Dextroamphetamine Sulfate, Dextroamphetamine Saccharate, Amphetamine Sulfate and Amphetamine Aspartate

ADDERALL XR, a CNS stimulant, is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years and older. ( 1 ) Limitations of Use The use of ADDERALL XR is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage. ( 5.5 , 8.4 )

1.1 Attention Deficit Hyperactivity Disorder ADDERALL XR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years and older. Limitations of Use The use of ADDERALL XR is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g., weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.4 )].

ADDERALL XR 5 mg extended-release capsules: Clear/blue (imprinted ADDERALL XR 5 mg) ADDERALL XR 10 mg extended-release capsules: Blue/blue (imprinted ADDERALL XR 10 mg) ADDERALL XR 15 mg extended-release capsules: Blue/white (imprinted ADDERALL XR 15 mg) ADDERALL XR 20 mg extended-release capsules: Orange/orange (imprinted ADDERALL XR 20 mg) ADDERALL XR 25 mg extended-release capsules: Orange/white (imprinted ADDERALL XR 25 mg) ADDERALL XR 30 mg extended-release capsules: Natural/orange (imprinted ADDERALL XR 30 mg) Extended-release capsules: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg ( 3 )

ADDERALL XR administration is contraindicated in patients: known to be hypersensitive to amphetamine, or other components of ADDERALL XR. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other amphetamine products [see Adverse Reactions ( 6.2 )] . taking monoamine oxidase inhibitors (MAOIs), or within 14 days of stopping MAOIs (including MAOIs such as linezolid or intravenous methylene blue), because of an increased risk of hypertensive crisis [see Warnings and Precautions ( 5.8 ), Drug Interactions ( 7.1 )]. Known hypersensitivity or idiosyncrasy to amphetamine. ( 4 ) During or within 14 days following the administration of monoamine oxidase inhibitors (MAOI). ( 4 , 7.1 )

Risks to Patients with Serious Cardiac Disease: Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. ( 5.2 ) Increased Blood Pressure and Heart Rate: Monitor blood pressure and pulse at appropriate intervals. ( 5.3 ) Psychiatric Adverse Reactions: Prior to initiating ADDERALL XR, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing ADDERALL XR. ( 5.4 ) Long-Term Suppression of Growth in Pediatric Patients: Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. ( 5.5 ) Seizures: May lower the convulsive threshold. Discontinue in the presence of seizures. ( 5.6 ) Peripheral Vasculopathy, including Raynaud’s Phenomenon: Careful observation for digital changes is necessary during ADDERALL XR treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy. ( 5.7 ) Serotonin Syndrome: Increased risk when coadministered with serotonergic agents (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans), but also during overdosage situations. If it occurs, discontinue ADDERALL XR and initiate supportive treatment. ( 4 , 5.8 , 10 ) Motor and Verbal Tics, and Worsening of Tourette’s Syndrome: Before initiating ADDERALL XR, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome. Discontinue treatment if clinically appropriate. ( 5.9 )

5.1 Abuse, Misuse, and Addiction ADDERALL XR has a high potential for abuse and misuse. The use of ADDERALL XR exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. ADDERALL XR can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence ( 9.2 )] . Misuse and abuse of CNS stimulants, including ADDERALL XR, can result in overdose and death [see Overdosage ( 10 )] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing ADDERALL XR, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store ADDERALL XR in a safe place, preferably locked, and instruct patients to not give ADDERALL XR to anyone else. Throughout ADDERALL XR treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

5.2 Risks to Patients with Serious Cardiac Disease Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage. Avoid ADDERALL XR use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

5.3 Increased Blood Pressure and Heart Rate CNS stimulants may cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Monitor all ADDERALL XR-treated patients for hypertension and tachycardia.

5.4 Psychiatric Adverse Reactions Exacerbation of Pre-Existing Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disease CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating ADDERALL XR treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression). New Psychotic or Manic Symptoms CNS stimulants, at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing ADDERALL XR.

