Adderall

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, overstimulation, restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, tics, aggression, anger, logorrhea, dermatillomania. Eye Disorders Vision blurred, mydriasis. Gastrointestinal Dryness of the mouth, unpleasant taste, diarrhea, constipation, intestinal ischemia and other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects. Allergic Urticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Endocrine Impotence, changes in libido, frequent or prolonged erections. Skin Alopecia. Musculoskeletal Rhabdomyolysis. To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CONTRAINDICATIONS In patients known to be hypersensitive to amphetamine, or other components of Adderall ® . Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other amphetamine products [see ADVERSE REACTIONS ]. Patients 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 DRUG INTERACTIONS ].

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. EACH TABLET CONTAINS 5 mg 7.5 mg 10 mg 12.5 mg 15 mg 20 mg 30 mg Dextroamphetamine Saccharate 1.25 mg 1.875 mg 2.5 mg 3.125 mg 3.75 mg 5 mg 7.5 mg Amphetamine Aspartate Monohydrate Equivalent 1.25 mg 1 1.875 mg 2 2.5 mg 3 3.125 mg 4 3.75 mg 5 5 mg 6 7.5 mg 7 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 7.5 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 1 1.25 mg of Amphetamine Aspartate Monohydrate equivalent to 1.17 mg Amphetamine Aspartate (Anhydrous) as supplied 2 1.875 mg of Amphetamine Aspartate Monohydrate equivalent to 1.755 mg Amphetamine Aspartate (Anhydrous) as supplied 3 2.5 mg of Amphetamine Aspartate Monohydrate equivalent to 2.34 mg Amphetamine Aspartate (Anhydrous) as supplied 4 3.125 mg of Amphetamine Aspartate Monohydrate equivalent to 2.925 mg Amphetamine Aspartate (Anhydrous) as supplied 5 3.75 mg of Amphetamine Aspartate Monohydrate equivalent to 3.51 mg Amphetamine Aspartate (Anhydrous) as supplied 6 5 mg of Amphetamine Aspartate Monohydrate equivalent to 4.6 mg Amphetamine Aspartate (Anhydrous) as supplied 7 7.5 mg of Amphetamine Aspartate Monohydrate equivalent to 7.03 mg Amphetamine Aspartate (Anhydrous) as supplied Inactive Ingredients: colloidal silicon dioxide, compressible sugar, corn starch, magnesium stearate, microcrystalline cellulose and saccharin sodium. 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 Aluminum Lake as a color additive. Adderall ® 12.5 mg, 15 mg, 20 mg and 30 mg contain FD&C Yellow #6 Aluminum Lake as a color additive.

DOSAGE AND ADMINISTRATION Regardless of indication, amphetamines should be administered at the lowest effective dosage, and dosage should be individually adjusted according to the therapeutic needs and response of the patient. Late evening doses should be avoided because of the resulting insomnia. Attention Deficit Hyperactivity Disorder 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 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. Prior to treating patients with Adderall ® assess: for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) (see WARNINGS ). the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating Adderall ® (see WARNINGS ) . 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 to 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.

INDICATIONS AND USAGE Adderall ® (Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets (Mixed salts of a single entity amphetamine product)) is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and Narcolepsy. Attention Deficit Hyperactivity Disorder (ADHD) 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; 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.

