Cotempla Xr-Odt

Drug overview for COTEMPLA XR-ODT (methylphenidate):

Generic name: methylphenidate (METH-il-FEN-i-date)
Drug class: Amphetamines/Anorexiants/Stimulants
Therapeutic class: Central Nervous System Agents

Methylphenidate, a piperidine-derivative, is a CNS stimulant.

Methylphenidate is used for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. The drug is available in various dosage forms and preparations as methylphenidate or methylphenidate hydrochloride; FDA-labeled indications and patient populations vary based on the specific preparation. Methylphenidate also has been used in the management of autism spectrum disorder (ASM)+, amphetamine-type stimulant use disorder+, and idiopathic hypersomnia+.

DRUG IMAGES

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The following indications for COTEMPLA XR-ODT (methylphenidate) have been approved by the FDA:

Indications:
Attention-deficit hyperactivity disorder

Professional Synonyms:
ADD with hyperactivity

The following dosing information is available for COTEMPLA XR-ODT (methylphenidate):

Dosing
Administration
COTEMPLA XR-ODT
Generic

Dosage of oral formulations of methylphenidate hydrochloride generally is expressed in terms of the salt; however, dosage of the extended-release orally disintegrating tablets (Cotempla XR-ODT(R)) is expressed in terms of methylphenidate. Each 8.6, 17.3,

or 25.9 mg of methylphenidate is equivalent to 10, 20, or 30 mg, respectively, of methylphenidate hydrochloride. Dosage of methylphenidate transdermal systems is expressed in terms of methylphenidate.

Some patients receiving longer-acting preparations may require supplemental therapy with an immediate-release formulation of the drug to increase the efficacy, particularly in the morning, or to extend the duration of therapeutic effects later in the day.

Extended-release oral formulations may contain both immediate-release and extended-release methylphenidate in various proportions, generally ranging from 20% immediate-release and 80% extended-release drug to equal proportions of each in various delivery systems. Differences among the commercially available methylphenidate preparations (e.g., method of drug delivery, drug release characteristics, onset and duration of activity, ease of administration) allow for individualization of therapy based on patient needs.

Dosage of methylphenidate hydrochloride must be carefully adjusted according to individual requirements and response.

If no improvement in symptoms is observed after dosage adjustment over a 1-month period, methylphenidate should be discontinued.

If adverse effects or paradoxical symptoms occur with methylphenidate therapy, dosage reduction, or potentially, discontinuation is recommended.

Pharmacologic treatment may be required for extended periods. The long-term usefulness of the drug should be reevaluated periodically and dosage adjusted as needed.

Methylphenidate hydrochloride is administered orally. Methylphenidate is also administered percutaneously by topical application of a transdermal system.

Dosing information for COTEMPLA XR-ODT
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
COTEMPLA XR-ODT 8.6 MG TABLET	Maintenance	Adults place 1 tablet (8.6 mg) on top of tongue, allow to dissolve then swallow by translingual route once daily in the morning
COTEMPLA XR-ODT 17.3 MG TABLET	Maintenance	Adults place 1 tablet (17.3 mg) on top of tongue, allow to dissolve then swallow by translingual route once daily in the morning
COTEMPLA XR-ODT 25.9 MG TABLET	Maintenance	Adults place 1 tablet (25.9 mg) on top of tongue, allow to dissolve then swallow by translingual route once daily in the morning

No generic dosing information available.

The following drug interaction information is available for COTEMPLA XR-ODT (methylphenidate):

Contraindicated
Severe
Moderate

There are 2 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Mixed & Indirect Sympathomimetics; Oral Phenylephrine/MAOIs SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Catecholamine stores increased by MAOIs can be released by indirect acting sympathomimetics such as ephedrine and amphetamine. MAO inhibitors also interfere with gut and liver metabolism of direct acting sympathomimetics (e.g oral phenylephrine). CLINICAL EFFECTS: Concurrent use of MAOIs may result in potentiation of sympathomimetic effects, which may result in headaches, hypertensive crisis, toxic neurological effects, and malignant hyperpyrexia. Fatalities have occurred. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of monoamine oxidase inhibitors and sympathomimetics is contraindicated. The manufacturers of sympathomimetic agents recommend waiting 14 days after discontinuation of MAO inhibitors before initiating the sympathomimetic. DISCUSSION: Indirect acting sympathomimetic amines may cause abrupt elevation of blood pressure when administered to patients taking monoamine oxidase inhibitors, resulting in a potentially fatal hypertensive crisis. Mixed (direct and indirect) acting sympathomimetics have also been shown to interact with monoamine oxidase inhibitors depending on their degree of indirect action. The direct-acting sympathomimetics have not been reported to interact. Dopamine is metabolized by monoamine oxidase, and its pressor effect is enhanced by monoamine oxidase inhibitors. Since procarbazine, an antineoplastic agent, is a weak monoamine oxidase inhibitor, hypertensive reactions may result from its concurrent use with indirect and mixed acting sympathomimetics. Furazolidone, an antibacterial with monoamine oxidase inhibitor action, has also been shown to interact with indirect acting sympathomimetics. Linezolid is another antibacterial with monoamine oxidase inhibitor properties. Metaxalone is a weak inhibitor of MAO. Foods containing large amounts of tyramine have also been implicated in this interaction. Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. At recommended dosages, rasagiline, oral selegiline, and transdermal selegiline up to 6mg/day are selective for MAO-B; however, at higher dosages they have been shown to lose their selectivity. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.	EMSAM, FURAZOLIDONE, MARPLAN, MATULANE, METAXALONE, METHYLENE BLUE, NARDIL, PARNATE, PHENELZINE SULFATE, PROCARBAZINE HCL, PROVAYBLUE, SELEGILINE HCL, TRANYLCYPROMINE SULFATE
Dihydroergotamine/Sympathomimetics SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Concurrent use of dihydroergotamine and sympathomimetics may result in additive or synergistic effect on peripheral blood vessels.(1) CLINICAL EFFECTS: Concurrent use of dihydroergotamine and sympathomimetics may result in increased blood pressure due to peripheral vasoconstriction.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Dihydroergotamine is contraindicated with sympathomimetics because the combination may result in additive or synergistic elevation of blood pressure.(1) DISCUSSION: Significant elevation in blood pressure has been reported in patients treated with dihydroergotamine.(1) Sympathomimetics can be expected to have additional effects on blood pressure.	BREKIYA, DIHYDROERGOTAMINE MESYLATE, MIGRANAL, TRUDHESA

Drug Interaction

Drug Names

Mixed & Indirect Sympathomimetics; Oral Phenylephrine/MAOIs

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Catecholamine stores increased by MAOIs can be released by indirect acting sympathomimetics such as ephedrine and amphetamine. MAO inhibitors also interfere with gut and liver metabolism of direct acting sympathomimetics (e.g oral phenylephrine).

