ADDERALL® XR CAPSULES
`
`
`
` CII Rx Only
`
`AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION OF
`AMPHETAMINES FOR PROLONGED PERIODS OF TIME MAY LEAD TO DRUG
`DEPENDENCE. PARTICULAR ATTENTION SHOULD BE PAID TO THE POSSIBILITY OF
`SUBJECTS OBTAINING AMPHETAMINES FOR NON-THERAPEUTIC USE OR DISTRIBUTION
`TO OTHERS AND THE DRUGS SHOULD BE PRESCRIBED OR
`DISPENSED SPARINGLY.
`
`MISUSE OF AMPHETAMINE MAY CAUSE SUDDEN DEATH AND SERIOUS
`CARDIOVASCULAR ADVERSE EVENTS.
`
`DESCRIPTION
`ADDERALL XR® is a once daily extended-release, single-entity amphetamine product. ADDERALL XR®
`combines the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of
`amphetamine saccharate and d,l-amphetamine aspartate monohydrate. The ADDERALL XR® capsule contains
`two types of drug-containing beads designed to give a double-pulsed delivery of amphetamines, which prolongs
`the release of amphetamine from ADDERALL XR® compared to the conventional ADDERALL® (immediate-
`release) tablet formulation.
`
`5 mg 10 mg 15 mg 20 mg 25 mg 30 mg
`EACH CAPSULE CONTAINS:
`Dextroamphetamine Saccharate 1.25 mg 2.5 mg 3.75 mg 5.0 mg 6.25 mg 7.5 mg
`Amphetamine Aspartate Monohydrate 1.25 mg 2.5 mg 3.75 mg 5.0 mg 6.25 mg 7.5 mg
`Dextroamphetamine Sulfate USP
`1.25 mg 2.5 mg 3.75 mg 5.0 mg 6.25 mg 7.5 mg
`Amphetamine Sulfate USP
` 1.25 mg 2.5 mg 3.75 mg 5.0 mg 6.25 mg 7.5 mg
`Total amphetamine base equivalence 3.1 mg 6.3 mg 9.4 mg 12.5 mg 15.6 mg 18.8 mg
`
`Inactive Ingredients and Colors: The inactive ingredients in ADDERALL XR® capsules include: gelatin capsules,
`hydroxypropyl methylcellulose, methacrylic acid copolymer, opadry beige, sugar spheres, talc, and triethyl
`citrate. Gelatin capsules contain edible inks, kosher gelatin, and titanium dioxide. The 5 mg, 10 mg, and 15 mg
`capsules also contain FD&C Blue #2. The 20 mg, 25 mg, and 30 mg capsules also contain red iron oxide and
`yellow iron oxide.
`
`CLINICAL PHARMACOLOGY
`Pharmacodynamics
`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 are thought
`to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of
`these monoamines into the extraneuronal space.
`
`Pharmacokinetics
`Pharmacokinetic studies of ADDERALL XR® have been conducted in healthy adult and pediatric (6-12 yrs)
`subjects, and adolescent (13-17 yrs) and pediatric patients with ADHD. Both ADDERALL® (immediate-
`release) tablets and ADDERALL XR® capsules contain d-amphetamine and l-amphetamine salts in the ratio of
`3:1. Following administration of ADDERALL® (immediate-release), the peak plasma concentrations occurred
`in about 3 hours for both d-amphetamine and l-amphetamine.
`
`The time to reach maximum plasma concentration (Tmax) for ADDERALL XR® is about 7 hours, which is about
`4 hours longer compared to ADDERALL® (immediate-release). This is consistent with the extended-release
`nature of the product.
`
`Amerigen Ex. 1043, p. 1
`
`1
`
`

`
`DEXTROAMPHETAMINE
`
`ADDERALL XR® 20 mg qd
`ADDERALL® 10 mg bid
`LEVOAMPHETAMINE
`
`ADDERALL XR® 20 mg qd
`ADDERALL® 10 mg bid
`
`0
`
`4
`
`8
`
`12
`TIME (HOURS)
`
`16
`
`20
`
`24
`
`30
`
`25
`
`20
`
`15
`
`10
`
`5
`
`0
`
`MEAN PLASMA CONCENTRATIONS OF DEXTRO AND LEVOAMPHETAMINE (ng/mL)
`
`Figure 1 Mean d-amphetamine and l-amphetamine plasma concentrations following administration of
`ADDERALL XR® 20 mg (8am) and ADDERALL® (immediate-release) 10 mg bid (8am and 12 noon) in
`the fed state.
