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  • CLASSES

    Psychostimulants, Amphetamines
    Stimulant Narcolepsy Agents

    BOXED WARNING

    Alcoholism, substance abuse

    Amphetamine has a high potential for abuse; the immediate-release tablets are specifically contraindicated in patients with a history of substance abuse. Patients should be evaluated for a personal or family history of abuse or dependence on alcohol (alcoholism), prescription medications, or street drugs. Administration of amphetamines for a prolonged period of time may lead to physical and psychological drug dependence. Misuse of amphetamines may cause sudden death and serious cardiovascular adverse events. The least amount reasonable should be prescribed or dispensed at one time in order to limit the potential for overuse or drug diversion. Symptoms of chronic intoxication include insomnia, irritability, change in personality, and psychotic symptoms that may be clinically indistinguishable from psychotic disorders.

    DEA CLASS

    Rx, schedule II

    DESCRIPTION

    Sympathomimetic amine; a racemic mixture of L-amphetamine and D-amphetamine
    Used for attention-deficit hyperactivity disorder (ADHD) and narcolepsy
    Used as an anorectic agent in the short-term (8 to 12 weeks) exogenous treatment of obesity; abuse and addiction potential; not generally recommended by guidelines due to lack of longer-term health benefits

    COMMON BRAND NAMES

    Adzenys, Adzenys XR, Dyanavel XR, Evekeo

    HOW SUPPLIED

    Adzenys XR Oral Tab Orally Dis DR: 3.1mg, 6.3mg, 9.4mg, 12.5mg, 15.7mg, 18.8mg
    Amphetamine Sulfate/Evekeo Oral Tab: 5mg, 10mg
    Amphetamine/Dyanavel XR Oral Susp ER: 1mL, 1.25mg, 2.5mg
    Evekeo On the tongue Tab Orally Dis: 5mg, 10mg, 15mg, 20mg

    DOSAGE & INDICATIONS

    For the treatment of narcolepsy.
    Oral dosage (immediate-release tablet)
    Adults, Adolescents, and Children 12 years and older

    10 mg PO once daily in the morning initially. May titrate in 10 mg/day increments at weekly intervals to minimum effective dose. Max: 60 mg/day. Give the first dose on awakening; additional doses may be given at intervals of 4 to 6 hours. If insomnia or anorexia appear, reduce dosage.

    Children 6 to 11 years

    5 mg PO once daily in the morning initially. May titrate in 5 mg/day increments at weekly intervals to minimum effective dose. Max: 60 mg/day. Give the first dose on awakening; additional doses may be given at intervals of 4 to 6 hours. If insomnia or anorexia appear, reduce dosage.

    For the treatment of attention-deficit hyperactivity disorder (ADHD).
    Oral dosage (immediate-release tablets; e.g., Evekeo)
    Adults†

    Dosing information from the manufacturer is not specifically available for this indication. However, treatment of adult ADD/ADHD is expected to be similar in adults as in children, with higher maximum doses. Initially, give 5 or 10 mg PO daily upon awakening. May titrate in increments of 5 to 10 mg at weekly intervals until optimal response is obtained. After the morning dose, may give additional doses (5 or 10 mg) at intervals of 4 to 6 hours. Dose range: 5 to 60 mg/day PO, given in divided doses. If bothersome side effects appear (e.g., insomnia or anorexia), reduce dosage. Use the lowest effective dosage after stabilization. Late evening doses should be avoided to reduce risk of insomnia. Amphetamine has not been systematically studied in geriatric adults; it is advisable to begin at the low end of the dosage range and titrate cautiously.

    Children and Adolescents 6 to 17 years

    5 mg PO once or twice daily initially. May titrate in 5 mg/day increments at weekly intervals to minimum effective dose. An additional dose may be given after 4 to 6 hours if needed. Use the lowest effective dose after stabilization. Rarely is it necessary to exceed 40 mg/day.

    Children 3 to 5 years

    2.5 mg PO once daily in the morning. May titrate in 2.5 mg/day increments at weekly intervals to minimum effective dose. An additional 1 to 2 doses may be given at 4 to 6 hour intervals if needed. Maximum dosage information is not available; however, doses should not exceed 40 mg/day, the maximum recommended dose for children 6 years and older. Although this dosing information is available in the FDA-approved package labeling, the American Academy of Pediatrics (AAP) does not recommend the use of amphetamine in this age group due to lack of safety and efficacy data.

    Oral dosage (immediate-release orally disintegrating tablets; e.g., Evekeo ODT)
    Children and Adolescents 6 to 17 years

    5 mg PO once or twice daily initially. May titrate in 2.5 to 5 mg/day increments at weekly intervals to minimum effective dose. An additional dose may be given after 4 to 6 hours if needed. Use the lowest effective dose after stabilization. Rarely is it necessary to exceed 40 mg/day. Switching from immediate-release tablets to immediate-release orally disintegrating tablets can be done on a mg-per-mg basis. Do not substitute for other amphetamine products on a mg-per-mg basis due to different amphetamine base compositions and differing pharmacokinetic profiles.

    Children 3 to 5 years

    2.5 mg PO once daily in the morning. May titrate in 2.5 mg/day increments at weekly intervals to minimum effective dose. An additional dose may be given after 4 to 6 hours if needed. Maximum dosage information is not available; however, doses should not exceed 40 mg/day, the maximum recommended dose for children 6 years and older. Switching from immediate-release tablets to immediate-release orally disintegrating tablets can be done on a mg-per-mg basis. Do not substitute for other amphetamine products on a mg-per-mg basis due to different amphetamine base compositions and differing pharmacokinetic profiles. Although this dosing information is available in the FDA-approved package labeling, the American Academy of Pediatrics (AAP) does not recommend the use of amphetamine in this age group due to lack of safety and efficacy data.

    Oral dosage (e.g., Dyanavel XR extended-release oral suspension)
    Children and Adolescents 6 to 17 years

    2.5 to 5 mg PO once daily in the morning. May titrate in 2.5 to 10 mg/day increments every 4 to 7 days to minimum effective dose. Max: 20 mg/day. Use lowest effective dose after stabilization. When switching from other amphetamine products, discontinue that treatment, and titrate extended-release oral suspension after starting with 2.5 or 5 mg PO once daily. Do not substitute for other amphetamine products on a mg-per-mg basis due to different amphetamine base compositions and differing pharmacokinetic profiles.

    Oral dosage (extended-release ODT or extended-release suspension; e.g., Adzenys XR-ODT and Adzenys ER oral suspension)
    Adults

    ADULTS NOT CURRENTLY TAKING AN AMPHETAMINE PRODUCT: 12.5 mg PO once daily in the morning. Amphetamine has not been systematically studied in geriatric adults; it is advisable to begin at the low end of the dosage range and titrate cautiously. SWITCHING FROM ANOTHER AMPHETAMINE PRODUCT (EXCEPT ADDERALL XR): Discontinue the other amphetamine product, and then initiate Adzenys XR. The usual recommended dosage for adults is 12.5 mg PO once daily in the morning, but individualize to optimal clinical response. Do not substitute for other amphetamine products on a mg-per-mg basis due to different compositions and pharmacokinetic profiles. ADULTS CURRENTLY TAKING 5 MG/DAY OF ADDERALL XR: Initially, 3.1 mg PO once daily in the morning; titrate if needed. ADULTS CURRENTLY TAKING 10 MG/DAY OF ADDERALL XR: Initially, 6.3 mg PO once daily in the morning; titrate if needed. ADULTS CURRENTLY TAKING 15 MG/DAY OF ADDERALL XR: Initially, 9.4 mg PO once daily in the morning; titrate if needed. ADULTS CURRENTLY TAKING 20 MG/DAY OF ADDERALL XR: 12.5 mg PO once daily in the morning.

    Adolescents

    ADOLESCENTS NOT CURRENTLY TAKING AN AMPHETAMINE PRODUCT: Initially, 6.3 mg PO once daily in the morning. May titrate by 3.1 or 6.3 mg/day at weekly intervals. Max: 12.5 mg/day PO. SWITCHING FROM ANOTHER AMPHETAMINE PRODUCT (EXCEPT ADDERALL XR): After discontinuing the other amphetamine product, initiate Adzenys XR at 6.3 mg PO once daily in the morning. May titrate by 3.1 or 6.3 mg/day at weekly intervals. Individualize dosage to therapeutic effect. Max: 12.5 mg/day PO. Do not substitute for other amphetamine products on a mg-per-mg basis due to different compositions and pharmacokinetic profiles. ADOLESCENTS CURRENTLY TAKING 5 MG/DAY OF ADDERALL XR: Initially, 3.1 mg PO once daily in the morning, then titrate if needed. ADOLESCENTS CURRENTLY TAKING 10 MG/DAY OF ADDERALL XR: Initially, 6.3 mg PO once daily in the morning, then titrate if needed. ADOLESCENTS CURRENTLY TAKING 15 MG/DAY OF ADDERALL XR: Initially, 9.4 mg PO once daily in the morning, then titrate if needed. ADOLESCENTS CURRENTLY TAKING 20 MG/DAY OF ADDERALL XR: 12.5 mg PO once daily in the morning.

    Children 6 to 12 years

    CHILDREN NOT CURRENTLY TAKING AN AMPHETAMINE PRODUCT: Initially, 6.3 mg PO once daily in the morning. May titrate by 3.1 or 6.3 mg/day at weekly intervals. Max: 18.8 mg/day PO. SWITCHING FROM ANOTHER AMPHETAMINE PRODUCT (EXCEPT ADDERALL XR): After discontinuing the other amphetamine product, initiate Adzenys XR at 6.3 mg PO once daily in the morning. May titrate by 3.1 or 6.3 mg/day at weekly intervals. Individualize dosage to therapeutic effect. Max: 18.8 mg/day PO. Do not substitute for other amphetamine products on a mg-per-mg basis due to different compositions and pharmacokinetic profiles. CHILDREN CURRENTLY TAKING 5 MG/DAY OF ADDERALL XR: Initially, 3.1 mg PO once daily in the morning. May titrate in 3.1 or 6.3 mg/day increments at weekly intervals if needed. Max: 18.8 mg/day. CHILDREN CURRENTLY TAKING 10 MG/DAY OF ADDERALL XR: Initially, 6.3 mg PO once daily in the morning. May titrate in 3.1 or 6.3 mg/day increments at weekly intervals if needed. Max: 18.8 mg/day. CHILDREN CURRENTLY TAKING 15 MG/DAY OF ADDERALL XR: Initially, 9.4 mg PO once daily in the morning. May titrate in 3.1 or 6.3 mg/day increments at weekly intervals if needed. Max: 18.8 mg/day. CHILDREN CURRENTLY TAKING 20 MG/DAY OF ADDERALL XR: Initially, 12.5 mg PO once daily in the morning. May titrate in 3.1 or 6.3 mg/day increments at weekly intervals if needed. Max: 18.8 mg/day. CHILDREN CURRENTLY TAKING 25 MG/DAY OF ADDERALL XR: Initially, 15.7 mg PO once daily in the morning. May titrate in 3.1 mg/day increments at weekly intervals if needed. Max: 18.8 mg/day. CHILDREN CURRENTLY TAKING 30 MG/DAY OF ADDERALL XR: 18.8 mg PO once daily in the morning; do not exceed this dose.

    For the short-term (i.e., 8 to 12 weeks) treatment of exogenous obesity.
    Oral dosage (immediate-release tablet)
    Adults

    5 to 10 mg PO up to 3 times per day, taken 30 to 60 minutes before meals. Max: 30 mg/day. Continue only if the patient has satisfactory weight loss within the first 4 weeks of treatment (i.e., weight loss of at least 4 pounds, or as determined by the physician). When tolerance to the anorectic effect develops, do not exceed the recommended dose in an attempt to increase the effect; instead, the drug should be discontinued. Use for short-term (8 to 12 weeks) only. INTENDED USE: Use as monotherapy only. Not recommended for patients who used any other anorectic agents within the prior year. Use is for patients with an initial body mass index (BMI) of 30 kg/m2 or more who have not responded to diet and exercise alone. The limited usefulness of agents of this class should be weighed against possible risks inherent in their use. According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, short-term pharmacotherapy, such as with the amphetamine anorectics, has not been shown to produce longer-term health benefits in obese and overweight patients and cannot be generally recommended; these drugs should not be used for weight management long-term. Weight gain usually resumes after drug discontinuation.[62881]

    Children and Adolescents 12 years and older


    5 to 10 mg PO up to 3 times per day, taken 30 to 60 minutes before meals. Max: 30 mg/day. Only continue if the patient has satisfactory weight loss within the first 4 weeks of treatment. When tolerance to the anorectic effect develops, do not exceed the dosage in an attempt to increase the effect; instead, discontinue. Use only for patients refractory to alternative therapy (e.g., repeated diets, group programs, increased activity, and other drugs). Use as monotherapy; for short-term (8 to 12 weeks) use only. The limited usefulness of amphetamines should be weighed against possible risks inherent in the use of this drug class.[60070] Guidelines state that short-term pharmacotherapy, such as with the amphetamine anorectics, has not been shown to produce longer-term health benefits in pediatric patients and cannot be generally recommended. In general, children with a BMI below the 95th percentile should not be treated with antiobesity drugs. Pharmacotherapy for overweight children (BMI of at least 85th but less than 95th percentile) should be reserved for those with significant, severe comorbidities who have not responded to lifestyle modification.[58571] [63035]

    MAXIMUM DOSAGE

    Adults

    12.5 mg/day PO (Adzenys XR products); 60 mg/day PO (immediate-release products).

