Class: Respiratory and CNS Stimulants
VA Class: CN802
Chemical Name: d,l (racemic) methyl a-phenyl-2-piperidineacetate hydrochloride
Molecular Formula: C₁₄H₁₉NO₂•ClH
CAS Number: 298-59-9
Brands: Aptensio, Concerta, Daytrana, Metadate, Methylin, Quillivant, Ritalin

Medically reviewed by Drugs.com. Last updated on Nov 13, 2020.

• Uses
• Dosage
• Cautions
• Interactions
• Pharmacokinetics
• Patient advice
• Preparations
• FAQ

Introduction

Piperidine-derivative stimulant; pharmacologic actions qualitatively similar to those of amphetamines.

Uses for Methylphenidate

Attention Deficit Hyperactivity Disorder (ADHD)

Treatment of ADHD, alone or combined with behavioral treatment, as an adjunct to psychological, educational, social, and other remedial measures in carefully selected children ≥6 years of age, adolescents, and adults.

A drug of choice for the management of ADHD.

Used effectively in the management of ADHD in adolescents and adults, but experience is far less extensive than in children, and potential age-related differences in response remain to be elucidated.

Narcolepsy

Symptomatic treatment of narcolepsy.

Methylphenidate Dosage and Administration

General

• Carefully adjust dosage according to individual requirements and response.

• For patients whose symptoms are not severe outside school, may attempt drug holidays for all or part of the summer to assess continuing efficacy and need for therapy, as well as to minimize adverse effects.

• Discontinue therapy if a beneficial effect is not attained after appropriate dosage adjustment over 1 month.

• If paradoxical aggravation of symptoms occurs, reduce dosage or discontinue the drug.

• Periodically discontinue therapy to assess the patient’s condition.

Administration

Administer orally or percutaneously by topical application of a transdermal system.

Oral Administration

Conventional Tablets, Chewable Tablets, or Oral Solution

Administer orally 2 or 3 times daily.

The manufacturers recommend that conventional tablets, chewable tablets, or oral solution be taken 30–45 minutes before meals.

To avoid insomnia, administer the last daily dose before 6 p.m.

Administer chewable tablets with a full glass (i.e., ≥240 mL [8 ounces]) of water or other fluid to avoid choking. (See GI Effects under Cautions and also see Advice to Patients.)

Extended-release Tablets (Metadate ER, Ritalin–SR; generics)

Swallow tablets whole; do not crush or chew.

May be used once the daily dosage has been titrated using conventional tablets (when the 8-hour dosage of the extended-release preparation corresponds to the titrated 8-hour dosage of the conventional tablets).

Extended-release Capsules (Aptensio XR, Metadate CD, Ritalin LA; generics)

Administer orally once daily in the morning.

Manufacturer states that Metadate CD extended-release capsules should be administered before breakfast. Manufacturer states that administration of Ritalin LA relative to timing and composition of meals may need to be individually adjusted. Manufacturer states that Aptensio XR may be administered without regard to meals, but should be administered in a consistent manner relative to food intake.

Swallow capsules whole; do not crush, chew, or divide.

Alternatively, open capsule and sprinkle contents (pellets) on a small amount of applesauce; swallow immediately without chewing.

Patients receiving extended-release capsules should avoid consuming alcohol; alcohol may result in more rapid release of drug from these formulations.

Manufacturers state that extended-release capsules may be used to initiate methylphenidate therapy or for continued therapy in patients being switched from other methylphenidate formulations (see Switching to Extended-release Capsules [Metadate CD, Ritalin LA; generics] under Dosage and Administration).

Extended-release Trilayer Core Tablets (Concerta; generics)

Administer orally once daily in the morning without regard to meals.

Swallow tablets whole; do not crush or chew.

May be used to initiate methylphenidate therapy or for continued therapy in patients being switched from other methylphenidate formulations (see Switching to Extended-release Trilayer Core Tablets [Concerta; generics] under Dosage and Administration).

Powder for Extended-release Suspension (Quillivant XR)

Administer orally once daily in the morning without regard to meals.

Must be reconstituted prior to dispensing.