WARNINGS Abuse, Misuse, and Addiction Adderall ® has a high potential for abuse and misuse. The use of Adderall ® exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Adderall ® can be diverted for non-medical use into illicit channels or distribution (see DRUG ABUSE and DEPENDENCE : Abuse). Misuse and abuse of CNS stimulants, including Adderall ® , can result in overdose and death (see OVERDOSAGE ), and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing Adderall ® 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 amphetamine sulfate in a safe place, preferably locked, and instruct patients to not give Adderall ® to anyone else. Throughout Adderall ® treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction. 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 stimulant treatment at the recommended ADHD dosages. Avoid Adderall ® use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. Increased Blood Pressure and Heart Rate CNS stimulants cause an increase in blood pressure (mean increase about 2 to 4 mm Hg) and heart rate (mean increase about 3 to 6 bpm). Some patients may have larger increases. Monitor all Adderall ® -treated patients for potential tachycardia and hypertension. Psychiatric Adverse Reactions Exacerbation of Preexisting Psychosis CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder. Induction of a Manic Episode in Patients with Bipolar Disorder CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating 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 recommended doses, 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 with 0% of placebo-treated patients. If such symptoms occur, consideration discontinuing Adderall ® . Long-Term Suppression of Growth in Pediatric Patients CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Closely monitor growth (weight and height) in Adderall ® -treated pediatric patients treated with CNS stimulants. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted (see PRECAUTIONS , PEDIATRIC USE ). Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizure, in patients with prior EEG abnormalities in 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, the drug should be discontinued. Peripheral Vasculopathy, Including Raynaud’s Phenomenon Stimulants, including Adderall ® , used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae include 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 ® treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for Adderall ®- treated patients who develop signs or symptoms of peripheral vasculopathy. 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 monoamine oxidase inhibitors (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 ]. The coadministration with cytochrome P450 (CYP2D6) inhibitors increase the risk with increased exposure to Adderall ® . In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6 [see Drug Interactions ]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Concomitant use of Adderall ® with MAOI drugs is contraindicated [see CONTRAINDICATIONS ]. Discontinue treatment with Adderall ® and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Adderall ® with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate Adderall ® with lower doses, monitor patients for the emergence of serotonin syndrome during drug initiation or titration, and inform patients of the increased risk for serotonin syndrome. Motor and Verbal Tics, and Worsening of Tourette’s Syndrome CNS stimulants, including amphetamine sulfate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported. Assess the family history and clinically evaluate patients for tics or Tourette’s syndrome before initiating Adderall ® . Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome with Adderall ® , and discontinue treatment if clinically appropriate.

DRUG ABUSE AND DEPENDENCE Controlled Substance Adderall ® contains amphetamine, a Schedule II controlled substance. Abuse Adderall ® has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see WARNINGS and PRECAUTIONS ]. Adderall ® can be diverted for non-medical use into illicit channels or distribution. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of amphetamines may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including Adderall ® , can result in overdose and death [see OVERDOSAGE ], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Dependence Physical Dependence Adderall ® may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including Adderall ® include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation. Tolerance Adderall ® may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

OVERDOSAGE Clinical Effects of Overdose Overdose of CNS stimulants is characterized by the following sympathomimetic effects: Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop. CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur. Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop. Overdose Management Consider the possibility of multiple drug ingestion. D-amphetamine is not dialyzable. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

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 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 (t 1/2 ) for d-amphetamine was shorter than the t 1/2 of the l-isomer (9.77 to 11 hours vs. 11.5 to 13.8 hours). The PK parameters (C max , AUC 0-inf ) of d-and l-amphetamine increased approximately three-fold from 10 mg to 30 mg indicating dose-proportional pharmacokinetics. The effect of food on the bioavailability of Adderall ® has not been studied. 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 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. 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% to 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 affect 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 ] .

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 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 (t 1/2 ) for d-amphetamine was shorter than the t 1/2 of the l-isomer (9.77 to 11 hours vs. 11.5 to 13.8 hours). The PK parameters (C max , AUC 0-inf ) of d-and l-amphetamine increased approximately three-fold from 10 mg to 30 mg indicating dose-proportional pharmacokinetics. The effect of food on the bioavailability of Adderall ® has not been studied. 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 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. 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% to 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 affect 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 ] .