    Geriatric

    12.5 mg/day PO (Adzenys XR products); 60 mg/day PO (immediate-release products).

    Adolescents

    12.5 mg/day PO (Adzenys XR products); 20 mg/day PO (Dyanavel XR); 40 mg/day PO (immediate-release products).

    Children

    6 to 12 years: 18.8 mg/day PO (Adzenys XR products); 20 mg/day PO (Dyanavel XR); 40 mg/day PO (immediate-release products).
    3 to 5 years: 40 mg/day PO for immediate-release products; safety and efficacy have not been established for extended-release formulations.
    1 to 2 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use with caution; hepatic dysfunction has the potential to inhibit the elimination of amphetamine and result in prolonged exposures. However, specific guidelines for dosage adjustments in hepatic impairment are not available.

    Renal Impairment

    Use with caution; renal dysfunction has the potential to inhibit the elimination of amphetamine and result in prolonged exposures. However, specific guidelines for dosage adjustments in renal impairment are not available.

    ADMINISTRATION

    Oral Administration

    May administer with or without food.

    Oral Solid Formulations

    Immediate-release tablets
    Administer the first dose of the day upon awakening; additional doses may be given at 4 to 6 hour intervals.
    Late evening doses may result in insomnia; the last dose of the day should be administered at least 6 hours before bedtime to avoid sleep interference.
    When used as an anorectic, administer the dose 30 to 60 minutes before meals.[60070]
     
    Immediate-release oral disintegrating tablets (ODT) (e.g., Evekeo ODT)
    Administer once daily in the morning. May give with or without food or liquid.
    With dry hands, open the blister. Remove the tablet by pushing it through foil backing just prior to dosing. Do not store tablet for future use.
    Place tablet on the patient's tongue and allow to dissolve without chewing or crushing. Once dissolved, the patient may swallow with saliva.[63916]
     
    Extended-release oral disintegrating tablets (ODT) (e.g., Adzenys XR-ODT)
    Administer once daily in the morning. May give with or without food.
    Do NOT attempt to push ODT tablets through foil backing. With dry hands, bend the blister where indicated and peel back the foil to remove the tablet just prior to dosing.
    Place tablet on the patient's tongue and allow to dissolve without chewing or crushing. Once dissolved, the patient may swallow with saliva.[60524]

    Oral Liquid Formulations

    Extended-release oral suspension
    Administer once daily in the morning.
    Shake well prior to each administration.
    Measure dose with an oral syringe or calibrated measuring device.
    Do not add to food or mix with other liquids before consuming.

    STORAGE

    Adzenys:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Adzenys XR:
    - Product should always be stored in the blister and only removed immediately before use
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Dyanavel XR:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Evekeo:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Amphetamine is contraindicated for use in patients with known hypersensitivity or idiosyncrasy to the sympathomimetic amines or any component of these products.
     
    Cases of intestinal necrosis, including some deaths, have been reported with concomitant use of sodium polystyrene sulfonate and sorbitol, 2 of the inactive ingredients in Adzenys ER oral suspension. In these cases, sodium polystyrene sulfonate was used to treat hyperkalemia at doses more than 200 times the amount present in Adzenys ER; however, no absolute safe levels for the interaction of sodium polystyrene and sorbitol have been established.

    Alcoholism, substance abuse

    Amphetamine has a high potential for abuse; the immediate-release tablets are specifically contraindicated in patients with a history of substance abuse. Patients should be evaluated for a personal or family history of abuse or dependence on alcohol (alcoholism), prescription medications, or street drugs. Administration of amphetamines for a prolonged period of time may lead to physical and psychological drug dependence. Misuse of amphetamines may cause sudden death and serious cardiovascular adverse events. The least amount reasonable should be prescribed or dispensed at one time in order to limit the potential for overuse or drug diversion. Symptoms of chronic intoxication include insomnia, irritability, change in personality, and psychotic symptoms that may be clinically indistinguishable from psychotic disorders.

    Bipolar disorder, depression, mania, psychosis, schizophrenia, suicidal ideation

    Amphetamine immediate-release tablets are contraindicated in patients in an agitated state.[60070] Stimulants such as amphetamine should be used cautiously in those with bipolar disorder and/or mania due to the potential for manic episodes to occur. Prior to initiating treatment, patients with comorbid depressive symptoms should be adequately screened to determine whether they are at risk for bipolar disorder and/or mania; such screening should include a detailed psychiatric history, including family history of suicide, bipolar disorder, and depression. In psychotic individuals (e.g., schizophrenia), amphetamine may exacerbate behavioral disturbances, psychosis, or thought disorders. New onset psychotic symptoms (e.g., hallucinations, delusional thinking, mania) may occur in individuals without a prior history of psychosis. If such symptoms occur, discontinuation of treatment should be considered.[60070] [64025] Aggression, hostility, and suicidal ideation or behaviors have been reported in both clinical trials and postmarketing experience with ADHD medications.[28405] [28518] [43863] [56750] [56766] Although causality has not been established and these behaviors may be inherent to ADHD, close monitoring is recommended. Patients and their caregivers should be advised to promptly report any changes in mood or behavior. If suicide-related events emerge during treatment, consideration should be given to dose reduction or drug discontinuation, especially if symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Due to its toxic effects in overdose, amphetamine should only be used in those with major depression or suicidal ideation when absolutely necessary.[56765] [60070] [60232] [60524]

    Hypertension, tachycardia

    Amphetamines are contraindicated in patients with moderate to severe hypertension, advanced atherosclerosis, and symptomatic cardiovascular disease. Stimulant medications must be used very cautiously in patients with pre-existing mild hypertension, tachycardia, or other conditions in which a modest increase in blood pressure or heart rate could be detrimental. Stimulant medications cause a modest increase in average blood pressure (approximately 2 to 4 mmHg) and average heart rate (approximately 3 to 6 bpm); however, some individuals may have larger increases. Although these mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Elevated blood pressure may require a dose reduction, discontinuation, and/or initiation of appropriate antihypertensive medication.

    Acute myocardial infarction, aortic stenosis, arteriosclerosis, cardiac arrhythmias, cardiac disease, cardiomyopathy, congenital heart disease, coronary artery disease, heart failure, prosthetic heart valves, ventricular arrhythmias, ventricular dysfunction

    Amphetamine immediate-release tablets are contraindicated in patients with moderate to severe hypertension, advanced arteriosclerosis, or symptomatic cardiac disease. The FDA recommends that, in general, stimulant medications not be used in patients with known serious cardiac structural abnormalities, a history of acute myocardial infarction, aortic stenosis, prosthetic heart valves, valvular heart disease, cardiomyopathy, ventricular dysfunction or heart failure, cardiac arrhythmias, coronary artery disease, or other serious cardiac problems. Stimulant medications may increase blood pressure or heart rate in some individuals, but more serious cardiac effects have also been associated with stimulant use. Sudden unexplained death (SUD) and myocardial infarction have occurred in adults receiving stimulants at standard dosages for attention-deficit hyperactivity-disorder (ADHD). Sudden death has also been associated with stimulant medications at usual doses in pediatrics with structural cardiac abnormalities or other serious heart problems. A large retrospective cohort study including over 1.2 million pediatrics and young adults 2 to 24 years of age did not find an increased risk of serious cardiovascular events in current users of drugs for the treatment of ADHD compared to nonusers (adjusted hazard ratio 0.75; 95% CI 0.31 to 1.85). Similar results were seen when current users of ADHD drugs were compared to former users and when current users with severe underlying cardiovascular disease were included in the analysis. The authors concluded that although the absolute magnitude of risk appears to be low, a modest increase in risk could not be ruled out. The American Heart Association (AHA) states that it is reasonable to consider the use of these medications in pediatric patients with congenital heart disease without current hemodynamic or arrhythmic concerns or congenital heart disease that is considered stable by the patient's pediatric cardiologist, unless the cardiologist has specific concerns. However, these patients should be closely monitored and treatment discontinuation should be considered if the patient develops any of the following conditions: heart condition associated with sudden cardiac death (SCD), arrhythmia requiring cardiopulmonary resuscitation, direct current cardioversion/defibrillation or overdrive pacing, arrhythmia associated with SCD, any clinically significant arrhythmia that is not treated or controlled, QTc on electrocardiogram (ECG) more than 0.46 sec, or heart rate or blood pressure more than 2 standard deviations above the mean for age. All patients being considered for treatment with stimulant medications should have a careful history taken, including assessment for a family history of sudden death or ventricular arrhythmias, and a physical exam to assess for the presence of cardiac disease. If cardiac disease is suspected, further cardiac evaluation including an ECG and echocardiogram is warranted. For pediatric patients, the AHA states that it is reasonable to obtain a baseline ECG as a part of the initial evaluation. If a child or adolescent has any significant findings on physical examination, ECG, or family history, consult a pediatric cardiologist before initiating the stimulant medication. Once the medication is started, a repeat ECG may be helpful if the original ECG was obtained before the child was 12 years old, if cardiac symptoms develop, or there is a change in family history.

    Cerebrovascular disease, stroke

    Stroke has occurred in adults receiving stimulants at usual doses for attention-deficit hyperactivity disorder (ADHD); therefore, patients with cerebrovascular disease should be closely monitored while receiving amphetamine. Stimulant medications may increase blood pressure or heart rate in some individuals.

    Glaucoma, visual disturbance

    Use amphetamine with caution in patients with glaucoma. The sympathetic stimulation of amphetamines blocks aqueous outflow and raises intraocular pressure. Occasionally, visual disturbance, such as change in visual accomodation or blurred vision, have been reported in individuals without ocular disease while they are taking amphetamines. Patients should report any new visual disturbance as ophthalmic evaluation may be needed.

    Hyperthyroidism, thyrotoxicosis

    Amphetamine immediate-release tablets are contraindicated for use in thyroid disease patients with hyperthyroidism, including thyrotoxicosis, as sympathomimetic stimulation may induce cardiac arrhythmias or other side effects. Although not specifically contraindicated in the product labels, other amphetamine formulations should also be used with extreme caution in these patients.

    Tics, Tourette's syndrome

    Amphetamine may precipitate motor or phonetic tics in those with Tourette's syndrome; administer under close supervision and at the lowest effective dose.

    Driving or operating machinery

    The use of amphetamine may cause dizziness, mask signs of fatigue or the need for rest, or impair the ability of a patient to participate in activities that require mental alertness. Patients should not perform such tasks, including driving or operating machinery, until they are aware of how this medication affects them.

    Radiographic contrast administration, seizure disorder, seizures

    Use amphetamine with caution in patients with seizures or a history of a seizure disorder because the seizure threshold can be reduced, particularly during excess CNS stimulation (i.e., amphetamine overdosage). The effects of amphetamines on the seizure threshold, in normal therapeutic dosages, are less clear. Seizure threshold may be reduced in those with EEG abnormalities and rarely in patients without a seizure history or EEG abnormalities. If seizures occur, discontinuation of therapy is recommended. In addition, because of a potential increased risk of seizures, amphetamines should not be used during intrathecal radiographic contrast administration. Amphetamine should be discontinued 48 hours before the myelography and should not be resumed until at least 24 hours after the procedure.

    Surgery

    The use of inhalational anesthetics during surgery may sensitize the myocardium to the effects of amphetamines and other sympathomimetic drugs. Patients should check with their surgeon prior to elective surgery regarding any adjustments needed in timing of medications for surgical procedures.

    Hypercortisolism

    Amphetamine may cause hypercortisolism, as amphetamines can cause a significant elevation in plasma corticosteroid concentrations. The elevation is greatest in the evening. Amphetamines may interfere with urinary steroid determinations; consider the possible effect of amphetamine if determination of plasma corticosteroid concentrations is desired.

    Hepatic disease, renal impairment

    The elimination of amphetamines are dependent on hepatic metabolism, urinary pH and urinary flow rates, as well as active secretion. Both hepatic disease and renal impairment have the potential to inhibit the elimination of amphetamines and result in prolonged exposures.

    Peripheral vascular disease, Raynaud's phenomenon

    Stimulant medications, such as amphetamine, are associated with peripheral vasculopathy, including Raynaud's phenomenon. Worsening of peripheral vascular disease is possible. Effects on circulation have been observed with therapeutic doses at different times throughout therapy in all age groups. Signs and symptoms are usually intermittent and mild and generally improve after reduction in dose or discontinuation of drug. However, very rare sequelae include digital skin ulcer and/or soft tissue breakdown. Carefully monitor all patients for digital changes during treatment with stimulant medications, especially those with pre-existing circulation problems. Instruct patients to seek immediate medical attention if any new digital numbness, pain, skin discoloration, or temperature sensitivity occur, or if unexplained wounds appear on their fingers or toes. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

    Anorexia nervosa, bulimia nervosa, obesity treatment

    Obesity treatment with amphetamine should be initiated only in weight reduction programs for patients in whom alternative therapies, including repeated dietary reduction, exercise, or other medications have been ineffective. Eating disorders, such as anorexia nervosa or bulimia nervosa, should be ruled out prior to treatment with amphetamines. Patients with eating disorders may have physiologic complications, such as metabolic and electrolyte abnormalities, which increase their susceptibility to the adverse effects of stimulants. In addition, the abuse potential of stimulants in weight loss induction should be considered in patients with an eating disorder.

    Abrupt discontinuation

    Abrupt discontinuation of amphetamine after chronic use is not recommended. Discontinuation may unmask severe mental depression or extreme fatigue, or precipitate withdrawal symptoms. Gradual withdrawal of therapy is recommended.