To reconstitute powder, tap bottle until the powder flows freely, then remove bottle cap and add appropriate amount of water (53, 105, 131, or 158 mL of water to a bottle containing 300, 600, 750, or 900 mg, respectively, of the drug) to yield an extended-release suspension containing 25 mg/5 mL. Insert adapter into neck of bottle and replace bottle cap. Shake vigorously with back and forth motion for ≥10 seconds.

Use the bottle adapter and oral dosing dispenser supplied by manufacturer to administer the oral suspension. Adapter should remain in place as long as the bottle is in use (up to 4 months).

To dispense a dose, insert the oral dosing dispenser into the adapter in the upright bottle, then invert the bottle and withdraw the appropriate dose into the oral dosing dispenser. Consult manufacturer's patient information for more detailed information on administration.

Transdermal Administration

Apply once daily in the morning, 2 hours before an effect is needed; remove 9 hours after application.

Apply system immediately after opening individually sealed package and removing protective liner.

Do not use if package seal is broken. Do not cut transdermal systems. After separating the system from the protective liner, inspect the liner to ensure that no adhesive (which contains the drug) has been transferred to the liner. Discard the transdermal system if adhesive transfer has occurred or if the system is torn, appears to be damaged, or is difficult to separate from the liner. Use only intact transdermal systems.

Apply the transdermal system to a clean, dry area of the hip that is not oily, damaged, or irritated; avoid applying to the waistline or to areas under tight clothing, since system may rub off. Press system firmly in place with palm of hand for approximately 30 seconds, ensuring good contact with the skin, particularly around the edges. Alternate application sites daily (e.g., opposite hip) if possible.

Do not apply topical preparations (e.g., corticosteroids) immediately prior to system application; effects on adhesion, methylphenidate absorption, or adverse corticosteroid effects are not known.

Exposure to water during bathing, swimming, or showering can affect adherence to the skin. Do not apply or reapply transdermal systems with dressings, tape, or other common adhesives. If a system does not fully adhere to the skin upon application or becomes partially or fully dislodged during the intended period of use, replace it with a new system applied at a different site; do not exceed total wear time of 9 hours per day regardless of number of systems used.

Remove system by slowly peeling it off the skin. If necessary to facilitate removal, gently apply an oil-based product (i.e., petroleum jelly, olive oil, mineral oil) to the edges of the system and gently work the oil underneath the edges. To remove any adhesive remaining on the skin after system removal, apply an oil-based product to the application site to gently loosen and remove residual adhesive. In the unlikely event that a system remains tightly adhered to the skin despite these measures, patient's clinician or pharmacist should be consulted. Do not use nonmedical adhesive removers and acetone-based products (i.e., nail polish remover) to remove the system or adhesive.

After removal, fold system so that the adhesive side adheres to itself, then flush down the toilet or dispose of in an appropriate lidded container. For unused systems, remove from packaging, separate from the protective liner, fold so that the adhesive side adheres to itself, and then flush down the toilet or dispose of in an appropriate lidded container.

Encourage parents or caregiver to record and monitor the application and removal times and method of disposal for each system.

Dosage

Available as methylphenidate and methylphenidate hydrochloride; dosage of methylphenidate hydrochloride is expressed in terms of the salt.

Pediatric Patients

ADHD

Initial Therapy with Conventional Tablets, Chewable Tablets, or Oral Solution

Oral

Initially, 5 mg twice daily, before breakfast and lunch. Increase dosage by 5–10 mg daily at weekly intervals based on response and tolerance, up to 60 mg daily; administer daily dosage in 2 or 3 divided doses.

Some clinicians recommend an initial dosage of 0.25 mg/kg daily; if adverse effects are not observed, double daily dosage each week until 2 mg/kg daily is reached.

Alternatively, dosage has been titrated over 28 days via daily-switch titration involving 5 randomly ordered repeats each of placebo and 5-, 10-, 15-, or 20-mg daily dosages (higher for children weighing >25 kg); each dose is repeated at breakfast and lunch, with a half dose given in the afternoon. The best dosage is selected based on clinical assessment of response.

Switching to Extended-release Tablets (Metadate ER, Ritalin-SR; generics)

Oral

Extended-release tablets can be substituted for conventional tablets at the nearest equivalent total daily dosage (e.g., patients receiving 10 mg as conventional tablets twice daily can be switched to 20 mg as extended-release tablets once daily).

