Methylphenidate Hcl Er (Cd) (methylphenidate HCl)

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

Methylphenidate is a piperidine-derivative CNS stimulant. The pharmacologic action of the CNS stimulant effects involved in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy has not been fully elucidated, but is thought to be related to the blockade of norepinephrine and dopamine reuptake into presynaptic neurons and the increased release of norepinephrine and dopamine into the extraneuronal space. Methylphenidate is a racemic mixture of the d- and l-threo enantiomers.

The d-threo enantiomer exhibits more pharmacologic activity than the l-threo enantiomer.

Methylphenidate hydrochloride is commercially available as conventional tablets, chewable tablets, and an oral solution formulated for immediate release of the drug; extended-release tablets and extended-release capsules (Ritalin(R) LA; generics) with an intermediate duration of action; longer-acting, extended-release capsules (Aptensio XR(R); generics), extended-release trilayer core tablets (e.g., Concerta(R); generics), extended-release bilayer core tablets (e.g., Relexxii(R)), extended-release orally disintegrating tablets (Cotempla XR-ODT(R)), extended-release chewable tablets (QuilliChew ER(R)), and a powder for oral suspension formulated for extended release of the drug (Quillivant ER(R); generics); and delayed- and extended-release capsules (Jornay PM(R)), which have delayed-release and extended-release properties, with a longer duration of action following an initial release of not more than 5% of the total drug within the first 10 hours. Methylphenidate is commercially available as a transdermal system.

Various formulations of methylphenidate hydrochloride extended-release capsules are commercially available. Some methylphenidate hydrochloride extended-release capsules (methylphenidate hydrochloride CD) contain 30% of the dose in immediate-release beads and 70% of the dose in extended-release beads that slowly release methylphenidate, and some (e.g., Ritalin(R) LA) contain the drug in equal amounts in immediate- and extended-release beads. Other extended-release capsules (e.g., Aptensio XR(R)) contain multilayered beads that are composed of an immediate-release layer containing approximately 40% of the dose and an extended-release layer containing approximately 60% of the dose.

Extended-release trilayer (Concerta(R); generics) and bilayer (Relexxii(R)) core tablets of methylphenidate hydrochloride contain the drug in an oral osmotic delivery system formulation. The Concerta(R) osmotic delivery system consists of an osmotically active trilayer core (comprised of two layers containing the drug and a push layer containing osmotically active components) surrounded by a semipermeable membrane with an immediate-release drug overcoat and a laser-drilled delivery orifice. The Relexxi(R) osmotic delivery system consists of an osmotically active bilayer core (comprised of one layer of the drug and excipients, and a push layer containing osmotically active components) surrounded by a semipermeable membrane with an immediate-release drug overcoat and a laser-drilled delivery orifice.

When exposed to water in the GI tract, the drug overcoat is solubilized providing an initial dose of methylphenidate; as water enters the formulation, the osmotic layer expands and the drug is pushed out the delivery orifice of the membrane into the GI tract at a controlled rate. The inert tablet ingredients remain intact and are eliminated in feces.

Methylphenidate hydrochloride extended-release orally disintegrating tablets (Cotempla XR-ODT(R)) contain approximately 25% immediate-release and 75% extended-release methylphenidate hydrochloride.

Methylphenidate hydrochloride extended-release chewable tablets (QuilliChew ER(R)) contain approximately 30% immediate-release and 70% extended-release methylphenidate. Although dosage strength is expressed in terms of methylphenidate hydrochloride equivalents, only about 15% of the drug contained in the formulation is present as the hydrochloride salt with the remainder present as methylphenidate ionically bound to the sulfonate groups of sodium polystyrene sulfonate particles.

Methylphenidate hydrochloride delayed- and extended-release capsules (Jornay PM(R)) contain beads with 2 functional coatings (an outer delayed-release film coating designed to dissolve at pH exceeding 7 and an inner extended-release coating) surrounding a drug-containing core. The outer coating delays the initial release of methylphenidate, while the inner coating controls release of the drug throughout the day.

The powder for extended-release oral suspension contains approximately 20% immediate-release and 80% extended-release methylphenidate hydrochloride.

