Ritalin

• The first ADHD medication used since 1950s

* Comes in 3 preparations

• Immediate release [IR] (lasting ~2-4 hours)

• Sustained release [SR] (~4-6 hours, seldom used)

• Long acting [LA] (~8 hours)

* Advantage of Ritalin LA versus Concerta is this may be opened and sprinkled on food

* Many times, the IR form will be used as a bridge for kids to get them through evenings and homework

Ritalin Dosing

• IR comes in 5 mg, 10 mg, 20 mg tabs

* Often patients will take every 4 hours if just using IR form

* Younger Children often do better with smaller  amounts of IR medication if they cannot tolerate a  long-acting medication

• LA comes in 20 mg, 30 mg, 40 mg capsules

• Start low, generally do not exceed ~2 mg/kg/day

Stimulant and Related Medications: U.S. Food and Drug Administration-Approved Indications and Dosages for Use in Pediatric Patients

The therapeutic dosing recommendations for stimulant and related medications are based on U.S. Food and Drug Administration (FDA)-approved product labeling. Nevertheless, the dosing regimen is adjusted according to a patient’s individual response to pharmacotherapy. The FDA-approved dosages and indications for the use of stimulant and related medications in adults are provided in this table. All medication doses listed are for oral administration. Information on the generic availability of the stimulant and related medications can be found by searching the Electronic Orange Book at https://www.accessdata.fda.gov/scripts/cder/ob/default.cfm on the FDA website.

Medication Indication Age or Weight Dosing Information      Other Information       Generic Availability

methylphenidate ER (Ritalin LA®)†[20] 

ADHD 6 to 12 years

old Initial dose: 20 mg once a day; Maximum dose: 60 mg once a day in the morning.   

 May initiate treatment with 10 mg once a day based on clinical judgment; may increase daily dose by 10 mg at weekly intervals.                   

Yes

DESCRIPTION

Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is an extended-release

formulation of methylphenidate with a bi-modal release profile. Ritalin LA® uses the proprietary SODAS® (Spheroidal Oral Drug Absorption System) technology. Each bead-filled Ritalin LA capsule contains half the dose as immediate-release beads and half as enteric-coated, delayed-release beads, thus providing an immediate release of methylphenidate and a second delayed release of methylphenidate. Ritalin LA 10, 20, 30, and 40 mg capsules provide in a single dose the same amount of methylphenidate as dosages of 5, 10, 15, or 20 mg of Ritalin® tablets given b.i.d. 

CLINICAL PHARMACOLOGY

Pharmacodynamics

Methylphenidate hydrochloride, the active ingredient in Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, is a central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) 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. Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. 

Pharmacokinetics Absorption

Ritalin LA produces a bi-modal plasma concentration-time profile (i.e., two distinct peaks approximately four hours apart) when orally administered to children diagnosed with ADHD and to healthy adults. The initial rate of absorption for Ritalin LA is similar to that of Ritalin tablets as shown by the similar rate parameters between the two formulations, i.e., initial lag time (Tlag), first peak concentration (Cmax1), and time to the first peak (Tmax1), which is reached in 1-3 hours. The mean time to the interpeak minimum (Tminip), and time to the second peak (Tmax2) are also similar for Ritalin LA given once daily and Ritalin tablets given in two doses 4 hours apart (see Figure 1 and Table 1), although the ranges observed are greater for Ritalin LA.

Ritalin LA given once daily exhibits a lower second peak concentration (Cmax2), higher interpeak minimum concentrations (Cminip), and less peak and trough fluctuations than Ritalin tablets given in two doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1 and Table 1).

The relative bioavailability of Ritalin LA given once daily is comparable to the same total dose of Ritalin tablets given in two doses 4 hours apart in both children and in adults

Dose Proportionality

After oral administration of Ritalin LA 20 mg and 40 mg capsules to adults there is a slight upward trend in the methylphenidate area under the curve (AUC) and peak plasma concentrations (Cmax1 and Cmax2).

Elimination

In studies with Ritalin LA and Ritalin tablets in adults, methylphenidate from Ritalin tablets is eliminated from plasma with an average half-life of about 3.5 hours, (range 1.3 - 7.7 hours). In children the average half-life is about 2.5 hours, with a range of about 1.5 - 5.0 hours. The rapid halflife in both children and adults may result in unmeasurable concentrations between the morning and Reference ID: 2863882  mid-day doses with Ritalin tablets. No accumulation of methylphenidate is expected following multiple once a day oral dosing with Ritalin LA. The half-life of ritalinic acid is about 3-4 hours.

The systemic clearance is 0.40±0.12 L/h/kg for d-methylphenidate and 0.73±0.28 L/h/kg for lmethylphenidate. After oral administration of an immediate release formulation of methylphenidate, 78%-97% of the dose is excreted in the urine and 1%-3% in the feces in the form of metabolites within 48-96 hours. Only small quantities (

Food Effects

Administration times relative to meals and meal composition may need to be individually titrated. When Ritalin LA was administered with a high fat breakfast to adults, Ritalin LA had a longer lag time until absorption began and variable delays in the time until the first peak concentration, the time until the interpeak minimum, and the time until the second peak. The first peak concentration and the extent of absorption were unchanged after food relative to the fasting state, although the second peak was approximately 25% lower. The effect of a high fat lunch was not examined.

There were no differences in the pharmacokinetics of Ritalin LA when administered with applesauce, compared to administration in the fasting condition. There is no evidence of dose dumping in the presence or absence of food.

