the serotonergic neurotransmitter system may result in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. >10% (Evekeo) Decreased appetite (28%) Infections (22%) Abdominal pain (15%) Irritability (14%) Headache (13%) >10% (Adzenys ER) Appetite loss (22-36%) Dry mouth (1.6-35%) Headache (1.6-26%) Insomnia (5.2-17%) Abdominal pain (11-14%) 1-10% (Evekeo) Insomnia (10%) Fatigue (10%) Affect lability, includes mood swings (9%) Tachycardia (9%) Nausea (6%) Vomiting (6%) Dry mouth (6%) Decreased appetite (4%) Insomnia (4%) Abdominal pain (3%) Affect lability (3%) Injury (3%) 1-10% (Dyanavel XR) Epistaxis (3.8%) Rhinitis allergic (3.8%) Upper abdominal pain (3.8%) 1-10% (Adzenys ER) Weight loss (4-9%) Emotional lability (9%) Nausea (5-8%) Agitation (8%) Anxiety (2.1-8%) Dizziness (2-7%) Vomiting (7%) Diarrhea (6%) Nervousness (6%) Urinary tract infection (5%) Fever (5%) Infection (4%) Accidental injury (3%) Asthenia (1-2%) Dyspepsia (2%) Nervousness (1.6%) Tachycardia (1.6%) Postmarketing Reports Cardiovascular: Palpitations, tachycardia, sudden death, myocardial infarction; elevation of blood pressure; isolated reports of cardiomyopathy associated with chronic use Central nervous system: Psychotic episodes at recommended doses (rare), overstimulation, restlessness, dizziness, insomnia, depression, aggression, anger, logorrhea, and paresthesia (including formication). euphoria, dyskinesia, dysphoria, tremor, headache, exacerbation of motor and phonic tics and Tourette’s syndrome Gastrointestinal: Dry mouth, unpleasant taste, diarrhea, constipation, intestinal ischemia, anorexia, and weight loss may occur as undesirable effects when amphetamines are used for other than the anorectic effect 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, and frequent or prolonged erections Skin: Alopecia Eye Disorders: Vision blurred, mydriasis Vascular disorders: Raynaud phenomenon Musculoskeletal: Rhabdomyolysis Black Box Warnings Abuse and dependence CNS stimulants, other amphetamine-containing products, and methylphenidate, have a high potential for abuse and dependence Assess risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy Contraindications Advanced arteriosclerosis, symptomatic cardiovascular disease, or moderate-to-severe hypertension In patients known to be hypersensitive to amphetamine, or other components Patients with a history of drug abuse During or within 14 days following the administration of MAOIs (hypertensive crises may result) Cautions Sudden death reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems May cause a modest increase in average blood pressure (~2-4 mmHg) and heart rate (~3-6 bpm); caution with hypertension and other cardiovascular conditions May exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder CNS stimulants may induce a mixed or manic episode in patients with bipolar disorder; before initiating treatment, screen for risk factors for developing a manic episode (eg, comorbid or has a history of depressive symptoms or a family history of suicide, bipolar disorder, and depression) Treatment emergent psychotic or manic symptoms (eg, hallucinations, delusional thinking, mania) in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD; monitor for the worsening of aggressive behavior or hostility Monitor childhood growth during treatment; patients who are not growing or gaining height or weight as expected may need to interrupt their treatment May lower seizure threshold in patients with prior history of seizures Stimulants are associated with peripheral vasculopathy, including Raynaud phenomenon Visual disturbances reported (eg, difficulties with accommodation, blurred vision) Medication errors, including substitution and dispensing errors, between amphetamine products could occur, leading to possible overdosage; avoid substitution errors and overdosage, do not substitute for other amphetamine products on a mg-per-mg basis because of different amphetamine salt compositions and differing pharmacokinetic profile Drug interactions overview Amphetamines can cause a significant elevation in plasma corticosteroid levels (greatest increase in the evening); may interfere with urinary steroid determinations Concomitant use of amphetamines with alkalizing agents (eg, proton pump inhibitors) may increase exposure to amphetamine and exacerbate the action of amphetamine Coadministration with acidifying agents (eg, ascorbic acid) may lower blood levels and efficacy of amphetamines 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 Amphetamines are metabolized by CYP2D6 and minor iCYP2D6 inhibitors; coadministration with CYP2D6 inhibitors may increase exposure to amphetamines; consider alternative non-serotonergic drug or alternative drug that does not inhibit CYP2D6 If concomitant use with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted, initiate therapy with lower doses, monitor for emergence of serotonin syndrome during drug initiation or titration, and inform patients of increased risk for serotonin syndrome Pregnancy Pregnancy exposure registry monitors pregnancy outcomes in women exposed to amphetamines during pregnancy Encourage patients to register 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 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 Adverse pregnancy outcomes, including premature delivery and low birth weight, were seen in infants born to mothers taking amphetamines during pregnancy Dextroamphetamine sulfate shown to have embryotoxic and teratogenic effects when administered to A/Jax mice and C57BL mice in doses ~41 times the maximum human dose Clinical considerations Amphetamines cause vasoconstriction and thereby decrease placental perfusion Also, may 