`
`A single dose of ADDERALL XR® 20 mg capsules provided comparable plasma concentration profiles of both
`d-amphetamine and l-amphetamine to ADDERALL®(immediate-release) 10 mg bid administered 4 hours apart.
`
`The mean elimination half-live for d-amphetamine is 10 hours in adults; 11 hours in adolescents aged 13-17
`years and weighing less than or equal to 75 kg/165 lbs; and 9 hours in children aged 6 to 12 years. For the l-
`amphetamine, the mean elimination half-life in adults is 13 hours; 13 to 14 hours in adolescents; and 11 hours in
`children aged 6 to 12 years. On a mg/kg body weight basis children have a higher clearance than adolescents or
`adults (See Special Populations).
`
`ADDERALL XR(cid:147) demonstrates linear pharmacokinetics over the dose range of 20 to 60 mg in adults and
`adolescents weighing greater than 75 kg/165lbs, and over the dose range of 10 to 40 mg in adolescents weighing
`less than or equal to 75 kg/165 lbs, and 5 to 30 mg in children aged 6 to 12 years. There is no unexpected
`accumulation at steady state in children.
`
`Food does not affect the extent of absorption of d-amphetamine and l-amphetamine, but prolongs Tmax by 2.5
`hours (from 5.2 hrs at fasted state to 7.7 hrs after a high-fat meal) for d-amphetamine and 2.1 hours (from 5.6 hrs
`at fasted state to 7.7 hrs after a high fat meal) for l-amphetamine after administration of ADDERALL XR® 30
`mg. Opening the capsule and sprinkling the contents on applesauce results in comparable absorption to the intact
`capsule taken in the fasted state. Equal doses of ADDERALL XR® strengths are bioequivalent.
`
`Metabolism and Excretion
`Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or
`on the side chain (cid:302) or (cid:533) carbons to form alpha-hydroxy-amphetamine or norephedrine, respectively.
`2
`Amerigen Ex. 1043, p. 2
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`

`
`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.
`
`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).
`
`Special Populations
`Comparison of the pharmacokinetics of d- and l-amphetamine after oral administration of ADDERALL XR® in
`pediatric (6-12 years) and adolescent (13-17 years) ADHD patients and healthy adult volunteers indicates 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 to infinity (AUC(cid:102)) and maximum
`plasma concentration (Cmax) decreased with increases in body weight, while oral volume of distribution (Vz/F),
`oral clearance (CL/F), and elimination half-life (t 1/2) increased with increases in body weight.
`
`Pediatric Patients
`On a mg/kg weight basis, children eliminated amphetamine faster than adults. The elimination half-life (t1/2) is
`approximately 1 hour shorter for d-amphetamine and 2 hours shorter for l-amphetamine in children than in
`adults. However, children had higher systemic exposure to amphetamine (Cmax and AUC) than adults for a given
`dose of ADDERALL XR®, which was attributed to the higher dose administered to children on a mg/kg body
`weight basis compared to adults. Upon dose normalization on a mg/kg basis, children showed 30% less systemic
`exposure compared to adults.
`
`Gender
`Systemic exposure to amphetamine was 20-30% higher in women (N=20) than in men (N=20) due to the higher
`dose administered to women on a mg/kg body weight basis. When the exposure parameters (Cmax and AUC) were
`normalized by dose (mg/kg), these differences diminished. Age and gender had no direct effect on the
`pharmacokinetics of d- and l-amphetamine.
`
`Race
`Formal pharmacokinetic studies for race have not been conducted. However, amphetamine pharmacokinetics
`appeared to be comparable among Caucasians (N=33), Blacks (N=8) and Hispanics (N=10).
`
`Amerigen Ex. 1043, p. 3
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`3
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`Clinical Trials
`Children
`A double-blind, randomized, placebo-controlled, parallel-group study was conducted in children aged 6-12
`(N=584) who met DSM-IV criteria for ADHD (either the combined type or the hyperactive-impulsive type).
`Patients were randomized to fixed dose treatment groups receiving final doses of 10, 20, or 30 mg of
`ADDERALL XR® or placebo once daily in the morning for three weeks. Significant improvements in patient
`behavior, based upon teacher ratings of attention and hyperactivity, were observed for all ADDERALL XR®
`doses compared to patients who received placebo, for all three weeks, including the first week of treatment, when
`all ADDERALL XR® subjects were receiving a dose of 10 mg/day. Patients who received ADDERALL XR®
`showed behavioral improvements in both morning and afternoon assessments compared to patients on placebo.