5.5 Long-Term Suppression of Growth in Pediatric Patients ADDERALL XR is not approved for use and is not recommended in pediatric patients below 6 years of age [see Use in Specific Populations ( 8.4 )]. CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in ADDERALL XR-treated pediatric patients treated with CNS stimulants. In a controlled trial of ADDERALL XR 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. Higher doses were associated with greater weight loss within the initial 4 weeks of treatment. Chronic use of amphetamines can be expected to cause a similar suppression of growth [see Adverse Reactions ( 6.1 )] . Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted.

5.6 Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in the absence of seizures, and very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, ADDERALL XR should be discontinued.

5.7 Peripheral Vasculopathy, including Raynaud’s Phenomenon CNS stimulants, including ADDERALL XR, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports and at the therapeutic dosage of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant. Careful observation for digital changes is necessary during ADDERALL XR treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for ADDERALL XR-treated patients who develop signs or symptoms of peripheral vasculopathy.

5.8 Serotonin Syndrome Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are used in combination with other drugs that affect the serotonergic neurotransmitter systems such as MAOIs, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort [see Drug Interactions ( 7.1 )] . Amphetamines and amphetamine derivatives are known to be metabolized, to some degree, by cytochrome P450 2D6 (CYP2D6) and display minor inhibition of CYP2D6 metabolism [see Clinical Pharmacology ( 12.3 )] . The potential for a pharmacokinetic interaction exists with the coadministration of CYP2D6 inhibitors which may increase the risk with increased exposure to ADDERALL XR. In these situations, consider an alternative nonserotonergic drug or an alternative drug that does not inhibit CYP2D6 [see Drug Interactions ( 7.1 )] . […]

