and heart rate. Use Caution/Monitor.phenylephrine POMonitor Closely (2)serdexmethylphenidate/dexmethylphenidate and phenylephrine PO both decrease sedation. Use Caution/Monitor. serdexmethylphenidate/dexmethylphenidate and phenylephrine PO both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Use Caution/Monitor.phenytoinMinor (1)serdexmethylphenidate/dexmethylphenidate increases effects of phenytoin by decreasing metabolism. Minor/Significance Unknown.pirbuterolMonitor Closely (1)pirbuterol and serdexmethylphenidate/dexmethylphenidate both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Use Caution/Monitor.primidoneMinor (1)serdexmethylphenidate/dexmethylphenidate increases effects of primidone by decreasing metabolism. Minor/Significance Unknown.procarbazineContraindicated (1)procarbazine increases effects of serdexmethylphenidate/dexmethylphenidate by pharmacodynamic synergism. Contraindicated. Risk of acute hypertensive episode.prochlorperazineMonitor Closely (1)prochlorperazine, serdexmethylphenidate/dexmethylphenidate. Mechanism: unknown. Use Caution/Monitor. Risk of cardiac arrhythmia or sudden death, more likely w/thioridazine than other phenothiazines. Interaction more likely in certain predisposed pts. only.promazineMonitor Closely (1)promazine, serdexmethylphenidate/dexmethylphenidate. Mechanism: unknown. Use Caution/Monitor. Risk of cardiac arrhythmia or sudden death, more likely w/thioridazine than other phenothiazines. Interaction more likely in certain predisposed pts. only.promethazineMonitor Closely (1)promethazine, serdexmethylphenidate/dexmethylphenidate. Mechanism: unknown. Use Caution/Monitor. Risk of cardiac arrhythmia or sudden death, more likely w/thioridazine than other phenothiazines. Interaction more likely in certain predisposed pts. only.propylhexedrineMonitor Closely (2)serdexmethylphenidate/dexmethylphenidate and propylhexedrine both decrease sedation. Use Caution/Monitor. serdexmethylphenidate/dexmethylphenidate and propylhexedrine both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Use Caution/Monitor.protamineMinor (1)serdexmethylphenidate/dexmethylphenidate increases effects of protamine by decreasing metabolism. Minor/Significance Unknown.protriptylineSerious - Use Alternative (1)protriptyline, serdexmethylphenidate/dexmethylphenidate. Other (see comment). Avoid or Use Alternate Drug. Comment: Tricyclic antidepressants increase or decrease effects of sympathomimetics, by blocking reuptake of NE, or blocking uptake of indirect sympathomimetics into the adrenergic neuron.Minor (1)serdexmethylphenidate/dexmethylphenidate increases effects of protriptyline by decreasing metabolism. Minor/Significance Unknown.pseudoephedrineMonitor Closely (2)serdexmethylphenidate/dexmethylphenidate and pseudoephedrine both decrease sedation. Use Caution/Monitor. serdexmethylphenidate/dexmethylphenidate and pseudoephedrine both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Use Caution/Monitor.rasagilineContraindicated (1)rasagiline increases effects of serdexmethylphenidate/dexmethylphenidate by pharmacodynamic synergism. Contraindicated. Risk of acute hypertensive episode. Dexmethylphenidate use is contraindicated during treatment with MAOIs and also within a minimum of 14 days following discontinuation of treatment with an MAOI.rufinamideMinor (1)serdexmethylphenidate/dexmethylphenidate increases effects of rufinamide by decreasing metabolism. Minor/Significance Unknown.safinamideContraindicated (1)serdexmethylphenidate/dexmethylphenidate, safinamide. Either increases toxicity of the other by serotonin levels. Contraindicated. Concomitant use could result in life-threatening serotonin syndrome.salmeterolMonitor Closely (1)salmeterol and serdexmethylphenidate/dexmethylphenidate both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Use Caution/Monitor.selegilineContraindicated (1)selegiline increases effects of serdexmethylphenidate/dexmethylphenidate by pharmacodynamic synergism. Contraindicated. Risk of acute hypertensive episode. Dexmethylphenidate use is contraindicated during treatment with MAOIs and also within a minimum of 14 days following discontinuation of treatment with an MAOI.selegiline transdermalContraindicated (1)selegiline transdermal increases effects of serdexmethylphenidate/dexmethylphenidate by pharmacodynamic