4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens that may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically significant for ADD/ADHD medications are summarized in Table 7. Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 7. Drug-Drug Interactions for ADD/ADHD Medications

Target Drug	Interacting Drug	Interaction	Recommendation	Clinical Significance Level*
amphetamines, amphetamine-related compounds, dexmethylphenidate, methylphenidate, serdexmethylphenidate	antihypertensive agents	combined administration decreases hypotensive effect of antihypertensive agents	closely monitor blood pressure and adjust antihypertensive therapy doses as necessary	Minor
amphetamines, amphetamine-related compounds	CYP2D6 Inhibitors	co-administration results in increased exposure to amphetamine and amphetamine related compounds	initiate at lower doses and monitor for signs and symptoms of serotonin syndrome, particularly after initiation and after dose increases. If serotonin syndrome occurs discontinue amphetamine or amphetamine related compound and CYP2D6 inhibitor	Moderate
amphetamines, amphetamine-related compounds, dexmethylphenidate, methylphenidate, serdexmethylphenidate	monoamine oxidase inhibitors (MAOIs) and drugs with MAOI-like actions (e.g., procarbazine)	combined administration increases risk of enhanced vasopressor effects and hypertensive crisis due to increased norepinephrine availability; amphetamines, dexmethyl-phenidate, and methylphenidate potentiate  catecholamine neurotransmitter effects, while MAOIS block catecholamine degradation and increase norepinephrine levels at nerve receptor sites	concurrent administration as well as amphetamine, dexmethyl-phenidate, methylphenidate, or serdexmethylphenidate administration within 14 days of MAOI use is contraindicated	Contraindicated
amphetamines, amphetamine-related compounds	phenothiazines	co-administration results in decreased effectiveness of both drug classes	avoid combination, if possible	Moderate
amphetamines, amphetamine-related compounds	SSRIs, SNRIs	combined administration may produce additive pharmacologic effects and  increase risk of serotonin syndrome as amphetamines may stimulate serotonin release in central nervous system (CNS)	administer cautiously together and observe for signs/ symptoms of serotonin syndrome; discontinue therapy and treat as necessary if serotonin syndrome develops	Moderate
amphetamines, amphetamine-related compounds	TCAs	adjunctive administration may potentiate amphetamine pharmacologic/ adverse effects including hypertension, other cardiac effects, and  CNS stimulation due to additive effects on norepinephrine release/activity	administer combination cautiously; observe for increased adverse effects	Moderate
amphetamines, amphetamine-related compounds	urinary alkalinizers	combination results in increased renal tubular absorption of amphetamines and amphetamine-related compounds, decreased urinary excretion and the potential for enhanced amphetamine therapeutic/ adverse effects	monitor for common amphetamine side effects including decreased appetite, anxiety, dizziness, dry mouth, irritability, insomnia, nausea, increased blood pressure, or increased heart rate	Moderate
atomoxetine	cisapride, dronedarone, ketoconazole, levoketoconazole, pimozide, thioridazine	concomitant use may increase the risk of torsade de pointes and QT/QTc prolongation	avoid concomitant use	contraindicated
atomoxetine	albuterol	combined administration may produce increased heart rate, blood pressure due to unknown mechanism	administer combination cautiously; monitor blood pressure and heart rate	major (DrugReax) 3-moderate (CP)
atomoxetine	MAOIs	co-administration may result in additive serotonergic effects/ increased risk of serotonin syndrome as atomoxetine inhibits serotonin reuptake and MAOIs inhibit catecholamine breakdown	concomitant administration as well as atomoxetine administration within 14 days of MAOI use contraindicated	contraindicated (DrugReax) 1-severe (CP)
clonidine	mirtazapine	co-administration may result in hypertension	monitor for signs of intense sweating, facial flushing, frequent headaches, racing, or pounding heartbeat	major (DrugReax)
clonidine	beta blockers	co-administration may result in sinus bradycardia & exaggerated clonidine withdrawal response	monitor heart rate when combined with beta blocker therapy. Gradual withdrawal of beta blocker recommended before discontinuing clonidine	major (DrugReax)