Usual dosage: 20–60 mg daily, given as 20–40 mg once daily or as 40 mg in the morning and 20 mg in the early afternoon.

Initial Therapy with Extended-release Capsules (Aptensio XR, Metadate CD, Ritalin LA; generics)

Oral

Aptensio XR: Initially, 10 mg once daily in the morning. Increase dosage by 10 mg daily at weekly intervals, up to 60 mg daily.

Metadate CD: Initially, 20 mg once daily in the morning. Increase dosage by 10 or 20 mg daily at weekly intervals, up to 60 mg daily.

Ritalin LA: Initially, 20 mg once daily in the morning. Alternatively, initiate with 10 mg once daily when a lower initial dosage is appropriate. Increase dosage by 10 mg daily at weekly intervals, up to 60 mg daily.

Switching to Extended-release Capsules (Metadate CD, Ritalin LA; generics)

Oral

Adjust dosage of Metadate CD by 10 or 20 mg daily at weekly intervals, up to 60 mg daily.

Adjust dosage of Ritalin LA by 10 mg daily at weekly intervals, up to 60 mg daily.

For other conventional tablet regimens, substitute Ritalin LA at the nearest daily dosage based on clinical judgment.

Initial Therapy with Extended-release Oral Suspension (Quillivant XR)

Oral

Initially, 20 mg once daily in the morning. Increase dosage by 10–20 mg daily at weekly intervals, up to 60 mg daily.

Initial Therapy with Extended-release Trilayer Core Tablets (Concerta; generics)

Oral

Initially, 18 mg once daily in the morning. If adequate response does not occur, increase dosage at approximately weekly intervals in increments of 18 mg daily up to 54 mg daily in children 6–12 years of age or 72 mg daily (maximum 2 mg/kg daily) in adolescents 13–17 years of age. Some clinicians state that dosage in children 6–12 years of age may be increased to 72 mg daily.

Switching to Extended-release Trilayer Core Tablets (Concerta; generics)

Oral

For patients being switched from other drugs to methylphenidate (as extended-release trilayer core tablets), follow dosage recommendations for initial therapy with the extended-release trilayer core tablets.

Initial dosage as extended-release trilayer core tablets in patients being switched from conventional tablets should not exceed 72 mg daily. Adjust dosage at weekly intervals in increments of 18 mg daily, up to 72 mg once daily.

A 27-mg extended-release trilayer core tablet also is available for patients who require a dosage in between 18 mg daily and 36 mg daily.

Initial Therapy with or Switching to Transdermal System

Transdermal

Individualize dosage titration, final dosage, and wear time according to patient’s needs and response.

Initially, apply one system delivering 10 mg/9 hours once daily (for initial therapy or for patients switching from other methylphenidate preparations). Increase dosage at weekly intervals, based on response and tolerance, by using the next larger dosage system (i.e., 1 system delivering 15 mg/9 hours, then 1 system delivering 20 mg/9 hours, and then 1 system delivering 30 mg/9 hours).

If shorter duration of effect is desired or if late-day adverse effects appear, may remove system earlier than 9 hours. If aggravation of symptoms or other adverse events occur, reduce dosage or wear time or, if necessary, discontinue therapy.

Adults

ADHD

Initial Therapy with Extended-release Trilayer Core Tablets (Concerta; generics)

Oral

Initially, 18 or 36 mg once daily in the morning. If adequate response does not occur, increase dosage at approximately weekly intervals in increments of 18 mg daily, up to 72 mg daily.

Narcolepsy

Oral

Usual dosage of 10 mg (as conventional tablets or oral solution) 2 or 3 times daily; dosage range of 10–60 mg daily.

Prescribing Limits

Pediatric Patients

ADHD

Conventional Tablets, Chewable Tablets, Oral Solution, Extended-release Tablets, Extended-release Capsules, and Extended-release Oral Suspension

Oral

Maximum 60 mg daily.

Extended-release Trilayer Core Tablets (Concerta; generics)

Oral

Maximum dosage of 54 mg daily for children 6–12 years of age or 72 mg daily (maximum 2 mg/kg daily) for adolescents 13–17 years of age; however, some clinicians state that dosage for children 6–12 years of age may be increased to 72 mg daily.