The following adverse reactions are discussed in greater detail in other sections of the labeling: Abuse, Misuse, and Addiction [see Boxed Warning , Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.2 , 9.3 )] Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions ( 5.2 )] Increased Blood Pressure and Heart Rate [see Warnings and Precautions ( 5.3 )] Psychiatric Adverse Reactions [see Warnings and Precautions ( 5.4 )] Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions ( 5.5 )] Seizures [see Warnings and Precautions ( 5.6 )] Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions ( 5.7 )] Serotonin Syndrome [see Warnings and Precautions ( 5.8 )] Motor and Verbal Tics, and Worsening of Tourette’s Syndrome [see Warnings and Precautions ( 5.9 )] Pediatric patients ages 6 to 12: Most common adverse reactions (≥5% and with a higher incidence than on placebo) were loss of appetite, insomnia, abdominal pain, emotional lability, vomiting, nervousness, nausea, and fever. ( 6.1 ) Pediatric patients ages 13 to 17: Most common adverse reactions (≥5% and with a higher incidence than on placebo) were loss of appetite, insomnia, abdominal pain, weight loss, and nervousness. ( 6.1 ) Adults: Most common adverse reactions (≥5% and with a higher incidence than on placebo) were dry mouth, loss of appetite, insomnia, headache, weight loss, nausea, anxiety, agitation, dizziness, tachycardia, diarrhea, asthenia, and urinary tract infections. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The premarketing development program for ADDERALL XR included exposures in a total of 1,315 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, 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 reactions, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs. Adverse reactions 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 reactions without first grouping similar types of reactions into a smaller number of standardized event categories. In the tables and listings that follow, COSTART terminology has been used to classify reported adverse reactions. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. Adverse Reactions Leading to 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 reactions (including three patients with loss of appetite, one of whom also reported insomnia) compared to 2.7% (7/259) receiving placebo. The most frequent adverse reactions leading to discontinuation of ADDERALL XR in controlled and uncontrolled, multiple-dose clinical trials of children (N=595) were anorexia (loss of appetite) (2.9%), insomnia (1.5%), weight loss (1.2%), emotional lability (1%), and depression (0.7%). Over half of these patients were exposed to ADDERALL XR for 12 months or more. In a separate placebo-controlled 4-week study in adolescents with ADHD, five patients (2.1%) discontinued treatment due to adverse events among ADDERALL XR-treated patients (N=233) compared to none who received placebo (N=54). The most frequent adverse event leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of ADDERALL XR-treated patients and at a rate at least twice that of placebo) was insomnia (1.3%, n=3). In one placebo-controlled 4-week study among adults with ADHD with doses 20 to 60 mg, 23 patients (12.0%) discontinued treatment due to adverse events among ADDERALL XR-treated patients (N=191) compared to one patient (1.6%) who received placebo (N=64). The most frequent adverse events leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of ADDERALL XR-treated patients and at a rate at least twice that of placebo) were insomnia (5.2%, n=10), anxiety (2.1%, n=4), nervousness (1.6%, n=3), dry mouth (1.6%, n=3), anorexia (1.6%, n=3), tachycardia (1.6%, n=3), headache (1.6%, n=3), and asthenia (1.0%, n=2). Adverse Reactions Occurring in Controlled Trials Adverse reactions reported in a 3-week clinical trial of children and a 4-week clinical trial in adolescents and adults, respectively, treated with ADDERALL XR or placebo are presented in the tables below. Table 1: Adverse Reactions Reported by 2% or More of Children (6 to 12 Years Old) Receiving ADDERALL XR with Higher Incidence than on Placebo in a 584 Patient Clinical Study Body System Preferred Term ADDERALL XR (n=374) Placebo (n=210) General Abdominal Pain (stomachache) Fever Infection Accidental Injury Asthenia (fatigue) 14% 5% 4% 3% 2% 10% 2% 2% 2% 0% Digestive System Loss of Appetite Vomiting Nausea Dyspepsia 22% 7% 5% 2% 2% 4% 3% 1% Nervous System Insomnia Emotional Lability Nervousness Dizziness 17% 9% 6% 2% 2% 2% 2% 0% Metabolic/Nutritional Weight Loss 4% 0% Table 2: Adverse Reactions Reported by 5% or More of Adolescents (13 to 17 Years Old) Weighing ≤75 kg/165 lbs Receiving ADDERALL XR with Higher Incidence than Placebo in a 287 Patient Clinical Forced Weekly-Dose Titration Study Included doses up to 40 mg. Body System Preferred Term ADDERALL XR (n=233) Placebo (n=54) Note: The following reactions did not meet the criterion for inclusion in Table 2 but were reported by 2 to 4% of adolescent patients receiving ADDERALL XR with a higher incidence than patients receiving placebo in this study: accidental injury, asthenia (fatigue), dry mouth, dyspepsia, emotional lability, nausea, somnolence, and vomiting. General Abdominal Pain (stomachache) 11% 2% Digestive System Loss of Appetite Dose-related adverse reactions. 36% 2% Nervous System Insomnia 12% 4% Nervousness 6% 6% Appears the same due to rounding. Metabolic/Nutritional Weight Loss 9% 0% Table 3: Adverse Reactions Reported by 5% or More of Adults Receiving ADDERALL XR with Higher Incidence than on Placebo in a 255 Patient Clinical Forced Weekly-Dose Titration Study Included doses up to 60 mg. Body System Preferred Term ADDERALL XR (n=191) Placebo (n=64) Note: The following reactions did not meet the criterion for inclusion in Table 3 but were reported by 2 to 4% of adult patients receiving ADDERALL XR with a higher incidence than patients receiving placebo in this study: infection, photosensitivity reaction, constipation, tooth disorder (e.g., teeth clenching, tooth infection), emotional lability, libido decreased, somnolence, speech disorder (e.g., stuttering, excessive speech), palpitation, twitching, dyspnea, sweating, dysmenorrhea, and impotence. General Headache Asthenia 26% 6% 13% 5% Digestive System Dry Mouth Loss of Appetite Nausea Diarrhea 35% 33% 8% 6% 5% 3% 3% 0% Nervous System Insomnia Agitation Anxiety Dizziness Nervousness 27% 8% 8% 7% 13% 13% 5% 5% 0% 13% Appears the same due to rounding. […]

