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  • CLASSES

    Psychostimulants, Methylphenidate Derivatives

    BOXED WARNING

    Abrupt discontinuation, alcoholism, substance abuse

    Chronic abuse of methylphenidate can lead to marked tolerance and psychological dependence, with varying degrees of abnormal behavior. Symptoms of chronic abuse of methylphenidate may include insomnia, irritability, change in personality, and psychotic symptoms that may be clinically indistinguishable from psychotic disorders, particularly with parenteral or inhalational abuse. Misuse of amphetamines may also cause sudden death and serious cardiovascular adverse events. Therefore, a careful assessment of benefit versus risk is recommended in patients with a known history of substance abuse or alcoholism.The least amount reasonable should be prescribed or dispensed at one time in order to limit the potential for overuse or drug diversion. Close supervision is required during drug withdrawal from misuse since severe depression may occur. Withdrawal or abrupt discontinuation following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. Drug 'holidays', the temporary discontinuation of drug during weekends, holidays, summer vacations and etc., is usually not associated with drug withdrawal symptoms, but such holidays are typically reserved for those patients with well-controlled ADHD symptoms.

    DEA CLASS

    Rx, schedule II

    DESCRIPTION

    CNS stimulant chemically similar to but with milder peripheral sympathomimetic actions than amphetamines
    Used for attention-deficit hyperactivity disorder (ADHD) and narcolepsy
    Pediatric patients with structural heart defects, cardiomyopathy, or heart-rhythm disturbances may be at risk for adverse cardiac events

    COMMON BRAND NAMES

    Aptensio XR, Concerta, Daytrana, Metadate CD, Metadate ER, Methylin, QuilliChew ER, QUILLIVANT XR, Ritalin, Ritalin LA, Ritalin SR

    HOW SUPPLIED

    Aptensio XR/Metadate CD/Methylphenidate Hydrochloride/Ritalin LA Oral Cap ER: 10mg, 15mg, 20mg, 30mg, 40mg, 50mg, 60mg
    Concerta/Metadate ER/Methylin/Methylphenidate Hydrochloride/Ritalin SR Oral Tab ER: 10mg, 18mg, 20mg, 27mg, 36mg, 54mg
    Daytrana Topical Film ER: 1h, 1.1mg, 1.6mg, 2.2mg, 3.3mg
    Methylin/Methylphenidate Hydrochloride Oral Sol: 5mL, 5mg, 10mg
    Methylin/Methylphenidate Hydrochloride Oral Tab Chew: 2.5mg, 5mg, 10mg
    Methylin/Methylphenidate Hydrochloride/Ritalin Oral Tab: 5mg, 10mg, 20mg
    QuilliChew ER Oral Tab Chew ER: 20mg, 30mg, 40mg
    QUILLIVANT XR Oral Susp ER: 5mL, 25mg

    DOSAGE & INDICATIONS

    For the treatment of attention-deficit hyperactivity disorder (ADHD).
    For once-daily product dosing.
    Oral dosage (extended-release once-daily tablets; e.g., Concerta)
    Adults up to 65 years not currently taking methylphenidate

    Initially, 18 to 36 mg PO once daily in the morning. Dose may be increased by 18 mg increments at weekly intervals. Max: 72 mg/day. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Adults up to 65 years currently taking 10 to 15 mg/day methylphenidate

    Initially, 18 mg PO once daily in the morning. Dose may be increased by 18 mg increments at weekly intervals. Max: 72 mg/day. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Adults up to 65 years currently taking 20 to 30 mg/day methylphenidate

    Initially, 36 mg PO once daily in the morning. Dose may be increased by 18 mg increments at weekly intervals. Max: 72 mg/day. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Adults up to 65 years currently taking 30 to 45 mg/day methylphenidate

    Initially, 54 mg PO once daily in the morning. Dose may be increased by 18 mg increments at weekly intervals. Max: 72 mg/day. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Adults up to 65 years currently taking 40 to 60 mg/day methylphenidate

    72 mg PO once daily in the morning. Max: 72 mg/day. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Children and Adolescents 6 years and older not currently taking methylphenidate

    Initially, 18 mg PO once daily in the morning. Dose may be increased by 18 mg increments at weekly intervals. A 27-mg tablet is available for prescribers who wish to utilize a dosage between 18 to 36 mg. FDA-approved Max: 54 mg/day in children and 72 mg/day (not to exceed 2 mg/kg/day) in adolescents; however, some experts recommend doses up to 108 mg, which may be appropriate in patients weighing more than 50 kg. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Children and Adolescents 6 years and older currently taking 10 to 15 mg/day methylphenidate

    Initially, 18 mg PO once daily in the morning. Titrate dose by 18 mg increments at weekly intervals as needed. A 27-mg tablet is available for patients who may benefit from a dosage between 18 to 36 mg. FDA-approved Max: 54 mg/day in children and 72 mg/day (not to exceed 2 mg/kg/day) in adolescents; however, some experts recommend doses up to 108 mg, which may be appropriate in patients weighing more than 50 kg. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Children and Adolescents 6 years and older currently taking 20 to 30 mg/day methylphenidate

    Initially, 36 mg PO once daily in the morning. Titrate dose by 18 mg increments at weekly intervals as needed. FDA-approved Max: 54 mg/day in children and 72 mg/day (not to exceed 2 mg/kg/day) in adolescents; however, some experts recommend doses up to 108 mg, which may be appropriate in patients weighing more than 50 kg. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Children and Adolescents 6 years and older currently taking 30 to 45 mg/day methylphenidate

    Initially, 54 mg PO once daily in the morning. Titrate dose by 18 mg increments at weekly intervals as needed and as clinically appropriate. FDA-approved Max: 54 mg/day in children and 72 mg/day (not to exceed 2 mg/kg/day) in adolescents; however, some experts recommend doses up to 108 mg, which may be appropriate in patients weighing more than 50 kg. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Adolescents currently taking 40 to 60 mg/day methylphenidate

    Initially, 72 mg PO once daily in the morning. While the FDA-approved maximum dosage is 72 mg/day (not to exceed 2 mg/kg/day), some experts recommend doses up to 108 mg, which may be appropriate in patients weighing more than 50 kg. Titrate dosage by 18 mg increments no more frequently than weekly intervals as clinically appropriate. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Oral dosage (extended-release once-daily capsules; e.g., Metadate CD)
    Adults not currently taking methylphenidate

    Initially, 20 mg PO once daily in the morning. When in the judgment of the clinician a lower dosage is indicated for initial treatment, it is recommended that patients begin treatment with an immediate-release product first. Dose may be increased by 10 to 20 mg increments at weekly intervals. Max: 60 mg/day. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Adults currently taking other dosage forms of methylphenidate

    Initially, 20 mg PO once daily in the morning. Alternatively, give an equivalent total daily dosage as the previous methylphenidate product PO once daily, rounded to the closest available capsule size. For example, patients already taking 10 mg of immediate-release methylphenidate twice daily (20 mg/day) should start with 20 mg Metadate CD once daily; those taking 20 mg twice daily (40 mg/day) should start with 40 mg Metadate CD once daily. Dose may be increased by 10 to 20 mg increments at weekly intervals. Max: 60 mg/day. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Children and Adolescents 6 years and older not currently taking methylphenidate

    Initially, 20 mg PO once daily in the morning. Dose may be increased by 10 to 20 mg increments at weekly intervals. FDA-approved Max: 60 mg/day; however, some experts recommend doses up to 100 mg/day for patients weighing more than 50 kg. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Children and Adolescents 6 years and older currently taking other dosage forms of methylphenidate

    Initially, 20 mg PO once daily in the morning. Alternatively, give no more than the equivalent total daily dose of the previous methylphenidate product, rounded to the nearest available capsule size, PO once daily. For example, patients already taking 10 mg of immediate-release methylphenidate twice daily (20 mg/day) should start with 20 mg Metadate CD once daily; those taking 20 mg twice daily (40 mg/day) could start with 40 mg Metadate CD once daily. Dose may be increased by 10 to 20 mg increments at weekly intervals. FDA-approved Max: 60 mg/day; however, some experts recommend doses up to 100 mg/day for patients weighing more than 50 kg. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Oral dosage (extended-release once-daily capsules; e.g., Ritalin LA)
    Adults not currently taking methylphenidate

    Initially, 20 mg PO once daily in the morning. If a lower initial dose is desired, patients may begin treatment with 10 mg PO once daily. Dose may be increased by 10 mg increments at weekly intervals. Max: 60 mg/day. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Adults currently taking other dosage forms of methylphenidate

    Initially, give no more than the total daily dosage of the previous methylphenidate product PO once daily in the morning. Dose may be increased by 10 mg increments at weekly intervals. Max: 60 mg/day. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Children and Adolescents 6 years and older not currently taking methylphenidate

    Initially, 20 mg PO once daily in the morning. If a lower initial dose is desired, 10 mg PO once daily may be used. Dose may be increased by 10 mg increments at weekly intervals. FDA-approved Max: 60 mg/day; however, some experts recommend doses up to 100 mg/day in patients weighing more than 50 kg. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Children and Adolescents 6 years and older currently taking other dosage forms of methylphenidate

    Initially, give no more than the total daily dosage of the previous methylphenidate product PO once daily in the morning. For example, patients already taking 10 mg of immediate-release methylphenidate twice daily (20 mg/day) should start with 20 mg Ritalin LA once daily; those taking 20 mg of extended-release methylphenidate once daily (20 mg/day) should also start with 20 mg of Ritalin LA once daily. Dose may be increased by 10 mg increments at weekly intervals. FDA-approved Max: 60 mg/day; however, some experts recommend doses up to 100 mg/day in patients weighing more than 50 kg. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Oral dosage (extended-release once-daily capsules; e.g., Aptensio XR)
    Children and Adolescents 6 years and older

    Initially, 10 mg PO once daily in the morning. Dose may be increased by 10 mg increments at weekly intervals. FDA-approved Max: 60 mg/day; however, some experts have recommended doses up to 100 mg/day of other methylphenidate formulations in patients weighing more than 50 kg. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Oral dosage (extended-release once-daily chewable tablets; e.g., QuilliChew ER)
    Children and Adolescents 6 years and older

    Initially, 20 mg PO once daily in the morning. Dose may be titrated up or down in increments of 10 mg, 15 mg, or 20 mg at weekly intervals. The 10 mg and 15 mg doses can each be achieved by breaking in half the functionally scored 20 mg and 30 mg tablets, respectively. FDA-approved Maximum: 60 mg/day PO; however, some experts have recommended doses up to 100 mg/day of other methylphenidate formulations in patients weighing more than 50 kg. If switching from another methylphenidate product, discontinue that treatment and titrate with QuilliChew ER as previously described; do not substitute QuilliChew ER for other methylphenidate products on a mg-for-mg basis. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Oral dosage (extended-release once-daily suspension; e.g., Quillivant XR)
    Children and Adolescents 6 years and older

    Initially, 20 mg PO once daily in the morning. Dose may be increased by 10 to 20 mg increments at weekly intervals. FDA-approved Max: 60 mg/day; however, some experts have recommended doses up to 100 mg/day of other methylphenidate formulations in patients weighing more than 50 kg. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Oral dosage (extended-release orally disintegrating tablets; e.g., Cotempla XR-ODT)
    Children and Adolescents 6 years and older

    Initially, 17.3 mg PO once daily in the morning; take consistently with or without food. Dose may be increased by 8.6 to 17.3 mg increments at weekly intervals. FDA-approved Max: 51.8 mg/day. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Transdermal dosage (transdermal system; e.g., Daytrana)
    Children and Adolescents 6 years and older

    Initially, apply a 10 mg/9-hour patch topically once daily in the morning, 2 hours before an effect is needed, regardless of previous methylphenidate therapy. If response is not maximized after 1 week, titrate to the next available patch strength in weekly intervals. The suggested upward titration schedule is Week 1: apply 10 mg/9-hour patch once daily; Week 2: apply 15 mg/9-hour patch once daily; Week 3: apply 20 mg/9-hour patch once daily; Week 4: apply 30 mg/9-hour patch once daily. Dose titration, final dosage, and wear time should be individualized according to the needs and response of the patient. Maximum: 30 mg/9-hour patch once daily. In clinical trials, there was no additional benefit of increasing the patch dose from 20 mg/9-hours to 30 mg/9-hours. Remove the patch 9 hours after application or may remove earlier if late day side effects appear and shorter duration of effect is desired.

    Oral dosage (immediate-release preparations, e.g., Ritalin, Methylin, Methylin oral solution, Methylin chewable tablets)
    Adults

    Average effective dose is 20 to 30 mg/day PO divided and given in 2 to 3 divided doses 30 to 45 minutes before meals. Range: 10 to 60 mg/day PO. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 pm.