synergism. Contraindicated. Risk of acute hypertensive episode.sertralineMinor (1)serdexmethylphenidate/dexmethylphenidate increases effects of sertraline by decreasing metabolism. Minor/Significance Unknown.sevofluraneSerious - Use Alternative (1)sevoflurane increases toxicity of serdexmethylphenidate/dexmethylphenidate by Mechanism: unknown. Avoid or Use Alternate Drug. Risk of V tach, HTN.sodium zirconium cyclosilicateMonitor Closely (1)sodium zirconium cyclosilicate will increase the level or effect of serdexmethylphenidate/dexmethylphenidate by increasing gastric pH. Applies only to oral form of both agents. Modify Therapy/Monitor Closely. Check specific recommendations for drugs that exhibit pH-dependent solubility that may affect their systemic exposure and efficacy. In general, administer drugs at least 2 hr before or after sodium zirconium cyclosilicate. Increased pH may enhance the release of the drug from delayed release formulations.solriamfetolMonitor Closely (1)serdexmethylphenidate/dexmethylphenidate and solriamfetol both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Use Caution/Monitor.sultiameMinor (1)serdexmethylphenidate/dexmethylphenidate increases effects of sultiame by decreasing metabolism. Minor/Significance Unknown.terbutalineMonitor Closely (1)terbutaline and serdexmethylphenidate/dexmethylphenidate both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Use Caution/Monitor.thioridazineMonitor Closely (1)thioridazine, serdexmethylphenidate/dexmethylphenidate. Mechanism: unknown. Use Caution/Monitor. Risk of cardiac arrhythmia or sudden death, more likely w/thioridazine than other phenothiazines. Interaction more likely in certain predisposed pts. only.tiagabineMinor (1)serdexmethylphenidate/dexmethylphenidate increases effects of tiagabine by decreasing metabolism. Minor/Significance Unknown.tinzaparinMinor (1)serdexmethylphenidate/dexmethylphenidate increases effects of tinzaparin by decreasing metabolism. Minor/Significance Unknown.topiramateMinor (1)serdexmethylphenidate/dexmethylphenidate increases effects of topiramate by decreasing metabolism. Minor/Significance Unknown.tranylcypromineContraindicated (1)tranylcypromine increases effects of serdexmethylphenidate/dexmethylphenidate by pharmacodynamic synergism. Contraindicated. Risk of acute hypertensive episode.trazodoneSerious - Use Alternative (1)trazodone, serdexmethylphenidate/dexmethylphenidate. Other (see comment). Avoid or Use Alternate Drug. Comment: Tricyclic antidepressants increase or decrease effects of sympathomimetics, by blocking reuptake of NE, or blocking uptake of indirect sympathomimetics into the adrenergic neuron.Minor (1)serdexmethylphenidate/dexmethylphenidate increases effects of trazodone by decreasing metabolism. Minor/Significance Unknown.trifluoperazineMonitor Closely (1)trifluoperazine, serdexmethylphenidate/dexmethylphenidate. Mechanism: unknown. Use Caution/Monitor. Risk of cardiac arrhythmia or sudden death, more likely w/thioridazine than other phenothiazines. Interaction more likely in certain predisposed pts. only.trimipramineSerious - Use Alternative (1)trimipramine, serdexmethylphenidate/dexmethylphenidate. Other (see comment). Avoid or Use Alternate Drug. Comment: Tricyclic antidepressants increase or decrease effects of sympathomimetics, by blocking reuptake of NE, or blocking uptake of indirect sympathomimetics into the adrenergic neuron.Minor (1)serdexmethylphenidate/dexmethylphenidate increases effects of trimipramine by decreasing metabolism. Minor/Significance Unknown.valproic acidMinor (1)serdexmethylphenidate/dexmethylphenidate increases effects of valproic acid by decreasing metabolism. Minor/Significance Unknown.venlafaxineMinor (1)serdexmethylphenidate/dexmethylphenidate increases effects of venlafaxine by decreasing metabolism. Minor/Significance Unknown.xylometazolineMonitor Closely (2)serdexmethylphenidate/dexmethylphenidate and xylometazoline both decrease sedation. Use Caution/Monitor. serdexmethylphenidate/dexmethylphenidate and xylometazoline both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Use Caution/Monitor.yerba mateMinor (1)yerba mate increases effects of serdexmethylphenidate/dexmethylphenidate by pharmacodynamic synergism. Minor/Significance Unknown.yohimbeSerious - Use Alternative (1)yohimbe, serdexmethylphenidate/dexmethylphenidate. Mechanism: pharmacodynamic synergism. Contraindicated. Risk of acute hypertensive episode.yohimbineMonitor Closely (2)serdexmethylphenidate/dexmethylphenidate and yohimbine both decrease sedation. Use Caution/Monitor. serdexmethylphenidate/dexmethylphenidate and yohimbine both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Use Caution/Monitor.zonisamideMinor (1)serdexmethylphenidate/dexmethylphenidate increases effects of zonisamide by decreasing metabolism. Minor/Significance Unknown. ≥5% Clinical trials with other methylphenidate products in pediatric and adult patients with ADHD commonly reported (≥5% and at least twice the rate of placebo) the following: Decreased appetite Decreased weight Nausea Abdominal pain Dyspepsia Vomiting Insomnia Anxiety Affect lability Irritability Dizziness Increased blood pressure Tachycardia Postmarketing Reports Blood and lymphatic system disorders: Pancytopenia, thrombocytopenia, thrombocytopenic purpura Cardiac disorders: Angina pectoris, bradycardia, extrasystole, supraventricular tachycardia, ventricular extrasystole, palpitations, increased heart rate Eye disorders: Diplopia, mydriasis, visual impairment, blurred vision General disorders: Chest pain, chest discomfort, hyperpyrexia Gastrointestinal disorders: Dry mouth Hepatobiliary disorders: Hepatocellular injury, acute hepatic failure Immune system disorders: Hypersensitivity reactions such as angioedema, anaphylactic reactions, auricular swelling, bullous conditions, exfoliative conditions, urticaria, pruritus, rashes, eruptions, and exanthemas Investigations: Alkaline phosphatase increased, bilirubin increased, hepatic enzyme increased, platelet count decreased, white blood cell count abnormal Musculoskeletal, connective-tissue and bone disorders: Arthralgia, myalgia, muscle twitching, rhabdomyolysis, muscle cramps Nervous system: Convulsion, grand mal convulsion, dyskinesia, serotonin syndrome in combination with serotonergic drugs, nervousness, headache, tremor, drowsiness, vertigo Psychiatric disorders: Disorientation, libido changes, hallucination, hallucination auditory, hallucination visual, logorrhea, mania, restlessness, agitation Skin and subcutaneous tissue disorders: Alopecia, erythema, hyperhidrosis Urogenital system: Priapism Vascular disorders: Raynaud phenomenon Black Box Warnings CNS stimulants, including serdexmethylphenidate/methylphenidate, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence Assess risk of abuse before prescribing and monitor for signs of abuse and dependence while on therapyContraindications Known hypersensitivity to serdexmethylphenidate, methylphenidate, or other components; bronchospasm, rash, and pruritus reported with serdexmethylphenidate/methylphenidate; hypersensitivity reactions (eg, angioedema) and anaphylactic reactions reported in patients treated with other methylphenidate products Concomitant use with MAOIs or within 14 days following discontinuation with an MAOI Cautions CNS stimulants have a high potential for abuse and dependence; assess risks before prescribing and carefully monitor while on therapy Priapism, sometimes requiring surgical intervention, reported with methylphenidate in both pediatric and adults patients; not reported upon initiating, but may develop after some time on the drug (often subsequent to increased dose or during drug withdrawal); seek immediate medical attention for abnormally sustained or frequent and painful erections Peripheral vasculopathy, including Raynaud phenomenon, reported with CNS stimulants; signs and symptoms generally improve after dose reduction or discontinuation; observe for digital changes during treatment; further clinical evaluation (eg, rheumatology referral) may be necessary Monitor growth in pediatric patients during treatment with stimulants; patients who are not growing or gaining weight as expected may need to have their treatment interrupted Periodically reevaluate long-term use and adjust dose; periodically discontinue to assess patient's condition Serious cardiovascular reactions CNS stimulants cause an increased blood pressure (mean increase ~2-4 mmHg) and heart rate (mean increase ~3-6 bpm); individuals may have larger increases; monitor all patients for hypertension and tachycardia; consider benefits and risks