Methylphenidate Hydrochloride Extended-release Capsules

Pharmacodynamics

Methylphenidate HCl 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

The pharmacokinetics of the METADATE CD methylphenidate hydrochloride formulation have been studied in healthy adult volunteers and in children with Attention Deficit Hyperactivity Disorder (ADHD).

Absorption And Distribution

Methylphenidate is readily absorbed. METADATE CD has a plasma/time concentration profile showing two phases of drug release with a sharp, initial slope similar to a methylphenidate immediate-release tablet, and a second rising portion approximately three hours later, followed by a gradual decline. (See Figure 1 below.)

Comparison Of Immediate Release (IR) And METADATE CD Formulations After Repeated Doses Of Methylphenidate HCl In Children With ADHD

METADATE CD was administered as repeated once-daily doses of 20 mg or 40 mg to children aged 7-12 years with ADHD for one week. After a dose of 20 mg, the mean (±SD) early Cmax was 8.6 (±2.2) ng/mL, the later Cmax was 10.9 (±3.9)* ng/mL and AUC0-9h was 63.0 (±16.8) ng•h/mL. The corresponding values after a 40 mg dose were 16.8 (±5.1) ng/mL, 15.1 (±5.8)* ng/mL and 120 (±39.6) ng•h/mL, respectively. The early peak concentrations (median) were reached about 1.5 hours after dose intake, and the second peak concentrations (median) were reached about 4.5 hours after dose intake. The means for Cmax and AUC following a dose of 20 mg were slightly lower than those seen with 10 mg of the immediate-release formulation, dosed at 0 and 4 hours.

*25-30% of the subjects had only one observed peak (Cmax) concentration of methylphenidate.

FIGURE 1 : Comparison of Immediate Release (IR) and METADATE CD Formulations After Repeated Doses of Methylphenidate HCl in Children with ADHD

Dose Proportionality

Following single oral doses of 10-60 mg methylphenidate free base as a solution given to ten healthy male volunteers, Cmax and AUC increased proportionally with increasing doses. After the 60 mg dose, tmax was reached 1.5 hours post-dose, with a mean Cmax of 31.8 ng/mL (range 24.7-40.9 ng/mL).

Following one week of repeated once-daily doses of 20 mg or 40 mg METADATE CD to children aged 7-12 years with ADHD, Cmax and AUC were proportional to the administered dose.

Food Effects

In a study in adult volunteers to investigate the effects of a high-fat meal on the bioavailability of a dose of 40 mg, the presence of food delayed the early peak by approximately 1 hour (range -2 to 5 hours delay). The plasma levels rose rapidly following the food-induced delay in absorption. Overall, a high-fat meal increased the Cmax of METADATE CD by about 30% and AUC by about 17%, on average (see DOSAGE AND ADMINISTRATION).

After a single dose, the bioavailability (Cmax and AUC) of methylphenidate in 26 healthy adults was unaffected by sprinkling the capsule contents on applesauce as compared to the intact capsule. This finding demonstrates that a 20 mg METADATE CD Capsule, when opened and sprinkled on one tablespoon of applesauce, is bioequivalent to the intact capsule.

Metabolism And Excretion

In humans, methylphenidate is metabolized primarily via deesterification to alpha-phenyl­piperidine acetic acid (ritalinic acid). The metabolite has little or no pharmacologic activity.

In vitro studies showed that methylphenidate was not metabolized by cytochrome P450 isoenzymes, and did not inhibit cytochrome P450 isoenzymes at clinically observed plasma drug concentrations.

The mean terminal half-life (t½) of methylphenidate following administration of METADATE CD (t½=6.8h) is longer than the mean terminal (t½) following administration of methylphenidate hydrochloride immediate-release tablets (t½=2.9h) and methylphenidate hydrochloride sustained-release tablets (t½=3.4h) in healthy adult volunteers. This suggests that the elimination process observed for METADATE CD is controlled by the release rate of methylphenidate from the extended-release formulation, and that the drug absorption is the rate-limiting process.

An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the METADATE CD 60 mg capsule dosage form. At an alcohol concentration of 40% there was an increase in the release rate of methylphenidate in the first hour, resulting in 84% of the methylphenidate being released. The results with the 60 mg capsule are considered to be representative of the other available capsule strengths. Patients should be advised to avoid alcohol while taking METADATE CD.