`
`In a classroom analogue study, patients (N=51) receiving fixed doses of 10 mg, 20 mg or 30 mg ADDERALL
`XR® demonstrated statistically significant improvements in teacher-rated behavior and performance measures,
`compared to patients treated with placebo.
`
`Adolescents
`A double-blind, randomized, multi-center, parallel-group, placebo-controlled study was conducted in adolescents
`aged 13-17 (N=327) who met DSM-IV-TR criteria for ADHD. The primary cohort of patients (n=287, weighing
`(cid:100) 75kg/165lbs) was randomized to fixed dose treatment groups and received four weeks of treatment. Patients
`were randomized to receive final doses of 10 mg, 20 mg, 30 mg, and 40 mg ADDERALL XR® or placebo once
`daily in the morning; patients randomized to doses greater than 10 mg were titrated to their final doses by 10 mg
`each week.. The secondary cohort consisted of 40 subjects weighing >75kg/165lbs who were randomized to
`fixed dose treatment groups receiving final doses of 50 mg and 60 mg ADDERALL XR® or placebo once daily
`in the morning for 4 weeks. The primary efficacy variable was the ADHD-RS-IV total scores for the primary
`cohort. Improvements in the primary cohort were statistically significantly greater in all four primary cohort
`active treatment groups (ADDERALL XR® 10 mg, 20 mg, 30 mg, and 40 mg) compared with the placebo group
`There was not adequate evidence that doses greater than 20 mg/day conferred additional benefit.
`
`Adults
`A double-blind, randomized, placebo-controlled, parallel-group study was conducted in adults (N=255) who met
`DSM-IV-TR criteria for ADHD. Patients were randomized to fixed dose treatment groups receiving final doses
`of 20, 40, or 60 mg of ADDERALL XR® or placebo once daily in the morning for four weeks. Significant
`improvements, measured with the Attention Deficit Hyperactivity Disorder-Rating Scale (ADHD-RS), an 18-
`item scale that measures the core symptoms of ADHD, were observed at endpoint for all ADDERALL XR®
`doses compared to patients who received placebo for all four weeks. There was not adequate evidence that doses
`greater than 20 mg/day conferred additional benefit.
`
`INDICATIONS
`ADDERALL XR® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).
`
`The efficacy of ADDERALL XR® in the treatment of ADHD was established on the basis of two controlled trials
`in children aged 6 to 12, one controlled trial in adolescents aged 13 to 17, and one controlled trial in adults who
`met DSM-IV criteria for ADHD (see CLINICAL PHARMACOLOGY), along with extrapolation from the
`known efficacy of ADDERALL®, the immediate-release formulation of this substance.
`
`A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of hyperactive-
`impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms
`must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be
`present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted
`for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have
`persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor
`listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort;
`4
`
`Amerigen Ex. 1043, p. 4
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`

`
`loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following
`symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate
`running/climbing; difficulty with quiet activities; "on the go;" excessive talking; blurting answers; can't wait turn;
`intrusive. The Combined Type requires both inattentive and hyperactive-impulsive criteria to be met.
`
`Special Diagnostic Considerations: Specific etiology of this syndrome is unknown, and there is no single
`diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational,
`and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete
`history and evaluation of the child and not solely on the presence of the required number of DSM-IV(cid:147)
`characteristics.
`
`Need for Comprehensive Treatment Program: ADDERALL XR® is indicated as an integral part of a total
`treatment program for ADHD that may include other measures (psychological, educational, social) for patients
`with this syndrome. Drug treatment may not be indicated for all children with this syndrome. Stimulants are not
`intended for use in the child who exhibits symptoms secondary to environmental factors and/or other primary
`psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial
`intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant
`medication will depend upon the physician's assessment of the chronicity and severity of the child's symptoms.
`
`Long-Term Use: The effectiveness of ADDERALL XR® for long-term use, i.e., for more than 3 weeks in
`children and 4 weeks in adolescents and adults, has not been systematically evaluated in controlled trials.
`Therefore, the physician who elects to use ADDERALL XR® for extended periods should periodically re-
`evaluate the long-term usefulness of the drug for the individual patient.
`
`CONTRAINDICATIONS
`to severe hypertension,
`Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate
`hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma.
`
`Agitated states.
`
`Patients with a history of drug abuse.
