Get your patient on Dexmethylphenidate Hydrochloride - Dexmethylphenidate Hydrochloride capsule, Extended Release (Dexmethylphenidate Hydrochloride)

Prior to treating patients with dexmethylphenidate hydrochloride extended-release capsules, 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) ] .

• the family history and clinically evaluate patients for motor or verbal tics or Tourette’s syndrome before initiating dexmethylphenidate hydrochloride extended-release capsules [see Warnings and Precautions (5.10)] .

Patients New to Methylphenidate

The recommended starting dosage of dexmethylphenidate hydrochloride extended-release capsules for patients who are not currently taking dexmethylphenidate or racemic methylphenidate, or for patients who are on stimulants other than methylphenidate are:

• Pediatric patients: Start with 5 mg orally once daily in the morning with or without food.

• Adult patients: Start with 10 mg orally once daily in the morning with or without food.

Patients Currently on Methylphenidate

The recommended starting dose of dexmethylphenidate hydrochloride extended-release capsules for patients currently using methylphenidate is half (1/2) the total daily dose of racemic methylphenidate.

Patients currently using dexmethylphenidate hydrochloride immediate-release tablets may be given the same daily dose of dexmethylphenidate hydrochloride extended-release capsules.

Titration Schedule

The dose may be titrated weekly in increments of 5 mg in pediatric patients and 10 mg in adult patients. The dose should be individualized according to the needs and response of the patient. Daily doses above 30 mg in pediatrics and 40 mg in adults have not been studied and are not recommended.

Dexmethylphenidate hydrochloride extended-release capsules are administered orally and may be taken whole or the capsule may be opened and the entire contents sprinkled onto applesauce. If the patient is using the sprinkled administration method, the sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. The dose of a single capsule should not be divided. The contents of the entire capsule should be taken, and patients should not take anything less than one capsule per day.

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

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including dexmethylphenidate hydrochloride extended-release capsules, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-­medications/.

Risk Summary

Dexmethylphenidate is the d-threo enantiomer of racemic methylphenidate. Published studies and post-marketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants during pregnancy ( see Clinical Considerations ). Embryo-fetal development studies in rats showed delayed fetal skeletal ossification at doses up to 5 times the maximum recommended human dose (MRHD) of 20 mg/day given to adults based on plasma levels. A decrease in pup weight in males was observed in a pre- and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 5 times the MRHD of 20 mg/day given to adults based on plasma levels ( see Data ).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

CNS stimulants, such as dexmethylphenidate hydrochloride extended-release capsules, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers.

Data

Animal Data

In embryo-fetal development 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 malformations 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, post-weaning 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 [area under the curves (AUCs)] of dexmethylphenidate in pregnant rats and rabbits were approximately 5 and 1 times, respectively, those in adults dosed with 20 mg/day. Plasma levels in adults were comparatively similar to plasma levels in adolescents.

Racemic methylphenidate has been shown to cause malformations (increased incidence of fetal spina bifida) in rabbits when given in doses of 200 mg/kg/day throughout organogenesis.

Risk Summary

Dexmethylphenidate is the d-threo enantiomer of racemic methylphenidate. Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for dexmethylphenidate hydrochloride extended-release capsules and any potential adverse effects on the breastfed infant from dexmethylphenidate hydrochloride extended-release capsules or from the underlying maternal condition.

Clinical Considerations

Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

The safety and effectiveness of dexmethylphenidate hydrochloride extended-release capsules for the treatment of ADHD have been established in pediatric patients aged 6 to 17 years in two adequate and well-controlled clinical trials [see Clinical Studies (14.2) ].

The safety and effectiveness of dexmethylphenidate hydrochloride extended-release capsules in pediatric patients aged less than 6 years have not been established.

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

Long Term Suppression of Growth

Growth should be monitored during treatment with stimulants, including dexmethylphenidate hydrochloride extended-release capsules. 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

Rats treated with racemic methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 6 times the MRHD of 60 mg/day given to children on a mg/m ² basis.

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 to14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day of racemic methylphenidate given to children on a mg/m ² basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m ² basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m ² basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

Dexmethylphenidate hydrochloride extended-release capsules has not been studied in the geriatric population.

Dexmethylphenidate hydrochloride extended-release capsules has a high potential for abuse and misuse. The use of dexmethylphenidate hydrochloride extended-release capsules exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Dexmethylphenidate hydrochloride extended-release capsules can be diverted for non-medical use into illicit channels or distribution [see Drug Abuse and Dependence (9.2) ] . Misuse and abuse of CNS stimulants, including dexmethylphenidate hydrochloride extended-release capsules, can result in overdose and death [see Overdosage (10) ] , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Before prescribing dexmethylphenidate hydrochloride extended-release capsules, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store dexmethylphenidate hydrochloride extended-release capsules in a safe place, preferably locked, and instruct patients to not give dexmethylphenidate hydrochloride extended-release capsules to anyone else. Throughout dexmethylphenidate hydrochloride extended-release capsules treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage.