CLINICAL EFFECTS: Concurrent use of MAOIs may result in potentiation of sympathomimetic effects, which may result in headaches, hypertensive crisis, toxic neurological effects, and malignant hyperpyrexia. Fatalities have occurred.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of monoamine oxidase inhibitors and sympathomimetics is contraindicated. The manufacturers of sympathomimetic agents recommend waiting 14 days after discontinuation of MAO inhibitors before initiating the sympathomimetic.

DISCUSSION: Indirect acting sympathomimetic amines may cause abrupt elevation of blood pressure when administered to patients taking monoamine oxidase inhibitors, resulting in a potentially fatal hypertensive crisis. Mixed (direct and indirect) acting sympathomimetics have also been shown to interact with monoamine oxidase inhibitors depending on their degree of indirect action. The direct-acting sympathomimetics have not been reported to interact.

Dopamine is metabolized by monoamine oxidase, and its pressor effect is enhanced by monoamine oxidase inhibitors. Since procarbazine, an antineoplastic agent, is a weak monoamine oxidase inhibitor, hypertensive reactions may result from its concurrent use with indirect and mixed acting sympathomimetics. Furazolidone, an antibacterial with monoamine oxidase inhibitor action, has also been shown to interact with indirect acting sympathomimetics.

Linezolid is another antibacterial with monoamine oxidase inhibitor properties. Metaxalone is a weak inhibitor of MAO. Foods containing large amounts of tyramine have also been implicated in this interaction.

Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A. At recommended dosages, rasagiline, oral selegiline, and transdermal selegiline up to 6mg/day are selective for MAO-B; however, at higher dosages they have been shown to lose their selectivity. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems.

This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

EMSAM, FURAZOLIDONE, MARPLAN, MATULANE, METAXALONE, METHYLENE BLUE, NARDIL, PARNATE, PHENELZINE SULFATE, PROCARBAZINE HCL, PROVAYBLUE, SELEGILINE HCL, TRANYLCYPROMINE SULFATE

Dihydroergotamine/Sympathomimetics

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Concurrent use of dihydroergotamine and sympathomimetics may result in additive or synergistic effect on peripheral blood vessels.(1)

CLINICAL EFFECTS: Concurrent use of dihydroergotamine and sympathomimetics may result in increased blood pressure due to peripheral vasoconstriction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Dihydroergotamine is contraindicated with sympathomimetics because the combination may result in additive or synergistic elevation of blood pressure.(1)

DISCUSSION: Significant elevation in blood pressure has been reported in patients treated with dihydroergotamine.(1) Sympathomimetics can be expected to have additional effects on blood pressure.