For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered (see DOSAGE AND ADMINISTRATION).

Special Populations

Age: The pharmacokinetics of Ritalin LA was examined in 18 children with ADHD between 7 and 12 years of age. Fifteen of these children were between 10 and 12 years of age. The time until the between peak minimum, and the time until the second peak were delayed and more variable in children compared to adults. After a 20-mg dose of Ritalin LA, concentrations in children were approximately twice the concentrations observed in 18 to 35 year old adults. This higher exposure is almost completely due to the smaller body size and total volume of distribution in children, as apparent clearance normalized to body weight is independent of age.

Gender: There were no apparent gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults when administered Ritalin LA.

Renal Insufficiency: Ritalin LA has not been studied in renally-impaired patients. Renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity.

Hepatic Insufficiency: Ritalin LA has not been studied in patients with hepatic insufficiency. Hepatic insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body. 

INDICATIONS AND USAGE

Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).

The efficacy of Ritalin LA in the treatment of ADHD was established in one controlled trial of children aged 6 to 12 who met DSM-IV criteria for ADHD (see CLINICAL PHARMACOLOGY).

A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type,

at least six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; “on the go;” excessive talking; blurting answers; can’t wait turn; intrusive. The Combined Types requires both inattentive and hyperactive-impulsive criteria to be met. 

Need for Comprehensive Treatment Program

Ritalin LA is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial

intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician’s assessment of the chronicity and severity of the child’s symptoms.

Long-Term Use

The effectiveness of Ritalin LA for long-term use, i.e., for more than 2 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Ritalin LA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION). 

CONTRAINDICATIONS

Agitation

Ritalin LA® (methylphenidate hydrochloride) extended-release capsules is contraindicated in marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.

Hypersensitivity to Methylphenidate

Ritalin LA is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product.

Glaucoma

Ritalin LA is contraindicated in patients with glaucoma.

Tics

Ritalin LA is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome. (See ADVERSE REACTIONS.)

Monoamine Oxidase Inhibitors

Ritalin LA is contraindicated during treatment with monoamine oxidase inhibitors, and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor (hypertensive crises may result). 

Long-Term Suppression of Growth

Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm

less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development. In the double-blind placebo-controlled study of Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, the mean weight gain was greater for patients receiving placebo (+1.0 kg) than for patients receiving Ritalin LA (+0.1 kg). Published data are inadequate to determine whether chronic use of amphetamines may cause a similar suppression of growth, however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted. 

Use in Children Under Six Years of Age

Ritalin LA should not be used in children under six years of age, since safety and efficacy in this agegroup have not been established.

Drug Dependence

Ritalin LA should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use, since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up. 

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with methylphenidate and should counsel them in its appropriate use. A patient Medication Guide is available for Ritalin LA. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Drug Interactions

Methylphenidate is metabolized primarily by de-esterification (nonmicrosomal hydrolytic esterases) to ritalinic acid and not through oxidative pathways. The effects of gastrointestinal pH alterations on the absorption of methylphenidate from Ritalin LA have not been studied. Since the modified release characteristics of Ritalin LA are pH dependent, the coadministration of antacids or acid suppressants could alter the release of methylphenidate. 

Pregnancy Category C

In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 40 times the maximum recommended human dose (MRHD) on a mg/m2  basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the MRHD on a mg/m2

 basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (7 times the MRHD on a mg/m2  basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (2 times the MRHD on a mg/m2  basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (4 times the MRHD on a mg/m2  basis), but no other effects on postnatal development were observed. The no effect level for pre- and postnatal development in rats was 15 mg/kg/day (equal to the MRHD on a mg/m2  basis).

Adequate and well-controlled studies in pregnant women have not been conducted. Ritalin LA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Ritalin LA is administered to a nursing woman.

Pediatric Use

Long-term effects of methylphenidate in children have not been well established. Ritalin LA should not be used in children under six years of age (see WARNINGS).

In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (Postnatal Day 7) and continuing through sexual maturity (Postnatal Week 10). When these animals were tested as adults (Postnatal Weeks 13­ 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] on a

mg/m2  basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (12 times the MRHD on a mg/m2

 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2  basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

ADVERSE REACTIONS

The clinical program for Ritalin LA® (methylphenidate hydrochloride) extended-release capsules consisted of six studies: two controlled clinical studies conducted in children with ADHD aged 6-12 years and four clinical pharmacology studies conducted in healthy adult volunteers. These studies included a total of 256 subjects; 195 children with ADHD and 61 healthy adult volunteers. The subjects received Ritalin LA in doses of 10-40 mg per day. Safety of Ritalin LA was assessed by evaluating frequency and nature of adverse events, routine laboratory tests, vital signs, and body weight. 

Methylphenidate Basics

• Medication inhibits Norepinephrine and Dopamine transporters

• Short ½ life: 2-4 hours

* First developed in 1944, Ritalin has been used in ADHD  since the 1960s

* Due to the short half-life, an industry has arisen trying to  get the medication to last longer and be delivered more  evenly

Metadate

• Very similar to Ritalin

* Controlled Dosing [CD] usually lasts ~8 hours and is comparable to Ritalin LA

• Can be opened and sprinkled

• Often insurance companies will approve one or the other

* Extended Release [ER] is comparable to Ritalin SR

• Lasts 4-6 hours

• Seldom used