Avoid dexmethylphenidate hydrochloride extended-release capsules use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 beats per minute). Some patients may have larger increases.

Monitor all dexmethylphenidate hydrochloride extended-release capsules-treated patients for hypertension and tachycardia.

Exacerbation of Preexisting 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 dexmethylphenidate hydrochloride extended-release capsules treatment, screen patients for risk factors for developing 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 the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. 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% of placebo-treated patients. If such symptoms occur, consider discontinuing dexmethylphenidate hydrochloride extended-release capsules.

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on methylphenidate, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation).

Dexmethylphenidate hydrochloride extended-release capsules-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

CNS stimulants, including dexmethylphenidate hydrochloride extended-release capsules, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports at and at the therapeutic dosage of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant.

Careful observation for digital changes is necessary during dexmethylphenidate hydrochloride extended-release capsules treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for dexmethylphenidate hydrochloride extended-release capsules-treated patients who develop signs or symptoms of peripheral vasculopathy.

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

In a 7-week, double-blind, placebo-controlled study of dexmethylphenidate hydrochloride extended-release capsules, the mean weight gain was greater for pediatric patients (ages 6 to 17 years) receiving placebo (+0.4 kg) than for patients receiving dexmethylphenidate hydrochloride extended-release capsules (-0.5 kg).

Careful follow-up of weight and height in pediatric 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 pediatric patients who received methylphenidate for 7 days per week throughout the year had 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 development period.

Closely monitor growth (weight and height) in dexmethylphenidate hydrochloride extended-release capsules-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

There have been reports of angle closure glaucoma associated with methylphenidate treatment.

Although the mechanism is not clear, dexmethylphenidate hydrochloride extended-release capsules-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.

There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2) ] .

Prescribe dexmethylphenidate hydrochloride tablets to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor dexmethylphenidate hydrochloride extended-release capsules-treated patients with a history of abnormally increased IOP or open angle glaucoma.

CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see Adverse Reactions (6.2) ] .

Before initiating dexmethylphenidate hydrochloride extended-release capsules, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor dexmethylphenidate hydrochloride tablets-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.

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.

Adverse Reactions in Studies with Dexmethylphenidate Hydrochloride Extended-Release Capsules in Pediatric Patients with ADHD

The safety data in this section is based on data from a 7-week controlled clinical study of dexmethylphenidate hydrochloride extended-release capsules in 100 (103 randomized)pediatric patients with ADHD ages 6 to 17 years (ages 6 to 12, n = 86; ages 13 to 17, n = 17).

This study was a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the time of onset, duration of efficacy, tolerability, safety of dexmethylphenidate hydrochloride extended-release capsules 5 mg to 30 mg/day who met The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for ADHD [see Clinical Studies (14.1)].

Most Common Adverse Reactions (incidence of greater than or equal to 5% and at least twice placebo): dyspepsia, decreased appetite, headache and anxiety.

Adverse Reactions Leading to Discontinuation : 50 of 684 (7.3%) pediatric patients treated with dexmethylphenidate immediate-release tablets 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 the placebo-controlled, parallel-group study in children and adolescents with ADHD at flexible dexmethylphenidate hydrochloride extended-release capsules doses of 5 to 30 mg/day. The table includes only those events that occurred in 5% or more of patients treated with dexmethylphenidate hydrochloride extended-release capsules and for which the incidence in patients treated with dexmethylphenidate hydrochloride extended-release capsules was at least twice the incidence in placebo-treated patients.

Table 1: Common Adverse Reactions in Pediatric Patients (6 to 17 years of age) With A

Abbreviation: ADHD, attention deficit hyperactivity disorder

Table 2 below enumerates the incidence of dose-related adverse reactions that occurred during a fixed-dose, double-blind, placebo-controlled trial in pediatric patients with ADHD taking dexmethylphenidate hydrochloride extended-release capsules up to 30 mg daily versus placebo. The table includes only those reactions that occurred in patients treated with dexmethylphenidate hydrochloride extended-release capsules for which the incidence was at least 5% and greater than the incidence among placebo-treated patients.

Table 2: Dose-Related Adverse Reactions in Pediatric Patients (6 to 17 years of age) With ADHD

Abbreviation: ADHD, attention deficit hyperactivity disorder.