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 (eg, feeding difficulties, irritability, agitation, excessive drowsiness) Animal data No effects on morphological development observed in embryo-fetal development studies with oral administration of amphetamine to rats and rabbits during organogenesis at doses that are approximately 3 and 16 times, respectively, the maximum recommended human dose (MRHD) of 20 mg/day (as base equivalents) on mg/m2 basis, given to adults However, long-term neurochemical and behavioral effects have been reported in published animal developmental studies using clinically relevant doses of amphetamine Lactation Based on limited published case reports, amphetamine (d- or d1) is present in human milk at relative infant doses of 2-13.8% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.9and 7.5 No reports of adverse effects on the breastfed infantLong-term neurodevelopmental effects on infants from amphetamine exposure are unknown Owing to the potential for serious adverse reactions in nursing infants, breast feeding is not recommended during treatmentPregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Noncatecholamine, sympathomimetic amine that elicits CNS stimulant activity Peripheral actions include increased systolic and diastolic blood pressures, and weak bronchodilator and respiratory stimulant action Absorption Adzenys XR-ODT Peak plasma time, d-amphetamine: 5 hr (fasted); 7 hr (fed) Peak plasma concentration, d-amphetamine: 44.9 ng/mL (fasted); 36.3 ng/mL (fed) AUC, d-amphetamine: 876.9 hr·ng/mL (fasted); 856.3 hr·ng/mL (fed) Coadministration of Adzenys XR-ODT and food prolonged peak plasma time by ~2 hr (d-amphetamine); 2.5 hr (l-amphetamine) Adzenys ER Peak plasma time: 5 hr Increase in amphetamine release occurred in the presence of 40% alcohol Dyanavel XR Peak plasma time: 4 hr Bioavailability of Dyanavel XR compared to an equal dose of mixed amphetamine salts IR tablets is 106% (d-amphetamine) and 111% (l-amphetamine) Evekeo ODT Peak plasma time (Evekeo ODT [d- and l-amphetamine]): ~3.5 hr (with water) and 3 hr (without water) Metabolism 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 Elimination Adzenys ER Half-life, d-amphetamine: 11.4 hr (adults); 12.7 hr (6-12 years) Half-life, l-amphetamine: 14.1 hr (adults); 15.3 hr (6-12 years) Excretion: Urine (30-40%) Adzenys XR-ODT Half-life, d-amphetamine: 11 hr (adults); 9-10 hr (6-12 years) Half-life, l-amphetamine: 14 hr (adults); 10-11 hr (6-12 years) Excretion: Urine (30-40%) Dyanavel XR Half-life, d-amphetamine: 12.36 hr (adults) Half-life, l-amphetamine: 15.12 hr (adults) Excretion: Urine (30-40%) Evekeo ODT Half-life (Evekeo ODT): 10 hr (d-amphetamine); 11.7 hr (l-amphetamine) Renally eliminated in a pH-dependent mannerRenal excretion rate of unchanged amphetamine at a urine pH= 6.6 averages 70% versus 17%; - 43% at urine pH of >6.7 Oral Administration Avoid late evening doses because of insomnia Tablet Take 30-60 minutes before meals Administer first dose on awakening; 1-2 additional doses at 4-6 hr intervals Oral suspension Shake suspension well before measuring dose with a calibrated measuring device Take with or without meals Dyanavel XR Firmly insert the bottle adapter into the bottle and do not remove once inserted Use oral dosing dispenser provided by pharmacist Oral disintegrating tablet May be taken with or without food Once blister is opened, remove tablet and place on patient’s tongue Place whole tablet on the tongue and allow tablet to disintegrate in saliva then swallow Extended-release tablets Chew or swallow whole May divide 5 mg extended-release tablet into equal halves (2.5 mg) at the score line Storage Evekeo: Store at 20-25°C (68-77°F); dispense in a well closed container Evekeo ODT: Store at 20-25°C (68- 77°F); excursions permitted from 15-30ºC (59-86ºF); store blister packages in the provided plastic sleeve Dyanavel XR: Dispense in a tight container with child resistant closure; store at 20-25°C (68- 77°F); excursions permitted from 15-30ºC (59-86ºF) Adzenys XR-ODT: Store blister packages in the rigid, plastic travel case provided after removal from the carton; store at 20-25°C (68- 77°F); excursions permitted from 15-30ºC (59-86ºF) Adzenys ER: Dispense in a tight container with child-resistant closure; store at 20-25°C (68- 77°F); excursions permitted from 15-30ºC (59-86ºF) No images available for this drug. No images available for this drug.A Patient Handout is not currently available for this monograph.Print FormularyPatient DiscountsAdding plans allows you to compare formulary status to other drugs in the same class.To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.Create Your List of PlansAdding plans allows you to:View the formulary and any restrictions for each plan.Manage and view all your plans together – even plans in different states.Compare formulary status to other drugs in the same class.Access your plan list on any device – mobile or desktop. The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information. View explanations for tiers and restrictions Tier Description 1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs. 2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs. 3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs. 4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products. 5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products. 6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products. NC NOT COVERED – Drugs that are not covered by the plan. Code Definition PA Prior Authorization Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription. QL Quantity Limits Drugs that have quantity limits associated with each prescription.