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Adderall Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate, and Amphetamine Sulfate DEXTROAMPHETAMINE SACCHARATE DEXTROAMPHETAMINE AMPHETAMINE ASPARTATE MONOHYDRATE AMPHETAMINE DEXTROAMPHETAMINE SULFATE DEXTROAMPHETAMINE AMPHETAMINE SULFATE AMPHETAMINE SILICON DIOXIDE SUCROSE MALTODEXTRIN STARCH, CORN MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE SACCHARIN SODIUM white to off-white 5;dp Adderall Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate, and Amphetamine Sulfate DEXTROAMPHETAMINE SACCHARATE DEXTROAMPHETAMINE AMPHETAMINE ASPARTATE MONOHYDRATE AMPHETAMINE DEXTROAMPHETAMINE SULFATE DEXTROAMPHETAMINE AMPHETAMINE SULFATE AMPHETAMINE SILICON DIOXIDE SUCROSE MALTODEXTRIN STARCH, CORN MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE SACCHARIN SODIUM FD&C BLUE NO. 1 ALUMINUM LAKE 7;5;d;p Adderall Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate, and Amphetamine Sulfate DEXTROAMPHETAMINE SACCHARATE DEXTROAMPHETAMINE AMPHETAMINE ASPARTATE MONOHYDRATE AMPHETAMINE DEXTROAMPHETAMINE SULFATE DEXTROAMPHETAMINE AMPHETAMINE SULFATE AMPHETAMINE SILICON DIOXIDE SUCROSE MALTODEXTRIN STARCH, CORN MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE SACCHARIN SODIUM FD&C BLUE NO. 1 ALUMINUM LAKE 1;0;dp Adderall Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate, and Amphetamine Sulfate DEXTROAMPHETAMINE SACCHARATE DEXTROAMPHETAMINE AMPHETAMINE ASPARTATE MONOHYDRATE AMPHETAMINE DEXTROAMPHETAMINE SULFATE DEXTROAMPHETAMINE AMPHETAMINE SULFATE AMPHETAMINE SILICON DIOXIDE SUCROSE MALTODEXTRIN STARCH, CORN MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE SACCHARIN SODIUM FD&C YELLOW NO. 6 peach 12;5;d;p Adderall Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate, and Amphetamine Sulfate DEXTROAMPHETAMINE SACCHARATE DEXTROAMPHETAMINE AMPHETAMINE ASPARTATE MONOHYDRATE AMPHETAMINE DEXTROAMPHETAMINE SULFATE DEXTROAMPHETAMINE AMPHETAMINE SULFATE AMPHETAMINE SILICON DIOXIDE SUCROSE MALTODEXTRIN STARCH, CORN MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE SACCHARIN SODIUM FD&C YELLOW NO. 6 peach 15;d;p Adderall Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate, and Amphetamine Sulfate DEXTROAMPHETAMINE SACCHARATE DEXTROAMPHETAMINE AMPHETAMINE ASPARTATE MONOHYDRATE AMPHETAMINE DEXTROAMPHETAMINE SULFATE DEXTROAMPHETAMINE AMPHETAMINE SULFATE AMPHETAMINE SILICON DIOXIDE SUCROSE MALTODEXTRIN STARCH, CORN MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE SACCHARIN SODIUM FD&C YELLOW NO. 6 peach 2;0;dp Adderall Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate, and Amphetamine Sulfate DEXTROAMPHETAMINE SACCHARATE DEXTROAMPHETAMINE AMPHETAMINE ASPARTATE MONOHYDRATE AMPHETAMINE DEXTROAMPHETAMINE SULFATE DEXTROAMPHETAMINE AMPHETAMINE SULFATE AMPHETAMINE SILICON DIOXIDE SUCROSE MALTODEXTRIN STARCH, CORN MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE SACCHARIN SODIUM FD&C YELLOW NO. 6 peach 3;0;dp

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/m 2 body surface area basis).

