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`ADDERALL® CII
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`Confidential
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`Rx ONLY
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`AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. ADMINISTRATION OF
`AMPHETAMINES FOR PROLONGED PERIODS OF TIME MAY LEAD TO DRUG
`DEPENDENCE AND MUST BE AVOIDED. 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:
`A single entity amphetamine product combining the neutral sulfate salts of dextroamphetamine and
`amphetamine, with the dextro isomer of amphetamine saccharate and d, l-amphetamine aspartate
`monohydrate.
`
`EACH TABLET CONTAINS:
`30 mg
`20mg
`15 mg
`12.5 mg
`10 mg
`7.5 mg
`5 mg
`7.5 mg
`1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg
`Dextroamphetamine Saccharate
`7.5 mg
`Amphetamine Aspartate Monohydrate1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg
`7.5 mg
`Dextroamphetamine Sulfate USP
`1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg
`7.5 mg
`Amphetamine Sulfate USP
`1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg
`Total amphetamine base equivalence 3.13 mg 4.7 mg
`6.3 mg 7.8 mg
`9.4 mg
`12.6 mg 18.8 mg
`
`Inactive Ingredients: lactitol, microcrystalline cellulose, colloidal silicon dioxide, and magnesium
`stearate, and other ingredients.
`
`Colors: ADDERALL® 5 mg is a white to off-white tablet, which contains no color additives.
` ADDERALL® 7.5 mg and 10 mg contain FD & C Blue #1.
` ADDERALL® 12.5 mg, 15 mg, 20 mg and 30 mg contain FD & C Yellow #6 as a color
` additive.
`
`CLINICAL PHARMACOLOGY:
`Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity.
`Peripheral actions include elevation of systolic and diastolic blood pressures and weak bronchodilator
`and respiratory stimulant action.
`
`There is neither specific evidence which clearly establishes the mechanism whereby amphetamine
`produces mental and behavioral effects in children, nor conclusive evidence regarding how these
`effects relate to the condition of the central nervous system.
`
`Pharmacokinetics
`ADDERALL® tablets contain d-amphetamine and l-amphetamine salts in the ratio of 3:1. Following
`administration of a single dose 10 or 30 mg of ADDERALL® to healthy volunteers under fasted
`conditions, peak plasma concentrations occurred approximately 3 hours post-dose for both d-
`amphetamine and l-amphetamine. The mean elimination half-life (t1/2 ) for d-amphetamine was
`shorter than the t1/2 of the l-isomer (9.77-11 hours vs. 11.5-13.8 hours). The PK parameters (Cmax,
`AUC0-inf) of d-and l-amphetamine increased approximately three-fold from 10 mg to 30 mg indicating
`dose-proportional pharmacokinetics.
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`KVK-TECH EXHIBIT 1032
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`Confidential
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`NDA 11-522
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`The effect of food on the bioavailability of ADDERALL® has not been studied.
`
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`INDICATIONS:
`Attention Deficit Disorder with Hyperactivity: ADDERALL® is indicated as an integral part of a
`total
`treatment program which
`typically
`includes other remedial measures (psychological,
`educational, social) for a stabilizing effect in children with behavioral syndrome characterized by the
`following group of developmentally inappropriate symptoms: moderate to severe distractibility, short
`attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome
`should not be made with finality when these symptoms are only of comparatively recent origin.
`Nonlocalizing (soft) neurological signs, learning disability and abnormal EEG may or may not be
`present, and a diagnosis of central nervous system dysfunction may or may not be warranted.
`
`In Narcolepsy
`
`CONTRAINDICATIONS:
`Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension,
`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 children, administration of amphetamine
`may exacerbate symptoms of behavior disturbance and thought disorder.
`
`Long-Term Suppression of Growth: Data are inadequate to determine whether chronic
`administration of amphetamine may be associated with growth inhibition; therefore, growth should be
`monitored during treatment.
`
`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 generally should not be used in children or adults with structural cardiac
`abnormalities.
`
`Usage in Nursing Mothers: Amphetamines are excreted in human milk. Mothers taking
`amphetamines should be advised to refrain from nursing.
`
`PRECAUTIONS:
`General: The least amount feasible should be prescribed or dispensed at one time in order to
`minimize the possibility of overdosage.