clonidine	calcium channel blockers	co-administration may result in sinus bradycardia	monitor heart rate when combined with calcium channel blocker therapy	major (DrugReax)
clonidine	opioid agonists	concurrent use may increase the risk of excessive sedation and somnolence	use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect	major
dexmethylphenidate, methylphenidate, serdexmethylphenidate	risperidone	concomitant administration may increase risk of extrapyramidal symptoms during doses changes of either medication	monitor for signs of extrapyramidal symptoms	major (Micromedex)
dexmethylphenidate, methylphenidate, serdexmethylphenidate	halogenated anesthetics	Concomitant use may increase risk of sudden blood pressure and heart rate increases during surgery	Avoid use in patients being treated with anesthetics on the day of surgery	major (Micromedex)
dexmethylphenidate, methylphenidate, serdexmethylphenidate	select anticonvulsants [e.g., phenobarbital, hydantoins (e.g., phenytoin) and primidone]	adjunctive administration may increase serum anticonvulsant levels of select anticonvulsants due to unknown mechanism; dexmethylphenidate,  methylphenidate may also lower seizure threshold	monitor serum anticonvulsant levels closely and monitor patients for increased adverse effects; adjust anticonvulsant doses as needed; also monitor seizure frequency	moderate (DrugReax) 2-major, 3-moderate (CP)
dexmethylphenidate, methylphenidate, serdexmethylphenidate	warfarin	co-administration may increase warfarin serum levels and enhance pharmacologic/adverse effects, including bleeding	closely monitor INR with combined therapy and adjust warfarin doses as necessary	moderate (DrugReax) 3-moderate (CP)
guanfacine	antihypertensive agents	combined administration may result in additive hypotensive effects	closely monitor blood pressure and adjust doses as necessary	3-moderate (CP)
guanfacine	CNS depressants	combined administration may result in additive pharmacologic (sedative) effects	administer cautiously together	3-moderate (CP)
guanfacine	strong CYP3A4 inhibitors (e.g., ketoconazole)	adjunctive administration may result in increased guanfacine concentrations and the potential for enhanced pharmacologic/ adverse effects as guanfacine is metabolized by CYP3A4	administer cautiously together and monitor for increased pharmacologic effects (e.g., hypotension, bradycardia, sedation)	unknown
guanfacine	CYP3A4 inducers (e.g., rifampin, phenytoin)	concurrent administration reduces guanfacine AUC by 70% and may result in decreased guanfacine serum levels and reduced pharmacologic/clinical effects (guanfacine metabolized by CYP3A4)	monitor for loss of guanfacine clinical effects; increased guanfacine doses may be necessary	3-moderate (CP)
guanfacine	valproic acid (VA)	combined administration may result in increased VA serum levels, potentially due to competition for glucuronidation metabolic pathway	monitor for additive CNS effects; VA dosage adjustments may be required	unknown
methylphenidate	bupropion	concurrent use may result in increased seizure risk	if combination is necessary, closely monitor patient	major (DrugReax) 2-major (CP)
methylphenidate	carbamazepine	co-administration may result in reduced methylphenidate serum levels and decreased pharmacologic effects due to unknown mechanism; methylphenidate may also lower seizure threshold	closely monitor patient response to methylphenidate therapy, monitor seizure frequency, and adjust methylphenidate doses as necessary with this drug combination	moderate (DrugReax) 2-major (CP)
viloxazine	CYP1A2 substrates, sensitive or narrow therapeutic range	viloxazine is a strong CYP1A2 inhibitor, increasing total exposure to sensitive CYP1A2 substrates	concurrent use is contraindicated	contraindicated (Micromedex)
viloxazine	CYP1A2 substrates, moderate sensitive	viloxazine is a strong CYP1A2 inhibitor, increasing total exposure to sensitive CYP1A2 substrates	concurrent administration is not recommended. Dose reduction may be warranted if coadministered	major (Micromedex)
viloxazine	MAOI	increased risk of potentially life-threatening hypertensive crisis	concurrent administration is contraindicated	contraindicated (Micromedex)

Legend:

• * CP = Clinical Pharmacology, Micromedex, product labeling