Special Populations

The pharmacokinetics of methylphenidate after a single dose of METADATE CD were similar between adult men and women.

The influence of race on the pharmacokinetics of methylphenidate after METADATE CD administration has not been studied.

The pharmacokinetics of methylphenidate after METADATE CD administration have not been studied in children less than 6 years of age.

There is no experience with the use of METADATE CD in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of ritalinic acid. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of METADATE CD.

There is no experience with the use of METADATE CD in patients with hepatic insufficiency.

Clinical Studies

METADATE CD was evaluated in a double-blind, parallel-group, placebo-controlled trial in which 321 untreated or previously treated pediatric patients with a DSM-IV diagnosis of Attention Deficit Hyperactivity Disorder (ADHD), 6 to 15 years of age, received a single morning dose for up to 3 weeks. Patients were required to have the combined or predominantly hyperactive-impulsive subtype of ADHD; patients with the predominantly inattentive subtype were excluded. Patients randomized to the METADATE CD group received 20 mg daily for the first week. Their dosage could be increased weekly to a maximum of 60 mg by the third week, depending on individual response to treatment.

The patient's regular school teacher completed the teachers' version of the Conners' Global Index Scale (TCGIS), a scale for assessing ADHD symptoms, in the morning and again in the afternoon on three alternate days of each treatment week. The change from baseline of the overall average (i.e., an average of morning and afternoon scores over 3 days) of the total TCGIS scores during the last week of treatment was analyzed as the primary efficacy parameter. Patients treated with METADATE CD showed a statistically significant improvement in symptom scores from baseline over patients who received placebo. (See Figure 2.) Separate analyses of TCGIS scores in the morning and afternoon revealed superiority in improvement with METADATE CD over placebo during both time periods. (See Figure 3.) This demonstrates that a single morning dose of METADATE CD exerts a treatment effect in both the morning and the afternoon.

Figure 2

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.

The active substance in Ritalin LA is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is

Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77.

Inactive ingredients: ammonio methacrylate copolymer, black iron oxide (10 and 40 mg capsules only), gelatin, methacrylic acid copolymer, polyethylene glycol, red iron oxide (10 and 40 mg capsules only), sugar spheres, talc, titanium dioxide, triethyl citrate, and yellow iron oxide (10, 30, and 40 mg capsules only).

Signs and Symptoms

Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.

Poison Control Center

Consult with a Certified Poison Control Center regarding treatment for up-to-date guidance and advice.

Recommended Treatment

As with the management of all overdosage, the possibility of multiple drug ingestion should be considered.

When treating overdose, practitioners should bear in mind that there is a prolonged release of methylphenidate from Ritalin LA® (methylphenidate hydrochloride) extended-release capsules.

Treatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage as indicated. Before performing gastric lavage, control agitation and seizures if present and protect the airway. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia.

Efficacy of peritoneal dialysis or extracorporeal hemodialysis for methylphenidate overdosage has not been established; also, dialysis is considered unlikely to be of benefit due to the large volume of distribution of methylphenidate.

RITALIN LA®
(methylphenidate hydrochloride) Extended-release Capsules

Read the Medication Guide that comes with RITALIN LA® before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your or your child's treatment with RITALIN LA® .

What is the most important information I should know about RITALIN LA®?

The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines.

1. Heart-related problems:

• sudden death in patients who have heart problems or heart defects
• stroke and heart attack in adults
• increased blood pressure and heart rate

Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems.

Your doctor should check you or your child carefully for heart problems before starting RITALIN LA® .

Your doctor should check your or your child's blood pressure and heart rate regularly during treatment with RITALIN LA® .

Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking RITALIN LA® .

2. Mental (Psychiatric) problems:

All Patients

• new or worse behavior and thought problems
• new or worse bipolar illness
• new or worse aggressive behavior or hostility

Children and Teenagers

• new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms

Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression.

Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking RITALIN LA®, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious.

What Is RITALIN LA®?

RITALIN LA® is a central nervous system stimulant prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). RITALIN LA® may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.

RITALIN LA® should be used as a part of a total treatment program for ADHD that may include counseling or other therapies.

RITALIN LA® is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep RITALIN LA® in a safe place to prevent misuse and abuse. Selling or giving away RITALIN LA® may harm others, and is against the law.

Tell your doctor if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs.

Who should not take RITALIN LA®?