ANDA040422

Adderall

Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate, and Amphetamine Sulfate

57844-110

HUMAN PRESCRIPTION DRUG

ORAL

Package/Label Display Panel NDC 57844-105-01 Adderall ® CII (Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets) (Mixed Salts of a Single Entity Amphetamine Product) 5 mg PHARMACIST: Dispense the accompanying Medication Guide to each patient. Rx only 100 Tablets 1

Dispense with Medication Guide available at: www.tevausa.com/medguides

MEDICATION GUIDE MEDICATION GUIDE Adderall ® ( ADD-ur-all ) CII (Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets (Mixed Salts of a Single Entity Amphetamine Product)) What is the most important information I should know about Adderall ® ? Adderall ® may cause serious side effects, including: Abuse, misuse, and addiction. Adderall ® has a high chance for abuse and misuse and may lead to substance use problems, including addiction. Misuse and abuse of Adderall ® , other amphetamine containing medicines, and methylphenidate containing medicines, can lead to overdose and death. The risk of overdose and death is increased with higher doses of Adderall ® or when it is used in ways that are not approved, such as snorting or injection. Your healthcare provider should check you or your child’s risk for abuse, misuse, and addiction before starting treatment with Adderall ® and will monitor you or your child during treatment. Adderall ® may lead to physical dependence after prolonged use, even if taken as directed by your healthcare provider. Do not give Adderall ® to anyone else. See “What is Adderall ® ?” for more information. Keep Adderall ® in a safe place and properly dispose of any unused medicine. See “How should I store Adderall ® ?” for more information. Tell your healthcare provider if you or your child have ever abused or been dependent on alcohol, prescription medicines, or street drugs. Risks for people with serious heart disease: Sudden death has happened in people who have heart defects or other serious heart disease. Your healthcare provider should check you or your child carefully for heart problems before starting treatment with Adderall ® . Tell your healthcare provider if you or your child have any heart problems, heart disease, or heart defects. Call your healthcare provider right away or go to the nearest hospital emergency room right away if you or your child have any signs of heart problems such as chest pain, shortness of breath, or fainting during treatment with Adderall ® . Increased blood pressure and heart rate. Your healthcare provider should check you or your child’s blood pressure and heart rate regularly during treatment with Adderall ® . Mental (psychiatric) Problems, including: new or worse behavior and thought problems new or worse bipolar illness new psychotic symptoms (such as hearing voices, or seeing or believing things that are not real) or new manic symptoms Tell your healthcare provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression. Call your healthcare provider right away if you or your child have any new or worsening mental symptoms or problems during treatment with Adderall ® , especially hearing voices, seeing or believing things that are not real, or new manic symptoms. What is Adderall ® ? Adderall ® is a central nervous system stimulant (CNS) prescription medicine used for the treatment of : Attention-Deficit Hyperactivity Disorder (ADHD) in children 3 to 17 years of age . Adderall ® may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD. a sleep disorder called Narcolepsy in people 6 years and older. It is not known if Adderall ® is safe and effective in children with ADHD under 3 years of age. It is not known if Adderall ® is safe and effective in children with Narcolepsy under 6 years of age. Adderall ® is a federally controlled substance (CII) because it contains amphetamine that can be a target for people who abuse prescription medicines or street drugs. Keep Adderall ® in a safe place to protect it from theft. Never give your Adderall ® to anyone else because it may cause death or harm them. Selling or giving away Adderall ® may harm others and is against the law. Do not take Adderall ® if you or your child: are allergic to amphetamine products or any of the ingredients in Adderall ® . See the end of this Medication Guide for a complete list of ingredients in Adderall ® . are taking or have taken within the past 14 days, a medicine used to treat depression called a monoamine oxidase inhibitor (MAOI) including the antibiotic linezolid or the intravenous medicine methylene blue. Before taking Adderall ® , tell your healthcare provider about all of your or your child’s medical conditions, including if you or your child: have heart problems, heart disease, heart defects, or high blood pressure have mental problems including psychosis, mania, bipolar illness, or depression, or have a family history of suicide, bipolar illness, or depression have kidney problems, including end stage renal disease (ERSD) have seizures or have had an abnormal brain wave test (EEG) have circulation problems in fingers or toes have or had repeated movements or sounds (tics) or Tourette’s syndrome, or have a family history of tics or Tourette’s syndrome are pregnant or plan to become pregnant. It is not known if Adderall ® will harm the unborn baby. Tell your healthcare provider if you or your child become pregnant during treatment with Adderall ® . are breastfeeding or plan to breastfeed. Adderall ® passes into breast milk. You or your child should not breastfeed during treatment with Adderall ® . Talk to your healthcare provider about the best way to feed the baby during treatment with