Methylphenidate transdermal system consists of a laminate film backing layer, an adhesive layer containing the drug, and a protective liner, which must be removed prior to application, that is attached to the adhesive surface. The methylphenidate dosage delivered is dependent on the size of the transdermal system and the length of time the system is worn.

Methylphenidate hydrochloride appears to be well absorbed from the GI tract; however, oral bioavailability of the drug is low (about 30%; range: 10-52%), which suggests substantial first-pass metabolism. 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 (the more pharmacologically active isomer) than a higher (on a mg/kg basis) oral dose of the drug. Following repeated transdermal administration of methylphenidate, l-methylphenidate is systemically available; on average, systemic exposure to l-methylphenidate is 27-45% less than exposure to d-methylphenidate.

Little, if any, l-methylphenidate is systemically available following oral administration of the drug.

While exposure to the drug may be higher in children than in adults following oral administration of equivalent dosages, the pharmacokinetic profile of methylphenidate in pediatric patients and adults generally is similar following adjustment for differences in body weight.

Following oral administration of methylphenidate hydrochloride as conventional tablets, oral solution, or chewable tablets (immediate-release formulations (Ritalin(R), Methylin(R))), peak plasma concentrations were attained at approximately 1-2 hours. The oral solution and chewable tablets are bioequivalent to the conventional tablets. Effects persist for approximately 3-4 hours after oral administration of immediate-release preparations of methylphenidate hydrochloride.

In adults, administration of methylphenidate hydrochloride 20 mg as an oral solution with a high-fat meal delayed the peak plasma concentration by approximately 1 hour and increased the average peak plasma concentration and AUC for methylphenidate by 13 and 25%, respectively; the magnitude of increase in peak plasma concentration and AUC is similar between methylphenidate hydrochloride oral solution and conventional tablets. Administration of methylphenidate hydrochloride 20 mg as chewable tablets with a high-fat meal in adults delayed the time to peak plasma concentration by approximately 1 hour and increased the AUC by about 20%; the magnitude of food effect is comparable to that observed with conventional tablets.

Extended-release methylphenidate hydrochloride tablets are absorbed more slowly but to the same extent as the conventional tablets. Following oral administration of the extended-release tablets in children, peak plasma concentrations were attained at 4.7 hours. Effects persist for about 8 hours after oral administration of the extended-release tablets.

Following oral administration of a single 40-mg dose of methylphenidate hydrochloride as extended-release chewable tablets (QuilliChew ER(R)) in the fasted state, peak plasma concentrations were achieved at a median of 5 hours. Peak concentrations and AUC achieved following a single 40-mg dose as extended-release chewable tablets were about 20 and 11% lower, respectively, than values achieved following oral administration of an equivalent dosage of an immediate-release chewable tablet (two 20-mg doses given 6 hours apart). Effects persist for about 8-12 hours after oral administration of the extended-release chewable tablets.

Administration of the extended-release chewable tablets (single 40-mg dose) with a high-fat meal had no effect on the time to peak concentration, and increased the peak concentration and AUC by about 20% and 4%, respectively. In vitro studies evaluating the effect of alcohol on the release of methylphenidate hydrochloride indicated that about 90% of the drug was released from the 40-mg extended-release chewable tablets within the first half hour at an alcohol concentration of 40%; the manufacturer states that these results are representative for the available strengths of this preparation.

In adults, the relative bioavailability of the extended-release trilayer (Concerta(R)) and bilayer (Relexxii(R)) core tablets of methylphenidate hydrochloride administered once daily are comparable to that of the conventional tablets administered 3 times daily. Following oral administration of a single 18-mg dose of the extended-release trilayer core tablets (Concerta(R)) of methylphenidate hydrochloride in healthy adults, an initial peak plasma concentration was attained within 1 hour while peak plasma concentrations of about 3.7 ng/mL were achieved at approximately 7 hours. Following oral administration of the extended-release bilayer core tablets (Relexxii(R)), an initial peak plasma concentration was attained in about 1.5 hours, with peak plasma concentrations achieved after a mean of 5.5 hours.