    Children and Adolescents 6 years and older

    Initially, 5 mg PO twice daily before breakfast and lunch. Dose may be increased by 5 to 10 mg/day at weekly intervals; some patients may require dosing up to 3 times daily (administer last dose of day before 6 pm to limit sleep interference). Max: 60 mg/day per FDA-approved labeling; however, some experts state that doses up to 100 mg/day may be needed in patients weighing more than 50 kg. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If no improvement within 1 month, discontinue methylphenidate and consider an alternative treatment/therapy. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Children 3 to 5 years†

    The National Institute of Mental Health's Preschool ADHD Treatment Study (PATS) provides clinical guidance for children with ADHD 3 to 5 years of age. In the PATS, the initial dose of immediate-release methylphenidate was 1.25 mg PO 3 times daily. Doses were increased gradually up to a maximum of 10 mg PO 3 times daily to reach optimum therapeutic response. The mean optimal total daily dose was 14.2 +/- 8.1 mg (0.7 +/- 0.4 mg/kg/day). Max: 30 mg/day. In all cases, treatment should start with a low dose and be titrated upward slowly. Use lowest effective dose. Higher doses have lead to social withdrawal in some children. Behavior therapy, parental training, and a structured preschool environment are considered first line treatment for preschool-aged children with ADHD; lack of significant improvement with such modalities may warrant the addition of methylphenidate.

    Oral dosage (extended-release tablets, e.g., Ritalin SR, Metadate ER, Methylin ER)
    Adults

    The extended-release (ER) tablets have a duration of action of approximately 8 hours. Use in place of immediate-release (IR) tablets when the 8-hour dosage of these ER tablets corresponds to the previously titrated 8-hour dosage of the IR tablets. Max: 20 mg PO 3 times daily. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    Children and Adolescents 6 years and older

    The extended-release (ER) tablets have a duration of action of approximately 8 hours. Use in place of immediate-release (IR) tablets when the 8-hour dosage of the ER tablets corresponds to the previously titrated 8-hour dosage of the IR tablets. Alternatively, some experts recommend an initial dose of 10 mg PO once daily. Ritalin SR may be administered once or twice daily. Max: 60 mg/day per FDA-approved labeling; however, some experts state that doses up to 100 mg/day may be needed in patients weighing more than 50 kg. Individualize dosage based on psychosocial and comorbid factors; use lowest effective dose. If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage or discontinue the drug.

    For the treatment of narcolepsy.
    Oral dosage (immediate-release formulations; e.g., Ritalin, Methylin)
    Adults

    Average dose 20 to 30 mg/day; range 10 to 60 mg/day PO in 2 to 3 divided doses, 30 to 45 minutes before meals. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m.

    Children and Adolescents 6 years and older

    Initially, 5 mg PO twice daily before breakfast and lunch. May increase by 5 to 10 mg/day PO at weekly intervals. Max: 60 mg/day.

    Oral dosage (extended-release tablets; e.g., Ritalin SR, Metadate ER)
    Adults, Adolescents, and Children 6 years and older

    The extended-release (ER) tablets have a duration of action of approximately 8 hours. Therefore, use in place of immediate-release (IR) tablets when the 8-hour dosage of the ER tablets corresponds to the previously titrated 8-hour dosage of the IR tablets. Max: 60 mg/day.

    For the treatment of major depression† or post-stroke depression refractory to other therapies.
    NOTE: The use of stimulants for the treatment of depressive disorders is usually limited to treatment-refractory cases or when standard medical therapies are not tolerated. Stimulants may aggravate coexisting anxiety or agitation in depressed patients.
    Oral dose (immediate-release tablets)
    Adults

    Initially, 2.5 mg PO twice daily administered in the morning and at noon; increase by 2.5—5 mg PO every 2 or 3 days as tolerated, until the desired response is achieved. Roughly 50% of patients appear to respond to treatment.

    Geriatric

    Initially, 2.5 mg PO twice daily administered in the morning and at noon; increase by 2.5—5 mg PO every 2 or 3 days as tolerated, until the desired response is achieved. Dosage in elderly patients with post-stroke depression has ranged from 15—40 mg/day PO after dosage titration for a mean of 15 days. Roughly 50% of patients appear to respond to treatment.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    72 mg/day PO.

    Geriatric

    72 mg/day PO.

    Adolescents

    72 mg/day (Max: 2 mg/kg/day) PO for Concerta (FDA-approved labeling) and 60 mg/day PO for all other oral formulations excluding Cotempla XR-ODT (FDA-approved labeling); 51.8 mg/day PO for Cotempla XR-ODT; however, doses up to 100 to 108 mg/day PO have been used in patients weighing more than 50 kg for some formulations. For the transdermal patch, 30 mg/9-hour patch per day is the maximum.

    Children

    6 to 12 years: 54 mg/day PO for Concerta (FDA-approved labeling) and 60 mg/day PO for all other oral formulations excluding Cotempla XR-ODT (FDA-approved labeling); 51.8 mg/day PO for Cotempla XR-ODT; however, doses up to 100 to 108 mg/day PO have been used in patients weighing more than 50 kg. For the transdermal patch, 30 mg/9-hour patch per day is the maximum.
    3 to 5 years: Safety and efficacy have not been established. Maximum doses have not been adequately studied; however The Preschool ADHD Treatment Study (PATS) has suggested immediate-release doses up to 30 mg/day PO.
    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

    Specific guidelines for dosage adjustments in hepatic impairment are not available.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Renal clearance is not an important predictor of methylphenidate clearance.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Methylin chewable tablets: Administer with at least 8 ounces of fluid to avoid choking.
    Immediate-release dosage forms (Ritalin, Methylin, Metadate, generic equivalents): Administer 30 to 45 minutes before meals. Depending on the patient's needs, twice-daily dosages may be administered in the morning and around noon. Individualized timing of the midday dose is usually necessary, as determined by the loss of positive drug effect which occurs in a range of 2 to 6 hours after the morning dose.
    Extended-release tablets (Ritalin SR, Metadate ER, generic methylphenidate ER): May be administered without regard to meals. Administer whole; do not cut, crush, or chew. Administer the last dose of the day several hours before bedtime. Extended-release tablets may be used when the determined 8 hour dose of immediate-release methylphenidate tablets equals the 8 hour dosage of the extended-release tablets.
    Once-daily extended-release tablets (Concerta): May be administered without regard to meals. Administer whole; do not cut, crush, or chew. The biologically inert portion of this tablet may appear intact in the stool; this is normal.
    Once-daily extended-release capsules (Metadate CD, Ritalin LA, Aptensio XR): May be administered without regard to meals; however, the manufacturer of Aptensio XR recommends that patients establish a routine pattern with regard to meals. Administer with an adequate amount of fluid. Do not cut, crush, or chew. If swallowing is difficult, the capsule may be opened and the contents gently sprinkled on one tablespoon of applesauce and swallowed immediately. The capsule contents (beads) should not be crushed or chewed. Instruct the patient to drink fluids (e.g., water, milk, or juice) after the intake of the sprinkles with applesauce.
    Once-daily extended-release chewable tablets (QuilliChew ER): Administer once daily in the morning with or without food. The 10 mg and 15 mg doses can be achieved by breaking in half the scored 20 mg and 30 mg tablets, respectively.
    Once-daily extended-release orally disintegrating tablets (Cotempla XR-ODT): Administer once daily in the morning consistently either with or without food. Do not remove tablet from the blister pack until just prior to dosing; use dry hands when opening the blister pack. Remove the tablet by peeling back the foil; do not push the tablet through the foil. Place the whole tablet on the tongue and allow it to disintegrate without chewing or crushing. No liquid is needed to take the tablet.

    Oral Liquid Formulations

    Immediate-release oral solution (Methylin)
    Measure methylphenidate dosage with an oral syringe or calibrated measuring device.
    Administer 30 to 45 minutes before meals in divided doses 2 to 3 times daily. Twice-daily dosages may be administered in the morning and around noon. Individualized timing of the midday dose is usually necessary, as determined by the loss of positive drug effect which occurs 2 to 6 hours after the morning dose. Administer the last dose of the day prior to 6 p.m.
     
    Once-daily extended-release oral suspension (Quillivant XR)
    Vigorously shake the bottle of suspension for a minimum of 10 seconds.
    Measure dosage with the calibrated oral dosing dispenser provided.
    Administer in the morning without regard to meals.
     
    Reconstitution of once-daily extended-release oral suspension (Quillivant XR)
    Review the manufacturer's reconstitution instructions for the particular product and package size.
    Prior to reconstitution, tap the bottle several times to loosen the powder.
    To prepare the suspension, add the specified amount of water to the bottle, fully insert the bottle adapter into the bottle neck, replace the cap, and vigorously shake the bottle for at least 10 seconds.
    Storage: Store reconstituted suspension at 77 degrees F; dispense in original packaging (bottle in container). The reconstituted suspension is stable for 4 months from date of reconstitution.

    Topical Administration
    Transdermal Patch Formulations

    Daytrana transdermal system:
    Patch should be applied 2 hours before the effect is needed.
    Do not cut or trim patch.
    Apply patch immediately after opening the pouch and removing protective liner. Do not use if pouch seal is broken. Do not touch the adhesive side of the patch during application to avoid absorption of methylphenidate. Wash hands immediately if adhesive side of the patch is touched. Discard the patch if difficulty is encountered in separating the patch from the release liner, or if tearing or other damage occurs. Discard patch if adhesive containing medication has transferred to the liner during removal of the patch from the liner.
    Place on a dry, clean area of the hip and hold in place for 30 seconds with the palm of the hand. Do not apply to oily, damaged, or irritated skin. Do not apply topical preparations to the application site immediately prior to patch application. Avoid the waistline area where the patch could be rubbed by clothing.
    Applications sites should be alternated from one hip to the next each day, avoiding sites where a patch was recently placed, when possible.
    Instruct patient on proper application and disposal of patch. Adherence of the patch may be affected by showering, bathing, or swimming. The carton contains an administration chart that can help the patient monitor application and removal time, which the patient and/or caregiver should be encouraged to use. If a patch was removed without the caregiver's knowledge, or if a patch is missing from the tray, the caregiver should be encouraged to ask the child when and how the patch was removed.
    Avoid exposing the application site to hair dryers, heating pads, electric blankets, heated water beds, or other direct external heat sources. The rate and extent of absorption of methylphenidate are significantly increased during application of heat to the patch during use. Temperature-dependent increases in absorption may be greater than 2-fold, potentially resulting in overdose.
    Do not apply or re-apply the patch with dressings, tape, or adhesives. If the patch is not fully adhered to the skin during application or wear time, discard the patch according to disposal instructions and apply a new patch.
    The total daily wear time should not exceed 9 hours, regardless of patch replacement.
    Patches should be peeled off slowly. Patch removal may be aided by applying an oil-based product (i.e., petroleum jelly, mineral oil, olive oil) to the patch edges and gently working the oil underneath the edges of the patch.
    Disposal: Instruct patient and/or caregiver to fold used patches, so that the adhesive side of the patch adheres to itself, and then flush it down the toilet or dispose of in an appropriate lidded container. If the patient stops using the prescription, each unused patch should be removed from its pouch, separated from the protective liner, folded onto itself, and flushed down the toilet or disposed of in an appropriate lidded container. Do not flush pouch and protective liner down the toilet. Instead, dispose of them in an appropriate container with a lid.

    STORAGE

    Generic:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Aptensio XR:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Concerta:
    - Avoid excessive humidity
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Daytrana:
    - Do not freeze
    - Do not refrigerate
    - Product should be used within 2 months after opening
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store unused product in foil pouch
    Metadate CD:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Metadate ER:
    - Protect from moisture
    - Store solution at 68 to 77 degrees F, excursions permitted to 59 to 86 degrees F
    Methylin:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    QuilliChew ER:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    QUILLIVANT XR:
    - Store and dispense in original container
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Ritalin:
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Ritalin LA:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Ritalin SR:
    - Protect from moisture
    - Store solution at 68 to 77 degrees F, excursions permitted to 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Methylphenidate is contraindicated in patients with known hypersensitivity to methylphenidate or any component of this product. Cross-sensitivity with dexmethylphenidate should be expected. Life-threatening hypersensitivity reactions, including angioedema and anaphylaxis, have been reported during methylphenidate administration. The use of transdermal methylphenidate may lead to contact sensitization. If contact sensitization is suspected, the methylphenidate patch should be discontinued. Patients who have previously developed contact dermatitis with transdermal methylphenidate may also be sensitized to oral methylphenidate and should be initiated on oral therapy under close supervision. Following initial development of contact dermatitis from the methylphenidate patch, re-exposure to the drug by other routes of administration may result in systemic sensitization or other systemic reactions. Symptoms may include a flare-up of a previous dermatitis, generalized skin eruptions to previously unaffected skin, headache, fever, malaise, arthralgia, diarrhea, or vomiting. Some patients who develop sensitization to the patch may not be able to use the oral products. Patients should alternate hip application sites each day to help prevent sensitization.
     