RITALIN LA® should not be taken if you or your child:

• are very anxious, tense, or agitated
• have an eye problem called glaucoma
• have tics or Tourette's syndrome, or a family history of Tourette's syndrome. Tics are hard to control repeated movements or sounds.
• are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI.
• are allergic to anything in RITALIN LA® . See the end of this Medication Guide for a complete list of ingredients.

RITALIN LA® should not be used in children less than 6 years old because it has not been studied in this age group.

RITALIN LA® may not be right for you or your child. Before starting RITALIN LA® tell your or your child's doctor about all health conditions (or a family history of) including:

• heart problems, heart defects, high blood pressure
• mental problems including psychosis, mania, bipolar illness, or depression
• tics or Tourette's syndrome
• seizures or have had an abnormal brain wave test (EEG)

Tell your doctor if you or your child is pregnant, planning to become pregnant, or breast-feeding.

Can RITALIN LA® be taken with other medicines?

Tell your doctor about all of the medicines that you or your child take including prescription and nonprescription medicines, vitamins, and herbal supplements. RITALIN LA® and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking RITALIN LA® .

Your doctor will decide whether RITALIN LA® can be taken with other medicines.

Especially tell your doctor if you or your child takes:

• anti-depression medicines including MAOIs
• seizure medicines
• blood thinner medicines
• blood pressure medicines
• stomach acid medicines
• cold or allergy medicines that contain decongestants

Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist.

Do not start any new medicine while taking RITALIN LA® without talking to your doctor first.

How should RITALIN LA® be taken?

• Take RITALIN LA® exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child.
• Take RITALIN LA® once a day in the morning. RITALIN LA® is an extended-release capsule. It releases medicine into your body throughout the day.
• Swallow RITALIN LA® capsules whole with water or other liquids. If you cannot swallow the capsule, open it and sprinkle the medicine over a spoonful of applesauce. Swallow the applesauce and medicine mixture without chewing. Follow with a drink of water or other liquid. Never chew or crush the capsule or the medicine inside the capsule.
• Ritalin LA should not be taken with alcohol. This may result in a more rapid release of the dose of Ritalin LA
• From time to time, your doctor may stop RITALIN LA® treatment for a while to check ADHD symptoms.
• Your doctor may do regular checks of the blood, heart, and blood pressure while taking RITALIN LA® . Children should have their height and weight checked often while taking RITALIN LA® .  RITALIN LA® treatment may be stopped if a problem is found during these check-ups.
• If you or your child takes too much RITALIN LA® or overdoses, call your doctor or poison control center right away, or get emergency treatment.

What are possible side effects of RITALIN LA®?

See “What is the most important information I should know about RITALIN LA®” for information on reported heart and mental problems.

Other serious side effects include:

• slowing of growth (height and weight) in children
• seizures, mainly in patients with a history of seizures
• eyesight changes or blurred vision

Common side effects include:

• headache
• stomach ache
• decreased appetite
• trouble sleeping

Talk to your doctor if you or your child has side effects that are bothersome or do not go away.

This is not a complete list of possible side effects. Ask your doctor or pharmacist for more information.

How should I store RITALIN LA®?

• Store RITALIN LA® in a safe place at room temperature, 59 to 86° F (15 to 30° C).
• Keep RITALIN LA® and all medicines out of the reach of children.

General information about RITALIN LA®

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RITALIN LA® for a condition for which it was not prescribed. Do not give RITALIN LA® to other people, even if they have the same condition. It may harm them and it is against the law.

This Medication Guide summarizes the most important information about RITALIN LA®. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about RITALIN LA® that was written for healthcare professionals. For more information about RITALIN LA® call 1-888-669-6682.

What are the ingredients in RITALIN LA®?

Active Ingredient: methylphenidate HCL

Inactive Ingredients: ammonio methacrylate copolymer, black iron oxide (10 and 40 mg capsules only), gelatin, methacrylic acid copolymer, polyethylene glycol, red iron oxide (10 and 40 mg capsules only), sugar spheres, talc, titanium dioxide, triethyl citrate, and yellow iron oxide (10, 30, and 40 mg capsules).

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

• ADHD Medication for Children
• ADHD Medications for Adults
• Adult ADHD (Attention Deficit Hyperactivity Disorder)
• Attention Deficit Hyperactivity Disorder (ADHD) in Teens
• Childhood ADD or ADHD (Attention Deficit Hyperactivity Disorder in Children)

Methylphenidate is a central nervous system stimulant. It affects chemicals in the brain and nerves that contribute to hyperactivity and impulse control.

