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ADDERALL

ADDERALL

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Published by torontostar

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Published by: torontostar on Sep 20, 2012
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07/10/2013

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 PRODUCT MONOGRAPH
 
ADDERALL XR
 ®*
 mixed salts amphetamine extended-release Capsules5mg, 10mg, 15mg, 20mg, 25mg, 30mg Capsules
Central Nervous System Stimulant
 for Attention Deficit Hyperactivity Disorder Shire Canada Inc.Saint- Laurent, QuebecH4S 2C9Date of Preparation:15 March 2012*ADDERALL XR is a registered trade-mark used under licence from Shire US, Inc.
Page 1 of 37
 
PRODUCT MONOGRAPH
 ADDERALL XR
 ® 
 mixed salts amphetamine extended-release Capsules
 
5mg, 10mg, 15mg, 20mg, 25mg, 30mg CapsulesCNS Stimulantfor Attention Deficit Hyperactivity Disorder 
ACTION AND CLINICAL PHARMACOLOGY
  Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Amphetamines arethought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increasethe release of these monoamines into the extraneuronal space.
Pharmacokinetics
Pharmacokinetic studies of ADDERALL XR (mixed salts amphetamine extended-release capsules) havebeen conducted in healthy adult and pediatric (aged 6-12 years) subjects, and adolescent (aged13-17 years) and pediatric patients with ADHD. ADDERALL XR capsules contain dextroamphetamine(
-amphetamine) and
 
levoamphetamine (
-amphetamine) salts in the ratio of 3:1. ADDERALL XR demonstrates linear pharmacokinetics over the dose range of 20 to 60mg in adults andadolescents aged 13 to 17 years weighing greater than 75kg/165lbs, over the dose range of 10 to 40mg inadolescents weighing less than or equal to 75kg/165lbs and 5 to 30mg in children aged 6 to 12 years.There was no unexpected accumulation at steady state.Comparison of the pharmacokinetics of d- and l-amphetamine after oral administration of ADDERALL XR inpediatric (aged 6-12 years) and adolescent (aged 13-17 years) ADHD patients and healthy adult volunteersindicates that body weight is the primary determinant of apparent differences in the pharmacokinetics of d-and l-amphetamine across the age range. Systemic exposure measured by area under the curve toinfinity (AUC
) and maximum plasma concentration (C
max
) decreased with increases in body weight, whileoral volume of distribution (V
z
/F), oral clearance (CL/F), and elimination half-life (t
1/2
) increased withincreases in body weight.Pharmacokinetic Results in Healthy Adult and Pediatric Subjects
 
Following oral administration of a single dose of ADDERALL XR in healthy adult subjects, peak plasmaconcentrations (C
max
) of 28.1ng/mL and 8.7ng/mL occurred in about 7 hours for 
d- 
amphetamine and8 hours for 
l- 
amphetamine, respectively . The AUC
0-inf 
for 
d- 
amphetamine and
l- 
amphetamine were567ng
hr/mL and 203ng
hr/mL, respectively.
Page 2 of 37
 
The mean elimination half-life is 1 hour shorter for 
d- 
amphetamine and 2 hours shorter for 
l- 
amphetaminein children aged 6 to 12 years compared to that in adults (t
1/2
is 10 hours for 
d- 
amphetamine and 13 hoursfor 
l- 
amphetamine in adults, and 9 hours and 11 hours, respectively, for children). Children had higher systemic exposure to amphetamine (C
max
and AUC) than adults for a given dose of ADDERALL XR, whichwas attributed to the higher dose administered to children on a mg/kg body weight basis compared toadults. Upon dose normalization on a mg/kg basis, children showed 30% less systemic exposurecompared to adults.Pharmacokinetic Results in Children and Adolescents with ADHD
 
In a 20mg single dose study in 51 children (aged 6-12 years) with ADHD, the mean T
max
for 
d- 
amphetamine was 6.8 hours and the mean C
max
was 48.8ng/mL. The corresponding mean T
max
andC
max
values for 
l- 
amphetamine were 6.9 hours and 14.8ng/mL, respectively. The mean elimination half-lifefor 
d- 
amphetamine and
l- 
amphetamine was 9.5 and 10.9 hours, respectively. Following dosing of childrenwith ADHD to steady state with ADDERALL XR 10, 20 and 30mg, the mean
d- 
amphetamine C
max
(ng/mL)in plasma for ADDERALL XR was 28.8 (10mg), 54.6 (20mg) and 89.0 (30mg). For 
l- 
amphetamine, themean C
max
values for the three ADDERALL XR doses were 8.8, 17.2 and 28.1ng/mL, respectively.In adolescents aged 13-17 years and weighing less than or equal to 75kg/165lbs, the mean eliminationhalf-life for 
-amphetamine is 11 hours, and 13-14 hours for 
-amphetamine
.
 Metabolism Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form4-hydroxyamphetamine, or on the side chain
α
or 
β
carbons to form alpha-hydroxy-amphetamine or norephedrine, respectively. Norephedrine and 4-hydroxy-amphetamine are both active and each issubsequently oxidized to form 4-hydroxy-norephedrine. Alpha-hydroxy-amphetamine undergoesdeamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycineconjugate hippuric acid. Although the enzymes involved in amphetamine metabolism have not been clearlydefined, CYP2D6 is known to be involved with formation of 4-hydroxy-amphetamine. Since CYP2D6 isgenetically polymorphic, population variations in amphetamine metabolism are a possibility. Amphetamine is known to inhibit monoamine oxidase, whereas the ability of amphetamine and itsmetabolites to inhibit various P450 isozymes and other enzymes has not been adequately elucidated.In vitro
 
experiments with human microsomes indicate minor inhibition of CYP2D6 by amphetamine andminor inhibition of CYP1A2, 2D6, and 3A4 by one or more metabolites. However, due to the probability of auto-inhibition and the lack of information on the concentration of these metabolites relative to in vivo
 
concentrations, no predications regarding the potential for amphetamine or its metabolites to inhibit themetabolism of other drugs by CYP isozymes in vivo
 
can be made.ExcretionWith normal urine pHs approximately half of an administered dose of amphetamine is recoverable in urineas derivatives of alpha-hydroxy-amphetamine and approximately another 30%-40% of the dose isrecoverable in urine as amphetamine itself. Since amphetamine has a pKa of 9.9, urinary recovery oamphetamine is highly dependent on pH and urine flow rates. Alkaline urine pHs result in less ionizationand reduced renal elimination, and acidic pHs and high flow rates result in increased renal elimination withclearances greater than glomerular filtration rates, indicating the involvement of active secretion. Urinaryrecovery of amphetamine has been reported to range from 1% to 75%, depending on urinary pH, with theremaining fraction of the dose hepatically metabolized. Consequently, both hepatic and renal dysfunction
Page 3 of 37

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