in patients for whom an increase in blood pressure would be problematic Adults: Sudden death, stroke, and myocardial infarction reported with CNS stimulant treatment at recommended doses Pediatric patients: Sudden death reported with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems Promptly evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during treatment Psychiatric adverse reactions May exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorders May induce manic or mixed mood episode; before prescribing, screen patients for risk factors for developing a manic episode (eg, comorbid or history of depressive symptoms, family history of suicide, bipolar disorder, or depression) At recommended doses, CNS stimulants may cause psychotic or manic symptoms (eg, hallucinations, delusional thinking, mania) in patients without a prior history; if such symptoms occur, consider discontinuing drug Drug interaction overview MAOIs Contraindicated Do not coadminister serdexmethylphenidate/methylphenidate with MAOIs or within 14 days after discontinuing MAOI treatment, owing to potential for hypertensive crisis Antihypertensives Monitor blood pressure and adjust antihypertensive dose as needed Serdexmethylphenidate/methylphenidate may decrease effectiveness of antihypertensives Halogenated anesthetics Avoid serdexmethylphenidate/methylphenidate on day of surgery Concomitant use of serdexmethylphenidate/methylphenidate with halogenated anesthetics (eg, halothane, isoflurane, enflurane, desflurane, sevoflurane) may increase risk of sudden blood pressure and heart rate increase during surgery Risperidone Monitor for extrapyramidal symptoms (EPSs) Coadministration of methylphenidate with risperidone may increase risk of EPSs when there is dosage change (increased or decreased) of either or both medications Pregnancy Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388 No data are available on use in pregnant females; dexmethylphenidate is the d-threo enantiomer of racemic methylphenidate; published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes However, there may be risks to the fetus associated with the use of CNS stimulants use during pregnancy Clinical considerations CNS stimulants can cause vasoconstriction and thereby decrease placental perfusion No fetal and/or neonatal adverse reactions reported with therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low-birth-weight infants reported in amphetamine-dependent mothers Lactation Serdexmethylphenidate: Data are unavailable on presence in human milk, effects on breastfed infants, or effects on milk production Dexmethylphenidate Limited published literature, based on milk sampling from 7 mothers, reports methylphenidate is present in human milk, which resulted in infant doses of 0.16-0.7% of the maternal weight–adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2. There are no reports of adverse effects on breastfed infants and no effects on milk production Clinical considerations: Monitor breastfeeding infants for adverse reactions (eg, agitation, anorexia, reduced weight gain)Pregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Dexmethylphenidate (d-MPH): CNS stimulant; blocks reuptake of norepinephrine and dopamine, causing an increase of their release into the extraneuronal space; mode of therapeutic action for ADHD is unknown Serdexmethylphenidate: Prodrug of d-MPH formulated with immediate-release d-MPH Absorption Peak plasma time: 2 hr (serdexmethylphenidate/d-MPH); 8 hr (serdexmethylphenidate alone) Peak plasma concentration: 14 ng/mL AUC: 186 hrng/mL Effect of food No clinically meaningful differences in dexmethylphenidate exposure observed when administered after an overnight fast, with a high-fat, high-caloric meal, or sprinkled onto applesauce or water Peak plasma time lengthened from 2 to 4-4.5 hr Distribution Protein bound Serdexmethylphenidate: 56% Dexmethylphenidate: 47% Vd Serdexmethylphenidate: 29.3 L/kg Dexmethylphenidate: 2.65 L/kg Metabolism Serdexmethylphenidate: Prodrug of dexmethylphenidate; likely converted to dexmethylphenidate mainly in lower GI tract; enzymes involved in conversion not identified Dexmethylphenidate: Metabolized primarily via de-esterification to dextro-alpha-phenyl-piperidine acetic acid (ie, dextro-ritalinic acid); ritalinic acid has little or