Adults

ADHD

Extended-release Trilayer Core Tablets (Concerta; generics)

Oral

Maximum 72 mg daily.

Narcolepsy

Oral

Maximum 60 mg daily.

Cautions for Methylphenidate

Contraindications

• Marked anxiety, tension, and agitation.

• Glaucoma.

• Motor tics or a family history or diagnosis of Tourette’s syndrome. However, the AAP states that the presence of tics before or during medical management of ADHD is not an absolute contraindication to stimulant drug use.

• Concomitant or recent (within 14 days) administration of MAO inhibitors. (See Specific Drugs under Interactions.)

• Known hypersensitivity to methylphenidate or any ingredient in the formulation.

Warnings/Precautions

Warnings

Abuse Potential

Marked tolerance and psychologic dependence with varying degrees of abnormal behavior may occur with chronic abuse. (See Boxed Warning.)

Psychotic episodes can occur, particularly with parenteral abuse. Abuse by unintended routes of administration (e.g., chewing, snorting, or injecting formulation) can result in overdosage and death.

Manifestations of stimulant abuse include increased heart rate, respiratory rate, BP, and/or sweating; dilated pupils; hyperactivity, restlessness, insomnia, loss of coordination, and tremors; flushed skin; decreased appetite; and vomiting and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation also observed.

Use with caution in patients with a history of drug or alcohol dependence. Caution may be indicated in patients with comorbid conduct disorder or a chaotic family. If the risk of drug abuse by the patient or the patient’s peers or family is considered high, a nonstimulant drug may be preferable.

Monitor patients for signs of abuse and dependence; periodically reevaluate the need for continued therapy.

Withdrawal Effects

Abrupt withdrawal following prolonged high-dose administration may result in withdrawal symptoms, including extreme fatigue and depression. Severe depression may occur during withdrawal from abusive use; careful supervision required.

Withdrawal following prolonged therapeutic administration may unmask symptoms of the underlying disorder, which may require follow-up.

Sudden Death and Serious Cardiovascular Events

Sudden unexplained death, stroke, and MI reported in adults with ADHD receiving usual dosages of stimulants; sudden death also reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of the drugs.

Although an initial epidemiologic study showed an association between use of stimulants (e.g., methylphenidate) and sudden unexplained death in healthy children and adolescents, several subsequent large epidemiologic studies in children and young adults or in adults 25–64 years of age found no association between ADHD drug use (stimulants, atomoxetine, pemoline [no longer commercially available in US]) and serious cardiovascular events (MI, stroke, sudden cardiac death), although small increases in cardiovascular risk could not be excluded.

Thoroughly review medical history (including evaluation for family history of sudden death or ventricular arrhythmia) and perform physical examination in all children, adolescents, and adults being considered for stimulant therapy; if initial findings suggest presence of cardiac disease, perform further cardiac evaluation (e.g., ECG, echocardiogram).

In general, avoid use of CNS stimulants in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, CAD, or other serious cardiac conditions.

Patients who develop exertional chest pain, unexplained syncope, or other manifestations suggestive of cardiac disease during stimulant therapy should undergo prompt cardiac evaluation.

Effects on BP and Heart Rate

Possible modest increases in average BP (i.e., by about 2–4 mm Hg) and heart rate (i.e., by about 3–6 bpm); larger increases may occur. Modest increases not expected to have short-term sequelae; however, monitor all patients for larger changes in BP and heart rate.

Caution advised in patients with underlying medical conditions that might be affected by increases in BP or heart rate (e.g., hypertension, heart failure, recent MI, ventricular arrhythmia).

Exacerbation or Precipitation of Psychotic Symptoms

May exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorder.

Psychotic symptoms (e.g., hallucinations, delusional thinking) may occur with usual dosages in children and adolescents without prior history of psychotic illness. If psychotic symptoms occur, consider causal relationship to stimulants, and discontinue therapy as appropriate.

Precipitation of Manic Symptoms

May precipitate mixed or manic episodes in ADHD patients with comorbid bipolar disorder; use with caution in these patients. Prior to initiating therapy, carefully screen patients with ADHD and comorbid depressive symptoms to identify risk for bipolar disorder; screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, or depression).