No substantial accumulation is observed with repeated once-daily administration of extended-release trilayer or bilayer tablets over the dose range of 18-144 mg. Effects persist for about 10-12 hours after oral administration of the extended-release trilayer core tablets (Concerta(R)). The duration of action of extended-release bilayer core tablets (Relexxii(R)) is approximately 8-12 hours.

Administration of the extended-release trilayer or bilayer core tablets with a high-fat meal does not alter pharmacokinetics or pharmacodynamics of this preparation of methylphenidate hydrochloride. In vitro studies evaluating the effect of alcohol on the release of methylphenidate hydrochloride indicated no increase in the amount of drug released from the 18-mg extended-release trilayer core tablet (Concerta(R)) within the first hour at an alcohol concentration of up to 40%; the manufacturer states that these results are representative for the available strengths of this preparation. No increase in the amount of drug released from extended-release bilayer core tablets (Relexxii(R)) was observed within the first 2 hours at alcohol concentrations of up to 40%.

Following oral administration of a single 51.8-mg dose of methylphenidate (equivalent to 60 mg of methylphenidate hydrochloride) given as two 25.9-mg extended-release orally disintegrating tablets (Cotempla XR-ODT(R)) under fasted conditions in healthy adults, peak concentrations were achieved at a median of 5 hours; peak concentration and AUC were about 26 and 6% higher, respectively, with the extended-release orally disintegrating tablets than with a 60-mg extended-release capsule formulation of methylphenidate hydrochloride. Effects persist for approximately 12 hours after oral administration of the extended-release orally disintegrating tablets. Administration of the extended-release orally disintegrating tablets with a high-fat meal decreased peak concentration by approximately 24%, increased AUC by approximately 16%, and decreased the time to peak concentration by about 30 minutes (from 5 hours in the fasted state to 4.5 hours in the fed state).

In vitro studies evaluating the effect of alcohol on the release of methylphenidate indicated the potential for increased drug release in the presence of 40% alcohol but not at lower alcohol concentrations.

Following oral administration of a single 60-mg dose of methylphenidate hydrochloride as extended-release oral suspension (Quillivant XR(R)) in the fasted state in healthy adults, peak plasma concentrations of d-methylphenidate (the more pharmacologically active isomer of the drug) were achieved at a median of 5 hours; bioavailability of the extended-release oral suspension (single 60-mg dose) relative to that of an immediate-release oral solution (given as two 30-mg doses 6 hours apart) was 95%. Effects persist for about 10-12 hours after oral administration of the extended-release oral suspension. Administration of the extended-release oral suspension (60-mg dose) with a high-fat meal in adults reduced the time to peak concentration of the drug by approximately 1 hour; peak plasma concentration and AUC were increased by approximately 28 and 19%, respectively, but these effects were not considered clinically important.

In vitro studies evaluating the effect of alcohol on the release of methylphenidate hydrochloride indicated no increase in the amount of drug released from the extended-release oral suspension at an alcohol concentration of 5 or 10%; at an alcohol concentration of 20%, drug exposure was increased, on average, by 20%.

Following oral administration of a single 20-mg dose of methylphenidate extended-release capsules (Ritalin(R) LA) in children or adults, peak plasma concentrations of the drug are attained at 2 hours and again at 5.5-6.6 hours after a dose. The relative bioavailability of Ritalin(R) LA extended-release capsules administered once daily is comparable to that of the conventional tablets administered twice daily 4 hours apart. The initial rate of absorption of methylphenidate hydrochloride and the time to first and second peak plasma concentrations were similar following administration of 40 mg of the drug once daily as the extended-release capsules or 20 mg twice daily (given 4 hours apart) as conventional tablets, but greater interindividual variability and a smaller difference between peak and trough plasma concentrations (resulting from a lower second peak concentration and a higher minimum concentration between the 2 peak concentrations) were observed with the extended-release capsules.

Effects persist for about 6-8 hours after oral administration of Ritalin(R) LA extended-release capsules. In a single-dose study in healthy adults, administration of Ritalin(R) LA extended-release capsules with a high-fat breakfast delayed the first and second peak plasma concentrations and decreased the second mean peak plasma concentration by 25% compared with administration in the fasting state. The bioavailability of the extended-release capsules was not affected by opening the capsules and sprinkling the contents onto applesauce.

