Dexmethylphenidate Hydrochloride

Prior to treating pediatric patients and adults with central nervous system (CNS) stimulants, including dexmethylphenidate hydrochloride, assess for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions 5.2].

Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically re-evaluate the need for dexmethylphenidate hydrochloride use [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].

Patients New to Methylphenidate

The recommended starting dose of dexmethylphenidate hydrochloride for pediatric patients who are not currently taking racemic methylphenidate, or for patients who are on stimulants other than methylphenidate, is 5 mg daily (2.5 mg twice daily) with or without food.

Patients Currently on Methylphenidate

The recommended starting dose of dexmethylphenidate hydrochloride for pediatric patients currently using methylphenidate is half the total daily dose of racemic methylphenidate.

Titration Schedule

The dose may be titrated weekly in increments of 2.5 to 5 mg to a maximum of 20 mg daily (10 mg twice daily). The dose should be individualized according to the needs and response of the patient.

Maintenance/Extended Treatment

Pharmacological treatment of ADHD may be needed for extended periods. Periodically re-evaluate the long-term use of dexmethylphenidate hydrochloride and adjust dosage as needed.

Dexmethylphenidate hydrochloride is administered orally twice daily, at least 4 hours apart.

If paradoxical aggravation of symptoms or other adverse reactions occur, reduce the dosage, or if necessary, discontinued dexmethylphenidate hydrochloride. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

CNS stimulants, including dexmethylphenidate hydrochloride, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Boxed Warning, Drug Abuse and Dependence (9.2, 9.3)].

Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in pediatric patients with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during dexmethylphenidate hydrochloride treatment.

CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.

Exacerbation of Pre-existing Psychosis

CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.

Induction of a Manic Episode in Patients With Bipolar Disorder

CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).

New Psychotic or Manic Symptoms

CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing dexmethylphenidate hydrochloride. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared to 0 in placebo-treated patients.

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

CNS stimulants, including dexmethylphenidate hydrochloride, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Careful follow-up of weight and height in patients 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 patients over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated pediatric patients (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.

Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including dexmethylphenidate hydrochloride, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials Experience With Dexmethylphenidate Hydrochloride in Pediatric Patients With ADHD

The safety data in this section is based on data related to dexmethylphenidate hydrochloride exposure during the premarketing development program in a total of 696 participants in clinical trials (684 patients, 12 healthy adult subjects). These participants received dexmethylphenidate hydrochloride 5, 10, or 20 mg/day. The 684 ADHD patients (ages 6 to 17 years) were evaluated in 2 controlled clinical studies, 2 clinical pharmacology studies, and 2 open-label long-term safety studies.

Most Common Adverse Reactions (incidence of greater than or equal to 5% and at least twice placebo)

Abdominal pain, fever, anorexia, and nausea

Adverse Reactions Leading to Discontinuation

Overall, 50 of 684 (7.3%) pediatric patients treated with dexmethylphenidate hydrochloride experienced an adverse reaction that resulted in discontinuation. The most common reasons for discontinuation were twitching (described as motor or vocal tics), anorexia, insomnia, and tachycardia (approximately 1% each). Table 1 enumerates adverse reactions for two, placebo-controlled, parallel group studies in pediatric patients with ADHD taking dexmethylphenidate hydrochloride doses of 5, 10, and 20 mg/day. The table includes only those reactions that occurred in patients treated with dexmethylphenidate hydrochloride for which the incidence was at least 5% and twice the incidence among placebo-treated patients.

The following additional adverse reactions have been identified during post approval use of dexmethylphenidate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal

Rhabdomyolysis

Immune System Disorders

Hypersensitivity reactions such as angioedema, anaphylactic reactions

Adverse Reactions Reported With all Ritalin and Dexmethylphenidate Hydrochloride Formulations

The following adverse reactions associated with the use of all Ritalin and dexmethylphenidate hydrochloride formulations were identified in clinical trials, spontaneous reports, and literature. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

Infections and Infestations

Nasopharyngitis

Blood and the Lymphatic System Disorders

Leukopenia, thrombocytopenia, anemia

Immune System Disorders

Hypersensitivity reactions, including angioedema and anaphylaxis

Metabolism and Nutrition Disorders

Decreased appetite, reduced weight gain, and suppression of growth during prolonged use in pediatric patients

Psychiatric Disorders

Insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood

Nervous System Disorders

Headache, dizziness, tremor, dyskinesia including choreoatheetoid movements, drowsiness, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents) , serotonin syndrome in combination with serotonergic drugs

Eye Disorders

Blurred vision, difficulties in visual accommodation

Cardiac Disorders

Tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris

Respiratory, Thoracic and Mediastinal Disorders

Cough

Gastrointestinal Disorders

Dry mouth, nausea, vomiting, abdominal pain, dyspepsia

Hepatobiliary Disorders

Abnormal liver function, ranging from transaminase elevation to severe hepatic injury

Skin and Subcutaneous Tissue Disorders

Hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura

Musculoskeletal and Connective Tissue Disorders

Arthralgia, muscle cramps, rhabdomyolysis

Investigations

Weight loss (adult ADHD patients)

Additional Adverse Reactions Reported With Other Methylphenidate-Containing Products

The list below shows adverse reactions not listed with Ritalin and dexmethylphenidate hydrochloride formulations [see Adverse Reactions (6.2)] that have been reported with other methylphenidate products based on clinical trials data and postmarketing spontaneous reports.