    Geriatric

    Amphetamine has not been systematically studied in the geriatric patient for the treatment of attention deficit disorder (ADD/ADHD) or narcolepsy.    Stimulant medications are used as the treatments of choice in the adult patient over 50 years of age with ADHD when behavioral and lifestyle modifications alone have failed to improve concerns associated with inattention, such as task focus and completion, or organization and time management. Medication should be titrated with low doses initially and with a slow increase. Debilitated or geriatric patients may be more susceptible to the CNS and sympathomimetic side effects of the amphetamines; use with caution in the older adult. Side effects of amphetamines or other stimulants are usually mild but may include mood or behavior changes, tremor, insomnia, increased blood pressure, headache, or gastroesophageal reflux or other GI complaints. Adults should have their blood pressure and heart rate checked at baseline and periodically during treatment. If treatment is considered necessary, periodically re-evaluate the long-term usefulness of the drug for the individual patient.

    Neonates, pregnancy

    There are no adequate or well-controlled studies of amphetamine use in pregnant women; therefore, amphetamine should only be used during pregnancy if the expected benefit to the mother outweighs the potential fetal risk.[60070] [60232] [62373] There is 1 case of a neonate born with a severe congenital bony deformity, tracheoesophageal fistula, and anal atresia following maternal exposure to dextroamphetamine sulfate and lovastatin during the first trimester of pregnancy.[28488] However, most available data indicate that amphetamines are not teratogenic in humans. Among 671 mother-child pairs enrolled in the Collaborative Perinatal Project who had first-trimester exposure to amphetamines and 1,898 mother-child pairs with amphetamine exposures at any time during pregnancy, there was no evidence suggesting a relationship to large categories of major or minor malformations.[48419] Non-teratogenic effects known to occur in human neonates who are born to mothers dependent on amphetamines include increased incidences of premature births, low birth weights and length, lower occipitofrontal circumference, and physical withdrawal symptoms (e.g., abnormal sleep patterns, poor feeding, tremor, agitation, fatigue, and hypertonia).[60070] [48417] In 1 prospective comparison study, neonates exposed to cocaine, methamphetamine, or a combination of cocaine and narcotic in utero had a 35.1% incidence of cranial abnormalities (i.e., intraventricular hemorrhage, echodensities known to be associated with necrosis, and cavitary lesions) compared to a 5.3% incidence in normal newborns as assessed by cranial ultrasonography.[48418] The authors speculated that the ultrasonographic abnormalities were probably related to the vasoconstrictive properties of the drugs. The effects of amphetamine during labor and delivery are unknown. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to amphetamine; information about the registry can be obtained at womensmentalhealth.org/research/pregnancyregistry/ or by calling 1-866-961-2388.[60070] [60232] [62373]

    Breast-feeding

    Amphetamines are excreted into breast milk, and women who are taking amphetamines should generally refrain from breast-feeding.[60070] [60232] [62373] The effect of stimulant medication exposure via breast milk on the neurological development of the infant has not been well studied. Breast milk concentrations in a woman taking 20 mg daily of amphetamine ranged from 55 to 138 ng/mL with milk to plasma ratios of 2.8 to 7.5. The infant was monitored for 24 months, and no adverse effects from amphetamine exposure were noted.[46147] Similarly, there were no reports of neonatal insomnia or stimulation in 103 nursing infants whose mothers were taking various amounts of amphetamine.[48388] In one study of 4 women with attention deficit hyperactivity disorder receiving d-amphetamine (median dose 18 mg/day) while breast-feeding, the mean relative infant dose was 5.7% of the weight-adjusted maternal dose (range: 3.9 to 13.8%).[48389] Of the 3 infants in whom blood samples were obtained, plasma d-amphetamine levels were undetectable in one; d-amphetamine levels were approximately 6% and 14% of the corresponding maternal plasma concentrations in the remaining two infants. None of the four infants in the study showed any adverse effects. Methylphenidate may be considered an alternative to amphetamine agents in women who are breast-feeding an infant. The AAP has previously considered amphetamines, when used as drugs of abuse, to be contraindicated in breast-feeding due to concerns of irritability and poor sleeping pattern in the infant.[27500] If breast-feeding cannot be avoided during the administration of a stimulant, the nursing infant should be monitored for signs of central nervous system hyperactivity, including decreased appetite, insomnia, and irritability. If possible, long-term infant exposure to stimulants through breast milk should be avoided since the consequences of such exposure are unknown.[60070] [60232] [62373]

    Children, growth inhibition, infants

    Children 3 years and older have been successfully treated for attention-deficit-hyperactivity-disorder (ADHD) with amphetamines. Safety and efficacy of amphetamine have not been established in infants or children less than 3 years old. Do not use amphetamines for the management of obesity in children under the age of 12 years. It should be noted that not all children with ADHD will require medication; non-drug measures are often instituted concurrently with drug therapy. Monitoring of the effectiveness of stimulant therapy by the health care prescriber, parents, and teachers is important; periodic reassessment of the need for medication is recommended. Appropriate stimulant therapy should not suppress normal emotions or intellectual ability; the occurrence of certain side effects may indicate a need for dosage reduction. In psychotic children, amphetamines may exacerbate behavioral disturbances, psychosis, or thought disorders. New onset psychotic or manic symptoms may develop in children and adolescents receiving therapeutic doses of stimulants. Discontinuation of therapy may be required. Although a direct causal relationship has not been established, aggressive behavior and hostility have been reported during use of some stimulants for attention-deficit hyperactivity-disorder (ADHD) in children. It is recommended to monitor for signs of aggression or worsening of pre-existing aggressive behavior when treatment is initiated. The potential for growth inhibition in pediatric patients should be monitored during stimulant therapy. Monitor height and weight parameters relative to age at treatment initiation and periodically thereafter (at minimum yearly). Patients who are not growing or gaining weight as expected may need to have their treatment interrupted. Data obtained on the effects of the stimulants on growth suppression in children 7 to 10 years of age suggested that regularly medicated children (7 days/week) had a temporary average slowing in growth of 2 cm in height and 2.7 kg in weight over 3 years. The long-term effects of stimulants on brain development and physical growth in children are unknown. Sudden death has been reported in association with CNS stimulant treatment at usual doses in children with structural cardiac abnormalities or other serious heart problems (i.e., aortic stenosis, cardiomyopathy, congenital heart disease, prosthetic heart valves, valvular heart disease, ventricular dysfunction). Some case reports have involved concomitant medications, such as tricyclic antidepressants. A large retrospective cohort study including over 1.2 million children and young adults 2 to 24 years of age did not find an increased risk of serious cardiovascular events, including sudden cardiac death, myocardial infarction, or stroke in current users of drugs for the treatment of ADHD compared to nonusers (adjusted hazard ratio 0.75; 95% CI 0.31—1.85). The authors concluded that although the absolute magnitude of risk appears to be low, a modest increase in risk could not be ruled out. Although some structural cardiac abnormalities alone may carry an increased risk of sudden death, stimulant products generally should not be used in patients with known structural cardiac abnormalities or other serious heart conditions. Exceptions to this warning do exist, but careful screening and monitoring is recommended by the American Heart Association (see separate paragraph detailing cardiac contraindications and precautions).

    MAOI therapy

    Amphetamine is contraindicated in patients who have received MAOI therapy, including linezolid or intravenous methylene blue, within the past 14 days. MAOI antidepressants slow amphetamine metabolism, potentiating their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings. This may precipitate hypertensive crisis, malignant hyperthermia, serotonin syndrome, and a variety of toxic neurologic effects; these events can be fatal. Increased risk for serotonin syndrome also may occur when amphetamines are co-administered with serotonergic agents (e.g., SSRIs, SNRIs, triptans, and others), and may also occur during overdosage situations. If serotonin syndrome occurs, discontinue amphetamine and all other serotonergic agents, and initiate supportive treatment.

    Ethanol ingestion

    Ethanol ingestion may result in a more rapid release of amphetamine from the extended-release product; advise patients taking these products to avoid alcohol. In vitro studies of both the extended-release suspension (Dyanavel) and extended-release ODT (Adzenys) showed alcohol-induced dose dumping potential in the presence of 40% alcohol. Dose dumping was not observed in the presence of lower alcohol concentrations.

    ADVERSE REACTIONS

    Severe

    Tourette's syndrome / Delayed / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    bowel necrosis / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    stroke / Early / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known

    Moderate

    constipation / Delayed / 1.0-10.0
    dyspnea / Early / 1.0-10.0
    impotence (erectile dysfunction) / Delayed / 2.0-4.0
    dysphemia / Delayed / 0-4.0
    psychosis / Early / 0.1-0.2
    palpitations / Early / 10.0
    sinus tachycardia / Rapid / 9.0
    euphoria / Early / Incidence not known
    supranormalization / Delayed / Incidence not known
    dyskinesia / Delayed / Incidence not known
    growth inhibition / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    hypertension / Early / Incidence not known
    priapism / Early / Incidence not known
    hallucinations / Early / Incidence not known
    formication / Early / Incidence not known
    mania / Early / Incidence not known
    teeth grinding (bruxism) / Delayed / Incidence not known
    hostility / Early / Incidence not known
    dysphoria / Early / Incidence not known
    depression / Delayed / Incidence not known
    blurred vision / Early / Incidence not known
    skin ulcer / Delayed / Incidence not known
    peripheral vasoconstriction / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known
    tachypnea / Early / Incidence not known
    delirium / Early / Incidence not known
    hyperreflexia / Delayed / Incidence not known
    confusion / Early / Incidence not known
    hyperthermia / Delayed / Incidence not known
    psychological dependence / Delayed / Incidence not known
    tolerance / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    physiological dependence / Delayed / Incidence not known

    Mild

    infection / Delayed / 2.0-22.0
    dyspepsia / Early / 1.0-10.0
    drowsiness / Early / 1.0-10.0
    fatigue / Early / 10.0-10.0
    diaphoresis / Early / 1.0-10.0
    asthenia / Delayed / 1.0-10.0
    fever / Early / 1.0-10.0
    emotional lability / Early / 2.0-9.0
    dysmenorrhea / Delayed / 2.0-4.0
    libido decrease / Delayed / 2.0-4.0
    epistaxis / Delayed / 3.8-3.8
    rhinitis / Early / 3.8-3.8
    vomiting / Early / 6.0
    insomnia / Early / 4.0
    weight loss / Delayed / 10.0
    headache / Early / 10.0
    nausea / Early / 6.0
    abdominal pain / Early / 3.0
    xerostomia / Early / 6.0
    anorexia / Delayed / 4.0
    irritability / Delayed / 10.0
    dizziness / Early / 10.0
    diarrhea / Early / 10.0
    anxiety / Delayed / 10.0
    dysgeusia / Early / Incidence not known
    restlessness / Early / Incidence not known
    syncope / Early / Incidence not known
    libido increase / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    agitation / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    rash / Early / Incidence not known
    mydriasis / Early / Incidence not known
    paranoia / Early / Incidence not known
    tremor / Early / Incidence not known

