdexamfetamine; substantial
hydrolysis occurred even at low hematocrit levels (33% of normal).  Lisdexamfetamine is
not metabolized by cytochrome P450 enzymes.  Following the oral administration of a 70
mg dose of radiolabeled lisdexamfetamine dimesylate to 6 healthy subjects,
approximately 96% of the oral dose radioactivity was recovered in the urine and only
0.3% recovered in the feces over a period of 120 hours.  Of the radioactivity recovered in
the urine, 42% of the dose was related to amphetamine, 25% to hippuric acid, and 2% to
intact lisdexamfetamine.  Plasma concentrations of unconverted lisdexamfetamine are
low and transient, generally becoming non-quantifiable by 8 hours after administration.
The plasma elimination half-life of lisdexamfetamine typically averaged less than one
hour in studies of lisdexamfetamine dimesylate in volunteers.

Drug interactions

 Acidifying and Alkalinizing Agents

Ascorbic acid and other agents that acidify urine increase urinary excretion and decrease
the half-life of amphetamine.  Sodium bicarbonate and other agents that alkalinize urine
decrease urinary excretion and extend the half-life of amphetamine. The dosage should
be adjusted accordingly.

Monoamine Oxidase Inhibitors

Lisdexamfetamine should not be administered concomitantly with monoamine oxidase

inhibitors or within 14 days after discontinuing MAOI treatment. Concomitant use of
MAOIs and CNS stimulants can cause hypertensive crisis.  Potential outcomes include
death, stroke, myocardial infarction, aortic dissection, ophthalmological complications,
eclampsia, pulmonary edema, and renal failure.

Effect of Other Drugs on Lisdexamfetamine

From a pharmacokinetic perspective, no dose adjustment of Lisdexamfetamine is

necessary when Lisdexamfetamine is coadministered with guanfacine, venlafaxine, or
omeprazole (Figure 1).
 Figure 1: Effect of Other Drugs on Lisdexamfetamine :

Effect of Lisdexamfetamine on Other Drugs

From a pharmacokinetic perspective, no dose adjustment of CYP1A2, CYP2D6,

CYP2C19, and CYP3A4 substrates are necessary when Lisdexamfetamine is
coadministered. In addition, no dose adjustment of guanfacine or venlafaxine is needed
when Lisdexamfetamine is coadministered (Figure 2).
 Figure 2: Effect of Lisdexamfetamine on Other Drugs:

7. Toxicological Data:

 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis
Carcinogenicity studies of lisdexamfetamine dimesylate have not been performed.  No
evidence of carcinogenicity was found in studies in which d-, l-amphetamine (enantiomer
ratio of 1:1) was administered to mice and rats in the diet for 2 years at doses of up to 30
mg/kg/day in male mice, 19 mg/kg/day in female mice, and 5 mg/kg/day in male and
female rats.

Mutagenesis
Lisdexamfetamine dimesylate was not clastogenic in the mouse bone marrow
 micronucleus test in vivo and was negative when tested in the E. coli and S. typhimurium
components of the Ames test and in the L5178Y/TK+- mouse lymphoma assay in vitro.

Impairment of Fertility
Amphetamine (d- to l-enantiomer ratio of 3:1) did not adversely affect fertility or early
embryonic development in the rat at doses of up to 20 mg/kg/day.

Animal Toxicology and/or Pharmacology

Acute administration of high doses of amphetamine (d- or d,l-) has been shown to
produce long-lasting neurotoxic effects, including irreversible nerve fiber damage, in
rodents.  The significance of these findings to humans is unknown.

8. Clinical Data:

The short-term efficacy of Lisdexamfetamine in the treatment of ADHD was established

on the basis of three controlled trials in children ages 6 to 12 years (Studies 1, 2, and 3),
one controlled trial in adolescents ages 13 to 17 years (Study 4), one controlled trial in
children and adolescents ages 6-17 years (Study 5), and two controlled trials in adults
(Study 7 and 8) who met Diagnostic and Statistical Manual of Mental Disorders, 4th
edition – text revision (DSM-IV-TR) criteria for ADHD.  Maintenance of efficacy after long-
term use (at least 6 months) of Lisdexamfetamine in the treatment of ADHD was
demonstrated in two randomized withdrawal trials in children and adolescents (Study 6),
and adults (Study 9).