Blood and Lymphatic Disorders

Pancytopenia

Immune System Disorders

Hypersensitivity reactions such as auricular swelling

Psychiatric Disorders

Affect lability, mania, disorientation, libido changes,

Nervous System Disorders

Migraine

Eye Disorders

Diplopia, mydriasis

Cardiac Disorders

Sudden cardiac death, myocardial infarction, bradycardia, extrasystole, supraventricular tachycardia, ventricular extrasystole

Vascular Disorders

Peripheral coldness, Raynaud's phenomenon

Respiratory, Thoracic and Mediastinal Disorders

Pharyngolaryngeal pain, dyspnea

Gastrointestinal Disorders

Diarrhea, constipation

Skin and Subcutaneous Tissue Disorders

Angioneurotic edema, erythema, fixed drug eruption

Musculoskeletal, Connective Tissue and Bone Disorders

Myalgia, muscle twitching

Renal and Urinary Disorders

Hematuria

Reproductive System and Breast Disorders

Gynecomastia

General disorders

Fatigue

Urogenital disorders

Priapism

Table 2 presents clinically important drug interactions with dexmethylphenidate hydrochloride.

Pregnancy Category C

In studies conducted in rats and rabbits, dexmethylphenidate was administered orally at doses of up to 20 and 100 mg/kg/day, respectively, during the period of organogenesis. No evidence of teratogenic activity was found in either the rat or rabbit study; however, delayed fetal skeletal ossification was observed at the highest dose level in rats. When dexmethylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 20 mg/kg/day, postweaning body weight gain was decreased in male offspring at the highest dose, but no other effects on postnatal development were observed. At the highest doses tested, plasma levels (AUCs) of dexmethylphenidate in pregnant rats and rabbits were approximately 5 and 1 times, respectively, those in adults dosed with the maximum recommended human dose (MRHD) of 20 mg/day.

Racemic methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day throughout organogenesis.

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

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

The safety and effectiveness of dexmethylphenidate hydrochloride have been established in pediatric patients ages 6 to 17 years in two adequate and well-controlled clinical trials [see Clinical Studies (14)].

The safety and effectiveness of dexmethylphenidate hydrochloride in pediatric patients less than 6 years have not been established.

The long-term efficacy of dexmethylphenidate hydrochloride in pediatric patients has not been established.

Long Term Suppression of Growth

Growth should be monitored during treatment with stimulants, including dexmethylphenidate hydrochloride. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7)].

Juvenile Animal Toxicity Data

In a study conducted in young rats, racemic 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 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 6 times the MRHD of 60 mg of racemic methylphenidate 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 of 60 mg of racemic methylphenidate on a mg/m² basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD of 60 mg of racemic methylphenidate on a mg/m² basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

Dexmethylphenidate hydrochloride has not been studied in the geriatric population.

Dexmethylphenidate hydrochloride like other methylphenidate products, are classified as a Schedule II controlled substance.

CNS stimulants, including dexmethylphenidate hydrochloride, other methylphenidate-containing products, and amphetamines have a high potential for abuse. Abuse is characterized by impaired control over drug use despite harm, and craving.

Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which may result in overdose and death [see Overdosage (10)].

To reduce the abuse of CNS stimulants including dexmethylphenidate hydrochloride, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants [see How Supplied/Storage and Handling (16)], monitor for signs of abuse while on therapy, and re-evaluate the need for dexmethylphenidate hydrochloride use.

Tolerance

Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug’s desired and/or undesired effects over time) can occur during chronic therapy with CNS stimulants, including dexmethylphenidate hydrochloride.

Dependence

Physical dependence (which is manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) can occur in patients treated with CNS stimulants including dexmethylphenidate hydrochloride. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Dexmethylphenidate hydrochloride is a CNS stimulant. The exact mode of therapeutic action in ADHD is not known.

Pharmacodynamics

Dexmethylphenidate is the more pharmacologically active d-enantiomer of racemic methylphenidate. 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.

Cardiac Electrophysiology

A formal QT study has not been conducted in patients taking dexmethylphenidate hydrochloride; however, a large QT effect is not expected. At the recommended maximum total daily dosage of 40 mg, Dexmethylphenidate hydrochloride extended-release capsule does not prolong the QTc interval to any clinically relevant extent.

Absorption

Dexmethylphenidate hydrochloride is readily absorbed following oral administration of dexmethylphenidate hydrochloride. In patients with ADHD, plasma dexmethylphenidate concentrations increase rapidly, reaching a maximum in the fasted state at about 1 to 1.5 hours postdose. No differences in the pharmacokinetics of dexmethylphenidate hydrochloride were noted following single and repeated twice daily dosing, thus indicating no significant drug accumulation in children with ADHD.