    DRUG INTERACTIONS

    Acarbose: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Acebutolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
    Acetaminophen; Caffeine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
    Acetaminophen; Codeine: (Moderate) If concomitant use of codeine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Acetaminophen; Hydrocodone: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Acetaminophen; Oxycodone: (Moderate) If concomitant use of oxycodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Acetazolamide: (Moderate) Urinary alkalinizers, such as acetazolamide, result in decreased renal excretion of amphetamines. Monitor for amphetamine-related side effects. Avoid concomitant use in amphetamine overdose situations. Urinary alkalinizers increase the proportion of non-ionized metabolites of the amphetamine molecule, resulting in decreased renal excretion of these compounds. Alkaline urine will significantly increase the half-life of the amphetamines.
    Aclidinium; Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Albiglutide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Albuterol: (Moderate) Caution and close observation should be used when albuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Alfentanil: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering alfentanil with amphetamines. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Aliskiren; Amlodipine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Aliskiren; Valsartan: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.
    Alkalinizing Agents: (Major) Concurrent use of amphetamines with urinary alkalinizing agents should be avoided if possible. If avoidance is not possible, the dose of the amphetamine therapy may need to be adjusted (decreased) in some patients. Monitor for increased blood pressure, increased heart rate, decreased appetite, palpitations, insomnia, irritability, anxiety, or other changes in moods and behaviors. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of the amphetamines. The half-life and therapeutic actions of amphetamines will be prolonged.
    Alogliptin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Alogliptin; Pioglitazone: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Alpha-glucosidase Inhibitors: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Aluminum Hydroxide: (Moderate) Antacids and other gastrointestinal alkalinizing agents increase the oral absorption of amphetamines. This may lead to increased amphetamine concentrations. To help limit an interaction, do not take antacids at the same time as the amphetamine product. It is recommended to separate times of administration.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Antacids and other gastrointestinal alkalinizing agents increase the oral absorption of amphetamines. This may lead to increased amphetamine concentrations. To help limit an interaction, do not take antacids at the same time as the amphetamine product. It is recommended to separate times of administration.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Antacids and other gastrointestinal alkalinizing agents increase the oral absorption of amphetamines. This may lead to increased amphetamine concentrations. To help limit an interaction, do not take antacids at the same time as the amphetamine product. It is recommended to separate times of administration.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Antacids and other gastrointestinal alkalinizing agents increase the oral absorption of amphetamines. This may lead to increased amphetamine concentrations. To help limit an interaction, do not take antacids at the same time as the amphetamine product. It is recommended to separate times of administration.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Antacids and other gastrointestinal alkalinizing agents increase the oral absorption of amphetamines. This may lead to increased amphetamine concentrations. To help limit an interaction, do not take antacids at the same time as the amphetamine product. It is recommended to separate times of administration.
    Amantadine: (Moderate) Careful observation is required when amantadine is administered concurrently with central nervous system (CNS) stimulants. An increase in stimulant effects, such as nervousness, irritability, insomnia, tremor, seizures, or cardiac arrhythmias may occur.
    Ambrisentan: (Minor) Sympathomimetics such as amphetamine or dextroamphetamine can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy of ambrisentan.
    Amifampridine: (Major) Carefully consider the need for concomitant treatment with amphetamines and amifampridine, as coadministration may increase the risk of seizures. If coadministration occurs, closely monitor patients for seizure activity. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Amphetamines may increase the risk of seizures.
    Amiloride; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Amlodipine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Amlodipine; Atorvastatin: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Amlodipine; Benazepril: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised. (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Amlodipine; Celecoxib: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Amlodipine; Olmesartan: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised. (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.
    Amlodipine; Valsartan: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised. (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised. (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Ammonium Chloride: (Major) Urinary acidifying agents, such as ammonium chloride, phosphorus salts, and methenamine salts (e.g., methenamine; sodium acid phosphate), reduce the tubular reabsorption of amphetamines. As a result, amphetamine clearance is accelerated and the duration of effect is reduced. Combination therapy should be avoided if possible.
    Amoxapine: (Major) Concomitant use of amoxapine with sympathomimetics should be avoided whenever possible; use with caution when concurrent use cannot be avoided. One drug information reference suggests that cyclic antidepressants potentiate the pharmacologic effects of indirect-acting sympathomimetics, such as amphetamine, however, the data are not consistent.
    Angiotensin II receptor antagonists: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.
    Angiotensin-converting enzyme inhibitors: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.
    Antacids: (Moderate) Antacids and other gastrointestinal alkalinizing agents increase the oral absorption of amphetamines. This may lead to increased amphetamine concentrations. To help limit an interaction, do not take antacids at the same time as the amphetamine product. It is recommended to separate times of administration.
    Arformoterol: (Moderate) Caution and close observation should be used when arformoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Armodafinil: (Moderate) The use of armodafinil with other psychostimulants, including amphetamines, (e.g., dextroamphetamine, lisdexamfetamine, amphetamine) has not been studied. In a single-dose study of dextroamphetamine combined with modafinil, a racemic compound containing armodafinil, no pharmacokinetic interactions occurred but a slight increase in stimulant-associated side effects was noted. Patients receiving combination therapy of armodafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other stimulant-related side effects.
    Articaine; Epinephrine: (Moderate) Amphetamines may potentiate the pressor effects of epinephrine.
    Ascorbic Acid, Vitamin C: (Moderate) Concurrent use of amphetamines and gastrointestinal acidifying agents, such as ascorbic acid, vitamin C, should be used with caution. Vitamin C lowers the absorption of amphetamines, resulting in reduced efficacy. It may be advisable to separate times of administration. In addition, ascorbic acid acts as a urinary acidifier, which reduces the renal tubular reabsorption of amphetamines, accelerating amphetamine clearance and reducing the duration of effect. If combined use is necessary, the amphetamine dose should be adjusted according to clinical response as needed.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine. (Moderate) If concomitant use of codeine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Aspirin, ASA; Caffeine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) If concomitant use of codeine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) Concurrent use of amphetamines with urinary alkalinizing agents should be avoided if possible. If avoidance is not possible, the dose of the amphetamine therapy may need to be adjusted (decreased) in some patients. Monitor for increased blood pressure, increased heart rate, decreased appetite, palpitations, insomnia, irritability, anxiety, or other changes in moods and behaviors. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of the amphetamines. The half-life and therapeutic actions of amphetamines will be prolonged.
    Aspirin, ASA; Oxycodone: (Moderate) If concomitant use of oxycodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Atenolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Atenolol; Chlorthalidone: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Atomoxetine: (Moderate) Consider monitoring heart rate and blood pressure at baseline and regularly throughout treatment if these agents must be used together. Amphetamines increase both systolic and diastolic blood pressure; atomoxetine has been reported to also increase blood pressure and heart rate, probably via inhibition of norepinephrine reuptake. Due to an additive pharmacodynamic effect, amphetamine; dextroamphetamine combinations and atomoxetine should be used together cautiously, particularly in patients with a history of cardiac disease.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) Amphetamines should not be administered during or within 14 days after the use of methylene blue. Methylene blue is a potent, reversible monoamine oxidase inhibitor (MAOI) which can prolong and intensify the cardiac stimulation and vasopressor effects of amphetamines, potentially resulting in hypertensive crisis. Methylene blue also has the potential to interact with serotonergic agents, such as amphetamines, which may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by 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, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), and in rare instances, death. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents, such as amphetamines, with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. (Major) Urinary acidifying agents, such as ammonium chloride, phosphorus salts, and methenamine salts (e.g., methenamine; sodium acid phosphate), reduce the tubular reabsorption of amphetamines. As a result, amphetamine clearance is accelerated and the duration of effect is reduced. Combination therapy should be avoided if possible.
    Azilsartan: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.
    Azilsartan; Chlorthalidone: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable. (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use dextroamphetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, the amphetamines may delay the intestinal absorption of phenobarbital; the extent of absorption of these seizure medications is not known to be affected.
    Benazepril: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.
    Benazepril; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Bendroflumethiazide; Nadolol: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) Amphetamines should not be administered during or within 14 days after the use of methylene blue. Methylene blue is a potent, reversible monoamine oxidase inhibitor (MAOI) which can prolong and intensify the cardiac stimulation and vasopressor effects of amphetamines, potentially resulting in hypertensive crisis. Methylene blue also has the potential to interact with serotonergic agents, such as amphetamines, which may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by 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, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), and in rare instances, death. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents, such as amphetamines, with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. (Major) Urinary acidifying agents, such as ammonium chloride, phosphorus salts, and methenamine salts (e.g., methenamine; sodium acid phosphate), reduce the tubular reabsorption of amphetamines. As a result, amphetamine clearance is accelerated and the duration of effect is reduced. Combination therapy should be avoided if possible.
    Beta-blockers: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Betaxolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Bethanechol: (Moderate) Bethanechol offsets the effects of sympathomimetics at sites where sympathomimetic and cholinergic receptors have opposite effects.
    Bisoprolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Bosentan: (Major) Avoid use of sympathomimetic agents with bosentan. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including bosentan. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Bretylium: (Moderate) Monitor blood pressure and heart rate closely when sympathomimetics are administered with bretylium. The pressor and arrhythmogenic effects of catecholamines are enhanced by bretylium.
    Brimonidine; Timolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Bromocriptine: (Moderate) Concurrent use of bromocriptine and some sympathomimetics such as amphetamines should be approached with caution. One case report documented worsening headache, hypertension, premature ventricular complexes, and ventricular tachycardia in a post-partum patient receiving bromocriptine for lactation suppression who was subsequently prescribed an isometheptene-containing medication for a headache. A second case involved a post-partum patient receiving bromocriptine who was later prescribed a phenylpropanolamine-expectorant combination and subsequently developed hypertension, tachycardia, seizures, and cerebral vasospasm.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Budesonide; Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Buprenorphine: (Moderate) If concomitant use of buprenorphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Buprenorphine; Naloxone: (Moderate) If concomitant use of buprenorphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Bupropion: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Bupropion; Naltrexone: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Buspirone: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and buspirone. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine. (Moderate) If concomitant use of codeine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Caffeine: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants. Patients may need to reduce, limit, or avoid caffeine intake. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
    Caffeine; Sodium Benzoate: (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
    Calcium Carbonate: (Moderate) Calcium carbonate is a gastrointestinal alkalinizing agent that may iincrease the oral absorption of amphetamines and increase amphetamine concentrations. To help limit an interaction, do not take caclium carbonate at the same time as the amphetamine product. It is recommended to separate times of administration.
    Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Calcium carbonate is a gastrointestinal alkalinizing agent that may iincrease the oral absorption of amphetamines and increase amphetamine concentrations. To help limit an interaction, do not take caclium carbonate at the same time as the amphetamine product. It is recommended to separate times of administration. (Moderate) The use of H2-blockers with amphetamine therapy may change the onset of action of amphetamine or dextroamphetamine due to the increase in gastric pH. The time to maximum concentration (Tmax) of these amphetamines is decreased compared to when administered alone, thus increasing stimulant concentrations, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) Calcium carbonate is a gastrointestinal alkalinizing agent that may iincrease the oral absorption of amphetamines and increase amphetamine concentrations. To help limit an interaction, do not take caclium carbonate at the same time as the amphetamine product. It is recommended to separate times of administration.
    Calcium Carbonate; Risedronate: (Moderate) Calcium carbonate is a gastrointestinal alkalinizing agent that may iincrease the oral absorption of amphetamines and increase amphetamine concentrations. To help limit an interaction, do not take caclium carbonate at the same time as the amphetamine product. It is recommended to separate times of administration.
    Calcium Carbonate; Simethicone: (Moderate) Calcium carbonate is a gastrointestinal alkalinizing agent that may iincrease the oral absorption of amphetamines and increase amphetamine concentrations. To help limit an interaction, do not take caclium carbonate at the same time as the amphetamine product. It is recommended to separate times of administration.
    Calcium, Magnesium, Potassium, Sodium Oxybates: (Moderate) Sodium oxybate has the potential to induce seizures; it has been speculated that this effect may be mediated through the action of sodium oxybate at GABA receptors. Although convulsant effects occur primarily at high dosages, sodium oxybate should be used cautiously with psychostimulants that are known to lower seizure threshold such as the amphetamines. Note that CNS stimulants, including the amphetamines, are frequently used in the treatment of narcolepsy, and clinical trials involving the use of psychostimulants with sodium oxybate have not found the combinations to be unsafe. Pharmacodynamic interactions cannot be ruled out, however.
    Calcium-channel blockers: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Canagliflozin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Canagliflozin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Candesartan: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.
    Candesartan; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Captopril: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.
    Captopril; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Carbamazepine: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
    Carbidopa; Levodopa: (Major) Levodopa, due to its conversion to dopamine, may increase the risk of developing amphetamine-induced cardiac arrhythmias; dosage reductions of amphetamines are recommended if the two agents are used concurrently.
    Carbidopa; Levodopa; Entacapone: (Major) Levodopa, due to its conversion to dopamine, may increase the risk of developing amphetamine-induced cardiac arrhythmias; dosage reductions of amphetamines are recommended if the two agents are used concurrently.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Cardiac glycosides: (Major) Concomitant use of cardiac glycosides with sympathomimetics can cause arrhythmias because sympathomimetics enhance ectopic pacemaker activity. Caution is warranted during co-administration of digoxin and sympathomimetics.
    Carteolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Carvedilol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Chlorothiazide: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Chlorpheniramine; Codeine: (Moderate) If concomitant use of codeine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Chlorpheniramine; Hydrocodone: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Chlorthalidone: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Chlorthalidone; Clonidine: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed in patients receiving clonidine and amphetamines. Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents
    Cimetidine: (Moderate) The use of H2-blockers with amphetamine therapy may change the onset of action of amphetamine or dextroamphetamine due to the increase in gastric pH. The time to maximum concentration (Tmax) of these amphetamines is decreased compared to when administered alone, thus increasing stimulant concentrations, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed.
    Cinacalcet: (Moderate) Warn patients that there are potentially serious drug interactions between cinacalcet and prescription amphetamine therapy or illicit amphetamine use. The risk of amphetamine toxicity may be increased during concurrent use of potent CYP2D6 inhibitors such as cinacalcet. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
    Citalopram: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and citalopram. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Citric Acid; Potassium Citrate; Sodium Citrate: (Major) Concurrent use of amphetamines with urinary alkalinizing agents should be avoided if possible. If avoidance is not possible, the dose of the amphetamine therapy may need to be adjusted (decreased) in some patients. Monitor for increased blood pressure, increased heart rate, decreased appetite, palpitations, insomnia, irritability, anxiety, or other changes in moods and behaviors. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of the amphetamines. The half-life and therapeutic actions of amphetamines will be prolonged.
    Clevidipine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Clobazam: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Clonazepam: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamine; dextroamphetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures.
    Clonidine: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed in patients receiving clonidine and amphetamines. Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents
    Cocaine: (Major) Avoid concomitant use of additional vasoconstrictor agents with cocaine. If unavoidable, prolonged vital sign and ECG monitoring may be required. Myocardial ischemia, myocardial infarction, and ventricular arrhythmias have been reported after concomitant administration of topical intranasal cocaine and vasoconstrictor agents during nasal and sinus surgery. The risk for nervousness, irritability, convulsions, and other cardiac arrhythmias may increase during coadministration.
    Codeine: (Moderate) If concomitant use of codeine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Codeine; Guaifenesin: (Moderate) If concomitant use of codeine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) If concomitant use of codeine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Codeine; Phenylephrine; Promethazine: (Moderate) If concomitant use of codeine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Codeine; Promethazine: (Moderate) If concomitant use of codeine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Colchicine: (Minor) The response to sympathomimetics may be enhanced by colchicine.