Manic symptoms may occur with usual dosages in children and adolescents without prior history of mania. If manic symptoms occur, consider causal relationship to stimulants, and discontinue therapy as appropriate.

Aggression

Aggressive behavior and hostility (frequently observed in children and adolescents with ADHD) reported in patients receiving drug therapy for ADHD. No systematic evidence that stimulants cause these adverse effects; however, monitor patients beginning treatment for ADHD for onset or worsening of aggressive behavior or hostility.

Priapism

Prolonged and painful erections, sometimes requiring surgical intervention, reported in adult and pediatric patients. Priapism often reported following an increase in dosage; also has occurred during temporary interruptions in therapy (e.g., drug holidays) or following drug discontinuance. Risk of permanent penile damage if not treated immediately.

Use caution if considering change in therapy because of this risk; certain alternative ADHD treatments (e.g., atomoxetine) also may cause priapism.

Peripheral Vascular Effects

Peripheral vascular disorders, including Raynaud’s phenomenon, reported in patients in all age groups receiving stimulants at therapeutic dosages and at various times throughout treatment course. Manifestations usually intermittent and mild, but ulceration of digits and/or breakdown of soft tissue occur rarely. Carefully observe for digital changes.

Improvement generally occurs following dosage reduction or drug discontinuance; however, some patients may require further evaluation (e.g., referral to rheumatologist).

Growth Suppression

Long-term (i.e., >14 months) administration expected to cause at least a temporary suppression of normal weight and/or height patterns in some children and adolescents.

Manufacturers recommend monitoring growth during treatment; patients not growing or gaining weight as expected may require temporary discontinuance of treatment. However, AAP states that studies of stimulants in children found little or no decrease in expected height, with any decrease in growth early in treatment being compensated for later on.

Seizures

Possible lowering of seizure threshold in patients with history of seizures, in those with prior EEG abnormalities but no history of seizures, and, very rarely, in those without history of seizures and with no prior evidence of EEG abnormalities. If seizures occur, discontinue therapy.

GI Disorders

Extended-release trilayer core tablets generally should not be used in patients with severe preexisting GI narrowing; obstruction may occur.

Adverse Ocular Effects

Visual disturbances (e.g., difficulty with accommodation, blurred vision) and eye pain reported with stimulants.

Hereditary Disorders of Carbohydrate Metabolism

Metadate CD extended-release capsules contain sucrose and should not be used in those with hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency.

Metadate ER extended-release tablets contain lactose and should not be used in those with hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Chemical Leukoderma

Permanent depigmentation or hypopigmentation reported in patients receiving methylphenidate transdermal system. Usually limited to application sites, but skin color changes affecting other areas of the body also reported. Time to onset has ranged from 2 months to 4 years; affected areas up to 8 inches in diameter reported.

Monitor skin for loss of pigmentation, especially at application sites. If such changes occur, discontinue transdermal methylphenidate and consider alternative therapy.

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions, including angioedema and anaphylaxis, reported.

Contact Sensitization

Possible contact sensitization following use of transdermal system. Discontinue transdermal therapy if contact sensitization is suspected (erythema accompanied by evidence of a more intense local reaction [e.g., edema, papules, vesicles] that does not substantially improve within 48 hours or that spreads beyond the application site).

Development of localized contact sensitization to methylphenidate during transdermal therapy may be associated with development of systemic sensitization with subsequent oral administration. Manifestations of systemic sensitization may include a flare-up of previous dermatitis or of prior positive patch test sites, or generalized skin eruptions in previously unaffected skin. Other systemic reactions may include headache, fever, malaise, arthralgia, diarrhea, or vomiting.

If contact sensitization occurs with transdermal therapy, monitor patients closely if oral therapy with the drug is initiated. Some patients sensitized to methylphenidate by exposure to transdermal system may not be able to receive methylphenidate in any form.

General Precautions

Nervous System Effects

Possible motor tics. (See Contraindications under Cautions.)

Hematologic Effects

Thrombocytopenia and/or easy bruisability, epistaxis, and gingival bleeding; leukopenia; anemia; pancytopenia; or eosinophilia reported rarely.