`
`Hypertension: Caution is to be exercised in prescribing amphetamines for patients with even mild
`hypertension. Blood pressure and pulse should be monitored at appropriate intervals in patients
`taking Adderall, especially patients with hypertension.
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`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, fruit juices, etc.) lower absorption of amphetamines.
`Urinary acidifying 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 blocker -Adrenergic blockers are inhibited by amphetamines.
`Alkalinizing agents -Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) increase
`absorption of amphetamines. 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 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 neurological toxic effects and malignant hyperpyrexia
`can occur, sometimes with fatal results.
`Antihistamines -Amphetamines may counteract the sedative effect of antihistamines.
`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.
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`Carcinogenesis/Mutagenesis: Mutagenicity studies and long-term studies in animals to determine
`the carcinogenic potential of amphetamine, have not been performed.
`
`Pregnancy - Teratogenic Effects: Pregnancy Category C. Amphetamine has been shown to have
`embryotoxic and teratogenic effects when administered to A/Jax mice and C57BL mice in doses
`approximately 41 times the maximum human dose. Embryotoxic effects were not seen in New
`Zealand white rabbits given the drug in doses 7 times the human dose nor in rats given 12.5 times the
`maximum human dose. While there are no adequate and well-controlled studies in pregnant women,
`there has been one report of severe congenital bony deformity, tracheoesophageal 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.
`
`Pediatric Use: 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 with Attention Deficit
`Disorder with Hyperactivity described under INDICATIONS AND USAGE.
`
`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.
`
`Drug treatment is not indicated in all cases of Attention Deficit Disorder with Hyperactivity and
`should be considered only in light of the complete history and evaluation of the child. The decision to
`prescribe amphetamines should depend on the physician’s assessment of the chronicity and severity
`of the child’s symptoms and their appropriateness for his/her age. Prescription should not depend
`solely on the presence of one or more of the behavioral characteristics. When these symptoms are
`associated with acute stress reactions, treatment with amphetamines is usually not indicated.
`
`ADVERSE REACTIONS:
`Cardiovascular: Palpitations, tachycardia, elevation of blood pressure, sudden death, myocardial
`infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine
`use.
`
`Central Nervous System: Psychotic episodes at recommended doses (rare), overstimulation,
`restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, depression, tremor, headache,
`exacerbation of motor and phonic tics and Tourette’s syndrome, seizures, stroke.
`
`Gastrointestinal: Dryness of
`taste, diarrhea, constipation, other
`the mouth, unpleasant
`gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects when
`amphetamines are used for other than the anorectic effect.
`
`Allergic: Urticaria.
`
`Endocrine: Impotence, changes in libido.
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`DRUG ABUSE AND DEPENDENCE:
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`Dextroamphetamine Sulfate, Amphetamine Sulfate, Amphetamine Aspartate Monohydrate, and
`Dextroamphetamine Saccharate are Schedule II controlled substance. Amphetamines have been
`extensively abused. Tolerance, extreme psychological dependence, and severe social disability have
`occurred. There are reports of patients who have increased the dosage to many times than
`recommended. Abrupt cessation following prolonged high dosage administration results in extreme
`fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic
`intoxication with amphetamines
`include severe dermatoses, marked
`insomnia,
`irritability,
`hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is
`psychosis, often clinically indistinguishable from schizophrenia. This is rare with oral amphetamines.
`
`OVERDOSAGE:
`Individual patient response to amphetamines varies widely. While toxic symptoms occasionally occur
`as an idiosyncrasy at doses as low as 2 mg, they are rare with doses of less than 15 mg; 30 mg can
`produce severe reactions, yet doses of 400 to 500 mg are not necessarily fatal.
`
`In rats, the oral LD50 of dextroamphetamine sulfate is 96.8 mg/kg.
`
`Symptoms: Manifestations of acute overdosage with amphetamines include restlessness, tremor,
`hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, panic states, hyperpyrexia
`and rhabdomyolysis.
`
`Fatigue and depression usually follow the central stimulation.
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`Cardiovascular effects include arrhythmias, hypertension or hypotension and circulatory collapse.
`
`Gastrointestinal symptoms include nausea, vomiting, diarrhea, and abdominal cramps. Fatal
`poisoning is usually preceded by convulsions and coma.
`
`Treatment: Consult with a Certified Poison Control Center for up to date guidance and advice.