Patients Ages 6 to 12 Years Old

A double-blind, randomized, placebo-controlled, parallel-group study (Study 1) was

conducted in children ages 6 to 12 years (N=290) who met DSM-IV criteria for ADHD
(either the combined type or the hyperactive-impulsive type).  Patients were randomized
to receive final doses of 30 mg, 50 mg, or 70 mg of Lisdexamfetamine or placebo once
daily in the morning for a total of four weeks of treatment.  All patients receiving
Lisdexamfetamine were initiated on 30 mg for the first week of treatment.  Patients
assigned to the 50 mg and 70 mg dose groups were titrated by 20 mg per week until they
achieved their assigned dose.  The primary efficacy outcome was change in Total Score
from baseline to endpoint in investigator ratings on the ADHD Rating Scale (ADHD-RS),
an 18-item questionnaire with a score range of 0-54 points that measures the core
symptoms of ADHD which includes both hyperactive/impulsive and inattentive subscales.
Endpoint was defined as the last post-randomization treatment week (i.e. Weeks 1
through 4) for which a valid score was obtained.  All Lisdexamfetamine dose groups were
superior to placebo in the primary efficacy outcome.  Mean effects at all doses were
similar; however, the highest dose (70 mg/day) was numerically superior to both lower
doses (Study 1 in Table 4).  The effects were maintained throughout the day based on
parent ratings (Conners' Parent Rating Scale) in the morning (approximately 10 am),
afternoon (approximately 2 pm), and early evening (approximately 6 pm).

A double-blind, placebo-controlled, randomized, crossover design, analog classroom

study (Study 2) was conducted in children ages 6 to 12 years (N=52) who met DSM-IV
criteria for ADHD (either the combined type or the hyperactive-impulsive type).  Following
a 3-week open-label dose optimization with Adderall XR®, patients were randomly
assigned to continue their optimized dose of Adderall XR (10 mg, 20 mg, or 30 mg),
Lisdexamfetamine (30 mg, 50 mg, or 70 mg), or placebo once daily in the morning for 1
week each treatment.  Efficacy assessments were conducted at 1, 2, 3, 4.5, 6, 8, 10, and
12 hours post-dose using the Swanson, Kotkin, Agler, M.Flynn, and Pelham Deportment
scores (SKAMP-DS), a 4-item subscale of the SKAMP with scores ranging from 0 to 24
points that measures deportment problems leading to classroom disruptions.  A
significant difference in patient behavior, based upon the average of investigator ratings
on the SKAMP-DS across the 8 assessments were observed between patients when
they received Lisdexamfetamine compared to patients when they received placebo
(Study 2 in Table 4).  The drug effect reached statistical significance from hours 2 to 12
post-dose, but was not significant at 1 hour.

A second double-blind, placebo-controlled, randomized, crossover design, analog

classroom study (Study 3) was conducted in children ages 6 to 12 years (N=129) who
met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive
type).  Following a 4-week open-label dose optimization with Lisdexamfetamine (30 mg,
50 mg, 70 mg), patients were randomly assigned to continue their optimized dose of
Lisdexamfetamine or placebo once daily in the morning for 1 week each treatment.  A
significant difference in patient behavior, based upon the average of investigator ratings
on the SKAMP-Deportment scores across all 7 assessments conducted at 1.5, 2.5, 5.0,
7.5, 10.0, 12.0, and 13.0 hours post-dose, were observed between patients when
they received Lisdexamfetamine compared to patients when they received placebo
(Study 3 in Table 4, Figure 4).

Patients Ages 13 to 17 Years Old

A double-blind, randomized, placebo-controlled, parallel-group study (Study 4) was

conducted in adolescents ages 13 to 17 years (N=314) who met DSM-IV criteria for
ADHD.  In this study, patients were randomized in a 1:1:1:1 ratio to a daily morning dose
of Lisdexamfetamine (30 mg/day, 50 mg/day or 70 mg/day) or placebo for a total of four
weeks of treatment.  All patients receiving Lisdexamfetamine were initiated on 30 mg for
the first week of treatment.  Patients assigned to the 50 mg and 70 mg dose groups were
titrated by 20 mg per week until they achieved their assigned dose.  The primary efficacy
outcome was change in Total Score from baseline to endpoint in investigator ratings on
the ADHD Rating Scale (ADHD-RS).  Endpoint was defined as the last post-
randomization treatment week (i.e. Weeks 1 through 4) for which a valid score was
obtained.  All Lisdexamfetamine dose groups were superior to placebo in the primary
efficacy outcome (Study 4 in Table 4).

Patients Ages 6 to 17 Years Old: Short-Term Treatment

A double-blind, randomized, placebo- and active-controlled parallel-group, dose-

optimization study (Study 5) was conducted in children and adolescents ages 6 to 17
years (n=336) who met DSM-IV criteria for ADHD.  In this eight-week study, patients
were randomized to a daily morning dose of Lisdexamfetamine (30, 50 or 70mg/day), an
active control, or placebo (1:1:1).  The study consisted of a Screening and Washout
Period (up to 42 days), a 7-week Double-blind Evaluation Period (consisting of a 4-week
Dose-Optimization Period followed by a 3-week Dose-Maintenance Period), and a 1-
week Washout and Follow-up Period.  During the Dose Optimization Period, subjects
were titrated until an optimal dose, based on tolerability and investigator's judgment, was
reached.  Lisdexamfetamine showed significantly greater efficacy than placebo.  The
placebo-adjusted mean reduction from baseline in the ADHD-RS-IV total score was 18.6.
Subjects on Lisdexamfetamine also showed greater improvement on the Clinical Global
Impression-Improvement (CGI-I) rating scale compared to subjects on placebo (Study 5
in Table 4).

