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

The recommended starting dose of dexmethylphenidate hydrochloride extended-release for patients who are not currently taking dexmethylphenidate or racemic methylphenidate, or for patients who are on stimulants other than methylphenidate, is 5 mg/day for pediatric patients and 10 mg/day for adult patients.

Dosage may be adjusted in 5 mg increments for pediatric patients and in 10 mg increments for adult patients. In general, dosage adjustments may proceed at approximately weekly intervals. The patient should be observed for a sufficient duration at a given dose to ensure that a maximal benefit has been achieved before a dose increase is considered. In dose-response (fixed-dose) studies (pediatric from 10 to 30 mg/day and adult from 20 to 40 mg/day), all doses were effective vs. placebo. There was no clear finding, however, of greater average benefits for the higher doses compared to the lower doses. Adverse events and discontinuations, however, were dose-related. Doses above 30 mg/day in pediatrics and 40 mg/day in adults have not been studied and are not recommended.

For patients currently using methylphenidate, the recommended starting dose of dexmethylphenidate hydrochloride extended-release is half the total daily dose of racemic methylphenidate. Patients currently using dexmethylphenidate hydrochloride may be switched to the same daily dose of dexmethylphenidate hydrochloride extended-release.

There is no body of evidence available from controlled trials to indicate how long the patient with ADHD should be treated with dexmethylphenidate hydrochloride extended-release. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use dexmethylphenidate hydrochloride extended-release for extended periods in patients with ADHD should periodically reevaluate the long-term usefulness of the drug for the individual patient with periods off medication to assess the patient’s functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued.

If paradoxical aggravation of symptoms or other adverse events occur, the dosage should be reduced, or, if necessary, the drug should be discontinued.

If improvement is not observed after appropriate dosage adjustment over a 1-month period, the drug should be discontinued.

Pregnancy Category C:

There are no adequate and well controlled studies of dexmethylphenidate hydrochloride in pregnant women. Dexmethylphenidate did not cause major malformations in rats or rabbits; however, it did cause delayed skeletal ossification and decreased postweaning weight gain in rats. Dexmethylphenidate hydrochloride extended-release should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 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.

Dexmethylphenidate hydrochloride extended-release has not been studied in labor and delivery.

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 extended-release is administered to a nursing woman. Information from 4 published case reports on the use of racemic methylphenidate during breastfeeding suggest that at maternal doses of 35 to 80 mg/day, milk concentrations of methylphenidate range from undetectable to 15.4 ng/mL. Based on these limited data, the calculated infant daily dose for an exclusively breastfed infant would be about 0.4 to 2.9 µg/kg/day or about 0.2 to 0.7% of the maternal weight adjusted dose.

The safety and efficacy of dexmethylphenidate hydrochloride extended-release in children under 6 years old have not been established. Long-term effects of dexmethylphenidate hydrochloride in children have not been well established [see Warnings and Precautions (5.13) ].

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 13-14), 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] of racemic methylphenidate 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 (12 times the racemic MRHD on a mg/m ² basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the racemic MRHD on a mg/m ² basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

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

Dexmethylphenidate hydrochloride extended-release is contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.

Dexmethylphenidate hydrochloride extended-release is contraindicated in patients known to be hypersensitive to methylphenidate, or other components of the product. Hypersensitivity reactions, including angioedema and anaphylactic reactions, have been observed in patients treated with methylphenidate [see Adverse Reactions (6.5 , 6.6 )].

Dexmethylphenidate hydrochloride extended-release is contraindicated in patients with glaucoma.

Dexmethylphenidate hydrochloride extended-release is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette’s syndrome [see Adverse Reactions (6.1) ].

Dexmethylphenidate hydrochloride extended-release 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).

Children and Adolescents

Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug.

Adults

Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs.

Stimulant medications cause a modest increase in average blood pressure (about 2 to 4 mmHg) and average heart rate (about 3 to 6 bpm), and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with preexisting hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.

Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.

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

Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3,482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients.

Aggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the post marketing experience of some medications indicated for the treatment of ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility.

Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication 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 7-week, double-blind, placebo-controlled study of dexmethylphenidate hydrochloride extended-release, the mean weight gain was greater for patients receiving placebo (+0.4 kg) than for patients receiving dexmethylphenidate hydrochloride extended-release (-0.5 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.

There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued.

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.

Stimulants, including dexmethylphenidate hydrochloride extended-release, 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 postmarketing 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.

Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.

Dexmethylphenidate hydrochloride extended-release should not be used in children under 6 years of age, since safety and efficacy in this age group have not been established.

Periodic CBC, differential, and platelet counts are advised during prolonged therapy.

Overall, 50 of 684 children treated with dexmethylphenidate hydrochloride immediate-release formulation (7.3%) experienced an adverse event 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). None of the 53 dexmethylphenidate hydrochloride extended-release-treated pediatric patients discontinued treatment due to adverse events in the 7-week, placebo-controlled study.

Table 1 enumerates treatment-emergent adverse events for the placebo-controlled, parallel-group study in children and adolescents with ADHD at flexible dexmethylphenidate hydrochloride extended-release 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 and for which the incidence in patients treated with dexmethylphenidate hydrochloride extended-release was at least twice the incidence in placebo-treated patients. 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 nondrug factors to the adverse event incidence rate in the population studied.

Table 2 below enumerates the incidence of dose-related adverse events that occurred during a fixed-dose, double-blind, placebo-controlled trial of dexmethylphenidate hydrochloride extended-release up to 30mg/day versus placebo in children and adolescents with ADHD.

In the adult placebo-controlled study, 10.7% of the dexmethylphenidate hydrochloride extended-release-treated patients and 7.5% of the placebo-treated patients discontinued for adverse events. Among dexmethylphenidate hydrochloride extended-release-treated patients, insomnia (1.8%, n=3), feeling jittery (1.8%, n=3), anorexia (1.2%, n=2), and anxiety (1.2%, n=2) were the reasons for discontinuation reported by more than 1 patient.

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

Two other adverse reactions occurring in clinical trials with dexmethylphenidate hydrochloride extended-release 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 in the treatment of ADHD.

The following additional adverse reactions have been identified during postapproval use of dexmethylphenidate hydrochloride extended-release. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency:

Musculoskeletal : rhabdomyolysis

Immune System Disorders : hypersensitivity reactions, including angioedema and anaphylaxis

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, serotonin syndrome in combination with serotonergic drugs, toxic psychosis

Vascular: blood pressure increased or decreased, cerebral arteritis and/or occlusion

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 severe hepatic injury

Psychiatric: transient depressed mood, aggressive behavior, libido changes

Skin/Subcutaneous: scalp hair loss

Urogenital: priapism

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 10-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.

Dexmethylphenidate hydrochloride, the active ingredient in dexmethylphenidate hydrochloride extended-release, is a central nervous system stimulant. Dexmethylphenidate, the more pharmacologically active d- enantiomer of racemic 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. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known.

Effects on QT Interval

The effect of dexmethylphenidate hydrochloride extended-release on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of dexmethylphenidate hydrochloride extended-release 40 mg in 75 healthy volunteers. ECGs were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was <5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident-exposure response relationship.

Absorption

Dexmethylphenidate hydrochloride extended-release produces a bi-modal plasma concentration-time profile (i.e., 2 distinct peaks approximately 4 hours apart) when orally administered to healthy adults. The initial rate of absorption for dexmethylphenidate hydrochloride extended-release is similar to that of dexmethylphenidate hydrochloride tablets as shown by the similar rate parameters between the 2 formulations, i.e., first peak concentration (C _max1 ), and time to the first peak (t _max1 ), which is reached in 1.5 hours (typical range 1 to 4 hours). The mean time to the interpeak minimum (t _minip ) is slightly shorter, and time to the second peak (t _max2 ) is slightly longer for dexmethylphenidate hydrochloride extended-release given once daily (about 6.5 hours, range 4.5 to 7 hours) compared to dexmethylphenidate hydrochloride tablets given in 2 doses 4 hours apart (see Figure 1), although the ranges observed are greater for dexmethylphenidate hydrochloride extended-release.