Manufacturers recommend periodic monitoring of CBC (with differential) and platelet counts during prolonged therapy; however, AAP and many clinicians consider routine hematologic monitoring unnecessary in the absence of clinical signs (e.g., fever, sore throat, unusual bleeding or bruising) suggestive of hematologic toxicity.

Radiographic Examinations

Extended-release trilayer core tablet may be visible on abdominal radiographs under certain circumstances, particularly when digital enhancing techniques are utilized.

GI Effects

Administration of chewable tablets without adequate fluid may cause tablet contents to swell, resulting in blockage of throat or esophagus and, possibly, choking. Therefore, administer with a full glass (i.e., ≥240 mL [8 ounces]) of water or other fluid. Do not administer in patients with difficulty swallowing. (See Advice to Patients.)

Phenylketonuria

Methylin 2.5-, 5-, and 10-mg chewable tablets contain aspartame (NutraSweet), which is metabolized in the GI tract to provide 0.42, 0.84, and 1.68 mg, respectively, of phenylalanine per tablet.

Exposure of Transdermal Application Site to External Heat

Percutaneous absorption of methylphenidate from the transdermal system may be increased, potentially resulting in overdosage, if the application site is exposed to direct external heat sources (e.g., hair dryers, heating pads, electric blankets, heated water beds) while the transdermal system is being worn.

Specific Populations

Pregnancy

Category C.

Lactation

Limited data (case reports) suggest breast-fed infants receive 0.2–0.7% of the maternal weight-adjusted dosage of methylphenidate; milk-to-plasma ratios of 1.1–2.7 reported. Adverse effects on breast-fed infants or on milk production not reported to date; however, any long-term neurodevelopmental effects are unknown.

Consider developmental and health benefits of breast-feeding, the importance of methylphenidate to the woman, and any potential adverse effects of either the drug or the underlying maternal condition on the breast-fed infant.

If used in a nursing woman, monitor breast-fed infant for adverse effects (e.g., agitation, anorexia, reduced weight gain).

Pediatric Use

Safety and efficacy not established in children <6 years of age.

Aggressive behavior, hostility, and psychotic (e.g., hallucinations, delusional thinking) or manic symptoms reported in children and adolescents receiving stimulants for management of ADHD. (See Warnings under Cautions.)

Sudden death reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of stimulants. (See Sudden Death and Serious Cardiovascular Events under Cautions.)

Long-term administration expected to cause at least a temporary suppression of normal weight and/or height patterns in some children and adolescents. (See Growth Suppression under Cautions.)

Common Adverse Effects

Nervous system (insomnia, delayed sleep onset, headache, nervousness, jitteriness, social withdrawal, anxiety, restlessness, affect lability, agitation, irritability, dizziness, vertigo, tremor), cardiovascular (increased BP, increased heart rate, tachycardia, palpitations), GI (decreased appetite/anorexia, nausea, abdominal pain, dyspepsia, dry mouth, vomiting), and other (weight loss, blurred vision, hyperhidrosis, pyrexia, tics) effects.

Interactions for Methylphenidate

Not metabolized by CYP isoenzymes; does not inhibit CYP isoenzymes.

Specific Drugs

Methylphenidate Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration. Low oral bioavailability (10–52%) suggests substantial first-pass metabolism.

Oral solution and chewable tablets are bioequivalent to conventional tablets.

Extended-release tablets are absorbed more slowly but to the same extent as conventional tablets.

Relative bioavailability of Ritalin LA extended-release capsules given once daily is similar to that of conventional tablets administered at the same total daily dosage in 2 divided doses given 4 hours apart.

Peak plasma concentrations and AUC were slightly lower for Metadate CD extended-release capsules (20 mg once daily) than for conventional tablets (10 mg twice daily).

Relative bioavailability of Aptensio XR extended-release capsules given once daily is comparable to that of conventional tablets administered 3 times daily.

Relative bioavailability of the extended-release oral suspension (single 60-mg dose) is 95% that of immediate-release oral solution (given as two 30-mg doses 6 hours apart).

Relative bioavailability of extended-release trilayer core tablets administered at a dosage of 18 mg once daily is similar to that of conventional tablets administered at a dosage of 5 mg 3 times daily (given every 4 hours).