`
`During or within 14 days following the administration of monoamine oxidase inhibitors (hypertensive crises may
`result).
`
`WARNINGS
`Psychosis: Clinical experience suggests that, in psychotic patients, administration of amphetamine may
`exacerbate symptoms of behavior disturbance and thought disorder.
`
`Long-Term Suppression of Growth: Data are inadequate to determine whether chronic use of stimulants in
`children, including amphetamine, may be causally associated with suppression of growth. Therefore, growth
`should be monitored during treatment, and patients who are not growing or gaining weight as expected should
`have their treatment interrupted.
`
`Sudden Death and Pre-existing Structural Cardiac Abnormalities: Sudden death has been reported in
`association with amphetamine treatment at usual doses in children with structural cardiac abnormalities.
`Adderall XR® generally should not be used in children, adolescents, or adults with structural cardiac
`abnormalities.
`
`PRECAUTIONS
`General: The least amount of amphetamine feasible should be prescribed or dispensed at one time in order to
`minimize the possibility of overdosage.
`
`Amerigen Ex. 1043, p. 5
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`5
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`Hypertension: Caution is to be exercised in prescribing amphetamines for patients with even mild hypertension
`(see CONTRAINDICATIONS). Blood pressure and pulse should be monitored at appropriate intervals in
`patients taking ADDERALL XR®, especially patients with hypertension.
`
`Sustained increases in blood pressure should be treated with dose reduction and/or appropriate medication.
`
`In a controlled 4-week outpatient clinical study of adolescents with ADHD, isolated systolic blood pressure
`elevations (cid:116)15 mmHg were observed in 7/64 (11%) placebo-treated patients and 7/100 (7%) patients receiving
`ADDERALL XR(cid:147) 10 or 20 mg. Isolated elevations in diastolic blood pressure (cid:116) 8 mmHg were observed in
`16/64 (25%) placebo-treated patients and 22/100 (22%) ADDERALL XR(cid:147)-treated patients. Similar results were
`observed at higher doses.
`
`In a single-dose pharmacokinetic study in 23 adolescents, isolated increases in systolic blood pressure (above the
`upper 95% CI for age, gender and stature) were observed in 2/17 (12%) and 8/23 (35%), subjects administered
`10 mg and 20 mg ADDERALL XR(cid:147), respectively. Higher single doses were associated with a greater increase
`in systolic blood pressure. All increases were transient, appeared maximal at 2 to 4 hours post dose and not
`associated with symptoms.
`
`Tics: Amphetamines have been reported to exacerbate motor and phonic tics and Tourette’s syndrome.
`Therefore, clinical evaluation for tics and Tourette’s Syndrome in children and their families should precede use
`of stimulant medications.
`
`Effects on Weight: Amphetamines have been associated with decreased appetite. Absolute weight increases in
`treated children over time, but the increases are smaller than expected based on CDC normative values. These
`reductions in expected weight attenuate over time and are greatest in the heaviest children. In the controlled trial
`in adolescents, mean weight change from baseline within the initial 4 weeks of therapy was -1.1 lbs. and –2.8
`lbs., respectively, for patients receiving 10 mg and 20 mg ADDERALL XR(cid:147). Higher doses were associated with
`greater weight loss within the initial 4 weeks of treatment.
`
`Information for Patients: Amphetamines may impair the ability of the patient to engage in potentially
`hazardous activities such as operating machinery or vehicles; the patient should therefore be cautioned
`accordingly.
`
`Drug Interactions: Acidifying agents -Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid
`HCl, ascorbic acid, etc.) lower absorption of amphetamines.
`Urinary acidifying agents -These agents (ammonium chloride, sodium acid phosphate, etc.) increase the
`concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both
`groups of agents lower blood levels and efficacy of amphetamines.
`Adrenergic blockers -Adrenergic blockers are inhibited by amphetamines.
`Alkalinizing agents -Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) increase absorption of
`amphetamines. Co-administration of ADDERALL XR® and gastrointestinal alkalinizing agents, such as antacids,
`should be avoided. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the
`non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents
`increase blood levels and therefore potentiate the actions of amphetamines.
`Antidepressants, tricyclic -Amphetamines may enhance the activity of tricyclic antidepressants or
`sympathomimetic agents; d-amphetamine with desipramine or protriptyline and possibly other tricyclics cause
`striking and sustained increases in the concentration of d-amphetamine in the brain;
`cardiovascular effects can be potentiated.
`MAO inhibitors -MAOI antidepressants, as well as a metabolite of furazolidone, slow amphetamine metabolism.
