SARGENINE

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.

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 1.25 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 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 Inactive Ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose and pregelatinized starch (botanical source: maize).

Dextroamphetamine Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets (Mixed Salts of a Single Amphetamine Product) 5 mg, 7.5 mg and 10 mg also contain FD&C Blue #1 Aluminum Lake as a color additive.

Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets (Mixed Salts of a Single Amphetamine Product) 12.5 mg, 15 mg, 20 mg and 30 mg also contain FD&C Yellow #6 Aluminum Lake as a color additive.

Not Available

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.

Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate 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 dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets 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).

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 dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets has not been studied.

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.

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.

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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 or a medical toxicologist for additional overdose management recommendations.

Abuse, Misuse, and Addiction DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS has a high potential for abuse and misuse. which can lead to the development of a substance use disorder, including addiction.

SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS can be diverted for non-medical use into illicit channels or distribution.

Misuse and abuse of

CNS stimulants, including DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS, can result in overdose and death, and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing DEXTROAMPHETAMINE

SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS, 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 DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS to anyone else.

SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS 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.

SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

CNS stimulants cause an increase in blood pressure (mean increase about to 4 mm Hg) and heart rate (mean increase about to 6 bpm).

Some patients may have larger increases.

Monitor all DEXTROAMPHETAMINE

SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS-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).

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, consider discontinuing DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS.

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

Closely monitor growth (weight and height) in DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS-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 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.

Vasculopathy, Including Raynaud’s Phenomenon Stimulants, including DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS, 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 post marketing 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 DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS treatment.

Further clinical evaluation (e.g., rheumatology referral) may be appropriate for DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS-treated patients who develop signs or symptoms of peripheral vasculopathy.

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.

The coadministration with cytochrome

P450 (CYP2D6) inhibitors increase the risk with increased exposure to DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS.

In these situations, consider an alternative non-serotonergic drug or an alternative drug that does not inhibit CYP2D6.

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 dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets with MAOI drugs is contraindicated.

Discontinue treatment with dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment.

If concomitant use of dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets 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.

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 DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS.

Regularly monitor patients for the emergence or worsening of tics or Tourette’s syndrome with, DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS, and discontinue treatment if clinically appropriate.

In patients known to be hypersensitive to amphetamine, or other components of dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets.

Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with other amphetamine products.

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.

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.

Not recommended for children under 3 years of age.

In children from 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 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 DEXTROAMPHETAMINE

SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE ANDAMPHETAMINE SULFATE TABLETS assess: for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) . the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating DEXTROAMPHETAMINE SACCHARATE, AMPHETAMINE ASPARTATE, DEXTROAMPHETAMINE SULFATE AND AMPHETAMINE SULFATE TABLETS.

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 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 to 6 hours.

Saccharate, Amphetamine Aspartate, Dextroamphetamine Sulfate and Amphetamine Sulfate Tablets (Mixed Salts of a Single Amphetamine Product) are supplied as follow: 12.5 mg: Peach, round, flat faced, beveled edge tablets, debossed “N32” on one side and quadrisect on the other side having functional score.

NDC: 72162-1236-1: 100 Tablets in a BOTTLE Store at 20° to 25°C (68° to 77°F) .

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.

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504.

Pregnancey Teratogenic Effects Pregnancy Category C

Amphetamine, in the enantiomer ratio present in dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets (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 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.

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.

Amphetamines are excreted in human milk.

Mothers taking amphetamines should be advised to refrain from nursing.

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 I NDICATIONS AND USAGE.

Dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate tablets have not been studied in the geriatric population.