In vitro studies evaluating the effect of alcohol on the release of methylphenidate hydrochloride indicated that 98% of the drug was released from Ritalin(R) LA 40-mg extended-release capsules within the first hour at an alcohol concentration of 40%; the manufacturer states that these results are representative for the available strengths of this preparation.

After oral administration of methylphenidate hydrochloride 20 or 40 mg as methylphenidate hydrochloride CD extended-release capsules (generic equivalents of Metadate(R) CD) in children, peak plasma concentrations were attained at 1.5 hours and again at 4.5 hours after a dose. In children, the mean peak plasma concentration and AUC for methylphenidate were slightly lower following administration of 20 mg of the drug once daily as the extended-release capsules than following administration of 10 mg twice daily as conventional tablets. Effects persist for about 6-8 hours after oral administration of methylphenidate hydrochloride CD extended-release capsules.

Administration of methylphenidate hydrochloride CD extended-release capsules (40-mg dose) with a high-fat meal in adults delayed the first peak plasma concentration by approximately 1 hour and increased the average peak plasma concentration and AUC for methylphenidate by 30 and 17%, respectively. The bioavailability was not affected by opening the capsules and sprinkling the contents onto applesauce. In vitro studies evaluating the effect of alcohol on the release of methylphenidate hydrochloride indicated that 84% of the drug was released from methylphenidate hydrochloride CD 60 mg extended-release capsules within the first hour at an alcohol concentration of 40%; the manufacturer states that these results are representative for the available strengths of this preparation.

Following oral administration of methylphenidate extended-release capsules (Aptensio XR(R)) in adults, peak plasma methylphenidate concentrations were attained at approximately 2 hours and again at approximately 8 hours after a dose. In adults, the relative bioavailability of Aptensio XR(R) extended-release capsules administered once daily is comparable to that of the conventional tablets administered 3 times daily. Effects persist for about 12 hours after oral administration of Aptensio XR(R) extended-release capsules.

Administration of Aptensio XR(R) extended-release capsules with a high-fat meal decreased the second peak plasma concentration, increased the average peak concentration by about 28%, and increased AUC by about 19%; in clinical trials, this formulation of the drug was administered without regard to meals. The bioavailability was not affected by opening the capsules and sprinkling the contents onto applesauce. In vitro studies evaluating the effect of alcohol on the release of methylphenidate hydrochloride indicated that 96% of the drug was released from Aptensio XR(R) 80 mg extended-release capsules within 2 hours at an alcohol concentration of up to 40%.

The manufacturer states that these results are representative for the available strengths of this preparation.

Following nighttime (9 p.m.) oral administration of methylphenidate delayed- and extended-release capsules (Jornay PM(R)) in adults, no more than 5% of the total dose is available within the first 10 hours; a single peak concentration occurs at a median of 14 hours following administration, followed by gradual decline in concentrations throughout the rest of the day. The relative bioavailability of the delayed- and extended-release capsules administered once daily is approximately 74% that of an immediate-release formulation administered in 3 divided doses daily. Following an initial delay in absorption of approximately 8-10 hours, effects persist for approximately 10-12 hours.

Administration of the delayed- and extended-release capsules at night with a high-fat meal decreased the mean peak concentration by 14% compared with administration in the fasted state and delayed the peak concentration by approximately 2.5 hours, but did not alter the extent of absorption. Following administration of the drug at night, a morning meal had no effect on the pharmacokinetics. The pharmacokinetic parameters are not affected by opening the capsules and sprinkling the contents onto applesauce.

In vitro studies evaluating the effect of alcohol on the release of methylphenidate hydrochloride indicated that 97% of the drug was released from the delayed- and extended-release capsules within 2 hours at an alcohol concentration of 40%; increased release of the drug was not observed at alcohol concentrations of 5-20%.

Systemic absorption of methylphenidate from transdermal systems (Daytrana(R)) is a function of both the length of time the system is worn and the size of the system. In patients with ADHD, peak plasma concentrations of methylphenidate are achieved about 10 hours after single-dose transdermal application and 8 hours after repeated applications of transdermal systems worn for up to 9 hours. Following single-dose transdermal application in children and adolescents, there was an average delay of 2 hours before d-methylphenidate was detectable in the circulation; with repeated administration, low concentrations of the drug were detected earlier after application because of a carry-over effect.