    All patients should be advised to avoid exposing the methylphenidate patch application site to direct external heat sources (i.e., heating pads, electric blankets, heated water beds) while wearing the patch. There is a potential for temperature-dependent increases in methylphenidate release of greater than 2-fold from the patch when there is extreme ambient temperature increase at the site of application.

    Hereditary fructose intolerance

    The Metadate CD product contains sucrose. The manufacturer of Metadate CD considers its product contraindicated in patients with hereditary fructose intolerance, glucose-galactose malabsorption, and sucrase-isomaltase insufficiency.

    Anxiety, bipolar disorder, depression, mania, psychosis, schizophrenia, suicidal ideation

    Methylphenidate tablets (immediate-release, extended-release, and immediate-release chewable), transdermal patch, immediate-release oral solution, and some extended-release capsules (e.g., Metadate CD, Ritalin LA) are contraindicated in patients with marked anxiety, tension, or agitation because the drug can aggravate these conditions. Other dosage forms, including some extended-release capsules (e.g., Aptensio XR), extended-release chewable tablets (e.g., QuilliChew ER), and methylphenidate extended-release oral suspension are not specifically contraindicated by the manufacturer in these patient populations; however, extreme caution should be exercised if the drug is used in these patients. Stimulants should be used cautiously in those with bipolar disorder and/or mania due to the potential for manic episodes to occur. An assessment should be performed prior to initiation of therapy to determine the risk for bipolar disorder in patients presenting with symptoms of depression. Due to its toxic effects in overdose, methylphenidate should only be used in those with major depression or suicidal ideation when absolutely necessary. Aggression, hostility, and suicidal ideation or behaviors have been reported in both clinical trials and post-marketing experience with ADHD medications. 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. In psychotic individuals (e.g., schizophrenia), stimulants may exacerbate behavioral disturbances, psychosis, or thought disorders; therefore, the drug should be avoided if possible in those with psychosis.

    Tics, Tourette's syndrome

    Methylphenidate tablets (immediate-release, extended-release, and immediate-release chewable), transdermal patch, immediate-release oral solution, and some extended-release capsules (e.g., Metadate CD, Ritalin LA) are contraindicated in patients with motor tics, Tourette's syndrome, or a family history of Tourette's syndrome because the drug may precipitate motor or phonetic tics. Other dosage forms, including some extended-release capsules (e.g., Aptensio XR), extended-release chewable tablets (e.g., QuilliChew ER), and methylphenidate extended-release oral suspension are not specifically contraindicated by the manufacturer in these patient populations; however, caution should be exercised if the drug is used in these patients. Tics did occur during clinical trials of the drug.

    Glaucoma, visual disturbance

    Use of methylphenidate tablets (immediate-release, extended-release, and immediate-release chewable), transdermal patch, immediate-release oral solution, and some extended-release capsules (e.g., Metadate CD, Ritalin LA) is contraindicated in patients with glaucoma, due to the ability of the drug to increase sympathetic stimulation and to raise intraocular pressure. Other dosage forms, including some extended-release capsules (e.g., Aptensio XR), extended-release chewable tablets (e.g., QuilliChew ER), and methylphenidate extended-release oral suspension are not specifically contraindicated by the manufacturer in these patient populations; however, use is not recommended. Occasionally, a visual disturbance, such as change in visual accommodation or blurred vision, has been reported in other individuals without ocular disease. Patients should report any new visual disturbance as ophthalmic evaluation may be needed.

    Abrupt discontinuation, alcoholism, substance abuse

    Chronic abuse of methylphenidate can lead to marked tolerance and psychological dependence, with varying degrees of abnormal behavior. Symptoms of chronic abuse of methylphenidate may include insomnia, irritability, change in personality, and psychotic symptoms that may be clinically indistinguishable from psychotic disorders, particularly with parenteral or inhalational abuse. Misuse of amphetamines may also cause sudden death and serious cardiovascular adverse events. Therefore, a careful assessment of benefit versus risk is recommended in patients with a known history of substance abuse or alcoholism.The least amount reasonable should be prescribed or dispensed at one time in order to limit the potential for overuse or drug diversion. Close supervision is required during drug withdrawal from misuse since severe depression may occur. Withdrawal or abrupt discontinuation following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. Drug 'holidays', the temporary discontinuation of drug during weekends, holidays, summer vacations and etc., is usually not associated with drug withdrawal symptoms, but such holidays are typically reserved for those patients with well-controlled ADHD symptoms.

    Hypertension

    Use stimulant medications, such as methylphenidate, with caution in patients with hypertension 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—4 mmHg) and average heart rate (approximately 3—6 bpm); however, some individuals may have larger increases. Elevated blood pressure may require a dose reduction, discontinuation, and/or initiation of appropriate antihypertensive medication. Periodic blood pressure and heart rate monitoring is recommended in all patients taking methylphenidate. In pediatric clinical trials, methylphenidate increased heart rate by roughly 2—6 bpm and blood pressure by 1—4 mmHg. In a clinical trial of the extended-release preparation in adolescents, patients experienced a mean increase in resting pulse of 5 and 3 bpm for methylphenidate and placebo, respectively. Mean increases in systolic blood pressure were equal (0.7 mm Hg) in both treatment groups, and diastolic pressure increased by 2.6 and 1.4 mm Hg for the active and placebo treatments, respectively.

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

    The FDA recommends that, in general, stimulant medications such as methylphenidate 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, advanced arteriosclerosis or other serious cardiac disease or conditions. Stimulant medications may increase blood pressure or heart rate in some individuals (see hypertension precaution); 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 children and young adults 2—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—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) > 0.46 sec, or heart rate or blood pressure > 2 SD 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, such as methylphenidate, at usual doses for ADHD; therefore, patients with cerebrovascular disease should be closely monitored. Stimulant medications may increase blood pressure or heart rate in some individuals (see hypertension precaution).

    Children, growth inhibition

    Children and adolescents 6 years of age and older have been successfully treated for attention-deficit hyperactivity disorder (ADHD) with methylphenidate; there is clinical off-label use with immediate-release oral products in younger children under close medical supervision. Concerta, Daytrana, Metadate CD, and Ritalin LA are not recommended for children < 6 years of age. 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, methylphenidate may exacerbate behavioral disturbances, psychosis, or thought disorders. New onset psychotic or manic symptoms may develop in children 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 ADHD in pediatric populations. 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 methylphenidate on growth suppression in children 7— 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. Data are inadequate to determine whether chronic use of stimulants causes long-term growth inhibition. Although data are limited, available studies do not indicate that stimulant use compromises the attainment of normal adult height and weight in most children. Sudden death has been reported in association with CNS stimulant treatment at usual doses in children or adolescents 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—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 cardiac problems. 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).

    Hyperthyroidism

    Methylphenidate should be used cautiously in patients with hyperthyroidism, as sympathomimetic stimulation may induce cardiac arrhythmias or other side effects.

    Seizure disorder, seizures

    Methylphenidate should be used cautiously in patients with a history of a seizure disorder because the seizure threshold can be reduced. Seizure threshold may be reduced in those with EEG abnormalities and rarely in patients without a seizure history or EEG abnormalities. Concomitant use of methylphenidate and anticonvulsants has not been established. If seizures occur, methylphenidate therapy should be discontinued.

    Neonates, pregnancy

    The safety of methylphenidate during human pregnancy has not been established; therefore, methylphenidate should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. There are limited published studies and small case series that report on the use of methylphenidate during pregnancy; however, the data are insufficient to determine any drug-associated risks. Because stimulants cause vasoconstriction, they may decrease placental perfusion. Neonates born to stimulant-dependent mothers are at increased risk for premature delivery and low birth weight. In addition, neonates with in utero exposure to stimulants may experience withdrawal after delivery; monitor the newborn for symptoms of withdrawal such as feeding difficulty, irritability, agitation, and excessive drowsiness. It is unclear what effect, if any, a CNS stimulant such as methylphenidate would have on the developing fetal brain. In animal studies, teratogenic effects (increased incidence of fetal spina bifida), fetal skeletal variations, maternal toxicity, and/or decreased offspring weight gain were observed at doses that were 4 to 40 times the maximum recommended human dose (MRHD). The no effect level for embryo-fetal development in rats was 2 times the MRHD. Prescribers should enroll women exposed to methylphenidate during a pregnancy in a registry by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. The effect of methylphenidate on labor and delivery in humans is unknown.

    Breast-feeding

    The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for methylphenidate and any potential adverse effects on the breastfed infant from methylphenidate or from the underlying maternal condition. Methylphenidate has a low molecular weight and is excreted in human breast milk. Limited data from published literature have indicated a resulting infant dose of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk to plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Based on data from 2 breast-feeding mothers, one receiving 15 mg/day and one receiving 80 mg/day, the estimated infant dose ranged from 0.38 mcg/kg/day to 2.3 mcg/kg/day or 0.16% to 0.2% of the maternal weight-adjusted dose. The mothers of the infants, one an approximately 6.5 month old who received most of his nutrition from breast milk and one an 11 month old who was only sporadically breast fed, reported no adverse events. Although methylphenidate may be considered as an alternative to other stimulants in breast-feeding women, the medical use of stimulant medications has not been formally evaluated in controlled studies. If breast-feeding cannot be avoided during the use of stimulant medications, the nursing infant should be monitored for signs of central nervous system hyperactivity, including decreased appetite, insomnia, and irritability. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. The effect of stimulant medication exposure via breast milk on the long-term neurological development of the infant is not known. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Driving or operating machinery

    The use of methylphenidate 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 use methylphenidate for the prevention or treatment of normal fatigue states. Patients should not perform such tasks, including driving or operating machinery, until they are aware of how this medication affects them.

    Surgery

    The use of inhalational anesthetics during surgery may sensitize the cardiovascular system to the effects of methylphenidate. The manufacturer of Metadate CD and Metadate ER states that these products are contraindicated on the day of surgery due to the risk of sudden blood pressure increases during administration of halogenated anesthetics.

    Radiographic contrast administration

    Patients with a history of seizures or previous EEG abnormalities are at risk for a decreased seizure threshold following administration of a stimulant. In rare instances, those with no risk factors for seizure activity may develop a lowered seizure threshold with stimulant use. Methylphenidate should be promptly discontinued if seizures occur. Because of a potential increased risk of seizures, methylphenidate should not be used during intrathecal radiographic contrast administration. Methylphenidate therapy should be discontinued 48 hours before and not restarted until at least 24 hours after myelography.

    Dysphagia, esophageal stricture, GI obstruction, ileus

    There is a potential for Concerta tablets to cause GI obstruction in susceptible patients. The Concerta extended-release tablet is nondeformable. Use with caution in patients who would have history of severe GI narrowing which would place them at risk, such as those patients with inflammatory bowel disease, past history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, diverticular disease, or ileus. Patients with dysphagia, esophageal motility disorders, or esophageal stricture may not be able to swallow extended-release methylphenidate dosage forms whole and may be at risk for GI obstruction.

    Hepatic disease

    Methylphenidate has not been evaluated in patients with hepatic disease, and caution is recommended.

    Geriatric

    The safety and efficacy of certain dosage forms of methylphenidate have not been specifically assessed in geriatric patients. 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 methylphenidate; 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. According to the Beers Criteria, methylphenidate is considered a potentially inappropriate medication (PIM) for use in geriatric patients with insomnia and should be avoided due to the potential for drug-induced CNS stimulant effects.

    MAOI therapy

    Methylphenidate is contraindicated in patients who have received MAOI therapy within the past 14 days because of the possibility of precipitating a hypertensive crisis.

    Peripheral vascular disease, Raynaud's phenomenon

    Stimulant medications 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.

    Chemical leukoderma, skin hypopigmentation, vitiligo

    Chemical leukoderma, a condition that causes the skin to lose color from repeated exposure to specific chemical compounds, may occur with use of the methylphenidate patch. The condition is not physically harmful, but it is disfiguring and is thought to be irreversible, which may cause emotional distress. The areas of skin color loss described with the methylphenidate patch have ranged up to 8 inches in diameter, with a time of onset ranging from 2 months to 4 years after starting the patch. Skin hypopigmentation has occurred under and around the patch, and less frequently on parts of the body where the patch was never applied. Chemical leukoderma can mimic the appearance of vitiligo, particularly at remote sites of skin hypopigmentation. Individuals with a history of vitiligo and/or a family history of vitiligo may be more at risk. Patients and caregivers should be advised to watch for new areas of lighter skin, especially under the drug patch, and immediately report these changes to their health care providers. Alternative treatment should be considered in patients who experience these skin changes.]

    Phenylketonuria

    Methylphenidate chewable tablets (e.g., Methylin, QuilliChew ER) contain aspartame. Phenylalanine is a component of aspartame and can be harmful to patients with phenylketonuria (PKU). Before prescribing these formulations in patients with PKU, consider the combined daily amount of phenylalanine from all sources.