Adverse Reactions in Studies with Dexmethylphenidate Hydrochloride Extended-Release Capsules in Adult Patients with ADHD

The safety data in this section is based on data from a 5-week controlled clinical study of dexmethylphenidate hydrochloride extended-release capsules in 218 adult patients (221 randomized) with ADHD ages 18 to 60 years. In this study, 101 adult patients were treated for at least 6 months.

This study was a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of dexmethylphenidate hydrochloride extended-release capsules 20 mg, 30 mg, or 40 mg daily who met DSM-IV criteria for ADHD [see Clinical Studies (14.2 )].

Most Common Adverse Reactions (incidence of greater than or equal to 5% and at least twice placebo): dry mouth, dyspepsia, headache, anxiety, and pharyngolaryngeal pain.

Adverse Reactions Leading to Discontinuation : During the double-blind phase of the study, 10.7% of the dexmethylphenidate hydrochloride extended-release capsules - treated patients and 7.5% of the placebo-treated patients discontinued due to adverse reactions. Three patients (1.8%) in the dexmethylphenidate hydrochloride extended-release capsules discontinued due to insomnia and jittery, respectively and two patients (1.2%) in the dexmethylphenidate hydrochloride extended-release capsules discontinued due to anorexia and anxiety, respectively.

Table 3 enumerates adverse reactions for the placebo-controlled, parallel-group study in adults with ADHD at fixed dexmethylphenidate hydrochloride extended-release capsules doses of 20, 30, or 40 mg/day. The table includes only those events that occurred in 5% or more of patients in a dexmethylphenidate hydrochloride extended-release capsules dose group and for which the incidences in patients treated with dexmethylphenidate hydrochloride extended-release capsules appeared to increase with dose.

Table 3: Dose-Related Adverse Reactions in Adult Patients (18 to 60 years of age) With ADHD

Two other adverse reactions occurring in clinical trials with dexmethylphenidate hydrochloride extended-release capsules at a frequency greater than placebo, but which were not dose related were: feeling jittery (12% and 2%, respectively) and dizziness (6% and 2%, respectively).

Table 4 summarizes changes in vital signs and weight that were recorded in the adult study (N=218) of dexmethylphenidate hydrochloride extended-release capsules in the treatment of ADHD.

Table 4: Changes (Mean ± SD) in Vital Signs and Weight by Randomized Dose During Double-Blind Treatment-Adults

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, including angioedema and anaphylaxis

Adverse Reactions Reported With All Methylphenidate Hydrochloride and Dexmethylphenidate Hydrochloride Formulations
The following adverse reactions associated with the use of all methylphenidate hydrochloride 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, depression
Nervous System Disorders: headache, dizziness, tremor, dyskinesia, including choreoathetoid 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, trismus

Investigations: weight loss (adult ADHD patients)

Vascular Disorders: peripheral coldness, Raynaud's phenomenon

Additional Adverse Reactions Reported with Other Methylphenidate Products

The list below shows adverse reactions not listed with methylphenidate hydrochloride and dexmethylphenidate hydrochloride formulations that have been reported with other methylphenidate products based on clinical trials data and post-marketing spontaneous reports.

Blood and Lymphatic Disorders: pancytopenia
Immune System Disorders: hypersensitivity reactions, such as auricular swelling, bullous conditions, eruptions, exanthemas
Psychiatric Disorders: affect lability, mania, disorientation, libido changes,
Nervous System Disorders: migraine, motor and verbal tics
Eye Disorders: diplopia, increased intraocular pressure, mydriasis
Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole, supraventricular tachycardia, ventricular extrasystole
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, hyperpyrexia
Urogenital Disorders: priapism

Table 5 presents clinically important drug interactions with dexmethylphenidate hydrochloride extended-release capsules.

Table 5: Clinically Important Drug Interactions With Dexmethylphenidate Hydrochloride Extended-Release Capsules

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/day of racemic methylphenidate given to children on a mg/m ² 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 (children) of 60 mg/day of racemic methylphenidate in children on a mg/m ² basis.



In a 24-week carcinogenicity study with racemic methylphenidate in the transgenic mouse strain p ^53+/- , 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 to74 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 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-times the MRHD of 60 mg/day of racemic methylphenidate given to adolescents on a mg/m ² basis.

A randomized, double-blind, placebo-controlled, parallel-group study (Study 1) was conducted in 103 pediatric patients (ages 6 to 12, n = 86; ages 13 to 17, n = 17) who met DSM-IV criteria for ADHD inattentive, hyperactive-impulsive or combined inattentive/hyperactive-impulsive subtypes (Study 1).