`Management of acute amphetamine intoxication is largely symptomatic and includes gastric lavage,
`administration of activated charcoal, administration of a cathartic and sedation. Experience with
`hemodialysis or peritoneal dialysis is inadequate to permit recommendation in this regard.
`Acidification of the urine increases amphetamine excretion, but is believed to increase risk of acute
`renal failure if myoglobinuria is present. If acute, severe hypertension complicates amphetamine
`overdosage, administration of intravenous phentolamine has been suggested. However, a gradual drop
`in blood pressure will usually result when sufficient sedation has been achieved. Chlorpromazine
`antagonizes the central stimulant effects of amphetamines and can be used to treat amphetamine
`intoxication.
`
`DOSAGE AND ADMINISTRATION:
`Regardless of indication, amphetamines should be administered at the lowest effective dosage and
`dosage should be individually adjusted. Late evening doses should be avoided because of the
`resulting insomnia.
`
`Attention Deficit Disorder with Hyperactivity: Not recommended for children under 3 years of
`age. In children from 3 to 5 years of age, start with 2.5 mg daily; daily dosage may be raised in
`increments of 2.5 mg at weekly intervals until optimal response is obtained.
`
`In children 6 years of age and older, start with 5 mg once or twice daily; daily dosage may be raised
`in increments of 5 mg at weekly intervals until optimal response is obtained. Only in rare cases will it
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`be necessary to exceed a total of 40 mg per day. Give first dose on awakening; additional doses (1 or
`2) at intervals of 4 to 6 hours.
`
`Where possible, drug administration should be interrupted occasionally to determine if there is a
`recurrence of behavioral symptoms sufficient to require continued therapy.
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`Narcolepsy: Usual dose 5 mg to 60 mg per day in divided doses, depending on the individual patient
`response.
`
`Narcolepsy seldom occurs in children under 12 years of age; however, when it does,
`dextroamphetamine sulfate may be used. The suggested initial dose for patients aged 6-12 is 5 mg
`daily; daily dose may be raised in increments of 5 mg at weekly intervals until optimal response is
`obtained. In patients 12 years of age and older, start with 10 mg daily; daily dosage may be raised in
`increments of 10 mg at weekly intervals until optimal response is obtained. If bothersome adverse
`reactions appear (e.g., insomnia or anorexia), dosage should be reduced. Give first dose on
`awakening; additional doses (1 or 2) at intervals of 4 to 6 hours.
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`HOW SUPPLIED:
`ADDERALL® 5 mg: A round, flat-faced beveled edge, white to off-white tablet, “5” embossed on
`one side with partial bisect and “AD” embossed on the other side (NDC 54092-371-01)
`
`ADDERALL® 7.5 mg: An oval, convex, blue tablet, “7.5” embossed on one side with a partial bisect
`and “AD” embossed on the other side with a full and partial bisect (NDC 54092-372-01)
`
`ADDERALL® 10 mg: A round, convex, blue tablet, “10” embossed on one side with a full and partial
`bisect and “AD” embossed on the other side (NDC 54092-373-01)
`
`ADDERALL® 12.5 mg: A round, flat-faced beveled edge, orange tablet, “12.5” embossed on one side
`and “AD” embossed on the other side with a full and partial bisect (NDC 54092-374-01)
`
`ADDERALL® 15 mg: An oval, convex, orange tablet, “15” embossed on one side with a partial
`bisect and “AD” embossed on the other side with a full and partial bisect (NDC 54092-375-01)
`
`ADDERALL® 20 mg: A round, convex, orange tablet, “20” embossed on one side with a full and
`partial bisect and “AD” embossed on the other side (NDC 54092-376-01)
`
`ADDERALL® 30 mg: A round, flat-faced beveled edge, orange tablet, “30” embossed on one side
`with a full and partial bisect and “AD” embossed on the other side (NDC 54092-377-01)
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`In bottles of 100 tablets.
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`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) [see USP Controlled Room
`Temperature]
`
`Rx only.
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`MG #XXXXX
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`Revised: 06/05
`371 0107 004
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`Confidential
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`Shire US Inc.
`725 Chesterbrook Blvd.
`Wayne, PA 19087
`DSM Pharmaceuticals Inc.
`5900 NW Greenville Blvd.
`Greenville, NC 27834
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`NDA 11-522
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`Manufactured for:
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`Manufactured by:
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`Made in USA
`1-800-828-2088
`©2005 Shire US Inc.
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