BREKIYA, DIHYDROERGOTAMINE MESYLATE, MIGRANAL, TRUDHESA

There are 11 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Select Indirect-Acting Sympathomimetics/Tricyclic Compounds SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Unknown. However, it is speculated that indirect-acting sympathomimetics would have decreased activity due to tricyclic blockage of their uptake into the adrenergic neuron. CLINICAL EFFECTS: Decreased effect of indirect acting sympathomimetics. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Use of tricyclic compounds and indirect-acting sympathomimetics should be approached with caution. Monitor patients receiving concurrent therapy for decreased sympathomimetic efficacy. DISCUSSION: The pressor effects of the indirect-acting sympathomimetic amines (e.g., amphetamines, ephedrine, and methylphenidate) are antagonized by tricyclic antidepressants.	AMITRIPTYLINE HCL, AMOXAPINE, ANAFRANIL, CHLORDIAZEPOXIDE-AMITRIPTYLINE, CLOMIPRAMINE HCL, DESIPRAMINE HCL, DOXEPIN HCL, IMIPRAMINE HCL, IMIPRAMINE PAMOATE, NORPRAMIN, NORTRIPTYLINE HCL, PAMELOR, PERPHENAZINE-AMITRIPTYLINE, PROTRIPTYLINE HCL, SILENOR, TRIMIPRAMINE MALEATE
Ergot Alkaloids/Sympathomimetics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of ergot alkaloids and sympathomimetics may result in additive or synergistic effect on peripheral blood vessels. CLINICAL EFFECTS: Concurrent use of ergot alkaloids and sympathomimetics may result in increased blood pressure due to peripheral vasoconstriction. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: When possible, avoid the concurrent use of ergot alkaloids and sympathomimetics. If concurrent use is warranted, monitor blood pressure and for signs of vasoconstriction. Decreasing the dose of one or both drugs may be necessary. DISCUSSION: There have been reports of severe vasoconstriction resulting in gangrene in patients receiving intravenous ergonovine with dopamine or norepinephrine.	CAFERGOT, ERGOLOID MESYLATES, ERGOMAR, ERGOTAMINE TARTRATE, ERGOTAMINE-CAFFEINE, METHYLERGONOVINE MALEATE, METHYSERGIDE MALEATE, MIGERGOT
Guanethidine/Sympathomimetics (Indirect Acting) SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Indirect-acting sympathomimetics may displace guanethidine from adrenergic neurons, thereby antagonizing the clinical effect. CLINICAL EFFECTS: Blood pressure may be increased. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: When possible, use an alternative antihypertensive agent or sympathomimetic. DISCUSSION: This interaction has been demonstrated with concomitant administration of anorexiant-type indirect-acting sympathomimetics and guanethidine. Increased blood pressure has been reported.	GUANETHIDINE HEMISULFATE
Selected Inhalation Anesthetic Agents/Sympathomimetics SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism is unknown. The anesthetics produce conduction changes that increase impulse re-entry into the myocardial tissue.(1) The anesthetics' ability to precipitate arrhythmias is enhanced by elevated arterial blood pressure, tachycardia, hypercapnia, and/or hypoxia, events that stimulate the release of endogenous catecholamines.(1) CLINICAL EFFECTS: Concurrent use of inhalation anesthetic agents and sympathomimetics may result in ventricular arrhythmias or sudden blood pressure and heart rate increase during surgery.(2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor blood pressure and avoid use of sympathomimetics in patients being treated with anesthetics on the day of surgery.(2) Intravenous use of epinephrine during surgery with halothane and related halogenated general anesthetics should be strongly discouraged. When intravenous epinephrine is necessary, nitrous oxide anesthesia supplemented with ether, muscle relaxants, or opioids should be used instead of halothane.(3,4) Epinephrine may safely be used subcutaneously with the following precautions: the patient is adequately ventilated to prevent hypoxia or respiratory acidosis; the total dose of epinephrine is limited to 100 mcg/10 minute period or 300 mcg/hour in adults, 3.5 mcg/Kg in infants, 2.5 mcg/Kg in children up to two years of age, and 1.45 mcg/Kg in children over two years of age; a minimum effective concentration of anesthetic is maintained; the drugs are not co-administered in patients with hypertension or other cardiovascular disorders; and the cardiac rhythm is continuously monitored during and after injection.(3-10) If arrhythmias occur after the administration of the epinephrine, the drugs of choice are lidocaine or propranolol, depending on the type of arrhythmia.(1) DISCUSSION: Administration of epinephrine during halothane anesthesia may may lead to serious ventricular arrhythmias.(3-6,11-18) This has occurred when epinephrine was administered intravenously,(6) when it was administered with lidocaine as a dental block,(11,14) or when it was administered supraperiosteally.(5) Norepinephrine has been shown to interact with halothane in a manner similar to epinephrine.(1) In two case reports, patients were given terbutaline (0.25 to 0.35 mg) for wheezing following induction of anesthesia with halothane. One patient's heart rate increased from 68 to 100 beats/minute, and the ECG showed premature ventricular contractions and bigeminy, while the other patient developed multiple unifocal premature ventricular contractions and bigeminy. The arrhythmias resolved in both patients following lidocaine administration.(19) Although not documented, isoproterenol causes effects on the heart similar to terbutaline(20) and would probably interact with halothane in a similar manner. Other inhalation anesthetics that increase the incidence of arrhythmias with epinephrine include chloroform,(20) methoxyflurane,(20) and enflurane.(12) A similar interaction may be expected between the other inhalation anesthetics and sympathomimetics.	DESFLURANE, FORANE, ISOFLURANE, SEVOFLURANE, SUPRANE, TERRELL, ULTANE
Mixed & Indirect Sympathomimetics; Oral Phenylephrine/Selected MAOIs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Catecholamine stores increased by MAOIs can be released by indirect acting sympathomimetics such as ephedrine and amphetamine. MAO inhibitors also interfere with gut and liver metabolism of direct acting sympathomimetics (e.g oral phenylephrine). CLINICAL EFFECTS: Concurrent use of MAOIs may result in potentiation of sympathomimetic effects, which may result in headaches, hypertensive crisis, toxic neurological effects, and malignant hyperpyrexia. Fatalities have occurred with combinations of sympathomimetics and MAO-A inhibitors. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of MAO-A inhibitors and sympathomimetics is contraindicated. The manufacturers of sympathomimetic agents recommend waiting 14 days after discontinuation of MAO inhibitors before initiating the sympathomimetic. Patients receiving indirect acting sympathomimetics should not receive linezolid unless they are monitored for potential increases in blood pressure. Initial dosages of dopamine should be reduced. At recommended dosages, oral selegiline and transdermal selegiline up to 6mg/day are selective for MAO-B; however, at higher dosages they have been shown to lose their selectivity. Patients receiving higher dosages of selegiline should be considered susceptive to this interaction. DISCUSSION: Indirect acting sympathomimetic amines may cause abrupt elevation of blood pressure when administered to patients taking monoamine oxidase inhibitors, resulting in a potentially fatal hypertensive crisis. Mixed (direct and indirect) acting sympathomimetics have also been shown to interact with monoamine oxidase inhibitors depending on their degree of indirect action. The direct-acting sympathomimetics have not been reported to interact. Dopamine is metabolized by monoamine oxidase, and its pressor effect is enhanced by monoamine oxidase inhibitors. Furazolidone, an antibacterial with monoamine oxidase inhibitor action, has also been shown to interact with indirect acting sympathomimetics. Foods containing large amounts of tyramine have also been implicated in this interaction. A significant pressor response was observed in normal subjects receiving linezolid and tyramine doses of more than 100 mg. Administration of linezolid (600 mg BID for 3 days) with pseudoephedrine (60 mg q 4 hours for 2 doses) increased blood pressure by 32 mmHg. Administration of linezolid (600 mg BID for 3 days) with phenylpropanolamine (25 mg q 4 hours for 2 doses) increased blood pressure by 38 mmHg. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.	EMSAM, LINEZOLID, LINEZOLID-0.9% NACL, LINEZOLID-D5W, SELEGILINE HCL, XADAGO, ZELAPAR, ZYVOX