After single dose administration of dexmethylphenidate hydrochloride to pediatric patients, dexmethylphenidate exposure (C_max and AUC_0-inf ) showed dose-proportional increase in the range of 2.5 mg to 10 mg. Comparable plasma dexmethylphenidate levels were achieved following single dl-threo-methylphenidate HCl doses given as capsules in twice the total mg amount (equimolar with respect to dexmethylphenidate hydrochloride).

Approximately 90% of the dose is absorbed after oral administration of radiolabeled racemic methylphenidate. However, due to first pass metabolism the mean absolute bioavailability of dexmethylphenidate when administered in various formulations was 22% to 25%.

Effect of Food

High fat breakfast did not significantly affect C_max or AUC_0-inf of dexmethylphenidate when two 10 mg dexmethylphenidate hydrochloride tablets were administered, but delayed T_max from 1.5 hours post dose to 2.9 hours post dose.

Distribution

The plasma protein binding of dexmethylphenidate is not known; racemic methylphenidate is bound to plasma proteins by 12% to 15%, independent of concentration. Dexmethylphenidate shows a volume of distribution of 2.65 ± 1.11 L/kg.

Elimination

Plasma dexmethylphenidate concentrations declined exponentially following oral administration of dexmethylphenidate hydrochloride. Intravenous dexmethylphenidate was eliminated with a mean clearance of 0.40 ± 0.12 L/hr/kg. The mean terminal elimination half-life of dexmethylphenidate was approximately 2.2 hours.

Metabolism

In humans, dexmethylphenidate is metabolized primarily via de-esterification to d-α-phenyl-piperidine acetic acid (also known as d-ritalinic acid). This metabolite has little or no pharmacological activity. There is little or no in vivo interconversion to the l-threo-enantiomer.

Excretion

After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite of racemic dl-methylphenidate was dl-ritalinic acid, accountable for approximately 80% of the dose. Urinary excretion of parent compound accounted for 0.5% of an intravenous dose.

Studies in Special Populations

Male and Female Patients

Pharmacokinetic parameters were similar for boys and girls (mean age 10 years).

In a single dose study conducted in adults, the mean dexmethylphenidate AUC_0-inf values (adjusted for body weight) following single two 10 mg doses of dexmethylphenidate hydrochloride were 25% to 35% higher in adult female volunteers (n=6) compared to male volunteers (n=9). Both t_max and t_½ were comparable for males and females.

Racial or Ethnic Groups

There is insufficient experience with the use of dexmethylphenidate hydrochloride to detect ethnic variations in pharmacokinetics.

Pediatric Patients

The pharmacokinetics of dexmethylphenidate after dexmethylphenidate hydrochloride administration have not been studied in children less than 6 years of age. When single doses of dexmethylphenidate hydrochloride were given to children between the ages of 6 to 12 years and healthy adult volunteers, C_max of dexmethylphenidate was similar, however, pediatric patients showed somewhat lower AUCs compared to the adults.

Patients With Renal Impairment

There is no experience with the use of dexmethylphenidate hydrochloride in patients with renal impairment. Since renal clearance is not an important route of methylphenidate clearance, renal impairment is expected to have little effect on the pharmacokinetics of dexmethylphenidate hydrochloride.

Patients With Hepatic Impairment

There is no experience with the use of dexmethylphenidate hydrochloride in patients with hepatic impairment.

Drug Interaction Studies

Methylphenidate is not metabolized by cytochrome P450 (CYP) isoenzymes to a clinically relevant extent. Inducers or inhibitors of CYPs are not expected to have any relevant impact on methylphenidate pharmacokinetics. Conversely, the d- and l-enantiomers of methylphenidate did not relevantly inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A. Clinically, methylphenidate coadministration did not increase plasma concentrations of the CYP2D6 substrate desipramine.

Carcinogenesis

Lifetime carcinogenicity studies have not been carried out with dexmethylphenidate. In a lifetime carcinogenicity study carried out in B6C3F1 mice, racemic methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas was seen at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the MRHD of 60 mg of racemic methylphenidate in pediatric patients on a mg/m² basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors and the significance of these results to humans is unknown.

Racemic methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD of 60 mg of racemic methylphenidate in pediatric patients on a mg/m² basis.

In a 24-week carcinogenicity study with racemic methylphenidate in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentrations as in the lifetime carcinogenicity study; the high-dose group was exposed to 60 to 74 mg/kg/day of racemic methylphenidate.

Mutagenesis

Dexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vivo mouse bone marrow micronucleus test. In an in vitro assay using cultured Chinese Hamster Ovary (CHO) cells treated with racemic methylphenidate, sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response.

Impairment of Fertility

No human data on the effect of methylphenidate on fertility are available. Fertility studies have not been conducted with dexmethylphenidate. Racemic methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses of up to 160 mg/kg/day, approximately 10-fold the maximum recommended dose of 60 mg of racemic methylphenidate in adolescents on a mg/m² basis.