Adderall ® . Tell your healthcare provider about all of the medicines that you or your child take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Adderall ® and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be changed during treatment with Adderall ® . Your healthcare provider will decide if Adderall ® can be taken with other medicines. Especially tell your healthcare provider if you or your child take: selective serotonin reuptake inhibitors (SSRIs) medicines used to treat migraine headaches called triptans lithium tramadol buspirone serotonin norepinephrine reuptake inhibitors (SNRIs) tricyclic antidepressants fentanyl tryptophan St. John’s Wort Know the medicines that you or your child take. Keep a list of your or your child’s medicines with you to show your healthcare provider and pharmacist when you or your child get a new medicine. Do not start any new medicine during treatment with Adderall ® without talking to your healthcare provider first. How should Adderall ® be taken? Take Adderall ® exactly as prescribed by your or your child’s healthcare provider. Your healthcare provider may change the dose if needed. The first dose of the day is usually taken when you first wake up. Adderall ® can be taken with or without food. Your healthcare provider may sometimes stop Adderall ® treatment for a while to check ADHD symptoms. If you or your child take too much Adderall ® , call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away. What should I avoid while taking Adderall ® ? Do not drive, operate heavy machinery, or do other potentially dangerous activities until you know how Adderall ® affects you. What are possible side effects of Adderall ® ? Adderall ® may cause serious side effects, including: See “What is the most important information I should know about Adderall ® ?” Slowing of growth (height and weight) in children . Children should have their height and weight checked often during treatment with Adderall ® . Your healthcare provider may stop your child’s Adderall ® treatment if they are not growing or gaining weight as expected. Seizures. Your healthcare provider may stop treatment with Adderall ® if you or your child have a seizure. Circulation problems in fingers and toes (peripheral vasculopathy, including Raynaud’s phenomenon). Signs and symptoms may include: fingers or toes may feel numb, cool, painful fingers or toes may change color from pale, to blue, to red Tell your healthcare provider if you have or your child has any numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes. Call your healthcare provider right away if you have or your child have any signs of unexplained wounds appearing on fingers or toes during treatment with Adderall ® . Serotonin syndrome . This problem may happen when Adderall ® is taken with certain other medicines and may be life-threatening. Stop taking Adderall ® and call your healthcare provider or go to the nearest hospital emergency room right away if you or your child develop any of the following signs and symptoms of serotonin syndrome: agitation, hallucinations, coma fast heartbeat flushing seizures loss of coordination confusion dizziness changes in blood pressure sweating or fever nausea, vomiting, or diarrhea muscle stiffness or tightness high body temperature (hyperthermia) New or worsening tics or worsening Tourette’s syndrome. Tell your healthcare provider if you or your child get any new or worsening tics or worsening Tourette’s syndrome during treatment with Adderall ® . The most common side effects of Adderall ® include: stomach ache decreased appetite nervousness Talk to your doctor if you or your child have side effects that are bothersome or do not go away. These are not all the possible side effects of Adderall ® . Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Adderall ® ? Store Adderall ® at room temperature between 68° to 77°F (20° to 25°C). Protect Adderall ® from light. Store Adderall ® in a safe place, like a locked cabinet. Dispose of remaining, unused, or expired Adderall ® by a medicine take-back program at a U.S. Drug Enforcement Administration (DEA) authorized collection site. If no take-back program or DEA authorized collector is available, mix Adderall ® with an undesirable, nontoxic substance such as dirt, cat litter, or used coffee grounds to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and throw away Adderall ® in the household trash. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. Keep Adderall ® and all medicines out of the reach of children. General information about the safe and effective use of Adderall ® Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Adderall ® for a condition for which it was not prescribed. Do not give Adderall ® to other people, even if they have the same condition. It may harm them and it is against the law. You can ask your healthcare provider or pharmacist for information about Adderall ® that is written for healthcare professionals. What are the ingredients in Adderall ® ? Active Ingredient: dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate. Inactive Ingredients: colloidal silicon dioxide, compressible sugar, corn starch, magnesium stearate, microcrystalline cellulose and saccharin sodium. The 5 mg is a white to off-white tablet, which contains no color additives. The 7.5 mg and 10 mg also contain FD&C Blue #1 Aluminum Lake as a color additive. The 12.5 mg, 15 mg, 20 mg and 30 mg also contain FD&C Yellow #6 Aluminum Lake as a color additive. Manufactured For: Teva Pharmaceuticals , Parsippany, NJ 07054 For more information about Adderall ® , please contact Teva at 1-888-838-2872. This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. L 9/2023

