Adderall XR
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Adderall XR - Scientific Information

Manufacture: Shire, Inc.
Country: Canada
Condition: ADHD (Attention Deficit Hyperactivity Disorder), Narcolepsy
Class: CNS stimulants
Form: Capsules
Ingredients: d-amphetamine saccharate, amphetamine aspartate monohydrate, d-amphetamine sulfate and amphetamine sulfate, edible inks, fd&c blue #2 (5mg, 10mg and 15mg capsules), hydroxypropyl methylcellulose, kosher gelatin, methacrylic acid copolymer, opadry beige, red iron oxide (20mg, 25mg and 30mg capsules), starch, sugar spheres, talc, titanium dioxide, triethyl citrate, yellow iron oxide (20mg, 25mg and 30mg capsules)

Pharmaceutical Information

Drug Substance

Proper Names:
1. d-amphetamine Saccharate
2. Amphetamine Aspartate Monohydrate
3. d-amphetamine Sulfate USP
4. Amphetamine Sulfate USP
Chemical Names:
1. (+)-α-Methylphenethylamine saccharate (2:1)
2. (±)-α-Methylphenethylamine aspartate monohydrate
3. (+)-α-Methylphenethylamine sulfate (2:1)
4. (±)-α-Methylphenethylamine sulfate (2:1)
Structural Formula and Molecular Weights:
1) d-amphetamine Saccharate
2) Amphetamine Aspartate Monohydrate
3) d-amphetamine Sulfate
4) Amphetamine Sulfate
Description: The four amphetamine salts are white to off-white, crystalline powder. The amphetamine
sulfate is freely soluble in water while d-amphetamine sulfate, amphetamine aspartate and
d-amphetamine saccharate are soluble in water. Also, the amphetamine salts are known
to be stable molecules.

Composition

ADDERALL XR (mixed salts amphetamine extended-release capsules) is a long-acting, modified-release, single-entity amphetamine product designed for once-daily administration combining the neutral sulfate salts of d-amphetamine and amphetamine, with the d-isomer of amphetamine saccharate and d,l-amphetamine aspartate. The ADDERALL XR capsule contains two types of drug-containing beads designed to give a double-pulsed delivery of amphetamines, which provides for its prolonged duration of action.

Each capsule contains: 5mg 10mg 15mg 20mg 25mg 30mg
d-amphetamine Saccharate 1.25 2.5 3.75 5 6.25 7.5
Amphetamine Aspartate Monohydrate 1.25 2.5 3.75 5 6.25 7.5
d-amphetamine Sulfate USP 1.25 2.5 3.75 5 6.25 7.5
Amphetamine Sulfate USP 1.25 2.5 3.75 5 6.25 7.5
Total amphetamine base equivalence 1.5 3 4.5 6 7.5 9
Total d-amphetamine base equivalence 1.6 3.3 4.9 6.5 8.1 9.8

Inactive Ingredients and Colors: The inactive ingredients in ADDERALL XR capsules include: gelatin capsules, hydroxypropyl methylcellulose, methacrylic acid copolymer, opadry beige, starch, sugar spheres, talc, and triethyl citrate. Gelatin capsules contain edible inks, kosher gelatin, and titanium dioxide.

The 5mg, 10mg and 15mg capsules also contain FD&C Blue #2. The 20mg, 25mg and 30mg capsules also contain red iron oxide and yellow iron oxide.

Stability and Storage Recommendations

Dispense in a tight, light-resistant container as defined in the USP.

Store at 25°C (77°F). Excursions permitted to 15-30°C (59-86°F).

Availability of Dosage Forms

ADDERALL XR 5mg Capsules: Clear/blue, imprinted "ADDERALL XR" on one end and "5mg" on the other. Bottles of 100.

ADDERALL XR 10mg Capsules: Blue/blue, imprinted "ADDERALL XR" on one end and "10mg" on the other. Bottles of 100.