Methylphenidate is used to treat attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), and narcolepsy.

Methylphenidate may also be used for purposes not listed in this medication guide.

Do not take methylphenidate if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) within the past 14 days. Serious, life-threatening side effects can occur if you use methylphenidate before the MAO inhibitor has cleared from your body.

Do not use this medication if you are allergic to methylphenidate or if you have:

• glaucoma;
• overactive thyroid;
• severe high blood pressure;
• angina (chest pain), heart failure, heart rhythm disorder, or recent heart attack;
• a personal or family history of tics (muscle twitches) or Tourette's syndrome;
• severe anxiety, tension, or agitation (methylphenidate can make these symptoms worse); or
• a hereditary condition such as fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency.

Some stimulants have caused sudden death in children and adolescents with serious heart problems or congenital heart defects. Tell your doctor if you have a congenital heart defect.

If you have any of these other conditions, you may need a dose adjustment or special tests:

• a congenital heart defect;
• a personal or family history of mental illness, psychotic disorder, bipolar illness, depression, or suicide attempt;
• epilepsy or other seizure disorder; or
• a history of drug or alcohol addiction.

FDA pregnancy category C. It is not known whether methylphenidate will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether methylphenidate passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Long-term use of methylphenidate can slow a child's growth. Tell your doctor if the child using this medication is not growing or gaining weight properly.

Do not give methylphenidate to a child younger than 6 years old without the advice of a doctor.

Methylphenidate may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Take the missed dose as soon as you remember. Skip the missed dose if it is later than 6:00 p.m. Do not take extra medicine to make up the missed dose.

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.

Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and listings that follow, MEDRA terminology has been used to classify reported adverse events. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adverse Events in a Double-Blind, Placebo-Controlled Clinical Trial with Ritalin LA

A placebo-controlled, double-blind, parallel-group study was conducted to evaluate the efficacy and safety of Ritalin LA in children with ADHD aged 6-12 years. All subjects received Ritalin LA for up to 4 weeks, and had their dose optimally adjusted, prior to entering the double-blind phase of the trial. In the two-week double-blind treatment phase of this study, patients received either placebo or Ritalin LA at their individually-titrated dose (range 10 mg-40 mg).

The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.

Adverse events with an incidence > 5% during the initial four-week single-blind Ritalin LA titration period of this study were headache, insomnia, upper abdominal pain, appetite decreased, and anorexia.

Treatment-emergent adverse events with an incidence > 2% among Ritalin LA-treated subjects, during the two-week double-blind phase of the clinical study, were as follows:

In the two-week double-blind treatment phase of a placebo-controlled parallel-group study in children with ADHD, only one Ritalin LA-treated subject (1/65, 1.5%) discontinued due to an adverse event (depression).

In the single-blind titration period of this study, subjects received Ritalin LA for up to 4 weeks. During this period a total of six subjects (6/161, 3.7%) discontinued due to adverse events. The adverse events leading to discontinuation were anger (in 2 patients), hypomania, anxiety, depressed mood, fatigue, migraine and lethargy.

Nervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed below may also occur.

Other reactions include:

Cardiac: angina, arrhythmia, palpitations, pulse increased or decreased, tachycardia

Gastrointestinal: abdominal pain, nausea

Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura.

Metabolism/Nutrition: anorexia, weight loss during prolonged therapy

Nervous System: dizziness, drowsiness, dyskinesia, headache, rare reports of Tourette's syndrome, toxic psychosis

Vascular: blood pressure increased or decreased; cerebrovascular vasculitis; cerebral occlusions; cerebral hemorrhages and cerebrovascular accidents

Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate:

Blood/Lymphatic: leukopenia and/or anemia

Hepatobiliary: abnormal liver function, ranging from transaminase elevation to hepatic coma

Psychiatric: transient depressed mood, aggressive behavior

Skin/Subcutaneous: scalp hair loss

Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause.

Drug Abuse And Dependence

Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, like other products containing methylphenidate, is a Schedule II controlled substance. (See WARNINGS for boxed warning containing drug abuse and dependence information.)

Read the entire FDA prescribing information for Ritalin LA (Methylphenidate Hydrochloride Extended-Release Capsules)