Alkalinizing agents (GI antacids and urinary): These agents increase blood levels of amphetamine. ( 2.7 , 7.1 ) Acidifying agents (GI and urinary): These agents reduce blood levels of amphetamine. ( 7.1 )

7.1 Clinically Important Interactions with Amphetamines Table 4: Drugs Having Clinically Important Interactions with Amphetamines Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact 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. Intervention Do not administer ADDERALL XR concomitantly or within 14 days after discontinuing MAOI [see Contraindications ( 4 )] . Serotonergic Drugs Clinical Impact The concomitant use of ADDERALL XR and serotonergic drugs increases the risk of serotonin syndrome. Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during ADDERALL XR initiation or dosage increase. If serotonin syndrome occurs, discontinue ADDERALL XR and the concomitant serotonergic drug(s) [see Warnings and Precautions ( 5.8 )] . CYP2D6 Inhibitors Clinical Impact The concomitant use of ADDERALL XR and CYP2D6 inhibitors may increase the exposure of ADDERALL XR compared to the use of the drug alone and increase the risk of serotonin syndrome. Intervention Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during ADDERALL XR initiation and after a dosage increase. If serotonin syndrome occurs, discontinue ADDERALL XR and the CYP2D6 inhibitor [see Warnings and Precautions ( 5.8 ), Overdosage ( 10 )] . Alkalinizing Agents Clinical Impact Increase blood levels and potentiate the action of amphetamine. Intervention Coadministration of ADDERALL XR and gastrointestinal or urinary alkalinizing agents should be avoided. Acidifying Agents Clinical Impact Lower blood levels and efficacy of amphetamines. Intervention Increase dose based on clinical response. Tricyclic Antidepressants Clinical Impact May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. Intervention Monitor frequently and adjust or use alternative therapy based on clinical response. Proton Pump Inhibitors Clinical Impact Time to maximum concentration (T max ) of amphetamine is decreased compared to when administered alone. Intervention Monitor patients for changes in clinical effect and adjust therapy based on clinical response.

7.2 Interference with Laboratory Tests Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations. Allow for an adequate washout period between administration of ADDERALL XR and radioactive diagnostic agents used for dopamine transporter (DAT) visualization. ADDERALL XR can interfere with the test results of a radioactive diagnostic agent (ioflupane I-123) that is used for DAT visualization by binding and internalization of the DAT, which may result in lower DAT in the striatum. This may lead to false-positive diagnostic results.

Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Breastfeeding not recommended. ( 8.2 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADDERALL XR during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/ . Risk Summary Available data from published epidemiologic studies and postmarketing reports on use of prescription amphetamine in pregnant women have not identified a drug-associated risk of major birth defects and miscarriage (see Data ) . Adverse pregnancy outcomes, including premature delivery and low birth weight, have been seen in infants born to mothers taking amphetamines during pregnancy (see Clinical Considerations ) . No apparent effects on morphological development were observed in embryo-fetal development studies, with oral administration of amphetamine to rats and rabbits during organogenesis at doses 2 and 12 times, respectively, the maximum recommended human dose (MRHD) of 20 mg/day given to adolescents, on a mg/m 2 basis. However, in a pre- and postnatal development study, amphetamine (d- to l- ratio of 3:1) administered orally to pregnant rats during gestation and lactation caused a decrease in pup survival and a decrease in pup body weight that correlated with a delay in developmental landmarks at clinically relevant doses of amphetamine. In addition, adverse effects on reproductive performance were observed in pups whose mothers were treated with amphetamine. Long-term neurochemical and behavioral effects have also been reported in animal developmental studies using clinically relevant doses of amphetamine (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Amphetamines, such as ADDERALL XR, cause vasoconstriction and thereby may decrease placental perfusion. In addition, amphetamines can stimulate uterine contractions, increasing the risk of premature delivery. Infants born to mothers taking amphetamines during pregnancy have an increased risk of premature delivery and low birth weight. Monitor infants born to mothers taking amphetamines for symptoms of withdrawal such as feeding difficulties, irritability, agitation, and excessive drowsiness. Data Animal Data Amphetamine (d- to l- enantiomer ratio of 3:1) had no apparent effects on embryofetal morphological development or survival when administered orally 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 2 and 12 times, respectively, the maximum recommended human dose (MRHD) of 20 mg/day given to adolescents, on a mg/m 2 basis. Fetal malformations and death have been reported in mice following parenteral administration of d-amphetamine doses of 50 mg/kg/day (approximately 10 times the MRHD given to adolescents on a mg/m 2 basis) or greater to pregnant animals. Administration of these doses was also associated with severe maternal toxicity. A study was conducted in which pregnant rats received daily oral doses of amphetamine (d- to l- enantiomer ratio of 3:1) of 2, 6, and 10 mg/kg from gestation Day 6 to lactation Day 20. These doses are approximately 0.8, 2, and 4 times the MRHD of 20 mg/day given to adolescents, on a mg/m 2 basis. All doses caused hyperactivity and decreased weight gain in the dams. A decrease in pup survival was seen at all doses. A decrease in pup body weight was seen at 6 and 10 mg/kg which correlated with delays in developmental landmarks, such as preputial separation and vaginal opening. Increased pup locomotor activity was seen at 10 mg/kg on Day 22 postpartum but not at 5 weeks postweaning. When pups were tested for reproductive performance at maturation, gestational weight gain, number of implantations, and number of delivered pups were decreased in the group whose mothers had been given 10 mg/kg. A number of studies from the literature 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.