ADDERALL XR 15mg Capsules: Blue/white, imprinted "ADDERALL XR" on one end and "15mg" on the other. Bottles of 100.

ADDERALL XR 20mg Capsules: Orange/orange, imprinted "ADDERALL XR" on one end and "20mg" on the other. Bottles of 100.

ADDERALL XR 25mg Capsules: Orange/white, imprinted "ADDERALL XR" on one end and "25mg" on the other. Bottles of 100.

ADDERALL XR 30mg Capsules: Clear/orange, imprinted "ADDERALL XR" on one end and "30mg" on the other. Bottles of 100.

Pharmacology

The behavioral manifestations of ADHD are believed to involve an interactive imbalance between dopaminergic and other neurotransmitter systems. However, a fundamental dopaminergic dysfunction appears to have special significance. Amphetamine increases the availability of synaptic dopamine at key sites in the brain by stimulating its release from newly synthesized (cytoplasmic) dopamine pools. Thus, unlike methylphenidate, which increases dopamine availability primarily by blocking reuptake, amphetamine’s effect does not appear to be highly dependent on impulse-released dopamine.

This primary mechanism of action of amphetamine is supported by experiments with reserpine and α-methyltyrosine. Pretreatment with reserpine, which is believed to reduce stored vesicular (but not cytoplasmic) dopamine, was ineffective in attenuating responses to amphetamine challenge. In contrast, the depletion of newly synthesized cytoplasmic dopamine through the inhibition of tyrosine hydroxylase (the rate limiting anabolic enzyme) using α-methyltyrosine, did reduce responses following amphetamine challenge.

Systemically administered amphetamine produced stimulation of dopamine release from the nucleus accumbens and dorsal caudate. Administration of a low acute dose of amphetamine produced a region specific decrease in dopamine from the “shell” in comparison to the “core” regions of the nucleus accumbens. Higher acute doses increased extracellular dopamine to the same extent in both regions.

In addition to a dopaminergic mechanism of action, there is experimental evidence to suggest involvement of other neurotransmitter systems in the regulation of behavioral effects (e.g., motor activity). These include interactions between dopaminergic, GABAergic and glutamatergic pathways and possible involvement of cholinergic pathways.

Amphetamine-induced effects are primarily mediated by D1 and D2 receptors. In addition, 5-HT2A and 5-HT3 receptors, and NMDA receptors are suggested to play a role in amphetamine-induced release of dopamine, and in the regulation of the firing rate and pattern of midbrain dopamine neurons, respectively.

Prenatal exposure to amphetamine was associated with a variety of responses in offspring that included increases in conditioned avoidance, exploratory behavior, and sexual behavior, and decreases in 5-HT content in the medial hypothalamus.

Repeated administration of high concentrations of amphetamine produced striatal, neostriatum, and frontal cortex dopamine nerve fiber degeneration.

Amphetamine interacted with a variety of compounds that included caffeine, cocaine, morphine, diazepam, phencyclidine, clonidine, fluoxetine, lithium, pentobarbital, ethanol, and THC. The mechanism of many of these interactions is currently not known.

Animal Pharmacokinetics

ADDERALL XR (mixed salts amphetamine extended-release capsules) is a once a day product containing immediate-release and delayed-release pellets that has been shown to provide a double-pulsed delivery of amphetamine in patients with ADHD.

Literature studies indicated a stereospecific distribution of the individual dextro (d-) and levo (l-) Distribution kinetics in the rat indicated that urine as parent drug and as the hydroxy enantiomers of amphetamine in the brain and heart of mice. similar amounts of both enantiomers were excreted in the metabolite.

Radiolabelled 3H-d-amphetamine was distributed in many tissues of pregnant and non-pregnant females and male mice. Amphetamine crossed the placenta and was present in the placenta, whole fetus, and in fetal brain and liver. Fetal tissue concentrations were generally much lower than maternal tissue concentrations.