`This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other
`monoamines from adrenergic nerve endings; this can cause headaches and other signs of hypertensive crisis. A
`variety of toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal results.
`Antihistamines -Amphetamines may counteract the sedative effect of antihistamines.
`Amerigen Ex. 1043, p. 6
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`6
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`Antihypertensives -Amphetamines may antagonize the hypotensive effects of antihypertensives.
`Chlorpromazine -Chlorpromazine blocks dopamine and norepinephrine receptors, thus inhibiting the central
`stimulant effects of amphetamines, and can be used to treat amphetamine poisoning.
`Ethosuximide -Amphetamines may delay intestinal absorption of ethosuximide.
`Haloperidol -Haloperidol blocks dopamine receptors, thus inhibiting the central stimulant effects of
`amphetamines.
`Lithium carbonate -The anorectic and stimulatory effects of amphetamines may be inhibited by lithium
`carbonate.
`Meperidine -Amphetamines potentiate the analgesic effect of meperidine.
`Methenamine therapy -Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying
`agents used in methenamine therapy.
`Norepinephrine -Amphetamines enhance the adrenergic effect of norepinephrine.
`Phenobarbital -Amphetamines may delay intestinal absorption of phenobarbital; co-administration of
`phenobarbital may produce a synergistic anticonvulsant action.
`Phenytoin -Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may
`produce a synergistic anticonvulsant action.
`Propoxyphene -In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal
`convulsions can occur.
`Veratrum alkaloids -Amphetamines inhibit the hypotensive effect of veratrum alkaloids.
`
`Drug/Laboratory Test Interactions: Amphetamines can cause a significant elevation in plasma corticosteroid
`levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations.
`
`Carcinogenesis/Mutagenesis and Impairment of Fertility: 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. These doses are approximately 2.4, 1.5, and 0.8 times, respectively, the maximum recommended
`human dose of 30 mg/day [child] on a mg/m 2 body surface area basis.
`
`Amphetamine, in the enantiomer ratio present in ADDERALL® (immediate-release)(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.
`
`Amphetamine, in the enantiomer ratio present in ADDERALL® (immediate-release)(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 30 mg/day on a mg/m2 body surface area
`basis).
`
`Pregnancy: Pregnancy Category C. Amphetamine, in the enantiomer ratio present in ADDERALL®(d- to l- ratio
`of 3:1), had no apparent effects on embryofetal morphological development or survival when orally administered
`to pregnant rats and rabbits throughout the period of organogenesis at doses of up to 6 and 16 mg/kg/day,
`respectively. These doses are approximately 1.5 and 8 times, respectively, the maximum recommended human
`dose of 30 mg/day [child] 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 50 mg/kg/day (approximately 6 times that
`of a human dose of 30 mg/day [child] 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- or 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.
`
`Amerigen Ex. 1043, p. 7
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`There are no adequate and well-controlled studies in pregnant women. There has been one report of severe
`congenital bony deformity, tracheo-esophageal fistula, and anal atresia (vater association) in a baby born to a
`woman who took dextroamphetamine sulfate with lovastatin during the first trimester of pregnancy.
`Amphetamines should be used during pregnancy only if the potential benefit justifies the potential risk to the
`fetus.
`
`Nonteratogenic Effects: Infants born to mothers dependent on amphetamines have an increased risk of
`premature delivery and low birth weight. Also, these infants may experience symptoms of withdrawal as
`demonstrated by dysphoria, including agitation, and significant lassitude.
`
`Usage in Nursing Mothers: Amphetamines are excreted in human milk. Mothers taking amphetamines should
`be advised to refrain from nursing.
`
`Pediatric Use: ADDERALL XR® is indicated for use in children 6 years of age and older.
`
`Use in Children Under Six Years of Age: Effects of ADDERALL XR® in 3-5 year olds have not been studied.
`Long-term effects of amphetamines in children have not been well established. Amphetamines are not
`recommended for use in children under 3 years of age.
`
`Geriatric Use: ADDERALL XR® has not been studied in the geriatric population.
`
`ADVERSE EVENTS
`The premarketing development program for ADDERALL XR® included exposures in a total of 1315 participants
`in clinical trials (635 pediatric patients, 350 adolescent patients, 248 adult patients, and 82 healthy adult
`subjects). Of these, 635 patients (ages 6 to 12) were evaluated in two controlled clinical studies, and one open-
`label clinical study, and two single-dose clinical pharmacology studies (N= 40). Safety data on all patients are
`included in the discussion that follows. Adverse reactions were assessed by collecting adverse events, results of
`physical examinations, vital signs, weights, laboratory analyses, and ECGs.