    ADVERSE REACTIONS

    Severe

    neuroleptic malignant syndrome / Delayed / 0-1.0
    myocardial infarction / Delayed / 0-1.0
    stroke / Early / 0-1.0
    rhabdomyolysis / Delayed / 0-1.0
    seizures / Delayed / Incidence not known
    Tourette's syndrome / Delayed / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatic encephalopathy / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known

    Moderate

    sinus tachycardia / Rapid / 0.7-4.8
    palpitations / Early / 2.0-3.1
    depression / Delayed / 1.7-1.7
    constipation / Delayed / 1.4-1.4
    confusion / Early / 1.2-1.2
    physiological dependence / Delayed / 0-1.0
    contact dermatitis / Delayed / 0.3-0.3
    psychosis / Early / 0.1-0.1
    blurred vision / Early / 1.7
    euphoria / Early / Incidence not known
    teeth grinding (bruxism) / Delayed / Incidence not known
    migraine / Early / Incidence not known
    hostility / Early / Incidence not known
    mania / Early / Incidence not known
    supranormalization / Delayed / Incidence not known
    hallucinations / Early / Incidence not known
    dyskinesia / Delayed / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    hypertension / Early / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    angina / Early / Incidence not known
    erythema / Early / Incidence not known
    bullous rash / Early / Incidence not known
    skin erosion / Delayed / Incidence not known
    chemical leukoderma / Delayed / Incidence not known
    atopic dermatitis / Delayed / Incidence not known
    growth inhibition / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    priapism / Delayed / Incidence not known
    skin ulcer / Delayed / Incidence not known
    peripheral vasoconstriction / Rapid / Incidence not known
    psychological dependence / Delayed / Incidence not known
    tolerance / Delayed / Incidence not known
    withdrawal / Early / Incidence not known