Alcohol increases the rate of drug release in vitro from the extended-release capsules but not from extended-release trilayer core tablets (Concerta); 98 or 84% of the drug was released from Ritalin LA 40-mg or Metadate CD 60-mg capsules within the first hour at an alcohol concentration of 40%, and 96% was released from Aptensio XR 80-mg capsules within 2 hours at an alcohol concentration up to 40%. Results are considered representative for available strengths of the respective preparations.

For timing of peak plasma concentrations for oral formulations, see Table 4.

Peak plasma methylphenidate concentrations for transdermal systems are attained in about 10 hours (single-dose application) or 8 hours (repeated applications of systems worn for up to 9 hours). Average lag of 2 hours until d-methylphenidate is detectable in plasma after single-dose application; with repeated administration, low concentrations of the drug are detected earlier because of carryover effect.

When applied to inflamed skin, time to peak plasma concentrations decreases (to 4 hours) and peak plasma concentration and AUC increase by threefold compared with application to intact skin. When heat is applied to transdermal system after application, peak plasma concentration occurs 0.5 hour earlier, and median peak plasma concentration and AUC are 2-fold and 2.5-fold higher, respectively, compared to application without heat.

Possible increased transdermal absorption following repeated administration. Steady state likely to be achieved by approximately day 14 of dosing.

Because of substantially greater first-pass metabolism following oral compared with transdermal administration, a lower transdermal dose of methylphenidate may result in greater systemic exposure to d-methylphenidate than a higher (on a mg/kg basis) oral dose of the drug. Little, if any, l-methylphenidate is systemically available following oral administration; however, systemic exposure to l-methylphenidate following transdermal administration is almost as great as that to d-methylphenidate.

Duration

Effects persist for 3–6 hours for conventional tablets, about 3–8 hours for extended-release tablets, and about 8–12 hours for extended-release trilayer core tablets, extended-release capsules, and extended-release oral suspension.

Food

Chewable tablets: Administration with high-fat meal delays time to peak plasma concentration by approximately 1 hour and increases AUC by about 20%; magnitude of food effect is comparable to that observed with conventional tablets.

Oral solution: Administration with high-fat meal delays time to peak plasma concentration by approximately 1 hour and increases peak plasma concentration and AUC by about 13 and 25%, respectively.

Extended-release oral suspension: Administration with high-fat meal reduces time to peak concentration by approximately 1 hour and increases peak plasma concentration and AUC by approximately 28 and 19%, respectively; not considered clinically important.

Extended-release capsules (Aptensio XR, Ritalin LA, Metadate CD): High-fat meal may alter absorption characteristics; opening the capsules and sprinkling the contents on applesauce does not alter bioavailability.

Extended-release trilayer core tablets: High-fat meal does not alter pharmacokinetics.

Distribution

Extent

Extent of distribution in humans is unknown.

Plasma Protein Binding

About 10–33%.

Elimination

Metabolism

Metabolized primarily by de-esterification by carboxylesterase 1A1 to form d-ritalinic acid, which has little or no pharmacologic activity.

Elimination Route

Excreted as metabolites (principally as ritalinic acid), mostly in urine and a small amount in feces.

Clearance increases with increasing weight; thus, patients with higher body weight may have lower exposures to total methylphenidate at similar doses.

Half-life

For methylphenidate elimination half-lives reported for various methylphenidate formulations, see Table 5.

Stability

Storage

Oral

Conventional, Chewable, and Extended-release Tablets

Room temperature, generally 20–25°C; consult manufacturer's labeling for specific recommendation. Protect from moisture.

Extended-release Capsules

Room temperature, generally 20–25°C; consult manufacturer's labeling for specific recommendation.

Extended-release Trilayer Core Tablets

25°C (may be exposed to 15–30°C). Protect from moisture.

Solution

20–25°C.

Powder for Suspension

25°C (may be exposed to 15–30°C).

Following reconstitution, 25°C (may be exposed to 15–30°C) in original container for up to 4 months.

Topical

Transdermal System

25°C (may be exposed to 15–30°C). Use all the systems in a tray within 2 months of opening the tray. Apply the system to the skin immediately after removal from the individually sealed package. Do not freeze or refrigerate.

