Dexmethylphenidate ER Capsule

Agitation

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

Hypersensitivity to Methylphenidate

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)].

Glaucoma

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

Tics

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)].

Monoamine Oxidase Inhibitors

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).

Dexmethylphenidate hydrochloride extended-release was administered to 46 children and 7 adolescents with ADHD for up to 7 weeks and 206 adults with ADHD in clinical studies. During the clinical studies, 101 adult patients were treated for at least 6 months.

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

Adverse Events Associated with Discontinuation of Treatment in Acute Clinical Studies with Dexmethylphenidate Hydrochloride Extended-Release-Children

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.

Adverse Events Occurring at an Incidence of 5% or More Among Dexmethylphenidate Hydrochloride Extended-Release-Treated Patients-Children

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.

Adverse Events Associated with Discontinuation of Treatment in Clinical Studies with Dexmethylphenidate Hydrochloride Extended-Release-Adults

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.

Adverse Events Occurring at an Incidence of 5% or More Among Dexmethylphenidate Hydrochloride Extended-Release-Treated Patients-Adults

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.

Postmarketing Experience

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

Adverse Events with Other Methylphenidate HCl Dosage Forms

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

Other reactions include:

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

Gastrointestinal: abdominal pain, nausea

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

Metabolism/Nutrition: anorexia, weight loss during prolonged therapy

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

Vascular: blood pressure increased or decreased, 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 hepatic coma

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.

Pregnancy

Teratogenic Effects: 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.

Labor and Delivery

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

Nursing Mothers

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 mcg/kg/day or about 0.2 to 0.7% of the maternal weight adjusted dose.

Pediatric Use

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

Geriatric Use

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

Mechanism of Action

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.

Pharmacodynamics

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.

Pharmacokinetics

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 (Cmax1), and time to the first peak (tmax1), which is reached in 1.5 hours (typical range 1 to 4 hours). The mean time to the interpeak minimum (tminip) is slightly shorter, and time to the second peak (tmax2) 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 (Cmax2), higher interpeak minimum concentrations (Cminip), 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 Cmax, Cmin, 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%.

Figure 1. Mean Dexmethylphenidate Plasma Concentration-Time Profiles After Administration of 1 x 20 mg Dexmethylphenidate Hydrochloride Extended-Release (n=24) Capsules and 2 x 10 mg Dexmethylphenidate Hydrochloride Immediate-Release Tablets (n=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, (Cmax1), 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)].

Dexmethylphenidate hydrochloride extended-release capsules contain white to off-white pellets and are available as follows:

5 mg –  Size 2 capsule with white opaque body and light purple opaque cap printed with  and 804 in black ink on both cap and body. Capsules are supplied in bottles of 100 (NDC 45963-804-11).

10 mg -  Size 2 capsule with white opaque body and dark purple opaque cap printed with  and 805 in black ink on both cap and body. Capsules are supplied in bottles of 100 (NDC 45963-805-11).

15 mg - Size 2 capsule with white opaque body and light pink opaque cap printed with  and 806 in black ink on both cap and body.  Capsules are supplied in bottles of 100 (NDC 45963-806-11).

20 mg - Size 0 capsule with white opaque body and dark pink opaque cap printed with  and 807 in black ink on both cap and body.  Capsules are supplied in bottles of 100 (NDC 45963-807-11).

30 mg - Size 00 capsule with white opaque cap and body printed with and 833 in black ink on both cap and body.  Capsules are supplied in bottles of 100 (NDC 45963-833-11).

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP.

Dexmethylphenidate Hydrochloride Extended-Release Capsules CII 5 mg, 100s Label Text

actavis

NDC 45963-804-11

Rx Only

Dexmethylphenidate

Hydrochloride

Extended-Release

Capsules

5 mg

CII

PHARMACIST: Dispense the Medication Guide

provided separately to each patient.

100 capsules