    Mild

    anorexia / Delayed / 2.0-30.6
    headache / Early / 2.4-22.2
    insomnia / Early / 2.0-16.6
    xerostomia / Early / 14.0-14.0
    nausea / Early / 2.4-12.8
    irritability / Delayed / 2.0-11.0
    vomiting / Early / 1.7-10.2
    emotional lability / Early / 1.4-9.0
    abdominal pain / Early / 4.8-8.2
    anxiety / Delayed / 2.0-8.2
    dizziness / Early / 0-6.7
    restlessness / Early / 2.0-3.1
    pharyngitis / Delayed / 0-2.8
    dyspepsia / Early / 2.2-2.2
    agitation / Early / 2.0-2.2
    fever / Early / 2.0-2.2
    infection / Delayed / 0-2.2
    vertigo / Early / 1.7-2.0
    rash (unspecified) / Early / 2.0-2.0
    ocular pain / Early / 2.0-2.0
    cough / Delayed / 1.9-1.9
    libido decrease / Delayed / 1.7-1.7
    tremor / Early / 2.0
    weight loss / Delayed / 2.4
    lethargy / Early / Incidence not known
    fatigue / Early / Incidence not known
    drowsiness / Early / Incidence not known
    diarrhea / Early / Incidence not known
    syncope / Early / Incidence not known
    myalgia / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    purpura / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    skin hypopigmentation / Delayed / Incidence not known
    skin irritation / Early / Incidence not known
    xerosis / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    ecchymosis / Delayed / Incidence not known
    diplopia / Early / Incidence not known
    mydriasis / Early / Incidence not known
    sinusitis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acarbose: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Acebutolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Caffeine is a CNS stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of methylphenidate. 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; Butalbital; Caffeine: (Moderate) Caffeine is a CNS stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of methylphenidate. 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; Butalbital; Caffeine; Codeine: (Moderate) Caffeine is a CNS stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of methylphenidate. 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) Caffeine is a CNS stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of methylphenidate. 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) Caffeine is a CNS stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of methylphenidate. 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) Caffeine is a CNS stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of methylphenidate. 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; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Acetaminophen; Guaifenesin; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Albiglutide: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Alogliptin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving alogliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Alogliptin; Metformin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving alogliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics, such as methylphenidate, may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Alogliptin; Pioglitazone: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving alogliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Alpha-blockers: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as alpha-blockers. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Alpha-glucosidase Inhibitors: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Aluminum Hydroxide: (Minor) The modified release characteristics of extended-release methylphenidate (Ritalin LA) are pH-dependent. Administration of antacids could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with antacids should be monitored for adverse effects and/or reduced efficacy.
    Aluminum Hydroxide; Magnesium Carbonate: (Minor) The modified release characteristics of extended-release methylphenidate (Ritalin LA) are pH-dependent. Administration of antacids could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with antacids should be monitored for adverse effects and/or reduced efficacy.
    Aluminum Hydroxide; Magnesium Hydroxide: (Minor) The modified release characteristics of extended-release methylphenidate (Ritalin LA) are pH-dependent. Administration of antacids could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with antacids should be monitored for adverse effects and/or reduced efficacy.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Minor) The modified release characteristics of extended-release methylphenidate (Ritalin LA) are pH-dependent. Administration of antacids could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with antacids should be monitored for adverse effects and/or reduced efficacy.
    Aluminum Hydroxide; Magnesium Trisilicate: (Minor) The modified release characteristics of extended-release methylphenidate (Ritalin LA) are pH-dependent. Administration of antacids could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with antacids should be monitored for adverse effects and/or reduced efficacy.
    Amantadine: (Moderate) Careful observation is required when amantadine is administered concurrently with central nervous system (CNS) stimulants such as methylphenidate. An increase in stimulant effects, such as nervousness, irritability, insomnia, tremor, seizures, or cardiac arrhythmias may occur.
    Ambrisentan: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Amiloride: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as potassium-sparing diuretics. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as potassium-sparing diuretics. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Amitriptyline: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and tricyclic antidepressants (TCAs). There are rare reports of serotonin syndrome occurring during use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented. There does not appear to be a pharmacokinetic interaction between methylphenidate and TCAs. In one study, use of methylphenidate did not increase plasma concentrations of the CYP2D6 substrate desipramine. Nevertheless, a dose adjustment of the TCA, and monitoring of TCA plasma concentrations when applicable, may be required when initiating or discontinuing methylphenidate.
    Amitriptyline; Chlordiazepoxide: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and tricyclic antidepressants (TCAs). There are rare reports of serotonin syndrome occurring during use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented. There does not appear to be a pharmacokinetic interaction between methylphenidate and TCAs. In one study, use of methylphenidate did not increase plasma concentrations of the CYP2D6 substrate desipramine. Nevertheless, a dose adjustment of the TCA, and monitoring of TCA plasma concentrations when applicable, may be required when initiating or discontinuing methylphenidate.
    Amoxapine: (Moderate) Both methylphenidate and amoxapine may lower the seizure threshold; therefore, caution is particularly advisable when this combination is administered to patients susceptible to seizures. In addition, methylphenidate is thought to exert some of its beneficial effects through dopamine re-uptake blockade while amoxapine has central dopamine antagonist properties. In theory, the therapeutic effects of either agent may be reduced.
    Amoxicillin; Clarithromycin; Lansoprazole: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Per the manufacturer of extended-release methylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release methylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Per the manufacturer of extended-release methylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release methylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Amphetamine: (Severe) Amphetamines and methylphenidate should not be coadministered. These drugs represent duplicate treatments for certain conditions. Nervousness, irritability, insomnia, palpitations, arrhythmias, seizures, or other serious stimulant-related adverse effects may occur.
    Amphetamine; Dextroamphetamine: (Severe) Amphetamines and methylphenidate should not be coadministered. These drugs represent duplicate treatments for certain conditions. Nervousness, irritability, insomnia, palpitations, arrhythmias, seizures, or other serious stimulant-related adverse effects may occur.
    Amphetamines: (Severe) Amphetamines and methylphenidate should not be coadministered. These drugs represent duplicate treatments for certain conditions. Nervousness, irritability, insomnia, palpitations, arrhythmias, seizures, or other serious stimulant-related adverse effects may occur.
    Angiotensin II receptor antagonists: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as angiotensin II receptor antagonists. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Angiotensin-converting enzyme inhibitors: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as angiotensin-converting enzyme inhibitors. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Antacids: (Minor) The modified release characteristics of extended-release methylphenidate (Ritalin LA) are pH-dependent. Administration of antacids could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with antacids should be monitored for adverse effects and/or reduced efficacy.
    Apomorphine: (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and dopamine agonists such as pergolide, pramipexole, apomorphine, and ropinirole. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible.
    Aripiprazole: (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Armodafinil: (Major) The use of armodafinil with other psychostimulants, including methylphenidate, has not been studied. 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.
    Asenapine: (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Caffeine is a CNS stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of methylphenidate. 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) Caffeine is a CNS stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of methylphenidate. 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) Caffeine is a CNS stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of methylphenidate. 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; Omeprazole: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Per the manufacturer of extended-release methylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release methylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Atenolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Atenolol; Chlorthalidone: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Atomoxetine: (Major) Use methylphenidate cautiously in patients receiving atomoxetine, a selective norepinephrine reuptake inhibitor. If coadministration is necessary, monitor patients closely for tachycardia and hypertension. Although coadministration of methylphenidate and atomoxetine did not increase the cardiovascular effects seen with administration of methylphenidate alone during clinical trials, concurrent use of sympathomimetic agents may result in an increased risk of noradrenergic effects. Also monitor for appropriate clinical response and for any unusual changes in moods or behavior.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Theoretically, concurrent use of methylene blue and methylphenidate may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and methylphenidate increases central serotonin effects. 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 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. Serotonin syndrome is characterized by the rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Psychostimulants, such as methylphenidate, may lower the seizure threshold, thereby reducing the efficacy of anticonvulsants such as phenobarbital. In addition, case reports suggest a potential pharmacokinetic interaction between methylphenidate and phenobarbital; however, a kinetic interaction was not confirmed when evaluated at higher sample sizes. Nevertheless, a dose adjustment of phenobarbital and more frequent monitoring of plasma concentrations may be required when initiating or discontinuing methylphenidate. It should be noted that methylphenidate is not metabolized by the cytochrome P450 system to a relevant extent and methylphenidate has no relevant inhibitory effect on CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.
    atypical antipsychotic: (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Psychostimulants, such as methylphenidate, may lower the seizure threshold, thereby reducing the efficacy of anticonvulsants such as phenobarbital. In addition, case reports suggest a potential pharmacokinetic interaction between methylphenidate and phenobarbital; however, a kinetic interaction was not confirmed when evaluated at higher sample sizes. Nevertheless, a dose adjustment of phenobarbital and more frequent monitoring of plasma concentrations may be required when initiating or discontinuing methylphenidate. It should be noted that methylphenidate is not metabolized by the cytochrome P450 system to a relevant extent and methylphenidate has no relevant inhibitory effect on CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.
    Bendroflumethiazide; Nadolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Theoretically, concurrent use of methylene blue and methylphenidate may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and methylphenidate increases central serotonin effects. 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 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. Serotonin syndrome is characterized by the rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Benzphetamine: (Severe) Amphetamines and methylphenidate should not be coadministered. These drugs represent duplicate treatments for certain conditions. Nervousness, irritability, insomnia, palpitations, arrhythmias, seizures, or other serious stimulant-related adverse effects may occur.
    Beta-blockers: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Betaxolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Bethanechol: (Moderate) Bethanechol offsets the effects of sympathomimetics at sites where sympathomimetic and cholinergic receptors have opposite effects.
    Bisoprolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Brexpiprazole: (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Brimonidine; Timolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Bromocriptine: (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and dopamine agonists such as bromocriptine. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible.
    Brompheniramine; Carbetapentane; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Bupropion: (Major) Drugs which may lower the seizure threshold, such as methylphenidate, should be used with great caution or avoided in patients taking bupropion. The manufacturer recommends low initial dosing and slow dosage titration of bupropion if this combination must be used concurrently; the patient should be closely monitored.
    Bupropion; Naltrexone: (Major) Drugs which may lower the seizure threshold, such as methylphenidate, should be used with great caution or avoided in patients taking bupropion. The manufacturer recommends low initial dosing and slow dosage titration of bupropion if this combination must be used concurrently; the patient should be closely monitored.
    Caffeine: (Moderate) Caffeine is a CNS stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of methylphenidate. 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.
    Caffeine; Ergotamine: (Moderate) Caffeine is a CNS stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Avoid excessive caffeine intake during use of methylphenidate. 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: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Because the modified release characteristics are pH-dependent, it is possible that the administration of antacids or other acid suppressants could alter the release of extended-release methylphenidate. Patients receiving an antacid should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Calcium Carbonate; Magnesium Hydroxide: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Because the modified release characteristics are pH-dependent, it is possible that the administration of antacids or other acid suppressants could alter the release of extended-release methylphenidate. Patients receiving an antacid should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate. (Minor) The modified release characteristics of extended-release methylphenidate (Ritalin LA) are pH-dependent. Administration of antacids could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with antacids should be monitored for adverse effects and/or reduced efficacy.
    Calcium Carbonate; Risedronate: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Because the modified release characteristics are pH-dependent, it is possible that the administration of antacids or other acid suppressants could alter the release of extended-release methylphenidate. Patients receiving an antacid should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Calcium; Vitamin D: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Because the modified release characteristics are pH-dependent, it is possible that the administration of antacids or other acid suppressants could alter the release of extended-release methylphenidate. Patients receiving an antacid should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Calcium-channel blockers: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents, including calcium-channel blockers. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Canagliflozin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving canagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Canagliflozin; Metformin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving canagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics, such as methylphenidate, may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Carbamazepine: (Moderate) Psychostimulants, such as methylphenidate, may lower the seizure threshold, thereby reducing the efficacy of anticonvulsants such as carbamazepine. In addition, the therapeutic effect of methylphenidate in treating attention-deficit hyperactivity disorder (ADHD) may be decreased during coadministration of carbamazepine. One case report describes an adolescent girl who experienced decreases in peak methylphenidate concentrations and reduced methylphenidate efficacy following initiation and dose titration of carbamazepine. Subsequent dose increases of methylphenidate were needed to elicit a therapeutic response. In a separate case, a 7 year old boy receiving 1,000 mg/day of carbamazepine for epilepsy was administered up to 50 mg of methylphenidate every 4 hours for ADHD, with blood concentrations failing to show any trace of methylphenidate or its metabolites. Controlled trials are needed to confirm the case report findings.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Carbetapentane; Guaifenesin; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Carbetapentane; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Carbetapentane; Phenylephrine; Pyrilamine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Carbidopa; Levodopa: (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and medications that increase dopaminergic activity such as levodopa. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible.
    Carbidopa; Levodopa; Entacapone: (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and COMT inhibitors such as tolcapone and entacapone. Inhibiting the catechol-O-methyltransferase (COMT) enzyme reduces the metabolism of levodopa to metabolites, thereby prolonging the dopaminergic effects of levodopa. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible during concurrent use of methylphenidate and a COMT inhibitor. (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and medications that increase dopaminergic activity such as levodopa. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Carbinoxamine; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    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.
    Cariprazine: (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Carteolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Carvedilol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Chlophedianol; Guaifenesin; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Chlorpheniramine; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Chlorpromazine: (Moderate) Antipsychotics, such as phenothiazines, and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Chlorthalidone; Clonidine: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents, including clonidine. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and clonidine, particularly during initial coadministration and after dosage increases of methylphenidate.
    Cimetidine: (Minor) The modified release characteristics of extended-release methylphenidate are pH-dependent. Administration of H2-blockers could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with acid suppressants should be monitored for adverse effects and therapeutic efficacy.
    Citalopram: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs). There are rare reports of serotonin syndrome occurring during use of an SSRI and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Clomipramine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and tricyclic antidepressants (TCAs). There are rare reports of serotonin syndrome occurring during use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented. There does not appear to be a pharmacokinetic interaction between methylphenidate and TCAs. In one study, use of methylphenidate did not increase plasma concentrations of the CYP2D6 substrate desipramine. Nevertheless, a dose adjustment of the TCA, and monitoring of TCA plasma concentrations when applicable, may be required when initiating or discontinuing methylphenidate.
    Clonidine: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents, including clonidine. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and clonidine, particularly during initial coadministration and after dosage increases of methylphenidate.
    Clozapine: (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Codeine; Phenylephrine; Promethazine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Colchicine: (Minor) The response to sympathomimetics may be enhanced by colchicine.
    COMT inhibitors: (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and COMT inhibitors such as tolcapone and entacapone. Inhibiting the catechol-O-methyltransferase (COMT) enzyme reduces the metabolism of levodopa to metabolites, thereby prolonging the dopaminergic effects of levodopa. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible during concurrent use of methylphenidate and a COMT inhibitor.
    Dapagliflozin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Dapagliflozin; Metformin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving dapagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics, such as methylphenidate, may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Desflurane: (Moderate) Inhalational general anesthetics (e.g., enflurane, halothane, isoflurane, and methoxyflurane) may sensitize the cardiovascular system to the effects of methylphenidate. While the sympathomimetic effects of methylphenidate are weaker than those of the amphetamines, and evidence of interaction is lacking, caution is advised. The use of Metadate CD is contraindicated on the day of surgery due to the risk of sudden blood pressure increases during administration of halogenated anesthetics.
    Desiccated Thyroid: (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.
    Desipramine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and tricyclic antidepressants (TCAs). There are rare reports of serotonin syndrome occurring during use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented. There does not appear to be a pharmacokinetic interaction between methylphenidate and TCAs. In one study, use of methylphenidate did not increase plasma concentrations of the CYP2D6 substrate desipramine. Nevertheless, a dose adjustment of the TCA, and monitoring of TCA plasma concentrations when applicable, may be required when initiating or discontinuing methylphenidate.
    Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome has been reported during concurrent use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. There is also a case of a neuroleptic malignant syndrome-like reaction occurring in a child on chronic methylphenidate therapy 45 minutes after ingesting a dose of venlafaxine. It is unclear if the reaction was the result of a drug interaction. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Dexlansoprazole: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Per the manufacturer of extended-release methylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release methylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Dexmethylphenidate: (Severe) Avoid coadministration of methylphenidate and dexmethylphenidate. These drugs represent duplicate treatments. Serious side effects such as nervousness, irritability, arrhythmias, palpitations, seizures, or other stimulant-related adverse effects may occur or get worse during concurrent use.
    Dextroamphetamine: (Severe) Amphetamines and methylphenidate should not be coadministered. These drugs represent duplicate treatments for certain conditions. Nervousness, irritability, insomnia, palpitations, arrhythmias, seizures, or other serious stimulant-related adverse effects may occur.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    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.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Diphenhydramine; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    dopamine agonists: (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and dopamine agonists such as pergolide, pramipexole, apomorphine, and ropinirole. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible.
    Dopamine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Dorzolamide; Timolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Doxazosin: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as alpha-blockers. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Doxepin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and tricyclic antidepressants (TCAs). There are rare reports of serotonin syndrome occurring during use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented. There does not appear to be a pharmacokinetic interaction between methylphenidate and TCAs. In one study, use of methylphenidate did not increase plasma concentrations of the CYP2D6 substrate desipramine. Nevertheless, a dose adjustment of the TCA, and monitoring of TCA plasma concentrations when applicable, may be required when initiating or discontinuing methylphenidate.
    Dronabinol, THC: (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.
    Droxidopa: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Dulaglutide: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Duloxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome has been reported during concurrent use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. There is also a case of a neuroleptic malignant syndrome-like reaction occurring in a child on chronic methylphenidate therapy 45 minutes after ingesting a dose of venlafaxine. It is unclear if the reaction was the result of a drug interaction. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Dyphylline: (Major) Coadministration of dyphylline with sympathomimetics should be approached with caution. Coadministration may lead to adverse effects, such as tremors, insomnia, seizures, or cardiac arrhythmias, and should be avoided if possible.
    Dyphylline; Guaifenesin: (Major) Coadministration of dyphylline with sympathomimetics should be approached with caution. Coadministration may lead to adverse effects, such as tremors, insomnia, seizures, or cardiac arrhythmias, and should be avoided if possible.
    Empagliflozin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Empagliflozin; Linagliptin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Empagliflozin; Metformin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving empagliflozin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics, such as methylphenidate, may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Enflurane: (Moderate) Inhalational general anesthetics (e.g., enflurane, halothane, isoflurane, and methoxyflurane) may sensitize the cardiovascular system to the effects of methylphenidate. While the sympathomimetic effects of methylphenidate are weaker than those of the amphetamines, and evidence of interaction is lacking, caution is advised. The use of Metadate CD is contraindicated on the day of surgery due to the risk of sudden blood pressure increases during administration of halogenated anesthetics.
    Entacapone: (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and COMT inhibitors such as tolcapone and entacapone. Inhibiting the catechol-O-methyltransferase (COMT) enzyme reduces the metabolism of levodopa to metabolites, thereby prolonging the dopaminergic effects of levodopa. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible during concurrent use of methylphenidate and a COMT inhibitor.
    Ephedrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Eplerenone: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as eplerenone. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Epoprostenol: (Major) Sympathomimetics can antagonize the antihypertensive effects of adrenergic agonists when administered concomitantly. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Escitalopram: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs). There are rare reports of serotonin syndrome occurring during use of an SSRI and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Esmolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Esomeprazole: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Per the manufacturer of extended-release methylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release methylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Esomeprazole; Naproxen: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Per the manufacturer of extended-release methylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release methylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Ethanol: (Major) Ethanol consumption should be avoided during treatment with certain extended-release dosage forms of methylphenidate (e.g., Ritalin LA, Metadate CD). Consumption of ethanol may increases the release rate of methylphenidate. In addition, concurrent use may exacerbate the CNS-related adverse effects of methylphenidate. (Major) Ethanol consumption should be avoided during treatment with certain extended-release dosage forms of methylphenidate (e.g., Ritalin LA, Metadate CD). Results from an in vitro study showed that at an alcohol concentration of 40%, there was a 98% release of extended-release methylphenidate (Ritalin LA) from the 40 mg capsule in the first hour. In addition, concurrent use with alcohol may exacerbate the CNS-related adverse effects of methylphenidate.
    Ethotoin: (Moderate) Psychostimulants, such as methylphenidate, may lower the seizure threshold, thereby reducing the efficacy of anticonvulsants such as hydantoins. In addition, case reports suggest a potential pharmacokinetic interaction between methylphenidate and phenytoin; however, a kinetic interaction was not confirmed when evaluated at higher sample sizes. Nevertheless, a dose adjustment of phenytoin and more frequent monitoring of plasma concentrations may be required when initiating or discontinuing methylphenidate. It should be noted that methylphenidate is not metabolized by the cytochrome P450 system to a relevant extent and methylphenidate has no relevant inhibitory effect on CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.
    Exenatide: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Famotidine: (Minor) The modified release characteristics of extended-release methylphenidate are pH-dependent. Administration of H2-blockers could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with acid suppressants should be monitored for adverse effects and therapeutic efficacy.
    Famotidine; Ibuprofen: (Minor) The modified release characteristics of extended-release methylphenidate are pH-dependent. Administration of H2-blockers could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with acid suppressants should be monitored for adverse effects and therapeutic efficacy.
    Fluoxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs). There are rare reports of serotonin syndrome occurring during use of an SSRI and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Fluoxetine; Olanzapine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs). There are rare reports of serotonin syndrome occurring during use of an SSRI and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented. (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Fluphenazine: (Moderate) Antipsychotics, such as phenothiazines, and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    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: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs). There are rare reports of serotonin syndrome occurring during use of an SSRI and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Fosphenytoin: (Moderate) Psychostimulants, such as methylphenidate, may lower the seizure threshold, thereby reducing the efficacy of anticonvulsants such as hydantoins. In addition, case reports suggest a potential pharmacokinetic interaction between methylphenidate and phenytoin; however, a kinetic interaction was not confirmed when evaluated at higher sample sizes. Nevertheless, a dose adjustment of phenytoin and more frequent monitoring of plasma concentrations may be required when initiating or discontinuing methylphenidate. It should be noted that methylphenidate is not metabolized by the cytochrome P450 system to a relevant extent and methylphenidate has no relevant inhibitory effect on CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.
    Glipizide; Metformin: (Moderate) Sympathomimetics, such as methylphenidate, may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Glyburide; Metformin: (Moderate) Sympathomimetics, such as methylphenidate, may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Green Tea: (Moderate) The CNS stimulant effects of methylphenidate can be additive when used concurrently with most other psychostimulants, such as caffeine, including foods, herbal or dietary supplement products containing high amounts of caffeine like green tea. The combination of methylphenidate with other CNS stimulants may increase the incidence of side effects. Patients should avoid excessive caffeine intake, and observe for signs of nervousness, irritability, insomnia, tremor, arrhythmias, or other stimulant-related problems.
    Guaifenesin; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Guanabenz: (Major) Sympathomimetics can antagonize the antihypertensive effects of adrenergic agonists when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Guanfacine: (Moderate) Psychostimulants, such as methylphenidate, 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 methylphenidate in the treatment of attention deficit hyperactivity disorder (ADHD). Pharmacokinetic studies reveal that guanfacine does not influence methylphenidate pharmacokinetics and methylphenidate does not affect guanfacine pharmacokinetics. No dosage adjustments are required when used together. Patients should be monitored for heart rate, blood pressure, and for sedation during ADHD treatment.
    Guarana: (Major) Caffeine, an active constituent of guarana, is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. Use of guarana should be avoided with amphetamine, dextroamphetamine, methylphenidate, modafinil, pemoline, pseudoephedrine, beta-agonists or other sympathomimetics. When combined with any of these medications, nervousness, irritability, insomnia, and/or cardiac arrhythmias may result.
    H2-blockers: (Minor) The modified release characteristics of extended-release methylphenidate are pH-dependent. Administration of H2-blockers could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with acid suppressants should be monitored for adverse effects and therapeutic efficacy.
    Halogenated Anesthetics: (Moderate) Inhalational general anesthetics (e.g., enflurane, halothane, isoflurane, and methoxyflurane) may sensitize the cardiovascular system to the effects of methylphenidate. While the sympathomimetic effects of methylphenidate are weaker than those of the amphetamines, and evidence of interaction is lacking, caution is advised. The use of Metadate CD is contraindicated on the day of surgery due to the risk of sudden blood pressure increases during administration of halogenated anesthetics.
    Haloperidol: (Moderate) Antipsychotics, such as haloperidol, and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Halothane: (Moderate) Inhalational general anesthetics (e.g., enflurane, halothane, isoflurane, and methoxyflurane) may sensitize the cardiovascular system to the effects of methylphenidate. While the sympathomimetic effects of methylphenidate are weaker than those of the amphetamines, and evidence of interaction is lacking, caution is advised. The use of Metadate CD is contraindicated on the day of surgery due to the risk of sudden blood pressure increases during administration of halogenated anesthetics.
    Hydantoins: (Moderate) Psychostimulants, such as methylphenidate, may lower the seizure threshold, thereby reducing the efficacy of anticonvulsants such as hydantoins. In addition, case reports suggest a potential pharmacokinetic interaction between methylphenidate and phenytoin; however, a kinetic interaction was not confirmed when evaluated at higher sample sizes. Nevertheless, a dose adjustment of phenytoin and more frequent monitoring of plasma concentrations may be required when initiating or discontinuing methylphenidate. It should be noted that methylphenidate is not metabolized by the cytochrome P450 system to a relevant extent and methylphenidate has no relevant inhibitory effect on CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Major) Methylphenidate can reduce the hypotensive effect of antihypertensive agents, including methyldopa. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Hydrochlorothiazide, HCTZ; Propranolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as potassium-sparing diuretics. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as potassium-sparing diuretics. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Hydrocodone; Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Theoretically, concurrent use of methylene blue and methylphenidate may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and methylphenidate increases central serotonin effects. 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 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. Serotonin syndrome is characterized by the rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Iloperidone: (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Iloprost: (Major) Sympathomimetics can antagonize the antihypertensive effects of adrenergic agonists when administered concomitantly. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Imipramine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and tricyclic antidepressants (TCAs). There are rare reports of serotonin syndrome occurring during use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented. There does not appear to be a pharmacokinetic interaction between methylphenidate and TCAs. In one study, use of methylphenidate did not increase plasma concentrations of the CYP2D6 substrate desipramine. Nevertheless, a dose adjustment of the TCA, and monitoring of TCA plasma concentrations when applicable, may be required when initiating or discontinuing methylphenidate.
    Incretin Mimetics: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Indacaterol: (Moderate) Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Caution and close observation is needed if indacaterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Indacaterol; Glycopyrrolate: (Moderate) Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Caution and close observation is needed if indacaterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Indapamide: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as indapamide. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Insulin Degludec; Liraglutide: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Insulin Glargine; Lixisenatide: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Insulins: (Moderate) Monitor patients receiving insulin closely for worsening glycemic control when sympathomimetic agents are instituted. Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism.
    Isocarboxazid: (Severe) In general, all types of sympathomimetics and psychostimulants 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 even 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: (Moderate) Inhalational general anesthetics (e.g., enflurane, halothane, isoflurane, and methoxyflurane) may sensitize the cardiovascular system to the effects of methylphenidate. While the sympathomimetic effects of methylphenidate are weaker than those of the amphetamines, and evidence of interaction is lacking, caution is advised. The use of Metadate CD is contraindicated on the day of surgery due to the risk of sudden blood pressure increases during administration of halogenated anesthetics.
    Labetalol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Lansoprazole: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Per the manufacturer of extended-release methylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release methylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Lansoprazole; Naproxen: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Per the manufacturer of extended-release methylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release methylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Levobetaxolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Levobunolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Levodopa: (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and medications that increase dopaminergic activity such as levodopa. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible.
    Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome has been reported during concurrent use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. There is also a case of a neuroleptic malignant syndrome-like reaction occurring in a child on chronic methylphenidate therapy 45 minutes after ingesting a dose of venlafaxine. It is unclear if the reaction was the result of a drug interaction. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    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.
    Linagliptin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Linagliptin; Metformin: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving linagliptin should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. (Moderate) Sympathomimetics, such as methylphenidate, may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Linezolid: (Major) Psychostimulants, such as methylphenidate, exhibit sympathomimetic actions and should be avoided with other drugs, such as linezolid, that enhance the pressor response of sympathomimetic agents. A clinically significant rise in systolic blood pressure is possible. In addition, serotonin syndrome has been reported during the concurrent use of linezolid, a non-selective monoamine oxidase inhibitor (MAOI), and medications that enhance central serotonergic activity. Monoamine oxidase (MAO) is the enzyme responsible for the degradation of norepinephrine, dopamine, and serotonin. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    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.
    Liotrix: (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) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Lisdexamfetamine: (Severe) Amphetamines and methylphenidate should not be coadministered. These drugs represent duplicate treatments for certain conditions. Nervousness, irritability, insomnia, palpitations, arrhythmias, seizures, or other serious stimulant-related adverse effects may occur.
    Lithium: (Moderate) Methylphenidate can occasionally worsen mania in those with bipolar disorder, potentially reducing the overall effectiveness of treatment with mood stabilizers. According to some literature and the product labeling of many stimulants, lithium may antagonize the anorectic and stimulant effects of amphetamines. Despite this precaution, some data indicate a beneficial effect based upon the clinical circumstances of the patient. Further study is needed to fully assess the benefits and risks that may occur from concomitant administration of methylphenidate and lithium. Close monitoring is advisable when combination therapy is initiated or dosages are increased.
    Lixisenatide: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Loop diuretics: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as loop diuretics. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Loxapine: (Moderate) Antipsychotics, such as loxapine, and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Lurasidone: (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Macitentan: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking macitentan with a sympathomimetic.
    Magnesium Hydroxide: (Minor) The modified release characteristics of extended-release methylphenidate (Ritalin LA) are pH-dependent. Administration of antacids could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with antacids should be monitored for adverse effects and/or reduced efficacy.
    Maprotiline: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Meglitinides: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Mephobarbital: (Moderate) Psychostimulants, such as methylphenidate, may lower the seizure threshold, thereby reducing the efficacy of barbiturates such as mephobarbital in treating seizures. In addition, case reports suggest a potential pharmacokinetic interaction between methylphenidate and barbiturates such as phenobarbital; however, a kinetic interaction was not confirmed when evaluated at higher sample sizes. Nevertheless, a dose adjustment of the barbiturate may be required when initiating or discontinuing methylphenidate. It should be noted that methylphenidate is not metabolized by the cytochrome P450 system to a relevant extent and methylphenidate has no relevant inhibitory effect on CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.
    Mesoridazine: (Moderate) Antipsychotics, such as phenothiazines, and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Metformin: (Moderate) Sympathomimetics, such as methylphenidate, may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Metformin; Pioglitazone: (Moderate) Sympathomimetics, such as methylphenidate, may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Metformin; Repaglinide: (Moderate) Sympathomimetics, such as methylphenidate, may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Metformin; Rosiglitazone: (Moderate) Sympathomimetics, such as methylphenidate, may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Metformin; Saxagliptin: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia. (Moderate) Sympathomimetics, such as methylphenidate, may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Metformin; Sitagliptin: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia. (Moderate) Sympathomimetics, such as methylphenidate, may increase blood sugar via stimulation of beta-2 receptors which leads to increased glycogenolysis. Patients receiving antidiabetic agents should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted.
    Methamphetamine: (Severe) Amphetamines and methylphenidate should not be coadministered. These drugs represent duplicate treatments for certain conditions. Nervousness, irritability, insomnia, palpitations, arrhythmias, seizures, or other serious stimulant-related adverse effects may occur.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Theoretically, concurrent use of methylene blue and methylphenidate may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and methylphenidate increases central serotonin effects. 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 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. Serotonin syndrome is characterized by the rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Methyldopa: (Major) Methylphenidate can reduce the hypotensive effect of antihypertensive agents, including methyldopa. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Methylene Blue: (Moderate) Theoretically, concurrent use of methylene blue and methylphenidate may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and methylphenidate increases central serotonin effects. 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 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. Serotonin syndrome is characterized by the rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Metoclopramide: (Moderate) In theory, metoclopramide and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Patients receiving this combination should be monitored for loss of effectiveness of either agent. Methylphenidate blocks central dopamine reuptake, which increases central dopaminergic functioning, while metoclopramide is a dopamine antagonist.
    Metoprolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Midodrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Miglitol: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome has been reported during concurrent use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. There is also a case of a neuroleptic malignant syndrome-like reaction occurring in a child on chronic methylphenidate therapy 45 minutes after ingesting a dose of venlafaxine. It is unclear if the reaction was the result of a drug interaction. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Mirtazapine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and mirtazapine. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Modafinil: (Major) The use of modafinil with other psychostimulants, including methylphenidate, 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. Single dose studies of methylphenidate combined with modafinil noted that the rate of absorption of modafinil was delayed up to one hour by the presence of methylphenidate; no changes occurred in the metabolism and extent of absorption of either medication.
    Molindone: (Moderate) Antipsychotics, such as molindone, and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Monoamine oxidase inhibitors: (Severe) In general, all types of sympathomimetics and psychostimulants 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 even 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.
    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: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Nebivolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Nebivolol; Valsartan: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Nefazodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and nefazodone. 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. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Nitrates: (Major) Concomitant use of nitrates with sympathomimetics can result in antagonism of the antianginal effects of nitrates. In addition, amyl nitrite can block the alpha-adrenergic effects of epinephrine, possibly precipitating tachycardia and severe hypotension.
    Nizatidine: (Minor) The modified release characteristics of extended-release methylphenidate are pH-dependent. Administration of H2-blockers could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with acid suppressants should be monitored for adverse effects and therapeutic efficacy.
    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. Methylphenidate should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Norepinephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Nortriptyline: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and tricyclic antidepressants (TCAs). There are rare reports of serotonin syndrome occurring during use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented. There does not appear to be a pharmacokinetic interaction between methylphenidate and TCAs. In one study, use of methylphenidate did not increase plasma concentrations of the CYP2D6 substrate desipramine. Nevertheless, a dose adjustment of the TCA, and monitoring of TCA plasma concentrations when applicable, may be required when initiating or discontinuing methylphenidate.
    Olanzapine: (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Omeprazole: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Per the manufacturer of extended-release methylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release methylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Omeprazole; Sodium Bicarbonate: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Per the manufacturer of extended-release methylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release methylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate. (Minor) The modified release characteristics of extended-release methylphenidate (Ritalin LA) are pH-dependent. Administration of antacids could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with antacids should be monitored for adverse effects and/or reduced efficacy.
    Paliperidone: (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Pantoprazole: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Per the manufacturer of extended-release methylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release methylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Paroxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs). There are rare reports of serotonin syndrome occurring during use of an SSRI and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Penbutolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Pergolide: (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and dopamine agonists such as pergolide, pramipexole, apomorphine, and ropinirole. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible.
    Perphenazine: (Moderate) Antipsychotics, such as phenothiazines, and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Perphenazine; Amitriptyline: (Moderate) Antipsychotics, such as phenothiazines, and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and tricyclic antidepressants (TCAs). There are rare reports of serotonin syndrome occurring during use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented. There does not appear to be a pharmacokinetic interaction between methylphenidate and TCAs. In one study, use of methylphenidate did not increase plasma concentrations of the CYP2D6 substrate desipramine. Nevertheless, a dose adjustment of the TCA, and monitoring of TCA plasma concentrations when applicable, may be required when initiating or discontinuing methylphenidate.
    Phenelzine: (Severe) In general, all types of sympathomimetics and psychostimulants 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 even 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: (Moderate) Psychostimulants, such as methylphenidate, may lower the seizure threshold, thereby reducing the efficacy of anticonvulsants such as phenobarbital. In addition, case reports suggest a potential pharmacokinetic interaction between methylphenidate and phenobarbital; however, a kinetic interaction was not confirmed when evaluated at higher sample sizes. Nevertheless, a dose adjustment of phenobarbital and more frequent monitoring of plasma concentrations may be required when initiating or discontinuing methylphenidate. It should be noted that methylphenidate is not metabolized by the cytochrome P450 system to a relevant extent and methylphenidate has no relevant inhibitory effect on CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.
    Phenothiazines: (Moderate) Antipsychotics, such as phenothiazines, and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Phenoxybenzamine: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as alpha-blockers. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Phentolamine: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as alpha-blockers. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Phenylephrine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Phenylephrine; Promethazine: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Phenytoin: (Moderate) Psychostimulants, such as methylphenidate, may lower the seizure threshold, thereby reducing the efficacy of anticonvulsants such as hydantoins. In addition, case reports suggest a potential pharmacokinetic interaction between methylphenidate and phenytoin; however, a kinetic interaction was not confirmed when evaluated at higher sample sizes. Nevertheless, a dose adjustment of phenytoin and more frequent monitoring of plasma concentrations may be required when initiating or discontinuing methylphenidate. It should be noted that methylphenidate is not metabolized by the cytochrome P450 system to a relevant extent and methylphenidate has no relevant inhibitory effect on CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.
    Pimozide: (Major) Pimozide should not be used in patients taking drugs that may, themselves, cause motor and phonic tics (e.g., methylphenidate) until such patients have been withdrawn from these drugs to determine whether or not the drugs, rather than Tourette's Disorder, are responsible for the tics. Once this issue is excluded, use together may proceed with caution. Pimozide and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Pindolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Potassium-sparing diuretics: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as potassium-sparing diuretics. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Pramipexole: (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and dopamine agonists such as pergolide, pramipexole, apomorphine, and ropinirole. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible.
    Pramlintide: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Prazosin: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as alpha-blockers. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Primidone: (Moderate) Psychostimulants, such as methylphenidate, may lower the seizure threshold, thereby reducing the efficacy of anticonvulsants such as primidone. In addition, case reports suggest a potential pharmacokinetic interaction between methylphenidate and primidone; however, a kinetic interaction was not confirmed when evaluated at higher sample sizes. Nevertheless, a dose adjustment of primidone and more frequent monitoring of plasma concentrations may be required when initiating or discontinuing methylphenidate. It should be noted that methylphenidate is not metabolized by the cytochrome P450 system to a relevant extent and methylphenidate has no relevant inhibitory effect on CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.
    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.
    Prochlorperazine: (Moderate) Antipsychotics, such as phenothiazines, and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Propranolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Proton pump inhibitors: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Per the manufacturer of extended-release methylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release methylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Protriptyline: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and tricyclic antidepressants (TCAs). There are rare reports of serotonin syndrome occurring during use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented. There does not appear to be a pharmacokinetic interaction between methylphenidate and TCAs. In one study, use of methylphenidate did not increase plasma concentrations of the CYP2D6 substrate desipramine. Nevertheless, a dose adjustment of the TCA, and monitoring of TCA plasma concentrations when applicable, may be required when initiating or discontinuing methylphenidate.
    Quetiapine: (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Rabeprazole: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release methylphenidate (Ritalin LA) have not been studied. Per the manufacturer of extended-release methylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of proton pump inhibitors (PPIs) or other acid suppressants could alter the release of extended-release methylphenidate, resulting in reduced or increased absorption. Patients receiving a PPI should be monitored for adverse effects and reduced therapeutic efficacy of extended-release methylphenidate.
    Ranitidine: (Minor) The modified release characteristics of extended-release methylphenidate are pH-dependent. Administration of H2-blockers could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with acid suppressants should be monitored for adverse effects and therapeutic efficacy.
    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.
    Reserpine: (Major) Coadministration of methylphenidate and reserpine should be avoided if possible. Methylphenidate and reserpine may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on neurotransmitters. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space while reserpine depletes stores of serotonin and norepinephrine in the brain, adrenal medulla, and other tissues, and reduces the reuptake of catecholamines by adrenergic nerve terminals. Reserpine binds tightly to catecholamine storage vesicles in the adrenergic neuron, eventually destroying these vesicles so that the terminals cannot concentrate or store norepinephrine or dopamine. This process also occurs in vesicles that store serotonin.
    Riociguat: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking riociguat with a sympathomimetic.
    Risperidone: (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Ropinirole: (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and dopamine agonists such as pergolide, pramipexole, apomorphine, and ropinirole. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible.
    Safinamide: (Severe) Safinamide is contraindicated for use with methylphenidate due to the risk of serotonin syndrome. 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. Safinamide is a selective inhibitor of monoamine oxidase B, the enzyme which metabolizes dopamine. At high doses, diminished metabolism of serotonin and norepinephrine are also possible through inhibition of MAO-A. There is some evidence that the alteration of dopamine transport systems by methylphenidate may indirectly augment the action of serotonin.
    Saxagliptin: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Selective serotonin reuptake inhibitors: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs). There are rare reports of serotonin syndrome occurring during use of an SSRI and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Selegiline: (Severe) In general, all types of sympathomimetics and psychostimulants 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 even 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.
    Selexipag: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking selexipag with a sympathomimetic.
    Serotonin norepinephrine reuptake inhibitors: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome has been reported during concurrent use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. There is also a case of a neuroleptic malignant syndrome-like reaction occurring in a child on chronic methylphenidate therapy 45 minutes after ingesting a dose of venlafaxine. It is unclear if the reaction was the result of a drug interaction. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Sertraline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs). There are rare reports of serotonin syndrome occurring during use of an SSRI and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Sevoflurane: (Moderate) Inhalational general anesthetics (e.g., enflurane, halothane, isoflurane, and methoxyflurane) may sensitize the cardiovascular system to the effects of methylphenidate. While the sympathomimetic effects of methylphenidate are weaker than those of the amphetamines, and evidence of interaction is lacking, caution is advised. The use of Metadate CD is contraindicated on the day of surgery due to the risk of sudden blood pressure increases during administration of halogenated anesthetics.
    Sibutramine: (Major) The use of methylphenidate with sibutramine should be approached with great caution. Blood pressure and heart rate will require periodic monitoring, since additive effects may occur. Patients receiving this combination should also be monitored for the emergence of serotonin syndrome. Sibutramine is contraindicated with other centrally acting weight loss drugs. Sibutramine has not been studied in combination with similar drugs that are not used for weight loss, such as the CNS stimulants like methylphenidate. Sibutramine may cause serotonin syndrome, and serotonin syndrome has been rarely reported with methylphenidate-type agents. Serotonin syndrome risk increases when 2 or more drugs with this effect are used together. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Simvastatin; Sitagliptin: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Sitagliptin: (Moderate) Sympathomimetics may increase blood glucose concentrations. Monitor for loss of diabetic control when therapy with sympathomimetic agents is instituted. Also, adrenergic medications may increase glucose uptake by muscle cells and may potentiate the actions of some antidiabetic agents. Monitor blood glucose to avoid hypoglycemia or hyperglycemia.
    Sodium Bicarbonate: (Minor) The modified release characteristics of extended-release methylphenidate (Ritalin LA) are pH-dependent. Administration of antacids could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with antacids should be monitored for adverse effects and/or reduced efficacy.
    Sodium Oxybate: (Moderate) The stimulant effects of methylphenidate can be additive when used concurrently with other psychostimulants, such as sodium oxybate. The combination may increase the incidence of side effects; if these combinations cannot be avoided the patient should be closely observed for signs of nervousness, irritability, insomnia, arrhythmias, or other stimulant-related problems. 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. Note that CNS stimulants, including methylphenidate, 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.
    Sotalol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Spironolactone: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as potassium-sparing diuretics. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    St. John's Wort, Hypericum perforatum: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and St. John's Wort. There are rare reports of serotonin syndrome occurring during use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Sulfonylureas: (Moderate) Endogenous epinephrine is released in response to hypoglycemia; epinephrine, through stimulation of alpha- and beta- receptors, increases hepatic glucose production and glycogenolysis and inhibits insulin secretion in order to increase serum glucose concentrations. A pharmacodynamic interaction may occur when pseudoephedrine and other sympathomimetics are administered to patients as these agents may increase blood glucose concentrations by a similar mechanism. Patients receiving sulfonylureas should be closely monitored for loss of diabetic control when therapy with sympathomimetic agents is instituted. Fenfluramine and dexfenfluramine may potentiate the actions of some antidiabetic agents via increasing glucose uptake by muscle cells. Monitor patients taking either of these drugs in combination with glyburide for hypoglycemia.
    Tedizolid: (Moderate) Psychostimulants, such as methylphenidate, exhibit sympathomimetic actions and may interact with other drugs, such as tedizolid, that enhance the pressor response of sympathomimetic agents. In addition, serotonin syndrome has been reported during the concurrent use of linezolid, which is structurally related to tedizolid, and medications that enhance central serotonergic activity. Tedizolid inhibits monoamine oxidase (MAO), the enzyme responsible for the degradation of norepinephrine, dopamine, and serotonin. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented
    Terazosin: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as alpha-blockers. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Theophylline, Aminophylline: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia.
    Thiazide diuretics: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as thiazide diuretics. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Thiethylperazine: (Moderate) Antipsychotics, such as phenothiazines, and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Thioridazine: (Moderate) Antipsychotics, such as phenothiazines, and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Thiothixene: (Moderate) Antipsychotics, such as thiothixene, and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    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.
    Timolol: (Major) 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. Due to the risk of unopposed alpha-adrenergic activity, sympathomimetics should be used cautiously with beta-blockers. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation. Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed.
    Tolcapone: (Moderate) Increased dopaminergic effects may occur during coadministration of methylphenidate, an inhibitor of dopamine reuptake, and COMT inhibitors such as tolcapone and entacapone. Inhibiting the catechol-O-methyltransferase (COMT) enzyme reduces the metabolism of levodopa to metabolites, thereby prolonging the dopaminergic effects of levodopa. Dopaminergic side effects, such as nausea, loss of appetite, weight loss, insomnia, tremor, nervousness, or changes in mood or behavior, are possible during concurrent use of methylphenidate and a COMT inhibitor.
    Tranylcypromine: (Severe) In general, all types of sympathomimetics and psychostimulants 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 even 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.
    Triamterene: (Moderate) Methylphenidate can reduce the hypotensive effect of antihypertensive agents such as potassium-sparing diuretics. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate.
    Tricyclic antidepressants: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and tricyclic antidepressants (TCAs). There are rare reports of serotonin syndrome occurring during use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented. There does not appear to be a pharmacokinetic interaction between methylphenidate and TCAs. In one study, use of methylphenidate did not increase plasma concentrations of the CYP2D6 substrate desipramine. Nevertheless, a dose adjustment of the TCA, and monitoring of TCA plasma concentrations when applicable, may be required when initiating or discontinuing methylphenidate.
    Trifluoperazine: (Moderate) Antipsychotics, such as phenothiazines, and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.
    Trimipramine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and tricyclic antidepressants (TCAs). There are rare reports of serotonin syndrome occurring during use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented. There does not appear to be a pharmacokinetic interaction between methylphenidate and TCAs. In one study, use of methylphenidate did not increase plasma concentrations of the CYP2D6 substrate desipramine. Nevertheless, a dose adjustment of the TCA, and monitoring of TCA plasma concentrations when applicable, may be required when initiating or discontinuing methylphenidate.
    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.
    Vasodilators: (Major) Sympathomimetics can antagonize the antihypertensive effects of vasodilators when administered concomitantly. Also, vasodilators can antagonize pressor responses to epinephrine. Patients should be monitored to confirm that the desired antihypertensive effect is achieved.
    Vasopressors: (Major) Methylphenidate can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Venlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome has been reported during concurrent use of other serotonergic antidepressants (i.e., SSRIs) and methylphenidate. There is also a case of a neuroleptic malignant syndrome-like reaction occurring in a child on chronic methylphenidate therapy 45 minutes after ingesting a dose of venlafaxine. It is unclear if the reaction was the result of a drug interaction. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Vilazodone: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and vilazodone. 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. Patients receiving this combination should be monitored closely for toxicity. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Vortioxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and vortioxetine. 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. Patients receiving methylphenidate with vortioxetine should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Warfarin: (Moderate) Case reports suggest a potential interaction between methylphenidate and coumarin anticoagulants; however, pharmacokinetic interactions were not confirmed when explored at higher sample sizes. Nevertheless, a dose adjustment of warfarin and more frequent monitoring of the INR may be required when initiating or discontinuing methylphenidate.
    Ziprasidone: (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.