Ioflupane I 123/Dopamine Transporter Binders SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ioflupane binds to the dopamine transporter. Agents that also bind to this transporter may affect the results of single photon emission computed tomography (SPECT) brain imaging using ioflupane.(1) CLINICAL EFFECTS: SPECT imaging using ioflupane may not be accurate in patients taking other drugs that bind to the dopamine transporter binders.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: It is unknown if discontinuing other agents that bind to the dopamine transporter prior to a scan with ioflupane will decrease interference with the scan.(1) Make sure the radiologist interpreting the scan knows the patient is taking another agent that binds to the dopamine transporter. Alternative diagnostic tools may need to be considered. DISCUSSION: Ioflupane binds to the dopamine transporter. Agents that also bind to this transporter may affect the results of the scan. These agents include amoxapine, amphetamine, armodafinil, benztropine, bupropion, buspirone, citalopram, cocaine, dexmethylphenidate, escitalopram, fluoxetine, fluvoxamine, mazindol, methamphetamine, methylphenidate, modafinil, norephedrine, paroxetine, phentermine, phenylpropanolamine, selegiline, and sertraline.(1)	DATSCAN, IOFLUPANE I-123
Selected Extended-Release CNS Stimulants/Alcohol SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concomitant use of alcohol with selected extended or delayed release amphetamine, dextroamphetamine, and methylphenidate products may impair the integrity of the extended-release dose form resulting in accelerated medication release over a short period of time.(1-8) CLINICAL EFFECTS: Rapid release of amphetamine, dextroamphetamine, or methylphenidate may result in increased systemic concentrations and toxicities. PREDISPOSING FACTORS: The increased rate of release may be alcohol concentration-dependent. PATIENT MANAGEMENT: Patients are advised to avoid alcohol while taking these extended-release products.(1-8) Avoid the use of elixirs containing a high-percentage of alcohol in patients taking these products. DISCUSSION: Some, but not all manufacturers have evaluated the effects of alcohol on the kinetics of their extended release dose forms. An in vitro study explored the effect of alcohol on the release characteristics of amphetamine from Adzenys XR-OPD. There was a substantial increase in amphetamine release with 40% alcohol, but not 5%, 10%, or 20% alcohol.(1) An in vitro study explored the effect of alcohol on the release characteristics of amphetamine from Dyanavel XR. There was a substantial increase in amphetamine release with 40% alcohol, but not 5%, 10%, or 20% alcohol.(2) An in vitro study explored the effect of alcohol on the release characteristics of amphetamine from Mydayis. There was an increase in amphetamine release with 20% alcohol and a larger increase with 40% alcohol.(3) An in vitro study explored the effect of alcohol on the release characteristics of methylphenidate from Adhansia XR. At an alcohol concentration of 40%, 71% and 61% of a 70 mg and 100 mg dose, respectively, was released at 2 hours. A study in healthy adults found that 40% alcohol combined with Adhansia XR resulted in a 1.4-fold increase in peak plasma concentration and 1.3-fold increase in absorption.(4) An in vitro study explored the effect of alcohol on the release characteristics of methylphenidate for Concerta. At an alcohol concentration up to 40% there was no increased release of methylphenidate in the first hour.(5) An in vitro study explored the effect of alcohol on the release characteristics of methylphenidate from Cotempla XR-ODT. There was an increase in methylphenidate release with 40% alcohol, but not with lower alcohol concentration.(6) An in vitro study explored the effect of alcohol on the release characteristics of methylphenidate from Metadate CD. At an alcohol concentration of 40%, 84% of methylphenidate was released in the first hour.(7) An in vitro study explored the effect of alcohol on the release characteristics of methylphenidate from Ritalin LA. At an alcohol concentration of 40%, 98% of methylphenidate was released in the first hour.(8)	GENADUR
Iobenguane I 123/Agents that Affect Catecholamines SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1) CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1) DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)	ADREVIEW
Sodium Iodide I 131/Myelosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1) DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)	HICON, SODIUM IODIDE I-131
Methylphenidate XR-ODT/H2 Antagonists;Proton Pump Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The solubility of methylphenidate extended release orally disintegrating tablets (XR-ODT) is pH-dependent. At elevated pH, methylphenidate may be released from the tablets more quickly, resulting in increased absorption.(1) CLINICAL EFFECTS: Coadministration of H2 antagonists or proton pump inhibitors (PPIs) may result in an altered pharmacokinetic profile of methylphenidate XR-ODT, which may change the effectiveness and/or adverse effects of methylphenidate XR-ODT.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Coadministration of methylphenidate XR-ODT with H2 antagonists or PPIs is not recommended.(1,2) DISCUSSION: In in vitro studies, when media pH was increased from 1.2 to 6.8, percentage release of methylphenidate from the XR-ODT tablet was increased by 67% at 0.5 hours, and by 93% at 2.5 hours. The increased dissolution of methylphenidate at higher pH may result in increased drug absorption and change the concentration-time profile of methylphenidate, which is correlated with pharmacological effect.(1)	ACIPHEX, ACIPHEX SPRINKLE, CIMETIDINE, DEXILANT, DEXLANSOPRAZOLE DR, ESOMEPRAZOLE MAGNESIUM, ESOMEPRAZOLE SODIUM, FAMOTIDINE, IBUPROFEN-FAMOTIDINE, KONVOMEP, LANSOPRAZOL-AMOXICIL-CLARITHRO, LANSOPRAZOLE, NAPROXEN-ESOMEPRAZOLE MAG, NEXIUM, NIZATIDINE, OMECLAMOX-PAK, OMEPRAZOLE, OMEPRAZOLE-SODIUM BICARBONATE, PANTOPRAZOLE SODIUM, PANTOPRAZOLE SODIUM-0.9% NACL, PEPCID, PREVACID, PRILOSEC, PROTONIX, PROTONIX IV, RABEPRAZOLE SODIUM, RANITIDINE HCL, TALICIA, VOQUEZNA, VOQUEZNA DUAL PAK, VOQUEZNA TRIPLE PAK, YOSPRALA
Mixed & Indirect Sympathomimetics; Oral Phenylephrine/Rasagiline SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Catecholamine stores increased by MAOIs can be released by indirect acting sympathomimetics such as ephedrine and amphetamine. MAO inhibitors also interfere with gut and liver metabolism of direct acting sympathomimetics (e.g oral phenylephrine). CLINICAL EFFECTS: Concurrent use of MAOIs may result in potentiation of sympathomimetic effects, which may result in headaches, hypertensive crisis, toxic neurological effects, and malignant hyperpyrexia. Hypertensive crisis has been reported in patients taking recommended doses of rasagiline with sympathomimetic agents. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: At recommended dosages, rasagiline is selective for MAO-B; however, at higher dosages it has been shown to lose its selectivity. Patients receiving higher dosages of rasagiline should be considered susceptive to this interaction. Concurrent use should be approached with caution. DISCUSSION: Indirect acting sympathomimetic amines may cause abrupt elevation of blood pressure when administered to patients taking monoamine oxidase inhibitors, resulting in a potentially fatal hypertensive crisis. Mixed (direct and indirect) acting sympathomimetics have also been shown to interact with monoamine oxidase inhibitors depending on their degree of indirect action. The direct-acting sympathomimetics have not been reported to interact. Dopamine is metabolized by monoamine oxidase, and its pressor effect is enhanced by monoamine oxidase inhibitors.	AZILECT, RASAGILINE MESYLATE