    Dacomitinib: (Moderate) Warn patients that the risk of amphetamine toxicity, including serotonin syndrome, may be increased during concurrent use with dacomitinib. Concurrent use of dacomitinib, a strong CYP2D6 inhibitor, may increase exposure to the amphetamine increasing the risk for serotonin syndrome. If serotonin syndrome occurs, both the amphetamine and dacomitinib should be discontinued and appropriate medical treatment should be implemented.
    Dapagliflozin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Dapagliflozin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Dapagliflozin; Saxagliptin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
    Delavirdine: (Moderate) Warn patients that there are potentially serious drug interactions between delavirdine and prescription amphetamine therapy or illicit amphetamine use. The risk of amphetamine toxicity may be increased during concurrent use of potent CYP2D6 inhibitors such as delavirdine. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
    Desvenlafaxine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin norepinephrine reuptake inhibitors (SNRIs). At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Dextrin: (Major) Concurrent use of amphetamines with urinary alkalinizing agents should be avoided if possible. If avoidance is not possible, the dose of the amphetamine therapy may need to be adjusted (decreased) in some patients. Monitor for increased blood pressure, increased heart rate, decreased appetite, palpitations, insomnia, irritability, anxiety, or other changes in moods and behaviors. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of the amphetamines. The half-life and therapeutic actions of amphetamines will be prolonged.
    Dextromethorphan; Quinidine: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of quinidine, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
    Diazepam: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use dextroamphetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures.
    Digitoxin: (Major) Concomitant use of cardiac glycosides with sympathomimetics can cause arrhythmias because sympathomimetics enhance ectopic pacemaker activity. Caution is warranted during co-administration of digoxin and sympathomimetics.
    Digoxin: (Major) Concomitant use of cardiac glycosides with sympathomimetics can cause arrhythmias because sympathomimetics enhance ectopic pacemaker activity. Caution is warranted during co-administration of digoxin and sympathomimetics.
    Dihydroergotamine: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable.
    Diltiazem: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Dorzolamide; Timolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Doxazosin: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed in patients receiving doxazosin and amphetamines. Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as doxazosin.
    Dronabinol: (Moderate) Concurrent use of dronabinol, THC with sympathomimetics may result in additive hypertension, tachycardia, and possibly cardiotoxicity. Dronabinol, THC has been associated with occasional hypotension, hypertension, syncope, and tachycardia. In a study of 7 adult males, combinations of IV cocaine and smoked marijuana, 1 g marijuana cigarette, 0 to 2.7% delta-9-THC, increased the heart rate above levels seen with either agent alone, with increases plateauing at 50 bpm.
    Dulaglutide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Duloxetine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin norepinephrine reuptake inhibitors (SNRIs). At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Dyphylline: (Moderate) Use of sympathomimetics with dyphylline should be approached with caution. Coadministration may lead to adverse effects, such as tremors, insomnia, seizures, or cardiac arrhythmias.
    Dyphylline; Guaifenesin: (Moderate) Use of sympathomimetics with dyphylline should be approached with caution. Coadministration may lead to adverse effects, such as tremors, insomnia, seizures, or cardiac arrhythmias.
    Empagliflozin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Empagliflozin; Linagliptin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Empagliflozin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Enalapril, Enalaprilat: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.
    Enalapril; Felodipine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised. (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Enalapril; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Enflurane: (Major) Inhalational general anesthetics (e.g., enflurane, halothane, isoflurane, and methoxyflurane) may sensitize the myocardium to the effects of stimulants. Dosages of the amphetamines should be substantially reduced prior to surgery, and caution should be observed with concurrent use of anesthetics.
    Epinephrine: (Moderate) Amphetamines may potentiate the pressor effects of epinephrine.
    Eplerenone: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed in patients receiving eplerenone and amphetamines. Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents.
    Epoprostenol: (Major) Avoid use of sympathomimetic agents with epoprostenol. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including epoprostenol. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Eprosartan: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Ergoloid Mesylates: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable.
    Ergonovine: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable.
    Ergot alkaloids: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable.
    Ergotamine: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable.
    Ergotamine; Caffeine: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable. (Moderate) Avoid excessive caffeine intake during use of the amphetamine salts. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Excessive caffeine ingestion (via medicines, foods like chocolate, dietary supplements, or beverages including coffee, green tea, other teas, colas) may contribute to side effects like nervousness, irritability, nausea, insomnia, or tremor. Patients should avoid medications and dietary supplements which contain high amounts of caffeine.
    Ertugliflozin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Ertugliflozin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Ertugliflozin; Sitagliptin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Escitalopram: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and escitalopram. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Esketamine: (Major) Closely monitor blood pressure during concomitant use of esketamine and an amphetamine. Coadministration of psychostimulants, such as amphetamines, with esketamine may increase blood pressure, including the possibility of hypertensive crisis.
    Eslicarbazepine: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Esmolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Ethanol: (Major) Alcohol should not be consumerd with some dosage forms (e.g., Mydayis extended-release capsules) of amphetamine/dextroamphetamine salts. Consumption of alcohol while taking such dosage forms may result in a more rapid release of the dose of mixed amphetamine salts. Such effects may potentially lead to serious side effects such as acute anxiety, problems with sleep, or increases in heart rate or blood pressure that may lead to heart problems or stroke.Also, the use of amphetamine/dextroamphetamine salts may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or vehicles; the patient should therefore be cautioned accordingly. (Major) Alcohol should not be consumerd with some dosage forms (e.g., Mydayis extended-release capsules) of amphetamine/dextroamphetamine salts. Consumption of alcohol while taking such dosage forms may result in a more rapid release of the dose of mixed amphetamine salts. Such effects may potentially lead to serious side effects such as acute anxiety, problems with sleep, or increases in heart rate or blood pressure that may lead to heart problems or stroke.
    Ethotoin: (Major) Amphetamine or dextroamphetamine may delay the intestinal absorption of orally-administered phenytoin; the extent of phenytoin absorption is not known to be effected. Monitor the patient's neurologic status closely, as the amphetamines may also lower the seizure threshold in some patients on phenytoin or fosphenytoin.
    Etomidate: (Major) Inhalational general anesthetics may sensitize the myocardium to the effects of dextroamphetamine. Dosages of the amphetamines should be substantially reduced prior to surgery, and caution should be observed with concurrent use of anesthetics.
    Exenatide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Ezogabine: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Famotidine: (Moderate) The use of H2-blockers with amphetamine therapy may change the onset of action of amphetamine or dextroamphetamine due to the increase in gastric pH. The time to maximum concentration (Tmax) of these amphetamines is decreased compared to when administered alone, thus increasing stimulant concentrations, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed.
    Famotidine; Ibuprofen: (Moderate) The use of H2-blockers with amphetamine therapy may change the onset of action of amphetamine or dextroamphetamine due to the increase in gastric pH. The time to maximum concentration (Tmax) of these amphetamines is decreased compared to when administered alone, thus increasing stimulant concentrations, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed.
    Felbamate: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use dextroamphetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures.
    Felodipine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Fenfluramine: (Moderate) Use fenfluramine and amphetamines with caution due to an increased risk of serotonin syndrome. Monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Fentanyl: (Moderate) If concomitant use of fentanyl and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Fluoxetine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and fluoxetine. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. In addition, amphetamines are partially metabolized by CYP2D6 and fluoxetine is a strong CYP2D6 inhibitor. Increased systemic exposure to amphetamines from CYP2D6 inhibition may result in high blood pressure, tachycardia, anxiety, irritability, insomnia, or other amphetamine-related adverse effects.
    Fluticasone; Salmeterol: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Administer sympathomimetics with caution with beta-agonists such as vilanterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects.
    Fluticasone; Vilanterol: (Moderate) Administer sympathomimetics with caution with beta-agonists such as vilanterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects.
    Fluvoxamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and fluvoxamine. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Food: (Major) Avoid administering marijuana and amphetamines together as concurrent use may result in adverse cardiovascular effects, such as tachycardia and cardiac arrhythmias. Marijuana is known to produce significant increases in heart rate and cardiac output lasting for 2-3 hours. Further, rare case reports of myocardial infarction and cardiac arrhythmias have been associated with marijuana use. Amphetamines have also been reported to produce a wide range of cardiovascular effects including cardiac arrhythmias, palpitations, and sinus tachycardia. Coadministration of marijuana with amphetamines may result in significant cardiovascular adverse events and thus, should be avoided. (Moderate) In general, food does not significantly interact with the amphetamine stimulants, a dose may be taken with or without food. However, certain gastrointestinal acidifying agents (e.g., certain fruit juices, etc.) can lower the oral absorption of amphetamines. To ensure proper absorption, it may be prudent for the patient to avoid citrus fruits and citrus juices 1 hour before a dose, at the time of dosing, and for the 1 hour following a dose. In addition, the excretion of amphetamines is increased in acidic urine and decreased in alkaline urine. Foods that acidify the urine, such as cranberry juice, orange juice, or those that contain vitamin C (ascorbic acid) may increase amphetamine renal excretion. Conversely, foods that alkalinize the urine, such as beets, dairy products, kale, spinach may slightly slow urinary excretion of amphetamines. Patients should not significantly alter their diets, however, as these changes in urinary pH from foods are not expected to be clinically significant for most patients. (Minor) In general, food does not significantly interact with the amphetamine stimulants, a dose may be taken with or without food. Foods that alkalinize the urine, such as beets, dairy products, kale, spinach may slightly slow urinary excretion of amphetamines. Patients should not significantly alter their diets, however, as these alkaline changes in urinary pH from foods are not expected to be clinically significant for most patients.
    Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Formoterol; Mometasone: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Fosinopril: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Fosphenytoin: (Major) Amphetamine or dextroamphetamine may delay the intestinal absorption of orally-administered phenytoin; the extent of phenytoin absorption is not known to be effected. Monitor the patient's neurologic status closely, as the amphetamines may also lower the seizure threshold in some patients on phenytoin or fosphenytoin.
    Gabapentin: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, discontinue use of amphetamines.
    Glimepiride; Rosiglitazone: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Glipizide; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Glyburide; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Glycopyrrolate; Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Green Tea: (Major) Some green tea products contain caffeine. Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants; caffeine should be avoided or used cautiously.
    Guaifenesin; Hydrocodone: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Guanabenz: (Moderate) Sympathomimetics can antagonize the antihypertensive effects of guanabenz when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Guanfacine: (Moderate) Sympathomimetic agents, such as amphetamines, may increase blood pressure and reduce the antihypertensive effects of antihypertensive agents, such as guanfacine. Monitor blood pressure and heart rate periodically when prescribed together. Guanfacine may be used adjunctively to psychostimulants such as amphetamines in the treatment of attention deficit hyperactivity disorder (ADHD). Pharmacokinetic studies reveal that guanfacine does not influence lisdexamfetamine pharmacokinetics and lisdexamfetamine does not affect guanfacine pharmacokinetics. No dosage adjustments are required when guanfacine and amphetamines are used together for ADHD. Monitor heart rate, blood pressure and for sedation during ADHD treatment.
    H2-blockers: (Moderate) The use of H2-blockers with amphetamine therapy may change the onset of action of amphetamine or dextroamphetamine due to the increase in gastric pH. The time to maximum concentration (Tmax) of these amphetamines is decreased compared to when administered alone, thus increasing stimulant concentrations, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed.
    Halothane: (Major) Inhalational general anesthetics (e.g., enflurane, halothane, isoflurane, and methoxyflurane) may sensitize the myocardium to the effects of stimulants. Dosages of the amphetamines should be substantially reduced prior to surgery, and caution should be observed with concurrent use of anesthetics.
    Homatropine; Hydrocodone: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Hydantoins: (Major) Amphetamine or dextroamphetamine may delay the intestinal absorption of orally-administered phenytoin; the extent of phenytoin absorption is not known to be effected. Monitor the patient's neurologic status closely, as the amphetamines may also lower the seizure threshold in some patients on phenytoin or fosphenytoin.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Hydrochlorothiazide, HCTZ: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed in patients receiving methyldopa and amphetamines. Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents
    Hydrochlorothiazide, HCTZ; Moexipril: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Hydrocodone: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Hydrocodone; Ibuprofen: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Hydrocodone; Phenylephrine: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Hydrocodone; Pseudoephedrine: (Moderate) If concomitant use of hydrocodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Hydromorphone: (Moderate) If concomitant use of hydromorphone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Contraindicated) Amphetamines should not be administered during or within 14 days after the use of methylene blue. Methylene blue is a potent, reversible monoamine oxidase inhibitor (MAOI) which can prolong and intensify the cardiac stimulation and vasopressor effects of amphetamines, potentially resulting in hypertensive crisis. Methylene blue also has the potential to interact with serotonergic agents, such as amphetamines, which may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by 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, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), and in rare instances, death. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents, such as amphetamines, with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. (Major) Urinary acidifying agents, such as ammonium chloride, phosphorus salts, and methenamine salts (e.g., methenamine; sodium acid phosphate), reduce the tubular reabsorption of amphetamines. As a result, amphetamine clearance is accelerated and the duration of effect is reduced. Combination therapy should be avoided if possible.
    Ibritumomab Tiuxetan: (Major) Concurrent use of amphetamines with urinary alkalinizing agents should be avoided if possible. If avoidance is not possible, the dose of the amphetamine therapy may need to be adjusted (decreased) in some patients. Monitor for increased blood pressure, increased heart rate, decreased appetite, palpitations, insomnia, irritability, anxiety, or other changes in moods and behaviors. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of the amphetamines. The half-life and therapeutic actions of amphetamines will be prolonged.
    Ibuprofen; Oxycodone: (Moderate) If concomitant use of oxycodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Iloprost: (Major) Avoid use of sympathomimetic agents with iloprost. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including iloprost. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Incretin Mimetics: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Indacaterol: (Moderate) Administer sympathomimetics with caution with beta-agonists such as indacaterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects.
    Indacaterol; Glycopyrrolate: (Moderate) Administer sympathomimetics with caution with beta-agonists such as indacaterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects.
    Indapamide: (Moderate) Indapamide may increase blood levels and therefore potentiate the actions of amphetamines. Thiazide diuretics and related drugs like indapamide may increase urinary pH, acting as a urinary alkalinizer, thus reducing urinary excretion and increasing blood concentrations of the amphetamine. Co-administration of amphetamines and urinary alkalinizing agents should be avoided if possible. If needed, monitor for common amphetamine side effects, including decreased appetite, anxiety, dizziness, dry mouth, irritability, insomnia, nausea, increased blood pressure or increased heart rate.
    Insulin Degludec; Liraglutide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Insulin Glargine; Lixisenatide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Insulins: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Iobenguane I 131: (Major) Discontinue sympathomimetics for at least 5 half-lives before the administration of the dosimetry dose or a therapeutic dose of iobenguane I-131. Do not restart sympathomimetics until at least 7 days after each iobenguane I-131 dose. Drugs that reduce catecholamine uptake or deplete catecholamine stores, such as sympathomimetics, may interfere with iobenguane I-131 uptake into cells and interfere with dosimetry calculations resulting in altered iobenguane I-131 efficacy.
    Ipratropium; Albuterol: (Moderate) Caution and close observation should be used when albuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Irbesartan: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Isocarboxazid: (Contraindicated) In general, sympathomimetics should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use.
    Isoflurane: (Major) Inhalational general anesthetics (e.g., enflurane, halothane, isoflurane, and methoxyflurane) may sensitize the myocardium to the effects of stimulants. Dosages of the amphetamines should be substantially reduced prior to surgery, and caution should be observed with concurrent use of anesthetics.
    Isradipine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Ketamine: (Moderate) Closely monitor vital signs when ketamine and amphetamine; dextroamphetamine salts are coadministered; consider dose adjustment individualized to the patient's clinical situation. Amphetamine; dextroamphetamine salts may enhance the sympathomimetic effects of ketamine.
    Labetalol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Lacosamide: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
    Lamotrigine: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
    Lasmiditan: (Moderate) Serotonin syndrome may occur during coadministration of lasmiditan and amphetamines. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Levalbuterol: (Moderate) Caution and close observation should be used when albuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Levamlodipine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Levetiracetam: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
    Levobetaxolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Levobunolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Levodopa: (Major) Levodopa, due to its conversion to dopamine, may increase the risk of developing amphetamine-induced cardiac arrhythmias; dosage reductions of amphetamines are recommended if the two agents are used concurrently.
    Levomilnacipran: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin norepinephrine reuptake inhibitors (SNRIs). At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Levorphanol: (Moderate) If concomitant use of levorphanol and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Levothyroxine: (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Levothyroxine; Liothyronine (Porcine): (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Levothyroxine; Liothyronine (Synthetic): (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Linagliptin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Linezolid: (Contraindicated) Amphetamines should not be administered during or within 14 days after the use of linezolid. Linezolid possesses MAO-inhibiting activity and can prolong and intensify the cardiac stimulation and vasopressor effects of the amphetamines, potentially resulting in hypertensive crisis. Linezolid also has the potential to interact with serotonergic agents, such as amphetamines, which may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by 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, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), and in rare instances, death. If serotonin syndrome occurs, discontinue serotonergic drugs and institute appropriate medical management.
    Liothyronine: (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Liraglutide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Lisinopril: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Lithium: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and lithium. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Lixisenatide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Loop diuretics: (Minor) Amphetamine and Dextroamphetamine may increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as loop diuretics. Close monitoring of blood pressure is advised.
    Lopinavir; Ritonavir: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
    Lorazepam: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use dextroamphetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures.
    Lorcaserin: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and lorcaserin. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. Also, the safety and efficacy of coadministration of lorcaserin with other products for weight loss, including amphetamines, have not been established.
    Losartan: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.
    Losartan; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Loxapine: (Major) Concurrent use of antipsychotics and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Lurasidone: (Major) Concurrent use of antipsychotics and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Macitentan: (Major) Avoid use of sympathomimetic agents with macitentan. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including macitentan. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Magnesium Hydroxide: (Moderate) Antacids and other gastrointestinal alkalinizing agents increase the oral absorption of amphetamines. This may lead to increased amphetamine concentrations. To help limit an interaction, do not take antacids at the same time as the amphetamine product. It is recommended to separate times of administration.
    Maprotiline: (Moderate) Use maprotiline and sympathomimetics together with caution and close clinical monitoring. Regularly assess blood pressure, heart rate, the efficacy of treatment, and the emergence of sympathomimetic/adrenergic adverse events. Carefully adjust dosages as clinically indicated. Maprotiline has pharmacologic activity similar to tricyclic antidepressant agents and may cause additive sympathomimetic effects when combined with agents with adrenergic/sympathomimetic activity.
    Mecamylamine: (Major) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by mecamylamine. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Meglitinides: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Meperidine: (Moderate) If concomitant use of meperidine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Meperidine; Promethazine: (Moderate) If concomitant use of meperidine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Mephobarbital: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamine/dextroamphetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures.
    Metaproterenol: (Major) Caution and close observation should also be used when metaproterenol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Metformin; Repaglinide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Metformin; Rosiglitazone: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Metformin; Saxagliptin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Metformin; Sitagliptin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Methadone: (Moderate) If concomitant use of methadone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Methazolamide: (Moderate) Urinary alkalinizers, such as methazolamide, result in decreased renal excretion of amphetamines. Monitor for amphetamine-related side effects. Avoid concomitant use in amphetamine overdose situations.
    Methenamine: (Major) Urinary acidifying agents, such as ammonium chloride, phosphorus salts, and methenamine salts (e.g., methenamine; sodium acid phosphate), reduce the tubular reabsorption of amphetamines. As a result, amphetamine clearance is accelerated and the duration of effect is reduced. Combination therapy should be avoided if possible.
    Methenamine; Sodium Acid Phosphate: (Major) Urinary acidifying agents, such as ammonium chloride, phosphorus salts, and methenamine salts (e.g., methenamine; sodium acid phosphate), reduce the tubular reabsorption of amphetamines. As a result, amphetamine clearance is accelerated and the duration of effect is reduced. Combination therapy should be avoided if possible.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Contraindicated) Amphetamines should not be administered during or within 14 days after the use of methylene blue. Methylene blue is a potent, reversible monoamine oxidase inhibitor (MAOI) which can prolong and intensify the cardiac stimulation and vasopressor effects of amphetamines, potentially resulting in hypertensive crisis. Methylene blue also has the potential to interact with serotonergic agents, such as amphetamines, which may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by 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, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), and in rare instances, death. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents, such as amphetamines, with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. (Major) Urinary acidifying agents, such as ammonium chloride, phosphorus salts, and methenamine salts (e.g., methenamine; sodium acid phosphate), reduce the tubular reabsorption of amphetamines. As a result, amphetamine clearance is accelerated and the duration of effect is reduced. Combination therapy should be avoided if possible.
    Methohexital: (Major) Inhalational general anesthetics may sensitize the myocardium to the effects of dextroamphetamine. Dosages of the amphetamines should be substantially reduced prior to surgery, and caution should be observed with concurrent use of anesthetics.
    Methyclothiazide: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Methyldopa: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed in patients receiving methyldopa and amphetamines. Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents
    Methylene Blue: (Contraindicated) Amphetamines should not be administered during or within 14 days after the use of methylene blue. Methylene blue is a potent, reversible monoamine oxidase inhibitor (MAOI) which can prolong and intensify the cardiac stimulation and vasopressor effects of amphetamines, potentially resulting in hypertensive crisis. Methylene blue also has the potential to interact with serotonergic agents, such as amphetamines, which may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by 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, gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), and in rare instances, death. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents, such as amphetamines, with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma.
    Methylergonovine: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable.
    Methysergide: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable.
    Metolazone: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Metoprolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Miglitol: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Milnacipran: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin norepinephrine reuptake inhibitors (SNRIs). At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Mirtazapine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and mirtazapine. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Modafinil: (Moderate) The use of modafinil with other psychostimulants, including amphetamines (e.g., amphetamine, dextroamphetamine. lisdexamfetamine), has not been extensively studied. Patients receiving combination therapy of modafinil with other psychostimulants should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other CNS stimulant-related side effects. In single-dose studies of dextroamphetamine combined with modafinil, no significant pharmacokinetic interactions occurred, but a slight increase in stimulant-associated side effects was noted.
    Moexipril: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.
    Molindone: (Major) Concurrent use of antipsychotics and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Monoamine oxidase inhibitors: (Contraindicated) In general, sympathomimetics should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use.
    Morphine: (Moderate) If concomitant use of morphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Morphine; Naltrexone: (Moderate) If concomitant use of morphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Nabilone: (Moderate) Concurrent use of nabilone with sympathomimetics (e.g., amphetamine or cocaine) may result in additive hypertension, tachycardia, and possibly cardiotoxicity. In a study of 7 adult males, combinations of cocaine (IV) and smoked marijuana (1 g marijuana cigarette, 0 to 2.7% delta-9-THC) increased the heart rate above levels seen with either agent alone, with increases reaching a plateau at 50 bpm.
    Nadolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Nalbuphine: (Moderate) If concomitant use of nalbuphine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Nebivolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Nebivolol; Valsartan: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Nefazodone: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and nefazodone. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Nicardipine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Nicotine: (Moderate) Nicotine use may potentiate the effects of the adrenergic agonists and the ergot alkaloids. If significant changes in nicotine intake occur, the dosages of these drugs may need adjustment.
    Nifedipine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Nimodipine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Nisoldipine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Nitrates: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Nizatidine: (Moderate) The use of H2-blockers with amphetamine therapy may change the onset of action of amphetamine or dextroamphetamine due to the increase in gastric pH. The time to maximum concentration (Tmax) of these amphetamines is decreased compared to when administered alone, thus increasing stimulant concentrations, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed.
    Non-Ionic Contrast Media: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Amphetamines should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Olanzapine; Fluoxetine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and fluoxetine. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. In addition, amphetamines are partially metabolized by CYP2D6 and fluoxetine is a strong CYP2D6 inhibitor. Increased systemic exposure to amphetamines from CYP2D6 inhibition may result in high blood pressure, tachycardia, anxiety, irritability, insomnia, or other amphetamine-related adverse effects.
    Oliceridine: (Moderate) If concomitant use of oliceridine and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Olmesartan: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised. (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
    Omeprazole; Sodium Bicarbonate: (Major) Concurrent use of amphetamines with urinary alkalinizing agents should be avoided if possible. If avoidance is not possible, the dose of the amphetamine therapy may need to be adjusted (decreased) in some patients. Monitor for increased blood pressure, increased heart rate, decreased appetite, palpitations, insomnia, irritability, anxiety, or other changes in moods and behaviors. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of the amphetamines. The half-life and therapeutic actions of amphetamines will be prolonged.
    Oxycodone: (Moderate) If concomitant use of oxycodone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Oxymorphone: (Moderate) If concomitant use of oxymorphone and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Ozanimod: (Major) Avoid concurrent use of ozanimod and amphetamines when possible as this combination may increase the risk for serious adverse reactions such as hypertensive crisis. If use is necessary, monitor for hypertension. Amphetamines may increase blood pressure by increasing norepinephrine and serotonin concentrations and monoamine oxidase inhibitors (MAOIs) are known to potentiate these effects. An active metabolite of ozanimod inhibits MAO-B in vitro. Sympathomimetics are contraindicated for use with non-selective MAOIs, however the risk for hypertensive reactions may be lower with selective MAO-B inhibitors.
    Paroxetine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and paroxetine. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. In addition, amphetamines are partially metabolized by CYP2D6 and paroxetine is a strong CYP2D6 inhibitor. Increased systemic exposure to amphetamines from CYP2D6 inhibition may result in high blood pressure, tachycardia, anxiety, irritability, insomnia, or other amphetamine-related adverse effects.
    Penbutolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Pentobarbital: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use dextroamphetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures.
    Perampanel: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Pergolide: (Major) Amphetamines, which increase catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with amphetamines may be advisable.
    Perindopril: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.
    Perindopril; Amlodipine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised. (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Phenelzine: (Contraindicated) In general, sympathomimetics should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use.
    Phenobarbital: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use dextroamphetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, the amphetamines may delay the intestinal absorption of phenobarbital; the extent of absorption of these seizure medications is not known to be affected.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use dextroamphetamine with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, the amphetamines may delay the intestinal absorption of phenobarbital; the extent of absorption of these seizure medications is not known to be affected.
    Phenoxybenzamine: (Major) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents. Due to the risk of unopposed alpha-adrenergic activity, amphetamines should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. In particular, amphetamines can inhibit the antihypertensive response to guanadrel, an adrenergic antagonist that causes depletion of norepinephrine in the synapse. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Phentermine: (Moderate) Concurrent use of phentermine with amphetamines may result in additive cardiovascular and CNS adverse effects. Coadministration is not recommended when amphetamines are used for weight loss as safety and efficacy of phentermine in combination with other weight loss products has not been established.
    Phentermine; Topiramate: (Major) Concurrent use of amphetamines and urinary alkalinizers, such as topiramate, should be avoided. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of these compounds. The half-life and therapeutic actions of amphetamines will be prolonged in the presence of these drugs. In addition, patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. (Moderate) Concurrent use of phentermine with amphetamines may result in additive cardiovascular and CNS adverse effects. Coadministration is not recommended when amphetamines are used for weight loss as safety and efficacy of phentermine in combination with other weight loss products has not been established.
    Phentolamine: (Major) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents. Due to the risk of unopposed alpha-adrenergic activity, amphetamines should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Phentolamine may decrease, but not completely reverse, the pressor response of amphetamine overdose. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Phenytoin: (Major) Amphetamine or dextroamphetamine may delay the intestinal absorption of orally-administered phenytoin; the extent of phenytoin absorption is not known to be effected. Monitor the patient's neurologic status closely, as the amphetamines may also lower the seizure threshold in some patients on phenytoin or fosphenytoin.
    Pindolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Pioglitazone: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Pioglitazone; Glimepiride: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Pioglitazone; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Pirbuterol: (Moderate) Caution and close observation should also be used when pirbuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Potassium Bicarbonate: (Major) Concurrent use of amphetamines with urinary alkalinizing agents should be avoided if possible. If avoidance is not possible, the dose of the amphetamine therapy may need to be adjusted (decreased) in some patients. Monitor for increased blood pressure, increased heart rate, decreased appetite, palpitations, insomnia, irritability, anxiety, or other changes in moods and behaviors. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of the amphetamines. The half-life and therapeutic actions of amphetamines will be prolonged.
    Potassium Citrate: (Major) Concurrent use of amphetamines with urinary alkalinizing agents should be avoided if possible. If avoidance is not possible, the dose of the amphetamine therapy may need to be adjusted (decreased) in some patients. Monitor for increased blood pressure, increased heart rate, decreased appetite, palpitations, insomnia, irritability, anxiety, or other changes in moods and behaviors. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of the amphetamines. The half-life and therapeutic actions of amphetamines will be prolonged.
    Potassium Citrate; Citric Acid: (Major) Concurrent use of amphetamines with urinary alkalinizing agents should be avoided if possible. If avoidance is not possible, the dose of the amphetamine therapy may need to be adjusted (decreased) in some patients. Monitor for increased blood pressure, increased heart rate, decreased appetite, palpitations, insomnia, irritability, anxiety, or other changes in moods and behaviors. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of the amphetamines. The half-life and therapeutic actions of amphetamines will be prolonged.
    Potassium-sparing diuretics: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like potassium-sparing diuretics. Close monitoring of blood pressure is advised.
    Pramlintide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Prazosin: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed in patients receiving prazosin and amphetamines. Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as prazosin.
    Pregabalin: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Prilocaine; Epinephrine: (Moderate) Amphetamines may potentiate the pressor effects of epinephrine.
    Primidone: (Major) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures.
    Probenecid; Colchicine: (Minor) The response to sympathomimetics may be enhanced by colchicine.
    Procarbazine: (Major) Because procarbazine exhibits some monoamine oxidase inhibitory (MAOI) activity, sympathomimetic drugs should be avoided. As with MAOIs, the use of a sympathomimetic drug with procarbazine may precipitate hypertensive crisis or other serious side effects. In the presence of MAOIs, drugs that cause release of norepinephrine induce severe cardiovascular and cerebrovascular responses. In general, do not use a sympathomimetic drug unless clinically necessary (e.g., medical emergencies, agents like dopamine) within the 14 days prior, during or 14 days after procarbazine therapy. If use is necessary within 2 weeks of the MAOI drug, in general the initial dose of the sympathomimetic agent must be greatly reduced. Patients should be counseled to avoid non-prescription (OTC) decongestants and other drug products, weight loss products, and energy supplements that contain sympathomimetic agents.
    Propofol: (Major) Inhalational general anesthetics may sensitize the myocardium to the effects of dextroamphetamine. Dosages of the amphetamines should be substantially reduced prior to surgery, and caution should be observed with concurrent use of anesthetics.
    Propranolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Propranolol; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Proton pump inhibitors: (Moderate) The use of proton pump inhibitors (PPIs) with amphetamine and/or dextroamphetamine therapy may change the onset of action of these amphetamines due to the increase in gastric pH. The time to maximum concentration (Tmax) of amphetamines is decreased compared to when administered alone, thus increasing amphetamine concentrations and exposure, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed. Some extended-release dosage forms of amphetamine or dextroamphetamine salts should not be given with PPIs. The concomitant use of PPIs with some extended-release dosage forms may result in amphetamine dose-dumping.