Geriatric Use Adderall ® has not been studied in the geriatric population.

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 Hyperactivity Disorder described under INDICATIONS AND USAGE .

Pregnancy Teratogenic Effects 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/m 2 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/m 2 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. 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.

Teratogenic Effects 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/m 2 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/m 2 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. 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.

HOW SUPPLIED Adderall ® (Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets (Mixed salts of a single entity amphetamine product)) is supplied as follows: 5 mg: White to off-white, round, flat-faced beveled edge tablet with four partial bisects debossed with 5 on one side and debossed with dp on the other side. They are available in bottles of 100 tablets (NDC 57844-105-01). 7.5 mg: Blue, oval, biconvex tablet with two partial bisects debossed with 7.5 on one side and one full bisect and two partial bisects debossed with d | p on the other side. They are available in bottles of 100 tablets (NDC 57844-117-01). 10 mg: Blue, round, biconvex tablet with one full bisect and two partial bisects debossed with 1 | 0 on one side and debossed with dp on the other side. They are available in bottles of 100 tablets (NDC 57844-110-01). 12.5 mg: Peach, round, flat-faced beveled edge tablet debossed with 12.5 on one side and one full bisect and two partial bisects debossed with d | p on the other side. They are available in bottles of 100 tablets (NDC 57844-112-01). 15 mg: Peach, oval, biconvex tablet with two partial bisects debossed with 15 on one side and one full bisect and two partial bisects debossed with d | p on the other side. They are available in bottles of 100 tablets (NDC 57844-115-01). 20 mg: Peach, round, biconvex tablet with one full bisect and two partial bisects debossed with 2 | 0 on one side and debossed with dp on the other side. They are available in bottles of 100 tablets (NDC 57844-120-01). 30 mg: Peach, round, flat-faced beveled edge tablet with one full bisect and 2 partial bisects debossed with 3 | 0 on one side and dp on the other side. They are available in bottles of 100 tablets (NDC 57844-130-01). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. Brands listed are trademarks of their respective owners. Dispense with Medication Guide available at: www.tevausa.com/medguides Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. N 9/2023

WARNING: ABUSE, MISUSE, AND ADDICTION Adderall ® has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including Adderall ® , can result in overdose and death (see OVERDOSAGE ), and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection. Before prescribing Adderall ® , assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout Adderall ® treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction (see WARNINGS and DRUG ABUSE AND DEPENDENCE ).