Dexmethylphenidate hydrochloride extended-release given once daily exhibits a lower second peak concentration (C _max2 ), higher interpeak minimum concentrations (C _minip ), and fewer peak and trough fluctuations than dexmethylphenidate hydrochloride tablets given in 2 doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1).

The AUC (exposure) after administration of dexmethylphenidate hydrochloride extended-release given once daily is equivalent to the same total dose of dexmethylphenidate hydrochloride tablets given in 2 doses 4 hours apart. The variability in C _max , C _min , and AUC is similar between dexmethylphenidate hydrochloride extended-release and dexmethylphenidate hydrochloride IR with approximately a 3-fold range in each.

Radiolabeled racemic methylphenidate is well absorbed after oral administration with approximately 90% of the radioactivity recovered in urine. However, due to first pass metabolism the mean absolute bioavailability of dexmethylphenidate when administered in various formulations was 22% to 25%.

Dose Proportionality

Dose proportionality of dexmethylphenidate hydrochloride extended-release was evaluated in a randomized, single-dose, 5-period, cross-over study with administration of single doses of 5, 10, 20, 30, and 40 mg to healthy adults. Results confirmed dose proportionality within this dose range.

Food Effects

Administration times relative to meals and meal composition may need to be individually titrated.

No food effect study was performed with dexmethylphenidate hydrochloride extended-release. However, the effect of food has been studied in adults with racemic methylphenidate in the same type of extended-release formulation. The findings of that study are considered applicable to dexmethylphenidate hydrochloride extended-release. After a high fat breakfast, there was 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 is no evidence of dose dumping in the presence or absence of food. There were no differences in the plasma concentration-time profile, when administered with applesauce, compared to administration in the fasting condition. The results are expected not to differ for dexmethylphenidate hydrochloride extended-release.

For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered [see Dosage and Administration (2) ].

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. Plasma dexmethylphenidate concentrations decline monophasically following oral administration of dexmethylphenidate hydrochloride extended-release.

Metabolism and Excretion

In humans, dexmethylphenidate is metabolized primarily to d-α -phenyl-piperidine acetic acid (also known as d -ritalinic acid) by de-esterification. This metabolite has little or no pharmacological activity. There is no in vivo interconversion to the l-threo -enantiomer, based on a finding of no levels of l-threo -methylphenidate being detectable after administration of up to 40 mg dexmethylphenidate in adults. After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite of racemic ( d,l -) methylphenidate was d,l -ritalinic acid, accountable for approximately 80% of the dose. Urinary excretion of parent compound accounted for 0.5% of an intravenous dose.

In vitro studies showed that dexmethylphenidate did not inhibit cytochrome P450 isoenzymes at concentrations observed after therapeutic doses.

Intravenous dexmethylphenidate was eliminated with a mean clearance of 0.40±0.12 L/kg.h ^- 1 corresponding to 0.56±0.18 L/min. The mean terminal elimination half-life of dexmethylphenidate was just over 3 hours in healthy adults and typically varied between 2 and 4.5 hours with an occasional subject exhibiting a terminal half-life between 5 and 7 hours. Children tend to have slightly shorter half-lives with means of 2 to 3 hours.

Special Populations

Gender

After administration of dexmethylphenidate hydrochloride extended-release the first peak, (C _max1 ), was on average 45% higher in women. The interpeak minimum and the second peak also tended to be slightly higher in women although the difference was not statistically significant, and these patterns remained even after weight normalization. Pharmacokinetic parameters for dexmethylphenidate after dexmethylphenidate hydrochloride immediate-release tablets were similar for boys and girls.