There are 6 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Opioids (Immediate Release)/Selected Stimulants SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Opioids and stimulants exhibit opposing effects on the CNS. CLINICAL EFFECTS: Concurrent use of opioids and stimulants may have unpredictable effects and may mask overdose symptoms of the opioid, such as drowsiness and inability to focus. PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS stimulants such as amphetamines to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(1) Monitor patients receiving concurrent therapy for signs of substance abuse. Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). DISCUSSION: A total of 70,237 persons died from drug overdoses in the United States in 2017; approximately two thirds of these deaths involved an opioid.(2). The CDC analyzed 2016-2017 changes in age-adjusted death rates involving cocaine and psychostimulants by demographic characteristics, urbanization levels, U.S. Census region, 34 states, and the District of Columbia (DC). The CDC also examined trends in age-adjusted cocaine-involved and psychostimulant-involved death rates from 2003 to 2017 overall, as well as with and without co-involvement of opioids. Among all 2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333 (14.7%) involved psychostimulants. Death rates increased from 2016 to 2017 for both drug categories across demographic characteristics, urbanization levels, Census regions, and states. In 2017, opioids were involved in 72.7% and 50.4% of cocaine-involved and psychostimulant-involved overdoses, respectively, and the data suggest that increases in cocaine-involved overdose deaths from 2012 to 2017 were driven primarily by synthetic opioids.(3) There was opioid co-involvement in 72.7 percent of cocaine and 50.4 percent of stimulant-involved overdose deaths. This was largely driven by synthetic opioids such as fentanyl. However, stimulant-involved overdose without opioid co-involvement is also increasing.(2)	ACETAMIN-CAFF-DIHYDROCODEINE, ACETAMINOPHEN-CODEINE, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BELBUCA, BELLADONNA-OPIUM, BUPRENORPHINE HCL, BUPRENORPHINE-NALOXONE, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTORPHANOL TARTRATE, CARISOPRODOL-ASPIRIN-CODEINE, CODEINE PHOSPHATE, CODEINE SULFATE, DIHYDROCODEINE BITARTRATE, DILAUDID, DISKETS, DSUVIA, DURAMORPH, ENDOCET, FENTANYL CITRATE, FENTANYL CITRATE-0.9% NACL, FENTANYL CITRATE-D5W, FENTANYL CITRATE-STERILE WATER, FENTANYL CITRATE-WATER, FENTANYL-BUPIVACAINE-0.9% NACL, FENTANYL-BUPIVACAINE-NACL, FENTANYL-ROPIVACAINE-0.9% NACL, FENTANYL-ROPIVACAINE-NACL, HYDROCODONE BITARTRATE, HYDROCODONE-ACETAMINOPHEN, HYDROCODONE-IBUPROFEN, HYDROMORPHONE HCL, HYDROMORPHONE HCL-0.9% NACL, HYDROMORPHONE HCL-D5W, HYDROMORPHONE HCL-NACL, HYDROMORPHONE HCL-WATER, INFUMORPH, LEVORPHANOL TARTRATE, METHADONE HCL, METHADONE HCL-0.9% NACL, METHADONE HCL-NACL, METHADONE INTENSOL, METHADOSE, MITIGO, MORPHINE SULFATE, MORPHINE SULFATE-0.9% NACL, MORPHINE SULFATE-NACL, NALBUPHINE HCL, NALOCET, NUCYNTA, OPIUM TINCTURE, OXYCODONE HCL, OXYCODONE HYDROCHLORIDE, OXYCODONE-ACETAMINOPHEN, OXYMORPHONE HCL, PENTAZOCINE-NALOXONE HCL, PERCOCET, PRIMLEV, PROLATE, REMIFENTANIL HCL, ROXICODONE, ROXYBOND, SUBOXONE, SUFENTANIL CITRATE, TAPENTADOL HCL, TREZIX, ULTIVA, XYVONA, ZUBSOLV
Opioids (Extended Release)/Selected Stimulants SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Opioids and stimulants exhibit opposing effects on the CNS. CLINICAL EFFECTS: Concurrent use of opioids and stimulants may have unpredictable effects and may mask overdose symptoms of the opioid, such as drowsiness and inability to focus. PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS stimulants such as amphetamines to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(1) Monitor patients receiving concurrent therapy for signs of substance abuse. Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing opioid reversal agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). DISCUSSION: A total of 70,237 persons died from drug overdoses in the United States in 2017; approximately two thirds of these deaths involved an opioid.(2). The CDC analyzed 2016-2017 changes in age-adjusted death rates involving cocaine and psychostimulants by demographic characteristics, urbanization levels, U.S. Census region, 34 states, and the District of Columbia (DC). The CDC also examined trends in age-adjusted cocaine-involved and psychostimulant-involved death rates from 2003 to 2017 overall, as well as with and without co-involvement of opioids. Among all 2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333 (14.7%) involved psychostimulants. Death rates increased from 2016 to 2017 for both drug categories across demographic characteristics, urbanization levels, Census regions, and states. In 2017, opioids were involved in 72.7% and 50.4% of cocaine-involved and psychostimulant-involved overdoses, respectively, and the data suggest that increases in cocaine-involved overdose deaths from 2012 to 2017 were driven primarily by synthetic opioids.(3) There was opioid co-involvement in 72.7 percent of cocaine and 50.4 percent of stimulant-involved overdose deaths. This was largely driven by synthetic opioids such as fentanyl. However, stimulant-involved overdose without opioid co-involvement is also increasing.(2)	BRIXADI, BUPRENORPHINE, BUTRANS, FENTANYL, HYDROCODONE BITARTRATE ER, HYDROMORPHONE ER, HYSINGLA ER, MORPHINE SULFATE ER, MS CONTIN, NUCYNTA ER, OXYCODONE HCL ER, OXYCONTIN, OXYMORPHONE HCL ER, SUBLOCADE, TAPENTADOL ER, XTAMPZA ER
Benzodiazepines/Selected Stimulants SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Benzodiazepines and stimulants exhibit opposing effects on the CNS. CLINICAL EFFECTS: Concurrent use of benzodiazepine and stimulants may have unpredictable effects and may mask overdose symptoms of the benzodiazepine, such as drowsiness and inability to focus. PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing benzodiazepines with CNS stimulants such as amphetamines to patients for whom alternatives are inadequate. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Monitor patients receiving concurrent therapy for signs of substance abuse. DISCUSSION: Analysis of the 2015 and 2016 National Survey on Drug Use and Health found that misuse of benzodiazepines was strongly associated with misuse of or dependences on stimulants.(1) Benzodiazepines are used to reduce the adverse effects of stimulant use, such as insomnia.(2) Patients abusing benzodiazepines in combination with other drugs tend to consume higher dosages of benzodiazepines than patients abusing only benzodiazepines.(3)	ALPRAZOLAM, ALPRAZOLAM ER, ALPRAZOLAM INTENSOL, ALPRAZOLAM ODT, ALPRAZOLAM XR, ATIVAN, BYFAVO, CHLORDIAZEPOXIDE HCL, CHLORDIAZEPOXIDE-AMITRIPTYLINE, CHLORDIAZEPOXIDE-CLIDINIUM, CLOBAZAM, CLONAZEPAM, CLORAZEPATE DIPOTASSIUM, DIAZEPAM, DORAL, ESTAZOLAM, FLURAZEPAM HCL, HALCION, KLONOPIN, LIBRAX, LORAZEPAM, LORAZEPAM INTENSOL, LOREEV XR, MIDAZOLAM, MIDAZOLAM HCL, MIDAZOLAM HCL-0.8% NACL, MIDAZOLAM HCL-0.9% NACL, MIDAZOLAM HCL-D5W, MIDAZOLAM HCL-NACL, MIDAZOLAM-0.9% NACL, MIDAZOLAM-NACL, MKO (MIDAZOLAM-KETAMINE-ONDAN), NAYZILAM, ONFI, OXAZEPAM, QUAZEPAM, RESTORIL, SYMPAZAN, TEMAZEPAM, TRIAZOLAM, VALIUM, VALTOCO, XANAX, XANAX XR
