Drug Criteria & Outcomes: Methylphenidate: New formulations
Drug Criteria & Outcomes
Methylphenidate: New formulations
Prepared by Brenda Darling, PharmDScott & White Memorial Hospital
Temple, TX
Introduction
Methylphenidate hydrochloride compounds (Concerta, Methylin, and Metadate ER) are central nervous system (CNS) stimulants. Approval for Concerta 18 mg and 36 mg occurred in August 2000; the 54 mg dose was approved in December 2000. The U.S. Food and Drug Administration (FDA) approved Methylin 10 mg and 20 mg extended-release tablets in May 2000 and Metadate ER 10 mg tablet and Metadate ER 20 mg in October 1999. The newest addition to the methylphenidate "formulation family" is Metadate CD and was approved by the FDA in April 2001. These agents are used for the treatment of attention deficit/ hyperactivity disorder (ADHD) and narcolepsy.
Pharmacology
Methylphenidate is a mild central nervous system stimulant. The drug has similar pharmacological properties as the amphetamine CNS derivatives, with predominantly central activity and minimal effects on the cardiovascular system. Although the exact mechanism of action (MOA) is not known, methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. This MOA activates the brainstem arousal system, cortex, and subcortical structures, including the thalamus, to produce a significant stimulant effect. However, the specific mode of therapeutic action in ADHD is not known.
Pharmacokinetics
Concerta uses osmotic pressure to deliver methylphenidate HCl at a controlled rate. The system, which resembles a conventional tablet in appearance, comprises an osmotically active trilayer core surrounded by a semipermeable membrane with an immediate-release drug overcoat. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. There is a precision-laser-drilled orifice on the drug-layer end of the tablet.
In an aqueous environment, such as the gastrointestinal tract, the drug overcoat dissolves within one hour, providing an initial dose of methylphenidate. Water permeates through the membrane into the tablet core. As the osmotically active polymer excipients expand, methylphenidate is released through the orifice. The membrane controls the rate at which water enters the tablet core, which in turn controls drug delivery. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as a tablet shell along with insoluble core components.
Following oral administration of Concerta to adults, plasma methylphenidate concentrations increase rapidly, reaching an initial maximum at about 1-2 hours, then increasing gradually over the next several hours. Peak plasma concentrations are achieved at about 6-8 hours, after which a gradual decrease in plasma levels of methylphenidate begins.
No differences in the pharmacokinetics of Concerta were noted following single and repeated qd dosing, indicating no significant drug accumulation. The area under the curve (AUC) and t1/2 following repeated qd dosing are similar to those following the first dose of Concerta 18 mg.
Methylin in the ER tablets is more slowly but as extensively absorbed as the regular tablets. Relative bioavailability of the extended-release tablet compared to the immediate-release tablet, measured by the urinary excretion of methylphenidate major metabolite [(alpha)-phenyl-2-piperidine acetic acid] was 105% (range, 49-168%) in children and 101% (range, 85-152%) in adults. The time to peak rate in children was 4.7 hours (range, 1.3-8.2 hours) for the extended-release tablets and 1.9 hours (range, 0.3-4.4 hours) for the tablets. An average of 67% of the extended-release tablet dose was excreted in children as compared to 86% in adults.
Metadate ER in extended-release tablets is more slowly but as extensively absorbed as the regular tablets. Bioavailability of Metadate 20 mg ER tablets was compared to a sustained-release reference product and an immediate-release product. The extent of absorption for the three products was similar, and the rate of absorption of the two sustained-release products was not statistically different.
Based on rate of bioavailability (AUC0 to < infinity, Tmax, and Cmax), no significant statistical difference was found following single-dose administration, in fasting and fed adults, of two Metadate 10 mg ER tablets or one methylphenidate hydrochloride, USP sustained-release 20 mg tablet. The administration of the extended-release methylphenidate HCl, USP tablets with food resulted in a greater Cmax and AUC0 to < infinity than when administered in a fasting condition. Pharmacokinetic and statistical analyses for a multiple-dose study demonstrated that three times daily administration of two Metadate 10 mg ER tablets met the requirements for bioequivalence to one methylphenidate hydrochloride, USP sustained-release 20 mg tablet when administered every 8 hours. Pharmacokinetic parameters (i.e., AUC0 to < infinity, Tmax, Cmax, Cmin, and Cav) demonstrated achievement of steady state following three times daily administration of two Metadate 10 mg ER tablets was confirmed. (See Table 1)
Metadate CD is in the form of an extended-release Diffucap capsule containing 30% immediate-release beads and 70% extended-release beads. The dosage released from the immediate-release beads is 6 mg, and a dose of 14 mg is released from the extended-release bead formulation. Within the Diffucap bead-delivery system, one set of beads (immediate-release) consists of a neutral core upon which is layered a mixture of povidone and methylphenidate. The povidone serves as a binding agent for the active drug substance, methylphenidate. An aqueous protective coating is applied over the methylphenidate/ povidone layer. The second set of beads (extended-release) contains the same neutral core and layer of povidone/methylphenidate, but it also places an ethylcellulose coating on the top to act as another aqueous protective membrane.
Absorption of this new formulation is presented as a sharp, initial slope similar to a methylphenidate immediate-release tablet, and the second rising portion occurs approximately three hours later. The early peak concentration is reached approximately 1.5 hours after dose intake, and the second peak concentration is reached 4.5 hours after dose intake. The mean terminal half-life is 6.8 hours for Metadate CD, and the terminal half-life for methylphenidate hydrochloride immediate-release tablets and sustained-release tablets is 2.9 hours and 3.4 hours, respectively.