    PREGNANCY AND LACTATION

    Pregnancy

    The safety of methylphenidate during human pregnancy has not been established; therefore, methylphenidate should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. There are limited published studies and small case series that report on the use of methylphenidate during pregnancy; however, the data are insufficient to determine any drug-associated risks. Because stimulants cause vasoconstriction, they may decrease placental perfusion. Neonates born to stimulant-dependent mothers are at increased risk for premature delivery and low birth weight. In addition, neonates with in utero exposure to stimulants may experience withdrawal after delivery; monitor the newborn for symptoms of withdrawal such as feeding difficulty, irritability, agitation, and excessive drowsiness. It is unclear what effect, if any, a CNS stimulant such as methylphenidate would have on the developing fetal brain. In animal studies, teratogenic effects (increased incidence of fetal spina bifida), fetal skeletal variations, maternal toxicity, and/or decreased offspring weight gain were observed at doses that were 4 to 40 times the maximum recommended human dose (MRHD). The no effect level for embryo-fetal development in rats was 2 times the MRHD. Prescribers should enroll women exposed to methylphenidate during a pregnancy in a registry by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388. The effect of methylphenidate on labor and delivery in humans is unknown.

    MECHANISM OF ACTION

    Methylphenidate exhibits activity similar to that of the amphetamines, although the underlying pharmacology for these two drug classes may differ. Methylphenidate exerts many of its effects through dopamine uptake blockade of central adrenergic neurons, in contrast to the amphetamines and cocaine that increase catecholamine release as a primary mechanism. Specifically, methylphenidate blocks dopamine transport or carrier proteins. As a result, sympathomimetic activity in the central nervous system is increased. There is some evidence that the alteration of dopamine transport systems by methylphenidate may indirectly augment the action of serotonin, but further pharmacologic research is needed to understand these processes. The main sites of CNS activity appear to be the brain stem arousal system and the cerebral cortex, including the subcortical structures of the thalamus. Methylphenidate-induced CNS stimulation produces a decreased sense of fatigue, an increase in motor activity and mental alertness, mild euphoria, and brighter spirits. A mild anorexic effect may occur. Unlike the amphetamines and cocaine, physical dependence is infrequent with normal clinical use at therapeutic doses. Chronic use of methylphenidate may lead to tolerance of side-effects and psychic dependence, similar to other psychostimulants. Psychic dependence and addiction are more likely with parenteral or inhalational abuse, and are usually noted with illicit street use.
    •Peripheral actions: In the periphery, the sympathomimetic actions of methylphenidate are minimal at therapeutic doses, and are less than those of the amphetamines or cocaine. Because methylphenidate slowly blocks the dopamine-transport proteins, methylphenidate appears less likely than the amphetamines or cocaine to increase systolic and diastolic blood pressure or cause respiratory stimulation. Heart rate typically increases slightly with normal therapeutic doses of stimulants (about 3—6 bpm); however, a reflexive decrease in heart rate in response to increased blood pressure can also occur. At high doses, such as in overdoses, stimulants can cause significant hypertension, tachycardia, arrhythmias, and other serious complications.
    •Actions in ADHD: The mechanism(s) of action of the treatment of mental and behavioral conditions in ADHD are not established. 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. Current research suggests that the modulation of serotonergic pathways via changes in dopamine transport may contribute to the calming effects in the treatment of this disorder, but precise pharmacologic mechanisms have yet to be elucidated.

    PHARMACOKINETICS

    Methylphenidate is administered orally and transdermally. Distribution in humans is unknown, but it does cross the blood-brain-barrier. Plasma protein binding is low (10% to 33%). Metabolism occurs in the liver via de-esterification to the primary metabolite alpha-phenyl-piperidine acetic acid (also known as ritalinic acid), which is inactive. Small amounts of the hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in plasma. Therapeutic activity is primarily due to the parent compound. Ritalinic acid is almost completely eliminated in the urine, with approximately 95% of a dose being recovered as metabolites in urine within 90 hours. In studies with tablet and extended-release capsule (Ritalin LA) formulations, the average elimination half-life in adults was about 3.5 hours (range: 1.3 to 7.7 hours).
     
    Affected cytochrome P450 isoenzymes and drug transporters: none
    Methylphenidate is not metabolized by the cytochrome-P450 system to a clinically significant extent and does not appear to be a relevant inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.

    Oral Route

    The rapid half-life of immediate-release oral preparations may result in unmeasurable concentrations of the drug between the morning and midday doses; extended release preparations reduce these peak and trough variances. Extended-release once-daily oral preparations minimize the fluctuations between peak and trough concentrations associated with immediate-release formulations. The transdermal form of methylphenidate bypasses the liver upon first pass, unlike the oral formulation, resulting in higher serum concentrations with lower initial doses. Additionally, the concentration of l-methylphenidate is roughly equal to that of d-methylphenidate with patch administration, whereas with oral administration little l-methylphenidate is available due to first pass metabolism. However, the pharmacological activity of l-methylphenidate is less than d-methylphenidate.
    Immediate-release and extended-release dosage forms dosed more than once per day: Peak serum concentrations are achieved in about 1.9 hours and 4.7 hours for the regular and extended-release forms, respectively. The duration of action ranges from 3 to 6 hours with regular tablets and about 8 hours with the extended-release tablets.
    Concerta: These extended-release tablets for once daily administration follow a biphasic pharmacokinetic profile to provide day-long medication availability. Following oral administration of Concerta, plasma concentrations of methylphenidate increase rapidly reaching an initial maximum at about 1 hour, followed by a gradual increase in concentration over the next 5 to 9 hours. Thereafter, concentrations gradually decrease. Tmax across all doses occurs between 6 to 10 hours. The half-life of methylphenidate in adults and adolescents after oral administration of Concerta is about 3.5 hours.
    Metadate CD: These extended-release capsules for once-daily administration follow a biphasic pharmacokinetic profile to provide day-long medication availability. Using Diffucaps technology, the capsules contain the drug in both rapid release and continuous release beads such that 30% of the dose is rapidly released and 70% of the dose is continuously released. The product demonstrates an initial peak plasma level at about 1.5 hours and a second peak at about 4.5 hours. The Metadate CD capsule, when opened and sprinkled on a tablespoon of cool applesauce, is bioequivalent to the intact capsule.
    Ritalin LA: These extended-release capsules for once-daily administration follow a biphasic pharmacokinetic profile to provide day-long medication availability. Using SODAS technology, the capsules contain the drug in both rapid release and continuous release beads such that 50% of the dose is rapidly released and 50% of the dose is continuously released from enteric coated, delayed-release beads. The effects of altered gastric pH on the absorption of Ritalin LA have not been studied. Interactions with antacids or acid blockers are possible. The absolute oral bioavailability in children is 22 +/- 8% for d-methylphenidate and 5 +/- 3% for l-methylphenidate, which is suggestive of significant pre-systemic metabolism. The product demonstrates an initial peak plasma level at about 1 to 3 hours and a second peak at about 5 to 8 hours after dosing. There were no differences in pharmacokinetic parameters when this formulation was given with applesauce, but a high fat breakfast may delay absorption time. However, the capsules may be taken with food without clinically significant effects. The Ritalin LA capsule, when opened and sprinkled on a tablespoon of cool applesauce, is bioequivalent to the intact capsule.
    Aptensio XR: Aptensio XR follows an extended-release biphasic pharmacokinetic profile to provide day-long medication availability with once daily administration. Aptensio XR capsules contain multilayer beads, which are composed of an immediate-release layer containing approximately 40% of the methylphenidate dose, and a controlled-release layer which contains the remaining 60% of the dose. After oral administration, an initial peak plasma concentration occurs at about 2 hours, with a gradual descending concentration over the next 4 to 6 hours, after which a gradual increase begins reaching a second peak at about 8 hours. The relative bioavailability of Aptensio XR given once daily compared to a methylphenidate immediate-release oral product given 3 times daily in adults is approximately 102%. The pharmacokinetic profile of Aptensio XR administered as a whole capsule or opened and sprinkled onto applesauce under fasting conditions is similar. After a single dose administered to healthy adults under fasting conditions, the following pharmacokinetic parameters were calculated: Cmax = 23.47 (+/- 11.4) ng/mL, AUC = 258.1 (+/- 94.2) ng x hour/mL, and half-life = 5.09 hours. During pharmacokinetic trials, administration with a high fat meal decreased or diminished the second peak and increased the average Cmax and AUC by 28% and 19%, respectively. At an alcohol concentration up to 40%, there was 96% release of methylphenidate from Aptensio XR capsules within 2 hours; similar results are expected with other capsule strengths.
    QuilliChew ER: After a single 40 mg dose under fasting conditions, Cmax was obtained at a median time of 5 hours. Compared to immediate-release chewable tablets (two 20 mg doses given 6 hours apart), methylphenidate mean peak concentration and exposure (AUC) was about 20% and 11% lower, respectively, after a single dose administration of 40 mg QuilliChew ER. Administration with a high-fat meal had no effect on Tmax, and increased Cmax and AUC by about 20% and 4%, respectively, after a single 40 mg dose. Plasma methylphenidate concentrations declined monophasically. The mean elimination half-life was 5.2 hours in healthy volunteers. The presence of alcohol increases release of methylphenidate. At an alcohol concentration up to 40%, there was 90% release of methylphenidate from QuilliChew ER within half an hour; similar results are expected with other available tablet strengths.
    Quillivant XR: This extended-release suspension for once-daily administration provides a mean peak plasma concentration of 13.6 +/- 5.8 ng/mL over a median time of 5 hours when given to healthy adults. Food has no clinically significant effect on the bioavailability of the suspension. The relative bioavailability of Quillivant XR compared to immediate-release methylphenidate oral solution is 95%.
    Cotempla XR-ODT: After a single 51.8 mg dose under fasting conditions, Cmax was obtained at a median time of 5 hours. Compared to an extended-release capsule formulation of methylphenidate, methylphenidate mean peak concentration and exposure (AUC) was about 26% and 6% higher, respectively, after Cotempla XR-ODT administration. Administration with a high-fat meal shorted the median time to peak concentration (Tmax) by 0.5 hours and decreased the Cmax and increased AUC of total methylphenidate by approximately 24% and 16%, respectively. Plasma methylphenidate concentrations declined monophasically. The mean elimination half-life was about 4 hours in healthy volunteers. The presence of alcohol potentially increases release of methylphenidate. At an alcohol concentration of 40%, an in vitro dissolution study showed alcohol-induced dose dumping potential; dose dumping was not observed with lower alcohol concentrations.

    Other Route(s)

    Transdermal Route
    The extent of methylphenidate systemic absorption after patch administration is dependent on the length of time the patch is worn and the patch size. Peak plasma concentrations of methylphenidate are reached approximately 8 hours after patch application. Cmax and AUC increase significantly with repeated daily administration compared to single-dose administration. After either a 1-day or 7-day patch administration, the Cmax and AUC of d-methylphenidate were approximately 50% lower in adolescents (13 to 17 years of age) than in children (6 to 12 years of age). In clinical pharmacokinetic studies, when the 10 mg/9-hour methylphenidate patch was worn on the hip for 9 hours per day for 4 weeks, the steady state mean d-methylphenidate Cmax was 15.7 +/- 9.39 ng/mL in children 6 years of age and older and 8.32 +/- 4.6 ng/mL in adolescents, and the Cmin was 1.04 +/- 1.17 ng/mL and 0.544 +/- 0.383 ng/mL in children and adolescents, respectively. In patients who wore the 30 mg/9-hour patch, the mean d-methylphenidate Cmax was 42.9 +/- 22.4 ng/mL in children and 16.5 +/- 6.94 ng/mL in adolescents, and the Cmin was 1.96 +/- 1.73 ng/mL and 1.02 +/- 0.629 ng/mL in children and adolescents, respectively. In children 6 to 12 years of age, mean peak concentrations of transdermal methylphenidate were roughly 1.9 times higher than those observed for once daily oral methylphenidate. However, the Cmax of single dose administration of transdermal methylphenidate is comparable to the Cmax from a single dose of the once daily oral formulations. Transdermal absorption of methylphenidate may increase over time with chronic therapy; these changes cannot be explained by changes in clearance or rate of elimination. On average, steady-state is achieved after approximately 14 days of dosing. The time until any transdermally administered d-methylphenidate is detectable in the circulation averages 3.1 hours (range 1 to 6 hours). The absorption (rate and extent) is increased when methylphenidate patch is applied to inflamed skin or exposed to heat. Absorption characteristics in areas other than the hip are not known.
     
    Once the methylphenidate patch is removed after 9 hours of wear time, methylphenidate plasma concentrations decline in a biexponential manner most likely due to distribution of methylphenidate from the skin after patch removal. The transdermal form of methylphenidate bypasses the liver upon first pass, unlike the oral formulation, resulting in higher serum concentrations with lower initial doses. Results from single- and multiple-dose studies indicate that exposure to l-methylphenidate is 46% of the exposure to d-methylphenidate in children and 40% in adolescents. The pharmacological activity of l-methylphenidate is less than d-methylphenidate. With transdermal administration in children and adolescents, the mean elimination half-life of l-methylphenidate was shorter than for d-methylphenidate and ranged from 1.4 to 2.9 hours; whereas the mean elimination half-life of d-methylphenidate was about 4 to 5 hours.