Patients were randomized to receive either a flexible-dose of dexmethylphenidate hydrochloride extended-release capsules (5 to 30 mg/day) or placebo once daily for 7 weeks. During the first 5 weeks of treatment, patients were titrated to their optimal dose and remained on this optimal dose for the last 2 weeks of the study without dose changes or interruption.

Signs and symptoms of ADHD were evaluated by comparing the mean change from baseline to endpoint for dexmethylphenidate hydrochloride extended-release capsules and placebo-treated patients using an intent-to-treat analysis of the primary efficacy outcome measure, the DSM-IV total subscale score of the Conners ADHD/DSM-IV Scales for teachers (CADS-T). The CADS-T includes the ADHD Index (12 items) and the DSM-IV total subscale (18 items, total score range: 0 to 54); the latter is divided into inattentive (9 items) and hyperactive-impulsive (9 items) subscales. Teachers assessed behavior observed during the school day by completing the CADS-T weekly. A decrease in the CADS-T DSM-IV total subscale score from baseline indicates improvement.

The CADS-T total scores showed a statistically significant treatment effect in favor of dexmethylphenidate hydrochloride extended-release capsules than placebo (Table 6). There were insufficient adolescents enrolled in this study to assess the efficacy for dexmethylphenidate hydrochloride extended-release capsules in the adolescent population.However, pharmacokinetic considerations and evidence of effectiveness of immediate-release dexmethylphenidate hydrochloride tablets in adolescents support the effectiveness of dexmethylphenidate hydrochloride extended-release capsules in this population.

Table 6: Summary of Efficacy Results from ADHD Study in Pediatric Patients (6 to 17 years) (Study 1)

Abbreviations: ADHD, attention deficit hyperactivity disorder; SD, standard deviation; SE, standard error; LS Mean, least-squares mean; CI, confidence interval, not adjusted for multiple comparisons.

^a Difference (drug minus placebo) in least-squares mean change from baseline.

In 2 additional cross-over studies (Studies 2 and 3) in pediatric patients ages 6 to 12 years, who received 20 mg dexmethylphenidate hydrochloride extended-release capsules or placebo, dexmethylphenidate hydrochloride extended-release capsules were found to have a statistically significant treatment effect versus placebo on the Swanson, Kotkin, Agler, M-Flynn & Pelham (SKAMP) rating scale total scores at all-time points after dosing in each study (0.5, 1, 3, 4, 5, 7, 9, 10, 11, and 12 hours in Study 2 and 1, 2, 4, 6, 8, 9, 10, 11, and 12 hours in the study 3). SKAMP is a validated 13-item teacher-rated scale that assesses manifestations of ADHD in a classroom setting. A treatment effect was also observed 0.5 hours after administration of dexmethylphenidate hydrochloride extended-release capsules 20 mg in an additional study of ADHD patients ages 6 to 12 years.

A randomized, double-blind, placebo-controlled, parallel-group (Study 4) was conducted in 221 adult patients ages 18 to 60 years who met DSM-IV criteria for ADHD inattentive, hyperactive-impulsive or combined inattentive/hyperactive-impulsive subtypes (Study 4).

Patients were randomized to receive either a fixed dose of dexmethylphenidate hydrochloride extended-release capsules (20, 30, or 40 mg/day) or placebo once daily for 5 weeks. Patients randomized to dexmethylphenidate hydrochloride extended-release capsules were initiated on a 10 mg/day starting dose and titrated in increments of 10 mg/week to the randomly assigned fixed dose. Patients were maintained on their fixed dose (20, 30, or 40 mg/day) for a minimum of 2 weeks.

Signs and symptoms of ADHD were evaluated by comparing the mean change from baseline to endpoint for dexmethylphenidate hydrochloride extended-release capsules and placebo-treated patients using an intent-to-treat analysis of the primary efficacy outcome measure, the investigator-administered DSM-IV Attention-Deficit/Hyperactivity Disorder Rating Scale (DSM-IV ADHD RS).

The DSM-IV ADHD-RS is an 18-item questionnaire with a score range of 0 to 54 points that measures the core symptoms of ADHD and includes both hyperactive/impulsive and inattentive subscales.

All 3 dexmethylphenidate hydrochloride extended-release capsules doses (20, 30, and 40 mg/day) showed a statistically significant treatment effect compared to placebo.There was no obvious increase in effectiveness with increasing the dose.

Table 7: Summary of Efficacy Results from ADHD Study in Adults (Study 4)

Abbreviations:ADHD, attention deficit hyperactivity disorder; SD, standard deviation; SE, standard error; LS Mean, least-squares mean; CI, confidence interval, not adjusted for multiple comparisons.

^a Difference (drug minus placebo) in least-squares mean change from baseline