Indications
Concerta is indicated for the treatment of attention deficit/hyperactivity disorder.
Methylin is indicated as an integral part of a total treatment program that typically includes other remedial measures (psychological, educational, and social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity.
Metadate ER is indicated as an integral part of a total treatment program that typically includes other remedial measures (psychological, educational, and social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability and impulsivity.
Metadate CD is indicated for the treatment of attention deficit/hyperactivity disorder.
Efficacy and comparative efficacy
Concerta qd minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate tid. The relative bioavailability of Concerta qd and methylphenidate tid in adults is comparable.
Methylin in ER tablets is more slowly but as extensively absorbed as the regular tablets. Relative bioavailability of the extended-release tablet compared to the immediate-release tablet, measured by the urinary excretion of methylphenidate major metabolite [(alpha)-phenyl-2-piperidine acetic acid] was 105% (range, 49-168%) in children and 101% (range, 85-152%) in adults. The time to peak rate in children was 4.7 hours (range, 1.3-8.2 hours) for the extended-release tablets and 1.9 hours (range, 0.3-4.4 hours) for the tablets. An average of 67% of extended-release tablet dose was excreted in children as compared to 86% in adults.
Metadate ER in extended-release tablets is more slowly but as extensively absorbed as the regular tablets. Bioavailability of Metadate 20 mg ER tablets was compared to a sustained-release reference product and an immediate-release product. The extent of absorption for the three products was similar, and the rate of absorption of the two sustained-release products was not statistically different. Based on rate of bioavailability (AUC0 to < infinity, Tmax, and Cmax), no significant statistical difference was found following single-dose administration, in fasting and fed adults, of two Metadate 10 mg ER tablets, or one methylphenidate hydrochloride, USP sustained-release 20 mg tablet. The administration of the extended-release methylphenidate HCl, USP tablets with food, resulted in a greater Cmax and AUC0 to < infinity than when administered in a fasting condition. Pharmacokinetic and statistical analyses for a multiple-dose study demonstrated that three times daily administration of two Metadate 10 mg ER tablets met the requirements for bioequivalence to one methylphenidate hydrochloride, USP sustained-release 20 mg tablet when administered every 8 hours. Pharmacokinetic parameters (i.e., AUC0 to < infinity, Tmax, Cmax, Cmin, and Cav) demonstrated achievement of steady state following three times daily administration of two Metadate 10 mg ER tablets was confirmed.
Safety and adverse effects
In the four-week, placebo-controlled, parallel-group trial one Concerta-treated patient (0.9%; 1/106) and one placebo-treated patient (1.0%; 1/99) discontinued due to an adverse event (sadness and increase in tics, respectively). In uncontrolled Concerta studies lasting as long as 12 months, 6.6% (29/441) of patients discontinued for adverse events. Those events associated with discontinuation of Concerta in more than one patient included the following: twitching (tics, 1.8%); anorexia (loss of appetite, 0.9%); aggravation reaction (0.7%); hostility (0.7%); insomnia (0.7%); and somnolence (0.5%). Overall, headache occurred approximately in 14% of subjects; upper respiratory tract infection, stomachache, anorexia, insomnia, pharyngitis, increased cough, and dizziness occurred in 8-20% of subjects.
Nervousness and insomnia are the most common adverse reactions with Methylin and Metadate ER but usually are controlled by reducing the dosage and omitting the drug in the afternoon or evening. Other reactions include hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea; dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes (both up and down); tachycardia; angina; cardiac arrhythmia; abdominal pain; and weight loss during prolonged therapy. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently.
Metadate ER should not be prescribed for women of childbearing age unless, in the opinion of the physician, the potential benefits outweigh the possible risks.
The safety and efficacy of Concerta, Methylin, and Metadate ER in children younger than 6 years have not been established. Long-term effects of methylphenidate in children have not been well established.
Drug interactions
Concerta should be used cautiously with pressor agents. Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). Downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times) when initiating or discontinuing concomitant methylphenidate. Serious adverse events have been reported with concomitant use of clonidine, although no causality for the combination has been established. The safety of using methylphenidate in combination with clonidine or other centrally acting alpha-2 agonists has not been evaluated systematically.
Methylin and Metadate ER may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents and MAO inhibitors.
As with Concerta, Methylin and Metadate ER may demonstrate the same drug interactions listed above and caution should be taken to avoid serious adverse events.
Dosing and administration
Concerta is administered orally once daily in the morning with or without food. Concerta must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed. The recommended starting dose of Concerta for patients who are not currently taking methylphenidate, or for patients who are on stimulants other than methylphenidate is 18 mg once daily.
Dosage may be adjusted in 18 mg increments to a maximum of 54 mg/d taken once daily in the morning. In general, dosage adjustment may proceed at approximately weekly intervals. (See Table 2)
Methylin ER and Metadate ER:
Adults: Methylin ER and Metadate ER tablets have a duration of action of approximately 8 hours. Administer in divided doses 2-3 times daily, preferably 30-45 minutes before meals. Average dosage is 20-30 mg daily. Some patients may require 40-60 mg daily. In others, 10-15 mg daily will be adequate. Methylin ER and Metadate ER tablets must be swallowed whole and never crushed or chewed. In patients that have trouble sleeping, the last dose of Methylin or Metadate ER should be administered before 6 p.m.
Children (6 years and older): Methylin or Metadate ER should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is not recommended.
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