    Quinapril: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.
    Quinapril; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Quinidine: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of quinidine, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
    Racepinephrine: (Major) Racepinephrine is a sympathomimetic drug with agonist actions at both the alpha and beta receptors. Patients using racepinephrine inhalation are advised to avoid other non-prescription products containing sympathomimetics since additive adverse effects on the cardiovascular and nervous system are possible, some which may be undesirable. Side effects such as nausea, tremor, nervousness, difficulty with sleep, and increased heart rate or blood pressure may be additive. Patients should avoid use of non-prescription decongestants, such as phenylephrine and pseudoephedrine, while using racepinephrine inhalations. Patients should avoid dietary supplements containing ingredients that are reported or claimed to have a stimulant or weight-loss effect, such as ephedrine and ephedra, Ma huang, and phenylpropanolamine. Patients taking prescription sympathomimetic or stimulant medications (including amphetamines, methylphenidate, dexmethylphenidate, isometheptane, epinephrine) should seek health care professional advice prior to the use of racepinephrine inhalations; consider therapeutic alternatives to racepinephrine for these patients.
    Ramipril: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.
    Ranitidine: (Moderate) The use of H2-blockers with amphetamine therapy may change the onset of action of amphetamine or dextroamphetamine due to the increase in gastric pH. The time to maximum concentration (Tmax) of these amphetamines is decreased compared to when administered alone, thus increasing stimulant concentrations, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed.
    Rasagiline: (Moderate) The concomitant use of rasagiline and sympathomimetics was not allowed in clinical studies; therefore, caution is advised during concurrent use of rasagiline and sympathomimetics including stimulants for ADHD and weight loss, non-prescription nasal, oral, and ophthalmic decongestants, and weight loss dietary supplements containing Ephedra. Although sympathomimetics are contraindicated for use with other non-selective monoamine oxidase inhibitors (MAOIs), hypertensive reactions generally are not expected to occur during concurrent use with rasagiline because of the selective monoamine oxidase-B (MAO-B) inhibition of rasagiline at manufacturer recommended doses. One case of elevated blood pressure has been reported in a patient during concurrent use of the recommended dose of rasagiline and ophthalmic tetrahydrozoline. One case of hypertensive crisis has been reported in a patient taking the recommended dose of another MAO-B inhibitor, selegiline, in combination with ephedrine. It should be noted that the MAO-B selectivity of rasagiline decreases in a dose-related manner as increases are made above the recommended daily dose and interactions with sympathomimetics may be more likely to occur at these higher doses.
    Remifentanil: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering remifentanil with amphetamines. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Reserpine: (Major) Concurrent use of amphetamines and gastrointestinal acidifying agents, such as reserpine, lowers the absorption of amphetamines, reducing their efficacy. In addition, amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some agents for blood pressure such as reserpine. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Riociguat: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Ritonavir: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
    Rosiglitazone: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Rufinamide: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary. Additionally, amphetamines may delay the intestinal absorption of ethosuximide, ethotoin (hydantoin), phenobarbital, and phenytoin, the extent of absorption of these seizure medications is not known to be affected.
    Sacubitril; Valsartan: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.
    Safinamide: (Contraindicated) Safinamide, a selective monoamine oxidase-B inhibitor, is contraindicated for use with amphetamines due to the risk of serotonin syndrome or hypertensive crisis. The manufacturer of safinamide recommends that a period of at least 14 days elapse between the discontinuation of safinamide and the initiation of serotonergic agents. Hypertensive crisis has been reported in patients taking recommended doses of selective MAO-B inhibitors and sympathomimetic medications, such as amphetamines. Safinamide can cause hypertension or exacerbate existing hypertension, particularly at daily dosages exceeding those recommended by the manufacturer.
    Salmeterol: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Sedating H1-blockers: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers (i.e., diphenhydramine). This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
    Selegiline: (Contraindicated) The product labels for amphetamines contraindicate use with monoamine oxidase inhibitors (MAOIs), including selegiline, due to the risk of hypertensive crisis or serotonin syndrome. The manufacturers of selegiline products recommend caution and monitoring of blood pressure during concurrent use with sympathomimetics. Amphetamines should not be used concurrently with MAOIs or within 14 days before or after their use.
    Selexipag: (Major) Avoid use of sympathomimetic agents with selexipag. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including selexipag. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Semaglutide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Serotonin norepinephrine reuptake inhibitors: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin norepinephrine reuptake inhibitors (SNRIs). At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Serotonin-Receptor Agonists: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Although unlikely to occur during monotherapy with serotonin-receptor agonists (or "triptans"), serotonin syndrome may occur from combining these drugs with other medications that potentiate serotonin activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Sertraline: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and sertraline. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Sevoflurane: (Major) Inhalational general anesthetics (e.g., enflurane, halothane, isoflurane, and methoxyflurane) may sensitize the myocardium to the effects of stimulants. Dosages of the amphetamines should be substantially reduced prior to surgery, and caution should be observed with concurrent use of anesthetics.
    SGLT2 Inhibitors: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Sibutramine: (Contraindicated) Sibutramine is contraindicated in patients taking other centrally-acting appetite suppressant drugs (e.g., amphetamines). Consider alternatives. Concurrent use of sibutramine with amphetamines can raise blood pressure and heart rate. Use of sibutramine with other serotonergic agents, such as the amphetamines, also increases the risk for serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Discontinue treatment with the amphetamine and any concomitant serotonergic agents immediately if symptoms of serotonin syndrome occur, and initiate supportive symptomatic treatment.
    Sodium Bicarbonate: (Major) Concurrent use of amphetamines with urinary alkalinizing agents should be avoided if possible. If avoidance is not possible, the dose of the amphetamine therapy may need to be adjusted (decreased) in some patients. Monitor for increased blood pressure, increased heart rate, decreased appetite, palpitations, insomnia, irritability, anxiety, or other changes in moods and behaviors. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of the amphetamines. The half-life and therapeutic actions of amphetamines will be prolonged.
    Sodium Citrate; Citric Acid: (Major) Concurrent use of amphetamines with urinary alkalinizing agents should be avoided if possible. If avoidance is not possible, the dose of the amphetamine therapy may need to be adjusted (decreased) in some patients. Monitor for increased blood pressure, increased heart rate, decreased appetite, palpitations, insomnia, irritability, anxiety, or other changes in moods and behaviors. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of the amphetamines. The half-life and therapeutic actions of amphetamines will be prolonged.
    Sodium Lactate: (Major) Concurrent use of amphetamines with urinary alkalinizing agents should be avoided if possible. If avoidance is not possible, the dose of the amphetamine therapy may need to be adjusted (decreased) in some patients. Monitor for increased blood pressure, increased heart rate, decreased appetite, palpitations, insomnia, irritability, anxiety, or other changes in moods and behaviors. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of the amphetamines. The half-life and therapeutic actions of amphetamines will be prolonged.
    Sodium Oxybate: (Moderate) Sodium oxybate has the potential to induce seizures; it has been speculated that this effect may be mediated through the action of sodium oxybate at GABA receptors. Although convulsant effects occur primarily at high dosages, sodium oxybate should be used cautiously with psychostimulants that are known to lower seizure threshold such as the amphetamines. Note that CNS stimulants, including the amphetamines, are frequently used in the treatment of narcolepsy, and clinical trials involving the use of psychostimulants with sodium oxybate have not found the combinations to be unsafe. Pharmacodynamic interactions cannot be ruled out, however.
    Solriamfetol: (Moderate) Monitor blood pressure and heart rate during coadministration of solriamfetol, a norepinephrine and dopamine reuptake inhibitor, and amphetamines, which are CNS stimulants. Concurrent use of solriamfetol and other medications that increase blood pressure and/or heart rate may increase the risk of such effects. Coadministration of solriamfetol with other drugs that increase blood pressure or heart rate has not been evaluated.
    Sotalol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    St. John's Wort, Hypericum perforatum: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics.
    Succinimides: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. The amphetamines may also delay the intestinal absorption of ethosuximide; the extent of absorption of these seizure medications is not known to be affected.
    Sufentanil: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sufentanil with amphetamines. Inform patients taking this combination of the possible increased risks and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Sulfonylureas: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Tapentadol: (Moderate) If concomitant use of tapentadol and amphetamines is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Tedizolid: (Minor) Theoretically, drugs that possess MAO-inhibiting activity, such as tedizolid, can prolong and intensify the cardiac stimulation and vasopressor effects of amphetamines. Serious CNS reactions, such as serotonin syndrome, have been reported during the concurrent use of linezolid, which is structurally similar to tedizolid, and psychiatric medications that enhance central serotonergic activity; therefore, caution is warranted with concomitant use of other agents with serotonergic activity, including amphetamines.
    Telmisartan: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.
    Telmisartan; Amlodipine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised. (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Terazosin: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed in patients receiving terazosin and amphetamines. Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as terazosin.
    Terbutaline: (Major) Concomitant use of sympathomimetics with beta-agonists might result in additive cardiovascular effects such as increased blood pressure and heart rate.
    Theophylline, Aminophylline: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
    Thiazide diuretics: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Thiazolidinediones: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Thiopental: (Major) Inhalational general anesthetics may sensitize the myocardium to the effects of dextroamphetamine. Dosages of the amphetamines should be substantially reduced prior to surgery, and caution should be observed with concurrent use of anesthetics.
    Thiothixene: (Major) Concurrent use of antipsychotics, such as thiothixene, and amphetamines should generally be avoided. Antipsychotics and amphetamines may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Amphetamines are thought to block central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of amphetamines.
    Thyroid hormones: (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Tiagabine: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
    Timolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Tipranavir: (Moderate) Warn patients that there are potentially serious drug interactions between tipranavir and prescription amphetamine therapy or illicit amphetamine use. The risk of amphetamine toxicity may be increased during concurrent use of potent CYP2D6 inhibitors such as tipranavir. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, discontinue both the amphetamine and CYP2D6 inhibitor and initiate appropriate medical treatment.
    Topiramate: (Major) Concurrent use of amphetamines and urinary alkalinizers, such as topiramate, should be avoided. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of these compounds. The half-life and therapeutic actions of amphetamines will be prolonged in the presence of these drugs. In addition, patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
    Tramadol: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering amphetamines with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and tramadol. Patients receiving tramadol and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The amphetamine and tramadol should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. In addition, the risk of seizures from the use of tramadol may be increased with concomitant use of CNS stimulants that may induce seizures, including the amphetamines. Extreme caution and close clinical monitoring is recommended if these agents must be used together.
    Tramadol; Acetaminophen: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering amphetamines with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and tramadol. Patients receiving tramadol and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The amphetamine and tramadol should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. In addition, the risk of seizures from the use of tramadol may be increased with concomitant use of CNS stimulants that may induce seizures, including the amphetamines. Extreme caution and close clinical monitoring is recommended if these agents must be used together.
    Trandolapril: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised.
    Trandolapril; Verapamil: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like angiotensin-converting enzyme inhibitors (ACE inhibitors). Close monitoring of blood pressure is advised. (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Tranylcypromine: (Contraindicated) In general, sympathomimetics should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use.
    Trazodone: (Moderate) Coadministration of trazodone and amphetamines may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. The MAOI activity of amphetamines may also be of concern with trazodone. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Trazodone and the amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Treprostinil: (Major) Avoid use of sympathomimetic agents with treprostinil. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including treprostinil. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Triamterene; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Tricyclic antidepressants: (Moderate) Use of amphetamines with tricyclic antidepressants may increase the risk for serotonin syndrome or have effects on blood pressure or heart rate. Monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. Also monitor blood pressure and heart rate. If the patient experiences changes in heart rate or rhythm, an ECG may be indicated. A dose reduction of one or both agents may be needed if side effects occur.
    Tromethamine: (Major) Concurrent use of amphetamines with urinary alkalinizing agents should be avoided if possible. If avoidance is not possible, the dose of the amphetamine therapy may need to be adjusted (decreased) in some patients. Monitor for increased blood pressure, increased heart rate, decreased appetite, palpitations, insomnia, irritability, anxiety, or other changes in moods and behaviors. Urinary alkalinizers diminish the urinary excretion of amphetamines by increasing the proportion of non-ionized amphetamines, resulting in increased renal tubular reabsorption of the amphetamines. The half-life and therapeutic actions of amphetamines will be prolonged.
    Tryptophan, 5-Hydroxytryptophan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering amphetamines with other drugs that have serotonergic properties such as tryptophan. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and tryptophan. Patients receiving tryptophan and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. The amphetamine and tryptophan should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Umeclidinium; Vilanterol: (Moderate) Administer sympathomimetics with caution with beta-agonists such as vilanterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects.
    Valproic Acid, Divalproex Sodium: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and may increase the risk of seizures. If seizures occur, discontinue the amphetamine.
    Valsartan: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised.
    Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, such as angiotensin II receptor antagonists. Close monitoring of blood pressure is advised. (Minor) Amphetamines may counteract the activity of some antihypertensive agents, such as thiazide diuretics. Close monitoring of blood pressure is advised. Thiazide diuretics may also increase and prolong the actions of amphetamines by increasing the urinary pH.
    Vasodilators: (Moderate) Use sympathomimetic agents with caution in patients receiving therapy for hypertension. Patients should be monitored to confirm that the desired antihypertensive effect is achieved. Sympathomimetics can increase blood pressure and heart rate, and antagonize the antihypertensive effects of vasodilators when administered concomitantly. Anginal pain may be induced when coronary insufficiency is present.
    Venlafaxine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin norepinephrine reuptake inhibitors (SNRIs). At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Verapamil: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
    Vigabatrin: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.
    Vilazodone: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and vilazodone. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Vortioxetine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and vortioxetine. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Yohimbine: (Major) At high doses, yohimbine may nonselectively inhibit monoamine oxidase and also, at normal doses, activates the sympathetic nervous system via selective central alpha 2-adrenoceptor antagonism. Traditional MAOIs can cause serious adverse effects when taken concomitantly with sympathomimetics.
    Ziprasidone: (Minor) Serotonin syndrome has been reported during the combined use of amphetamine stimulants and other medications with serotonergic properties. Serotonin syndrome has been reported during postmarketing use of ziprasidone; however, a causal relationship has not been established.
    Zonisamide: (Moderate) Patients who are taking anticonvulsants for epilepsy/seizure control should use amphetamines with caution. Amphetamines may decrease the seizure threshold and increase the risk of seizures. If seizures occur, amphetamine discontinuation may be necessary.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate or well-controlled studies of amphetamine use in pregnant women; therefore, amphetamine should only be used during pregnancy if the expected benefit to the mother outweighs the potential fetal risk.[60070] [60232] [62373] There is 1 case of a neonate born with a severe congenital bony deformity, tracheoesophageal fistula, and anal atresia following maternal exposure to dextroamphetamine sulfate and lovastatin during the first trimester of pregnancy.[28488] However, most available data indicate that amphetamines are not teratogenic in humans. Among 671 mother-child pairs enrolled in the Collaborative Perinatal Project who had first-trimester exposure to amphetamines and 1,898 mother-child pairs with amphetamine exposures at any time during pregnancy, there was no evidence suggesting a relationship to large categories of major or minor malformations.[48419] Non-teratogenic effects known to occur in human neonates who are born to mothers dependent on amphetamines include increased incidences of premature births, low birth weights and length, lower occipitofrontal circumference, and physical withdrawal symptoms (e.g., abnormal sleep patterns, poor feeding, tremor, agitation, fatigue, and hypertonia).[60070] [48417] In 1 prospective comparison study, neonates exposed to cocaine, methamphetamine, or a combination of cocaine and narcotic in utero had a 35.1% incidence of cranial abnormalities (i.e., intraventricular hemorrhage, echodensities known to be associated with necrosis, and cavitary lesions) compared to a 5.3% incidence in normal newborns as assessed by cranial ultrasonography.[48418] The authors speculated that the ultrasonographic abnormalities were probably related to the vasoconstrictive properties of the drugs. The effects of amphetamine during labor and delivery are unknown. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to amphetamine; information about the registry can be obtained at womensmentalhealth.org/research/pregnancyregistry/ or by calling 1-866-961-2388.[60070] [60232] [62373]