The metabolism of amphetamine was affected by induction of the CYP450 system with phenobarbital. The direct benzene ring hydroxylation of parent drug was mediated by CYP2D1 in the rat and by the human homologue, CYP2D6, in human microsomes. The deamination of amphetamine was shown to be mediated by the CYP isoform 2C3 from the rabbit, but not the 2C11 and 2C13 isoforms from the rat. N-oxygenation of amphetamine to the hydroxylamine and oxime metabolites was demonstrated in vitro with flavin containing monooxygenase Form 3 from humans.

The urinary excretion of amphetamine and its major rat metabolite, 4-hydroxyamphetamine, was influenced by strain of rat, significant differences occurring between poor metabolizer versus extensive metabolizer strains.

Human Pharmacokinetics

Pharmacokinetic studies of ADDERALL XR have been conducted in healthy adult and pediatric (aged 6-12 years) subjects, and adolescent (aged 13-17 years) and pediatric patients with ADHD. ADDERALL XR capsules contain d-amphetamine and l-amphetamine salts in the ratio of 3:1.

ADDERALL XR demonstrates linear pharmacokinetics over the dose range of 20 to 60mg in adults and adolescents aged 13 to 17 years weighing greater than 75kg/165lbs, over the dose range of 10 to 40mg in adolescents 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 in children.

Pharmacokinetic Results in Healthy Adult and Pediatric Subjects

Following administration of a single dose of ADDERALL XR in healthy adult subjects, the peak plasma concentrations occurred in about 7 hours for d-amphetamine and 8 hours for l-amphetamine as seen in Table 1


Table 1: Pharmacokinetic Parameters for Single 20mg Dose of ADDERALL XR

Treatment d-amphetamine l-amphetamine
AUC0-inf
(ng•hr/mL)
Tmax
(hours)
Cmax
(ng/mL)
AUC0-inf
(ng•hr/mL)
Tmax
(hours)
Cmax
(ng/mL)
ADDERALL XR
(20mg, qd)
567 7 28.1 203 8.2 8.7

Figure 1: Mean d-amphetamine and l-amphetamine Plasma Concentrations following a single 20mg morning Administration of ADDERALL XR in the Fed State.


The mean elimination half-life is 1 hour shorter for d-amphetamine and 2 hours shorter for l- amphetamine in children aged 6 to 12 years compared to that in adults (t½ is 10 hours for d-amphetamine and 13 hours for l-amphetamine in adults, and 9 hours and 11 hours, respectively, for children).

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 Tmax for d-amphetamine was 6.8 hours and the mean Cmax was 48.8ng/mL. The corresponding mean Tmax and Cmax values for l-amphetamine were 6.9 hours and 14.8ng/mL, respectively. The mean elimination half-life for d-amphetamine and l-amphetamine was 9.5 and 10.9 hours, respectively. Following dosing of children with ADHD to steady state with ADDERALL XR 10, 20 and 30mg the mean d-amphetamine Cmax (ng/mL) in plasma for ADDERALL XR was 28.8 (10mg), 54.6 (20mg) and 89.0 (30mg). For l-amphetamine, the mean Cmax 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 elimination half-life for d-amphetamine is 11 hours, and 13-14 hours for l-amphetamine.

 Table 2: ADDERALL XR Pharmacokinetic Parameters at Steady State in Children with ADHD

Treatment d-amphetamine l-amphetamine
AUC0-24
(ng•hr/mL)
Tmax
(hours)
Cmax
(ng/mL)
AUC0-24
(ng•hr/mL)
Tmax
(hours)
Cmax
(ng/mL)
ADDERALL XR (10mg) 432 6.4 28.8 138 6.4 8.8
ADDERALL XR (20mg) 777 5.8 54.6 262 5.7 17.2
ADDERALL XR (30mg) 1364 5.5 89 444 5.5 28.1

Metabolism

Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-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 is subsequently oxidized to form 4-hydroxy-norephedrine. Alpha-hydroxy-amphetamine undergoes deamination to form phenylacetone, which ultimately forms benzoic acid and its glucuronide and the glycine conjugate hippuric acid. Although the enzymes involved in amphetamine metabolism have not been clearly defined, CYP2D6 is known to be involved with formation of 4-hydroxy-amphetamine. Since CYP2D6 is genetically polymorphic, population variations in amphetamine metabolism are a possibility.