PRECAUTIONS Information for Patients Advise the patient to read the FDA-approved patient labeling (Medication Guide). Abuse, Misuse, and Addiction Educate patients and their families about the risks of abuse, misuse, and addiction of Adderall ® , which can lead to overdose and death, and proper disposal of any unused drug [see WARNINGS , DRUG ABUSE AND DEPENDENCE , OVERDOSAGE ]. Advise patients to store Adderall ® in a safe place, preferably locked, and instruct patients to not give Adderall ® to anyone else. Risks to Patients with Serious Cardiac Disease Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with Adderall ® use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [ see WARNINGS ] . Increased Blood Pressure and Heart Rate Advise patients that Adderall ® can elevate blood pressure and heart rate [ see WARNINGS ] . Psychiatric Adverse Reactions Advise patients that Adderall ® , at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see WARNINGS ] . Long-Term Suppression of Growth in Pediatric Patients Advise patients that Adderall ® may cause slowing of growth including weight loss [see WARNINGS ]. Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud’s Phenomenon] Instruct patients beginning treatment with Adderall ® about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes. Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking Adderall ® . Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients. Serotonin Syndrome Caution patients about the risk of serotonin syndrome with concomitant use of Evekeo and other serotonergic drugs including SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort, and with drugs that impair metabolism of serotonin (in particular MAOIs, both those intended to treat psychiatric disorders and also others such as linezolid [see CONTRAINDICATIONS , WARNINGS , and DRUG INTERACTIONS ]. Advise patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome. Motor and Verbal Tics, and Worsening of Tourette’s Syndrome Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during treatment with Adderall ® . Instruct the patients to notify their healthcare provider if emergence or worsening of tics or Tourette’s syndrome occurs [ see WARNINGS ] . Drug Interactions MAO Inhibitors 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. Do not administer Adderall ® concomitantly or within 14 days after discontinuing MAOI [see CONTRAINDICATIONS and WARNINGS ]. Serotonergic Drugs The concomitant use of Adderall ® and serotonergic drugs increases the risk of serotonin syndrome. Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during Adderall ® initiation or dosage increase. If serotonin syndrome occurs, discontinue Adderall ® and the concomitant serotonergic drug(s) [see WARNINGS and PRECAUTIONS ]. CYP2D6 Inhibitors The concomitant use of Adderall ® and CYP2D6 inhibitors may increase the exposure of Adderall ® compared to the use of the drug alone and increase the risk of serotonin syndrome. Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during Adderall ® initiation and after a dosage increase. If serotonin syndrome occurs, discontinue Adderall ® and the CYP2D6 inhibitor [see WARNINGS , OVERDOSAGE ]. Acidifying Agents Lower blood levels and efficacy of amphetamines. Increase dose based on clinical response. Examples of acidifying agents include gastrointestinal acidifying agents and urinary acidifying agents. Adrenergic Blockers Adrenergic blockers are inhibited by amphetamines. Alkalinizing Agents Increase blood levels and potentiate the action of amphetamine. Co-administration of Adderall ® and gastrointestinal alkalinizing agents should be avoided. Examples of alkalinizing agents include gastrointestinal alkalinizing agents and urinary alkalinizing agents. Tricyclic Antidepressants 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. Monitor frequently and adjust or use alternative therapy based on clinical response. 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; coadministration of phenobarbital may produce a synergistic anticonvulsant action. Phenytoin Amphetamines may delay intestinal absorption of phenytoin; coadministration of phenytoin may produce a synergistic anticonvulsant action. Propoxyphene In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur. Proton Pump Inhibitors Time to maximum concentration (T max ) of amphetamine is decreased compared to when administered alone. Monitor patients for changes in clinical effect and adjust therapy based on clinical response. An example of a proton pump inhibitor is omeprazole. 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/m 2 body surface area basis). Pregnancy Teratogenic Effects 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/m 2 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/m 2 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. 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 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 Hyperactivity Disorder described under INDICATIONS AND USAGE . Geriatric Use Adderall ® has not been studied in the geriatric population.