Race

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

Age

The pharmacokinetics of dexmethylphenidate after dexmethylphenidate hydrochloride extended-release administration have not been studied in children less than 18 years of age. When a similar formulation of racemic methylphenidate was examined in 15 children between 10 and 12 years of age and 3 children with ADHD between 7 and 9 years of age, the time to the first peak was similar, although 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 administration of the same dose to children and adults, concentrations in children were approximately twice the concentrations observed in adults. This higher exposure is almost completely due to smaller body size as no relevant age-related differences in dexmethylphenidate pharmacokinetic parameters (i.e., clearance and volume of distribution) are observed after normalization to dose and weight.

Renal Insufficiency

There is no experience with the use of dexmethylphenidate hydrochloride extended-release in patients with renal insufficiency. After oral administration of radiolabeled racemic methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of racemic ritalinic acid which is pharmacologically inactive. Very little unchanged drug is excreted in the urine, thus renal insufficiency is expected to have little effect on the pharmacokinetics of dexmethylphenidate hydrochloride extended-release.

Hepatic Insufficiency

There is no experience with the use of dexmethylphenidate hydrochloride extended-release in patients with hepatic insufficiency [see Drug Interactions (7) ].

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 at a daily dose of approximately 60 mg/kg/day. 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.

In a 24-week study of racemic methylphenidate in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. 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, the in vitro mouse lymphoma cell forward mutation assay, or the in vivo mouse bone marrow micronucleus test.

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

Impairment of Fertility

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.

The effectiveness of dexmethylphenidate hydrochloride extended-release was established in a randomized, double-blind, placebo-controlled, parallel-group study in 103 pediatric patients (ages 6 to 12, n=86; ages 13 to 17, n=17) who met DSM-IV criteria for ADHD. Patients were randomized to receive either a flexible dose of dexmethylphenidate hydrochloride extended-release (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 in the last 2 weeks of the study patients remained on their optimal dose 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– 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).

There was a statistically significant treatment effect in favor of dexmethylphenidate hydrochloride extended-release. There were insufficient adolescents enrolled in this study to assess the efficacy for dexmethylphenidate hydrochloride extended-release in the adolescent population. However, pharmacokinetic considerations and evidence of effectiveness of immediate-release dexmethylphenidate hydrochloride in adolescents support the effectiveness of dexmethylphenidate hydrochloride extended-release in this population.

In 2 additional studies in pediatric patients aged 6 to 12 years who received 20 mg dexmethylphenidate hydrochloride extended-release or placebo in a cross-over design, dexmethylphenidate hydrochloride extended-release was found to have a statistically significant treatment effect versus placebo on the Swanson, Kotkin, Agler, M-Flynn & Pelham (SKAMP) rating scale combined score at all time points after dosing in each study (0.5, 1, 3, 4, 5, 7, 9, 10, 11, and 12 hours in one study and 1, 2, 4, 6, 8, 9, 10, 11, and 12 hours in the other study). A treatment effect was also observed 0.5 hours after administration of dexmethylphenidate hydrochloride extended-release 20 mg in an additional study of ADHD patients aged 6 to 12 years. The SKAMP is a reliable and validated scale that assesses specific classroom behaviors related to attention (e.g., getting started, sticking with activities, completing work, and stopping for transition) and deportment or behavior (e.g., remaining quiet, remaining seated, interacting with other students, and interacting with the teacher.) Each item is rated on a 7-point impairment scale, and an average rating per item is calculated for the subscales of Attention and Deportment.

The effectiveness of dexmethylphenidate hydrochloride extended-release was established in a randomized, double-blind, placebo-controlled, parallel-group study in 221 adult patients (ages 18 to 60) who met DSM-IV criteria for ADHD. Patients were randomized to receive either a fixed dose of dexmethylphenidate hydrochloride extended-release (20, 30, or 40 mg/day) or placebo once daily for 5 weeks. Patients randomized to dexmethylphenidate hydrochloride extended-release 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– 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).

All three dexmethylphenidate hydrochloride extended-release doses were statistically significantly superior to placebo. There was no obvious increase in effectiveness with increasing dose.