Amphetamine is known to inhibit monoamine oxidase, whereas the ability of amphetamine and its metabolites 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 and minor 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 the metabolism of other drugs by CYP isozymes in vivo can be made.

Excretion

With normal urine pHs approximately half of an administered dose of amphetamine is recoverable in urine as derivatives of alpha-hydroxy-amphetamine and approximately another 30%-40% of the dose is recoverable in urine as amphetamine itself. Since amphetamine has a pKa of 9.9, urinary recovery of amphetamine is highly dependent on pH and urine flow rates. Alkaline urine pHs result in less ionization and reduced renal elimination, and acidic pHs and high flow rates result in increased renal elimination with clearances greater than glomerular filtration rates, indicating the involvement of active secretion. Urinary recovery of amphetamine has been reported to range from 1% to 75%, depending on urinary pH, with the remaining fraction of the dose hepatically metabolized. Consequently, both hepatic and renal dysfunction have the potential to inhibit the elimination of amphetamine and result in prolonged exposures. In addition, drugs that effect urinary pH are known to alter the elimination of amphetamine, and any decrease in amphetamine’s metabolism that might occur due to drug interactions or genetic polymorphisms is more likely to be clinically significant when renal elimination is decreased, (see Precautions, DrugInteractions).

Bioequivalence of 1 x 20mg Capsule to 4 x 5mg Capsules

Children With ADHD

In a single dose study in 20 children (aged 6-12 years) with ADHD, a single administration of four 5mg capsules of ADDERALL XR was shown to be bioequivalent to a single 20mg capsule for both d- and l-amphetamine under fasting conditions.

Table 3: Pharmacokinetic Parameters for ADDERALL XR

Summary Table of the Comparative Bioavailability Data
ADDERALL XR 4 x 5mg Capsules vs 1 x 20mg Capsule - Under Fasting Conditions
From Measured Data
Parameter Geometric Mean
Arithmetic Mean (CV%)
% Ratio
of Geometric
Means
Confidence
Interval
(90% CI)
ADDERALL XR
4x5mg capsules
ADDERALL XR
1x20mg capsules
d-amphetamine
AUCT
(ng•h/mL)
823.5
843.5 (22.2%)
775.7
794.8 (22.6%)
106.2 101.0 -111.6
AUCI
(ng•h/mL)
845.8
863.9 (21.1%)
797.8
815.3 (21.4%)
106.0 101.5 - 110.7
Cmax
(ng/mL)
50.4
51.9 (24.5%)
49.9
51.9 (28.9%)
101.0 92.4 -110.3
Tmax*
(h)
4.65 (50.0%) 4.50 (37.8%)
T½*
(h)
8.10 (14.5%) 7.98 (17.0%)
l-amphetamine
AUCT
(ng•h/mL)
276.8
286.2 (26.4%)
238.5
247.0 (27.1%)
116.0 108.6 -124.0
AUCI
(ng•h/mL)
297.1
304.0 (22.3%)
263.7
269.6 (21.7%)
112.7 107.6 -118.0
Cmax
(ng/mL)
16.2
16.7 (24.1%)
15.2
15.8 (28.6%)
106.6 98.5 -115.3
Tmax*
(h)
4.95 (50.1%) 4.85 (39.7%)
T½*
(h)
9.16 (14.5%) 9.13 (18.5%)

* Arithmetic mean (CV%)

For both d- and l- amphetamine, statistically significant differences were noted between the two treatment groups for AUC, with the 4 x 5mg group showing higher AUC, but not for Cmax and Tmax.