Patients Ages 6 to 17 Years Old:  Maintenance Treatment

Maintenance of Efficacy Study (Study 6) - A double-blind, placebo-controlled, randomized
withdrawal study was conducted in children and adolescents ages 6 to 17 (N=276) who
met the diagnosis of ADHD (DSM-IV criteria).  A total of 276 patients were enrolled into
the study, 236 patients participated in Study 5 and 40 subjects directly enrolled.  Subjects
were treated with open-label Lisdexamfetamine for at least 26 weeks prior to being
assessed for entry into the randomized withdrawal period.  Eligible patients had to
demonstrate treatment response as defined by CGI-S <3 and Total Score on the ADHD-
RS ≤22.  Patients that maintained treatment response for 2 weeks at the end of the open
label treatment period were eligible to be randomized to ongoing treatment with the same
dose of Lisdexamfetamine (N=78) or switched to placebo (N=79) during the double-blind
phase.  Patients were observed for relapse (treatment failure) during the 6 week double
blind phase.  A significantly lower proportion of treatment failures occurred among
Lisdexamfetamine subjects (15.8%) compared to placebo (67.5%) at endpoint of the
randomized withdrawal period.  The endpoint measurement was defined as the last post-
randomization treatment week at which a valid ADHD-RS Total Score and CGI-S were
observed.  Treatment failure was defined as a ≥50% increase (worsening) in the ADHD-
RS Total Score and a ≥2-point increase in the CGI-S score compared to scores at entry
into the double-blind randomized withdrawal phase.  Subjects who withdrew from the
randomized withdrawal period and who did not provide efficacy data at their last on-
treatment visit were classified as treatment failures (Study 6, Figure 5).

Adults:  Short-Term Treatment

A double-blind, randomized, placebo-controlled, parallel-group study (Study 7) was

conducted in adults ages 18 to 55 (N=420) who met DSM-IV criteria for ADHD.  In this
study, patients were randomized to receive final doses of 30 mg, 50 mg, or 70 mg of
Lisdexamfetamine or placebo for a total of four weeks of treatment.  All patients receiving
Lisdexamfetamine were initiated on 30 mg for the first week of treatment.  Patients
assigned to the 50 mg and 70 mg dose groups were titrated by 20 mg per week until they
achieved their assigned dose.  The primary efficacy outcome was change in Total Score
from baseline to endpoint in investigator ratings on the ADHD Rating Scale (ADHD-RS). 
Endpoint was defined as the last post-randomization treatment week (i.e. Weeks 1
through 4) for which a valid score was obtained.  All Lisdexamfetamine dose groups were
superior to placebo in the primary efficacy outcome (Study 7 in Table 4).

The second study was a multi-center, randomized, double-blind, placebo-controlled,

cross-over, modified analog classroom study (Study 8) of Lisdexamfetamine to simulate a
workplace environment in 142 adults ages 18 to 55 who met DSM-IV-TR criteria for
ADHD.  There was a 4-week open-label, dose optimization phase with Lisdexamfetamine
(30 mg/day, 50 mg/day, or 70 mg/day in the morning).  Patients were then randomized to
one of two treatment sequences: 1) Lisdexamfetamine (optimized dose) followed by
placebo, each for one week, or 2) placebo followed by Lisdexamfetamine , each for one
week.  Efficacy assessments occurred at the end of each week, using the Permanent
Product Measure of Performance (PERMP), a skill-adjusted math test that measures
attention in ADHD.  PERMP total score results from the sum of the number of math
problems attempted plus the number of math problems answered correctly. 
Lisdexamfetamine treatment, compared to placebo, resulted in a statistically significant
improvement in attention across all post-dose time points, as measured by average
PERMP total scores over the course of one assessment day, as well as at each time
point measured.  The PERMP assessments were administered at pre-dose (-0.5 hours)
and at 2, 4, 8, 10, 12, and 14 hours post-dose (Study 8 in Table 4, Figure 6).