    MECHANISM OF ACTION

    Amphetamines are non-catecholamine sympathomimetic agents that stimulate the release of some biogenic amines (e.g., dopamine, norepinephrine) from storage sites in the nerve terminal and block the reuptake of these amines into the presynaptic neuron thereby increasing their availability in the extra-neuronal space. Amphetamines are relatively weak serotonin (5-HT) reuptake inhibitors. Finally, amphetamines may act as a direct agonist on central 5-HT receptors. Thus, amphetamines are both direct and indirect stimulants. It is thought that the release of dopamine is responsible for the reinforcing properties of amphetamines. Amphetamines may also inhibit monoamine oxidase (MAO), but this is a minor action.
     
    Peripheral actions: In the periphery, the actions of amphetamines are believed to occur through release of norepinephrine from the adrenergic nerve terminals and by a direct stimulant action on alpha- and beta-receptors. Amphetamines increase systolic and diastolic blood pressure and cause respiratory stimulation and weak bronchodilation. Heart rate typically increases slightly with normal therapeutic doses of stimulants (about 3 to 6 bpm); however, a reflexive decrease in heart rate in response to increased blood pressure can also occur. Amphetamine is a racemic mixture of l-amphetamine and d-amphetamine. The l-isomer is more potent than the d-isomer in cardiovascular activity, but much less potent in causing CNS excitatory effects. At high doses, such as in overdoses, amphetamine and its derivatives can cause significant hypertension, tachycardia, arrhythmias, and other serious complications. Amphetamines may produce mydriasis and contraction of the bladder sphincter.
     
    Actions in ADHD: There is no conclusive evidence for the mechanism(s) of action of amphetamines on the mental and behavioral conditions in ADHD. Improved attention spans, decreased distractibility, increased ability to follow directions or complete tasks, and decreased impulsivity and aggression have been noted when stimulants are prescribed for the treatment of ADHD.
     
    Anorectic actions: The action of the amphetamines in treating obesity may result from mechanisms besides appetite suppression at the lateral hypothalamic feeding center. It has been suggested that amphetamines decrease olfactory acuity, which may contribute to their anorexic properties. Amphetamines do not seem to alter the basal metabolic rate or nitrogen excretion. It is unknown if other CNS actions or metabolic effects may be involved in the promotion of weight loss with amphetamines. Amphetamine is less effective than dextro-amphetamine as an appetite suppressant.

    PHARMACOKINETICS

    Amphetamine is available as an oral formulation. Tissue redistribution of amphetamines is extensive and high lipid solubility leads to increased concentrations relative to serum liver, kidneys, and lungs. This results in large volumes of distribution. Cerebrospinal fluid concentrations are about 80% of plasma concentrations at steady state. Amphetamine is reported to be oxidized at the 4 position of the benzene ring to form 4-hydroxyamphetamine, or on the side chain alpha- or beta- 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. The formation of 4-hydroxy-amphetamine is known to involve CYP2D6. Amphetamine is a racemic compound (l-amphetamine and d-amphetamine). The mean elimination half-life ranges from 9.77 to 11 hours for d-amphetamine and 11.5 to 13.8 hours for l-amphetamine.
     
    Amphetamines and their metabolites are excreted in the urine. Recovery of amphetamine in the urine is highly dependent on pH and urine flow rates. The urinary elimination of amphetamines may be affected by agents that acidify or alkalinize the urinary fluids. Alkaline urine results in less ionization and reduced renal elimination of amphetamine. Conversely, acidification of the urine speeds amphetamine elimination. Urinary recovery of amphetamine has been reported to range from 1% to 75% depending on urinary pH. With normal urine pH, approximately 30% to 40% of the administered dose is recoverable in urine as amphetamine and 50% as alpha-hydroxy-amphetamine (inactive metabolite).
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6
    The specific enzymes involved in amphetamine metabolism have not been completely described; however, the formation of 4-hydroxy-amphetamine is known to involve CYP2D6. CYP2D6 inhibitors may increase exposure to amphetamine. Since CYP2D6 is genetically polymorphic, variations in amphetamine metabolism are a possibility.

    Oral Route

    Amphetamine is well-absorbed orally.
     
    Immediate-release tablets: Amphetamine tablets are easily absorbed from the GI tract following oral administration. In one clinical trial of amphetamine tablets for the treatment of ADHD in children 6 to 12 years of age, the onset of effect occurred 45 minutes post-dose, and the greatest effect was observed at 4 hours post-dose. The drug continued to demonstrate efficacy at 10 hours post-dose, which was the last time point measured. Amphetamine tablets may be administered with or without food.[60070]
    Immediate-release orally disintegrating tablets (ODT): Amphetamine demonstrates linear pharmacokinetics over the dose range of 5 to 40 mg. In a crossover study of healthy patients, exposures (Cmax and AUC) to d- and l-amphetamine were comparable to that after administration of an equal dose of immediate-release amphetamine tablets. Median Tmax of d- and l-amphetamine was reached at approximately 3.5 (2 to 8) hours and 3 (1 to 6 hours) hours after administration without water and with water, respectively. Administration of food (a high-fat meal) does not affect the observed AUC and Cmax of d- and l-amphetamine after single-dose oral administration of amphetamine ODT tablets. Median Tmax (range) increased from 2.5 (1.5 to 6) hours to 4.5 (2.5 to 8) hours when administered without food compared to with food. The average half-life of d- and l-amphetamine was 10 and 11.7 hours, respectively, in healthy adult volunteers.[63916]
    Extended-release suspensions: Amphetamine extended-release suspension is well absorbed after oral administration. In trials of healthy adults who received a single 18.8 mg dose of the oral suspension, the Tmax was 4 (range: 2 to 7) hours and the plasma terminal elimination t1/2 was approximately 11 to 12 hours and 14 to 15 hours for d-amphetamine and l-amphetamine, respectively. A high-fat meal delayed the Tmax by approximately 1 hour but did not significantly affect the extent of absorption. An in vitro dissolution study using the extended-release suspension showed alcohol-induced dose dumping potential in the presence of 40% alcohol. Dose dumping was not observed in the presence of lower alcohol concentrations. The relative bioavailability of extended-release suspension compared to an equal dose of mixed amphetamine salts tablets is 106% for d-amphetamine and 111% for l-amphetamine.[60232] [62373]
    Extended-release orally disintegrating tablets (ODT): In a trial of 40 healthy adults who received a single 18.8 mg dose of amphetamine extended-release ODT (fasting conditions), mean peak plasma concentrations of d-amphetamine (44.9 ng/mL) and l-amphetamine (14.5 ng/mL) were achieved approximately 5 hours after dosing and were similar to those achieved with 30 mg ER mixed amphetamine salts capsules (i.e., Adderall XR). AUC was 876.9 ng/mL x hour and half-life was approximately 11 hours. Administration with food did not affect the extent of absorption but resulted in a 19% reduction in Cmax (44.9 to 36.3 ng/mL) and prolonged the median Tmax by approximately 2 hours. These changes were not considered to be clinically significant. An in vitro study using the extended-release ODT showed alcohol-induced dose dumping potential in the presence of 40% alcohol. Dose dumping was not observed in the presence of lower alcohol concentrations.[60524]