8.2 Lactation Risk Summary Based on limited case reports in published literature, amphetamine (d- or d, l-) is present in human milk, at relative infant doses of 2 to 13.8% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.9 and 7.5. There are no reports of adverse effects on the breastfed infant. Long-term neurodevelopmental effects on infants from amphetamine exposure are unknown. It is possible that large dosages of amphetamine might interfere with milk production, especially in women whose lactation is not well established. Because of the potential for serious adverse reactions in nursing infants, advise patients that breastfeeding is not recommended during treatment with ADDERALL XR.

8.4 Pediatric Use The safety and effectiveness of ADDERALL XR have not been established in pediatric patients less than 6 years of age. The safety and effectiveness of ADDERALL XR have been established in pediatric patients with ADHD 6 years of age and older. In studies evaluating extended-release amphetamine products, patients 4 to <6 years of age had higher systemic amphetamine exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss. Long-Term Growth Suppression Growth should be monitored during treatment with stimulants, including ADDERALL XR, and pediatric patients aged 6 to 17 years who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions ( 5.5 )] . Juvenile Animal Toxicity Data Juvenile rats treated with mixed amphetamine salts early in the postnatal period through sexual maturation demonstrated transient changes in motor activity. Learning and memory was impaired at approximately 6 times the maximum recommended human dose (MRHD) given to children on a mg/m 2 basis. No recovery was seen following a drug-free period. A delay in sexual maturation was observed at a dose approximately 6 times the MRHD given to children on a mg/m 2 basis, although there was no effect on fertility. In a juvenile developmental study, rats received daily oral doses of amphetamine (d to l enantiomer ratio of 3:1) of 2, 6, or 20 mg/kg on Days 7 to 13 of age; from Day 14 to approximately Day 60 of age these doses were given b.i.d. for total daily doses of 4, 12, or 40 mg/kg. The latter doses are approximately 0.6, 2, and 6 times the MRHD of 30 mg/day, given to children on a mg/m 2 basis. Postdosing hyperactivity was seen at all doses; motor activity measured prior to the daily dose was decreased during the dosing period but the decreased motor activity was largely absent after an 18 day drug-free recovery period. Performance in the Morris water maze test for learning and memory was impaired at the 40 mg/kg dose, and sporadically at the lower doses, when measured prior to the daily dose during the treatment period; no recovery was seen after a 19 day drug-free period. A delay in the developmental milestones of vaginal opening and preputial separation was seen at 40 mg/kg but there was no effect on fertility. […]

Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The mode of therapeutic action in ADHD is not known.