Opioids (Cough & Cold)/Selected Stimulants SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Opioids and stimulants exhibit opposing effects on the CNS. CLINICAL EFFECTS: Concurrent use of opioids and stimulants may have unpredictable effects and may mask overdose symptoms of the opioid, such as drowsiness and inability to focus. PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing opioid analgesics with CNS stimulants such as amphetamines to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(1) Monitor patients receiving concurrent therapy for signs of substance abuse. Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing opioid reversal agents (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). DISCUSSION: A total of 70,237 persons died from drug overdoses in the United States in 2017; approximately two thirds of these deaths involved an opioid.(2). The CDC analyzed 2016-2017 changes in age-adjusted death rates involving cocaine and psychostimulants by demographic characteristics, urbanization levels, U.S. Census region, 34 states, and the District of Columbia (DC). The CDC also examined trends in age-adjusted cocaine-involved and psychostimulant-involved death rates from 2003 to 2017 overall, as well as with and without co-involvement of opioids. Among all 2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333 (14.7%) involved psychostimulants. Death rates increased from 2016 to 2017 for both drug categories across demographic characteristics, urbanization levels, Census regions, and states. In 2017, opioids were involved in 72.7% and 50.4% of cocaine-involved and psychostimulant-involved overdoses, respectively, and the data suggest that increases in cocaine-involved overdose deaths from 2012 to 2017 were driven primarily by synthetic opioids.(3) There was opioid co-involvement in 72.7 percent of cocaine and 50.4 percent of stimulant-involved overdose deaths. This was largely driven by synthetic opioids such as fentanyl. However, stimulant-involved overdose without opioid co-involvement is also increasing.(2)	HYCODAN, HYDROCODONE-CHLORPHENIRAMNE ER, HYDROCODONE-HOMATROPINE MBR, HYDROMET, PROMETHAZINE-CODEINE, TUXARIN ER
Tramadol/Methylphenidate SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Opioids and methylphenidate exhibit opposing effects on the CNS.(1) CLINICAL EFFECTS: Concurrent use of opioids and methylphenidate may have unpredictable effects and may mask overdose symptoms of the opioid, such as drowsiness and inability to focus. PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing tramadol with CNS stimulants such as methylphenidate to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Concurrent use of methylphenidate with tramadol should be approached with appropriate monitoring. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(1) Monitor patients receiving concurrent therapy for signs of substance abuse. Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). DISCUSSION: A total of 70,237 persons died from drug overdoses in the United States in 2017; approximately two thirds of these deaths involved an opioid.(2). The CDC analyzed 2016-2017 changes in age-adjusted death rates involving cocaine and psychostimulants by demographic characteristics, urbanization levels, U.S. Census region, 34 states, and the District of Columbia (DC). The CDC also examined trends in age-adjusted cocaine-involved and psychostimulant-involved death rates from 2003 to 2017 overall, as well as with and without co-involvement of opioids. Among all 2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333 (14.7%) involved psychostimulants. Death rates increased from 2016 to 2017 for both drug categories across demographic characteristics, urbanization levels, Census regions, and states. In 2017, opioids were involved in 72.7% and 50.4% of cocaine-involved and psychostimulant-involved overdoses, respectively, and the data suggest that increases in cocaine-involved overdose deaths from 2012 to 2017 were driven primarily by synthetic opioids.(3) There was opioid co-involvement in 72.7 percent of cocaine and 50.4 percent of stimulant-involved overdose deaths. This was largely driven by synthetic opioids such as fentanyl. However, stimulant-involved overdose without opioid co-involvement is also increasing.(2)	CONZIP, QDOLO, TRAMADOL HCL, TRAMADOL HCL ER, TRAMADOL HCL-ACETAMINOPHEN
Meperidine/Methylphenidate SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Opioids and methylphenidate exhibit opposing effects on the CNS.(1) CLINICAL EFFECTS: Concurrent use of opioids and methylphenidate may have unpredictable effects and may mask overdose symptoms of the opioid, such as drowsiness and inability to focus. PREDISPOSING FACTORS: Concurrent use of alcohol or other CNS depressants may increase the risk of adverse effects. PATIENT MANAGEMENT: Limit prescribing meperidine with CNS stimulants such as methylphenidate to patients for whom alternatives are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. If concurrent use is necessary, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(1) Monitor patients receiving concurrent therapy for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). Monitor patients receiving concurrent therapy for signs of substance abuse. DISCUSSION: A total of 70,237 persons died from drug overdoses in the United States in 2017; approximately two thirds of these deaths involved an opioid.(2). The CDC analyzed 2016-2017 changes in age-adjusted death rates involving cocaine and psychostimulants by demographic characteristics, urbanization levels, U.S. Census region, 34 states, and the District of Columbia (DC). The CDC also examined trends in age-adjusted cocaine-involved and psychostimulant-involved death rates from 2003 to 2017 overall, as well as with and without co-involvement of opioids. Among all 2017 drug overdose deaths, 13,942 (19.8%) involved cocaine, and 10,333 (14.7%) involved psychostimulants. Death rates increased from 2016 to 2017 for both drug categories across demographic characteristics, urbanization levels, Census regions, and states. In 2017, opioids were involved in 72.7% and 50.4% of cocaine-involved and psychostimulant-involved overdoses, respectively, and the data suggest that increases in cocaine-involved overdose deaths from 2012 to 2017 were driven primarily by synthetic opioids.(3) There was opioid co-involvement in 72.7 percent of cocaine and 50.4 percent of stimulant-involved overdose deaths. This was largely driven by synthetic opioids such as fentanyl. However, stimulant-involved overdose without opioid co-involvement is also increasing.(2)	DEMEROL, MEPERIDINE HCL, MEPERIDINE HCL-0.9% NACL