`
`Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical
`investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful
`estimate of the proportion of individuals experiencing adverse events without first grouping similar types of
`events into a smaller number of standardized event categories. In the tables and listings that follow, COSTART
`terminology has been used to classify reported adverse events.
`
`The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a
`treatment-emergent adverse event of the type listed.
`
`Adverse events associated with discontinuation of treatment: In two placebo-controlled studies of up to 5
`weeks duration among children with ADHD, 2.4% (10/425) of ADDERALL XR® treated patients discontinued
`due to adverse events (including 3 patients with loss of appetite, one of whom also reported insomnia) compared
`to 2.7% (7/259) receiving placebo. The most frequent adverse events associated with discontinuation of
`ADDERALL XR® in controlled and uncontrolled, multiple-dose clinical trials of pediatric patients (N=595) are
`presented below. Over half of these patients were exposed to ADDERALL XR® for 12 months or more.
`
`
`
`Adverse event
`Anorexia (loss of appetite)
`Insomnia
`
`
`Weight loss
`
`
`Emotional lability
`
`Depression
`
`
`
`
`
`
`
`
`
`
`% of pediatric patients discontinuing (n=595)
`
`2.9
`
`1.5
`
`1.2
`
`1.0
`
`0.7
`
`In a separate placebo-controlled 4-week study in adolescents with ADHD, eight patients (3.4%) discontinued
`8
`
`Amerigen Ex. 1043, p. 8
`
`

`
`treatment due to adverse events among ADDERALL XR®-treated patients (N=233). Three patients discontinued
`due to insomnia and one patient each for depression, motor tics, headaches, light-headedness, and anxiety.
`
`In one placebo-controlled 4-week study among adults with ADHD, patients who discontinued treatment due to
`adverse events among ADDERALL XR®-treated patients (N=191) were 3.1% (n=6) for nervousness including
`anxiety and irritability, 2.6% (n=5) for insomnia, 1% (n=2) each for headache, palpitation, and somnolence; and,
`0.5% (n=1) each for ALT increase, agitation, chest pain, cocaine craving, elevated blood pressure, and weight
`loss.
`
`Adverse events occurring in a controlled trial: Adverse events reported in a 3-week clinical trial of pediatric
`patients and a 4-week clinical trial in adolescents and adults, respectively, treated with ADDERALL XR® or
`placebo are presented in the tables below.
`
`The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the
`course of usual medical practice where patient characteristics and other factors differ from those which prevailed
`in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical
`investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the
`prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the
`adverse event incidence rate in the population studied.
`
`Table 1 Adverse Events Reported by More Than 1% of Pediatric Patients Receiving ADDERALL
`XR® with Higher Incidence Than on Placebo in a 584 Patient Clinical Study
`
`Body System
`
`General
`
`Digestive System
`
`Nervous System
`
`Metabolic/Nutritional
`
`Preferred Term
`
`Abdominal Pain (stomachache)
`Accidental Injury
`Asthenia (fatigue)
`Fever
`Infection
`Viral Infection
`Loss of Appetite
`Diarrhea
`Dyspepsia
`Nausea
`Vomiting
`Dizziness
`Emotional Lability
`Insomnia
`Nervousness
`Weight Loss
`
`ADDERALL XR®
`(n=374)
`14%
`3%
`2%
`5%
`4%
`2%
`22%
`2%
`2%
`5%
`7%
`2%
`9%
`17%
`6%
`4%
`
`Placebo
`(n=210)
`10%
`2%
`0%
`2%
`2%
`0%
`2%
`1%
`1%
`3%
`4%
`0%
`2%
`2%
`2%
`0%
`
`Table 2 Adverse Events Reported by 5% or more of Adolescents Weighing (cid:100) 75 kg/165 lbs
`Receiving ADDERALL XR® with Higher Incidence Than Placebo in a 287 Patient Clinical
`Forced Weekly-Dose Titration Study*
`
`Body System
`
`Preferred Term
`
`General
`
`Digestive System
`
`Nervous System
`
`Metabolic/Nutritional
`a Appears the same due to rounding
`b Dose-related adverse events
`
`Abdominal Pain (stomachache)
`
`Loss of Appetite b
`
`Insomnia b
`Nervousness
`
`Weight