Food Effect Study in Healthy Adult Subjects

A single dose study compared the relative bioavailability of d-amphetamine and l-amphetamine following administration of a single 30mg dose of ADDERALL XR fasted, fed (high fat meal) and sprinkled on food (otherwise fasted) in 21 healthy adult subjects. Food does not affect the extent of absorption of ADDERALL XR capsules, but prolongs Tmax by 2.5 hours by administration with food (from 5.2 hrs at fasted state to 7.7 hrs after a high-fat meal). Opening the capsule and sprinkling the contents on applesauce results in comparable absorption to the intact capsule taken in the fasted states.

Toxicology

Acute Toxicity Studies

The acute LD50 amphetamine is as follows:

Species LD50 (mg/kg)
Mice (i.v.) 52
Mice (oral) 353
Rat (i.p.) 70
Dog (i.v.) 8.5
Monkey (i.v., oral) 5

Acute toxicity studies conducted in mice, rats, dogs and monkeys showed similar dose-dependent responses. The order for comparative toxicity ranking, based upon the LD50 values, was monkey>dog>mouse.

Acute toxicity to dextro (d-), and levo (l-) amphetamine was age-dependent. Young mice (3-30 days old) tolerated higher doses (up to 180mg/kg i.p.) than adults. Toxicity increased from 18-days of age onward. Mortality response curves were biphasic for developing mice and polyphasic for adult mice.

Acute toxicity signs noted in mice (25-75mg/kg i.v.), rats (45-178mg/kg i.p.), dogs (5-9mg/kg i.v.) and monkeys (1-6mg/kg i.v.) included marked to severe hyperactivity, stereotypic behavior, mild to marked clonic and/or tonic convulsions, and (in monkeys) marked increase in respiratory rate, body temperature and pupil size. Death was associated with convulsions and, in dogs, massive endocardial hemorrhages in both ventricles.

Subacute and Subchronic Toxicity Studies

Subacute and subchronic toxicity signs noted in mice (0-2000 ppm of d,l-amphetamine in feed) and rats (0-750 ppm of d,l-amphetamine in feed) from 14-day and 13-week dietary studies included hyperactivity, decreased body weight and food consumption. Deaths in the order of 15 to 65% were reported in mice administered with 500-2000 ppm of d,l-amphetamine in feed. No treatment-related deaths occurred in the rat study.

Carcinogenicity Studies

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 30mg/kg/day in male mice, 19mg/kg/day in female mice, and 5mg/kg/day in male and female rats. These doses are approximately 2.4, 1.5, and 0.8 times respectively the maximum recommended human dose of 30mg/day on a mg/m2 body surface area basis.

Reproduction and Teratology Studies

Amphetamine, in the enantiomer ratio present in ADDERALL XR (mixed salts amphetamine extended-release capsules) (d- to l- 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 (approximately 5 times the maximum recommended human dose of 30mg/day on a mg/m2 body surface area basis). Fetal malformations and death have been reported in mice following parenteral administration of d-amphetamine doses of 50mg/kg/day (approximately 6 times the maximum recommended human dose of 30mg/day on a mg/m2 basis) or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity.

A number of studies in rodents indicate that prenatal or early postnatal exposure to amphetamine (d- d, l-), at doses similar to those used clinically, can result in long-term neurochemical and behavioral alterations. Reported behavioral effects include learning and memory deficits, altered locomotor activity, and changes in sexual function.

Mutagenicity Studies

Amphetamine, in the enantiomer ratio present in ADDERALL XR (d - to l- ratio of 3:1), was not clastogenic in the mouse bone marrow micronucleus test in vivo and was negative when tested in the E. coli component of the Ames test in vitro. d,l-Amphetamine (1:1 enantiomer ratio) has been reported to produce a positive response in the mouse bone marrow micronucleus test, an equivocal response in the Ames test, and negative responses in the in vitro sister chromatid exchange and chromosomal aberration assays.