The following contraindication information is available for COTEMPLA XR-ODT (methylphenidate):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

*Known hypersensitivity to methylphenidate or any ingredient in the formulation. *Concomitant or recent (within 14 days) administration of monoamine oxidase (MAO) inhibitors since hypertensive crisis could result. *Some methylphenidate hydrochloride extended-release capsules may contain sucrose and should not be used in patients with hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency.

There are 3 contraindications. Absolute contraindication.

Contraindication List
Congenital heart disease
Coronary artery disease
Valvular heart disease

There are 20 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Acrocyanosis
Alcohol use disorder
Bipolar disorder
Cardiac arrhythmia
Cerebrovascular accident
Chronic heart failure
Congenital long QT syndrome
Drug abuse
Esophageal dysmotility
Gastrointestinal obstruction
Gilles de la tourette syndrome
Glaucoma
History of drug abuse
Hypertension
Manic disorder
Motor tic disorder
Priapism
Psychotic disorder
Short bowel syndrome
Suicidal ideation

There are 2 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Peripheral vascular disease
Raynaud's phenomenon

The following adverse reaction information is available for COTEMPLA XR-ODT (methylphenidate):

Overview
Severe
Less Severe

Adverse reaction overview.

Common adverse effects reported in patients receiving immediate-release methylphenidate preparations (e.g., conventional tablets, oral solution) include tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain. Nervousness and insomnia were the most commonly reported adverse effects with immediate-release methylphenidate chewable tablets, although the manufacturer states that these effects can usually be minimized with dosage reduction and omitting administration in the afternoon or evening. The most common adverse effect reported in >5% of children and adolescents receiving extended-release methylphenidate trilayer (e.g., Concerta(R); generics) and bilayer (e.g., Relexxii(R)) core tablets was abdominal pain; in studies conducted in adults, the most common adverse effects reported in >5% of patients were decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight loss, irritability, and hyperhidrosis.

The most common adverse effects reported in >5% of patients receiving methylphenidate hydrochloride extended-release capsules (Ritalin(R) LA) were headache, insomnia, upper abdominal pain, decreased appetite, and anorexia. The most common adverse effects reported in >=5% of patients and twice the rate of placebo in patients receiving methylphenidate hydrochloride CD extended-release capsules include anorexia and insomnia. The most common adverse effects reported in >=5% of pediatric patients 6-12 years of age receiving the methylphenidate transdermal patch (Daytrana(R)) and twice the rate of placebo include a decreased appetite, insomnia, nausea, vomiting, weight loss, tics, affect lability, and anorexia.

In adolescents 13-17 years of age receiving the methylphenidate transdermal patch (Daytrana(R)), the most common adverse effects reported in >=5% of patients and twice the rate of placebo were decreased appetite, nausea, insomnia, weight loss, dizziness, abdominal pain, and anorexia. Most of these patients also had erythema at the application site. The most common adverse effects reported in >=5% of pediatric patients 6-17 years of age receiving methylphenidate hydrochloride extended-release capsules (Aptensio XR(R)) were abdominal pain, decreased appetite, and insomnia. Common adverse effects in patients receiving delayed- and extended-release capsules (Jornay PM(R)) not based on accumulated data from other methylphenidate products and occurring in >=5% of pediatric patients 6-12 years of age and twice the rate of placebo, include headache, psychomotor hyperactivity, and mood swings.

There are 39 severe adverse reactions.

More Frequent	Less Frequent
None.	Angina Chest pain Dyskinesia Hypertension Thrombocytopenic disorder

Rare/Very Rare
Abnormal hepatic function tests Acute hepatic failure Acute myocardial infarction Anaphylaxis Anemia Angioedema Bradycardia Bullous dermatitis Cerebral vasculitis Cerebrovascular accident Drug dependence Drug-induced psychosis Erythema multiforme Exfoliative dermatitis Extrasystoles Growth failure Hepatocellular damage Hyperbilirubinemia Idiopathic thrombocytopenic purpura Intracerebral hemorrhage Leukopenia Manic disorder Ocular hypertension Pancytopenia Priapism Raynaud's phenomenon Rhabdomyolysis Secondary angle-closure glaucoma Seizure disorder Suicidal ideation Supraventricular tachycardia Tonic clonic seizure Toxic psychosis Ventricular premature beats

Rare/Very Rare

Abnormal hepatic function tests
Acute hepatic failure
Acute myocardial infarction
Anaphylaxis
Anemia
Angioedema
Bradycardia
Bullous dermatitis
Cerebral vasculitis
Cerebrovascular accident
Drug dependence
Drug-induced psychosis
Erythema multiforme
Exfoliative dermatitis
Extrasystoles
Growth failure
Hepatocellular damage
Hyperbilirubinemia
Idiopathic thrombocytopenic purpura
Intracerebral hemorrhage
Leukopenia
Manic disorder
Ocular hypertension
Pancytopenia
Priapism
Raynaud's phenomenon
Rhabdomyolysis
Secondary angle-closure glaucoma
Seizure disorder
Suicidal ideation
Supraventricular tachycardia
Tonic clonic seizure
Toxic psychosis
Ventricular premature beats

There are 75 less severe adverse reactions.