Actions

• Appears to block norepinephrine and dopamine reuptake into the presynaptic neuron and increases their release into the extraneuronal space. Mechanism of action involved in the central effect not determined.

• Pharmacologic actions include CNS stimulation (e.g., increased motor activity, mental alertness, diminished sense of fatigue, brighter spirits, mild euphoria), respiratory stimulation, and weak sympathomimetic activity; also produces an anorexigenic effect.

• At usual therapeutic dosages, exhibits only moderate effects on the peripheral circulatory system.

• Racemic mixture; the d-enantiomer is the more pharmacologically active enantiomer.

• No clinically important changes in corrected QT (QT_c) interval observed in healthy individuals following 40-mg dose of extended-release dexmethylphenidate hydrochloride (the more active enantiomer).

Advice to Patients

• Provide patient or caregiver with a copy of the manufacturer’s patient information (medication guide); discuss and answer questions about its contents as needed. Instruct patient or caregiver to read and understand contents of medication guide before initiating therapy and each time the prescription is refilled.

• Importance of administering the last daily dose of conventional tablets or oral solution before 6 p.m.

• In patients receiving chewable tablets, importance of administering with a full glass (i.e., ≥240 mL [8 ounces]) of water or other fluid to avoid choking. Importance of seeking immediate medical attention if chest pain, vomiting, or difficulty in swallowing or breathing occurs following administration.

• Importance of not crushing or chewing extended-release tablets, extended-release capsules, or extended-release trilayer core tablets. Capsules may be opened and the contents sprinkled on applesauce.

• In patients receiving extended-release capsules, importance of not consuming alcohol, since alcohol may result in more rapid release of the drug dose.

• In patients receiving extended-release oral suspension, importance of instructing patients and/or their caregivers on proper use of the dosing dispenser for administration. Provide patient and/or caregiver with a copy of the manufacturer's instructions for administration.

• Importance of instructing patients and/or their caregivers regarding application and removal of the transdermal system (see Transdermal Administration under Dosage and Administration). Importance of not touching the adhesive layer during application to avoid absorption of the drug; if contact occurs, wash hands immediately after application.

• Inform male patients and their caregivers about the signs and symptoms of priapism, stressing the need for immediate medical treatment if it occurs. Younger males, especially prepubertal males, may not recognize the problem or may be embarrassed to tell anyone if it occurs.

• Inform patients about the risk of peripheral vascular disorders, including Raynaud's phenomenon, and the associated signs and symptoms (e.g., feelings of numbness, coolness, or pain in fingers or toes; changes in color from pale to blue to red). Advise patients to report any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes and to immediately contact their clinician if any signs of unexplained wounds appear on fingers or toes; further clinical evaluation may be appropriate.

• Importance of monitoring for changes in skin color (depigmentation, hypopigmentation) while receiving transdermal methylphenidate and informing clinician if such changes occur.

• In patients receiving transdermal therapy, importance of not exposing the application site to direct external heat sources (e.g., hair dryers, heating pads, electric blankets, heated water beds) while wearing the system.

• Possibility of dermatologic reactions in patients receiving transdermal therapy; importance of discontinuing use and contacting clinician if swelling or blistering occurs.

• Importance of informing patients and/or caregivers that methylphenidate is a drug of potential abuse and should be protected from theft or misuse. Importance of properly disposing of the drug when no longer needed.

• Importance of informing clinicians immediately of adverse cardiovascular (e.g., chest pain, shortness of breath, fainting) or psychiatric effects (e.g., hallucinations, delusional thinking, mania). Inform patient that the drug can increase BP and pulse rate.

• Importance of taking the drug only as prescribed; importance of not increasing the dosage unless otherwise instructed by a clinician.

• Potential for stimulants to impair ability to perform potentially hazardous tasks; use caution when driving or operating machinery until effects on individual are known.

• In patients receiving extended-release trilayer core tablets, presence of tablet-like substance in stool is not cause for concern.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products, as well as any concomitant illnesses/conditions (e.g., glaucoma, cardiac/cardiovascular disease, mental/psychiatric disorder, seizures, suicidal ideation or behaviors, history of substance abuse).

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule II (C-II) drug.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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