Application of the transdermal system to inflamed skin results in shorter time to peak plasma concentration (4 hours) and a threefold increase in peak plasma concentration and AUC compared with application to intact skin. When heat is applied to the transdermal system after application, time to peak plasma concentration occurs 0.5 hour earlier, and median peak plasma concentration and AUC are twofold and 2.5-fold higher, respectively, than those observed following application without heat. Application sites other than the hip can have different absorption characteristics and have not been adequately studied.

Some data suggest that transdermal absorption of methylphenidate may be increased with repeated administration; on average, steady state is likely to be achieved by approximately day 14 of dosing.

Methylphenidate is about 10-33% bound to plasma proteins. Methylphenidate is metabolized primarily by de-esterification by carboxylesterase 1A1 to form alpha-phenylpiperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity. Some data indicate that clearance of methylphenidate increases with increasing weight, suggesting that patients with higher body weight may have lower exposures to total methylphenidate at similar doses.

Following oral administration of methylphenidate hydrochloride conventional tablets in adults or children, the mean terminal elimination half-life was reported to be 3.5 or 2.5 hours, respectively. The mean terminal elimination half-life following oral administration of methylphenidate hydrochloride as an oral solution in adults is similar to that following administration of conventional tablets. The mean terminal half-life following oral administration of methylphenidate hydrochloride 20 mg as chewable tablets in adults is 3 hours, which is comparable to that following administration of conventional tablets.

Following oral administration of methylphenidate hydrochloride conventional (5 mg 3 times daily) or extended-release trilayer core tablets (Concerta(R)) (18 mg once daily) in adults, the plasma elimination half-life reportedly is 3 or 3.5 hours, respectively.

Following oral administration of a single 60-mg dose of methylphenidate hydrochloride as an extended-release oral suspension (Quillivant XR(R)), the mean terminal elimination half-life of d-methylphenidate was 5.6 hours in healthy adults. Following oral administration of a single 40-mg dose of extended-release chewable tablets (QuilliChew ER(R)) in healthy individuals, the mean terminal elimination half-life of methylphenidate was about 5.2 hours. Following a single methylphenidate dose of 51.8 mg as extended-release orally disintegrating tablets (Cotempla XR-ODT(R)) in healthy individuals, the mean terminal elimination half-life of methylphenidate was about 4 hours.

The mean half-life of methylphenidate following oral administration as Ritalin(R) LA extended-release capsules was 2.5 hours in children and 3.5 hours in adults. Following oral administration of a single 20-mg dose of methylphenidate hydrochloride CD extended-release capsules in adults, the mean terminal half-life of the drug was reported to be 6.8 hours. Following oral administration of a single 80-mg dose of methylphenidate hydrochloride as Aptensio XR(R) extended release-capsules in adults, the half-life was 5 hours.

Following oral administration of methylphenidate hydrochloride delayed- and extended-release capsules (Jornay PM(R)) in adults, the apparent half-life of methylphenidate was approximately 5.9 hours. Following oral administration of extended-release trilayer and bilayer core tablets of methylphenidate hydrochloride in adults and adolescents, the elimination half-life of methylphenidate was approximately 3.5 hours. The mean elimination half-life of methylphenidate following removal of the transdermal system in children and adolescents 6-17 years of age was approximately 4-5 hours for d-methylphenidate and 1.4-2.9 hours for l-methylphenidate.

Following oral administration of methylphenidate hydrochloride as conventional tablets, 78-97% of the dose is excreted in the urine and 1-3% as metabolites in feces within 48-96 hours.

Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since <1% of a radiolabeled dose of the drug is excreted in urine as unchanged drug and the major metabolite (ritalinic acid) has little or no pharmacologic activity. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since the main metabolic pathway involves de-esterification by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.

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+.

Generic name: methylphenidate HCl
Pronunciation: (METH-il-FEN-i-date)

The following indications are listed for Methylphenidate Hcl Er (Cd):

• Attention-Deficit Hyperactivity Disorder

Also known as: Add With Hyperactivity.

No ICD codes are available for this drug.