More Frequent	Less Frequent
Acute abdominal pain Anorexia Excitement Headache disorder Hyperhidrosis Insomnia Irritability Nausea Nervousness Upper abdominal pain Weight loss Xerostomia	Aggressive behavior Arthralgia Cough Dizziness Drowsy Dyspepsia Fever Pain in oropharynx Palpitations Pharyngitis Sinusitis Skin rash Symptoms of anxiety Tachycardia Tremor Upper respiratory infection Urticaria Vertigo Vomiting

Rare/Very Rare
Acute cognitive impairment Agitation Alopecia Blurred vision Bruising Bruxism Constipation Cramps Depression Diarrhea Diplopia Dry eye Dysmenorrhea Dyspnea Epistaxis Erectile dysfunction Erythema Fatigue Flushing General weakness Gynecomastia Hallucinations Hematuria Lethargy Libido changes Logorrhea Migraine Mood changes Motion sickness Motor tic disorder Muscle fasciculation Muscle spasm Myalgia Mydriasis Ocular pain Panic disorder Paresthesia Peripheral vasoconstriction Polydipsia Pruritus of skin Reversible ischemic neurological defect Sore throat Verbal tic Visual changes

Rare/Very Rare

Acute cognitive impairment
Agitation
Alopecia
Blurred vision
Bruising
Bruxism
Constipation
Cramps
Depression
Diarrhea
Diplopia
Dry eye
Dysmenorrhea
Dyspnea
Epistaxis
Erectile dysfunction
Erythema
Fatigue
Flushing
General weakness
Gynecomastia
Hallucinations
Hematuria
Lethargy
Libido changes
Logorrhea
Migraine
Mood changes
Motion sickness
Motor tic disorder
Muscle fasciculation
Muscle spasm
Myalgia
Mydriasis
Ocular pain
Panic disorder
Paresthesia
Peripheral vasoconstriction
Polydipsia
Pruritus of skin
Reversible ischemic neurological defect
Sore throat
Verbal tic
Visual changes

The following precautions are available for COTEMPLA XR-ODT (methylphenidate):

Pediatric
Pregnant
Lactation
Geriatric

Although safety and efficacy of methylphenidate in children <6 years of age have not been established, the drug has been used in several controlled clinical studies in preschool-aged children up to 6 years of age. AAP states that methylphenidate may be considered for treatment of ADHD in preschool-aged children+ (4 years of age to the sixth birthday) if first-line treatments (i.e., parent training in behavior management and/or behavioral classroom interventions) do not provide substantial improvement and there is continued, moderate to severe disturbance in the child's functioning. Some studies have reported higher rates of adverse effects in preschool-aged children up to 6 years of age, particularly with higher dosages, than had previously been reported in children 6 years of age and older and the adverse effects reported in preschool-aged children may be different than those reported in older children with ADHD.

Some behaviors reported as adverse stimulant effects in clinical studies in preschool-aged children receiving methylphenidate also were reported in those receiving placebo; some of these behaviors may actually improve in preschool-aged children receiving methylphenidate therapy. In placebo-controlled and 12-month open-label extension studies of methylphenidate hydrochloride extended-release capsules (Aptensio XR(R)) in children 4 to less than 6 years of age with ADHD, high rates of adverse effects, particularly weight loss, were observed. Systemic exposure to the drug in these preschool-aged children was approximately twofold to threefold higher than that observed in older children and adolescents receiving the same methylphenidate hydrochloride dosage.

Because some data suggest that the rate of methylphenidate metabolism may be slower in children 4-5 years of age, therapy with the drug should be initiated at a low dosage and increased in smaller increments; maximum dosages have not been adequately studied in preschool-aged children. Additional study and experience are required to elucidate further the safety and efficacy of the drug in this age group. Long-term administration of CNS stimulants has been associated with at least a temporary suppression of normal weight and/or height patterns in children.

Therefore, the manufacturers state that patients requiring long-term therapy with methylphenidate should be carefully monitored, and children who are not growing or gaining height or weight as expected may require temporary discontinuance of therapy. In juvenile animal toxicity studies, rats receiving methylphenidate beginning early in the postnatal period and continuing through sexual maturation at a dosage of 4 or more times the usual maximum recommended pediatric dosage of 60 mg daily exhibited decreased spontaneous locomotor activity in adulthood; in addition, female rats exhibited a deficit in acquisition of a specific learning task at a dosage of 8 times the usual maximum recommended pediatric dosage. The no-effect level for juvenile neurobehavioral development in rats was approximately 0.5

times the usual maximum recommended pediatric dosage. The clinical relevance of these long-term behavioral effects observed in rats is unknown.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Available data on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, spontaneous abortion, or adverse maternal or fetal outcomes; however, there may be fetal risks associated with use of CNS stimulants during pregnancy. CNS stimulants, such as methylphenidate, can cause vasoconstriction and thereby decrease placental perfusion. While no fetal and/or neonatal adverse reactions have been reported with the use of therapeutic dosages of methylphenidate during pregnancy, premature delivery and low birth-weight infants have been reported in amphetamine-dependent women.

In embryofetal development studies in rats and rabbits, no effects on morphologic development were observed following oral administration of methylphenidate during organogenesis at dosages up to 10 and 15 times, respectively, an adolescent dosage of 60 mg daily (based on body surface area); however, spina bifida was observed in rabbits at a dosage of 52 times this human dosage. In a pre- and postnatal development study in rats, oral administration of methylphenidate throughout pregnancy and lactation at dosages of 6 times an adolescent dosage of 60 mg daily was associated with a decrease in pup body weight. The National Pregnancy Registry for ADHD Medications monitors pregnancy outcomes in women exposed to ADHD medications during pregnancy.

Clinicians are encouraged to register women who become pregnant while receiving methylphenidate by calling 866-961-2388 or visiting https://womensmentalhealth.org/adhdmedications/ .

Limited data suggest that breast-fed infants receive 0.2-0.7% of the maternal weight-adjusted dosage of methylphenidate; in 5 case reports, the milk-to-plasma ratio of the drug ranged from 1.1-2.7.

Adverse effects on the breast-fed infant or on milk production have not been reported to date; however, any long-term neurodevelopmental effects are unknown. The developmental and health benefits of breast-feeding should be considered along with the importance of methylphenidate to the woman and any potential adverse effects on the breast-fed infant from either the drug or the underlying maternal condition. If a woman receiving methylphenidate breast-feeds, the infant should be monitored for adverse effects (e.g., agitation, insomnia, anorexia, reduced weight gain).

Methylphenidate hydrochloride has not been studied in patients >=65 years of age.

Attention-deficit hyperactivity disorder
F90	Attention-deficit hyperactivity disorders
F90.0	Attention-deficit hyperactivity disorder, predominantly inattentive type
F90.1	Attention-deficit hyperactivity disorder, predominantly hyperactive type
F90.2	Attention-deficit hyperactivity disorder, combined type
F90.8	Attention-deficit hyperactivity disorder, other type
F90.9	Attention-deficit hyperactivity disorder, unspecified type