Adults:  Maintenance Treatment

 A double-blind, placebo-controlled, randomized withdrawal design study (Study 9) was
conducted in adults ages 18 to 55 (N=123) who had a documented diagnosis of ADHD or
met DSM-IV criteria for ADHD.  At study entry, patients must have had documentation of
treatment with Lisdexamfetamine for a minimum of 6 months and had to demonstrate
treatment response as defined by Clinical Global Impression Severity (CGI-S) ≤3 and
Total Score on the ADHD-RS <22.  ADHD-RS Total Score is a measure of core
symptoms of ADHD.  The CGI-S score assesses the clinician's impression of the
patient's current illness state and ranges from 1 (not at all ill) to 7 (extremely ill).  Patients
that maintained treatment response at week 3 of the open label treatment phase (N=116)
were eligible to be randomized to ongoing treatment with the same dose of
Lisdexamfetamine (N=56) or switched to placebo (N=60) during the double-blind phase. 
Patients were observed for relapse (treatment failure) during the 6-week double-blind
phase.  The efficacy endpoint was the proportion of patients with treatment failure during
the double-blind phase.  Treatment failure was defined as a ≥50% increase (worsening)
in the ADHD-RS Total Score and ≥2-point increase in the CGI-S score compared to
scores at entry into the double-blind phase.  Maintenance of efficacy for patients treated
with Lisdexamfetamine was demonstrated by the significantly lower proportion of patients
with treatment failure (9%) compared to patients receiving placebo (75%) at endpoint
during the double-blind phase (Study 9, Figure 7).

Table 4: Summary of Primary Efficacy Results from 1-7 Week Studies of

Lisdexamfetamine in Children, Adolescents, and Adults with ADHD

STU
DY
NO.
(AG PRIM LISDEXAMF
E ARY LISDEXAMF LISDEXAMF LISDEXAMF ETAMINE
RAN ENDP MEAS PLAC ETAMINE ETAMINE ETAMINE 30, 50, OR
GE) OINT URE EBO 30 MG/DAY 50 MG/DAY 70 MG/DAY 70 MG/DAY
 1
(6 -
12  Mean
year ADHD Baselin
s) -RS-IV  e Score  42.4  43.2  43.3  45.1  -
LS
Mean
differen
ce from
Placeb
o -20.5
(95%  -15.6  -17.2 (-25.6, -
    CI)α  -  (-20.8, -10.4) (-22.3, -12.1) 15.4)   -
 2
(6 - Avera  Mean
12 ge Pre-
year SKAM dose
s) P-DS  Scoreb -   -  -  - - 
 LS
Mean
differen
ce from
Placeb
o (95% -0.9
    CI) α  -  -  - -  (-1.1, -0.7) 
 3
(6 - Avera  Mean
12 ge Pre-
year SKAM dose
s) P-DS  Score  0.7  -  -  -  0.9
 LS
Mean
differen
ce from
Placeb
o (95%  -0.7
    CI) α  -  -  -  - (-0.9, -0.6)
 4
(13 -
17  Mean
year ADHD Baselin
s) -RS-IV  e Score  38.5  38.3  37.3 37.0   -
 LS
Mean
differen
ce from
Placeb
o (95%  -5.5  -8.3  -7.9
    CI) α  - (-9.7, -1.3) (-12.5, -4.1) (-12.1, -3.8) - 
5 
(6-
17  ADH  Mean
year D-RS- Baselin
s) IV e Score  41.0  -  -  -  40.7
 LS
Mean
differen
ce from
Placeb
o(95%  -18.6
    CI) α  -  -  -  - (-21.5, -15.7)
7 
(18 -
55  ADH  Mean
year D-RS- Baselin
s)  IV e Score  39.4  40.5 40.8   41.0  -
 LS
Mean
differen
ce from
Placeb
o (95% -8.0  -9.2  -10.4
    CI) α  - (-12.1, -3.9)  (-13.2, -5.1) (-14.5, -6.3)  -
8
(18 -  Avera Mean
55 ge Pre-
year PERM dose
s)  P Score   261.4  -  -  -  260.1
  LS
Mean
differen
ce from
Placeb
o (95% 23.4
    CI) α -   -  - -  (15.6, 31.2) 

α- Difference (drug – placebo) in Least Squares Mean for the primary efficacy outcome
along with 95% confidence intervals.  If there are multiple Lisdexamfetamine dose arms,
adjusted CIs are reported.  For ADHD-RS-IV and SKAMP-DS scales, a higher score
indicates more severe symptoms, so a negative LS mean difference indicates
improvement from placebo (studies 1-5, and 7).  For the PERMP scale, a higher score
indicates less severe symptoms, so a positive LS mean difference indicates improvement
from placebo.

b- Pre-dose SKAMP-DS was not collected

CI: Confidence interval

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

None

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

10. 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.

11. 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

12. In case of imported drugs : Not applicable

13. Date of Submission :

14. Additional Information (if any) : Not applicable