DEXMETHYLPHENIDATE HYDROCHLORIDE- dexmethylphenidate hydrochloride tablet
Rhodes Pharmaceuticals L.P.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Dexmethylphenidate Hydrochloride Tablets safely and effectively. See full prescribing information for Dexmethylphenidate Hydrochloride Tablets.
Dexmethylphenidate Hydrochloride Tablets, for oral use. CII
Initial U.S. Approval: 2001
WARNING: ABUSE AND DEPENDENCE
See full prescribing information for complete boxed warning.
RECENT MAJOR CHANGES
INDICATIONS AND USAGE
Dexmethylphenidate hydrochloride tablets are a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) (1).
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Tablets: 2.5, 5, and 10 mg (3)
WARNINGS AND PRECAUTIONS
The most common adverse reactions (greater than or equal to 5% and twice the rate of placebo) in pediatric patients 6 to 17 years were abdominal pain, fever, nausea, and anorexia (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Rhodes Pharmaceuticals L.P. at 1-888-827-0616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
FULL PRESCRIBING INFORMATION: CONTENTS*
Dexmethylphenidate Hydrochloride Tablets are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) [see Clinical Studies (14)].
Prior to treating pediatric patients and adults with central nervous system (CNS) stimulants, including dexmethylphenidate hydrochloride tablets, assess for the presence of cardiac disease (i.e., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions 5.2].
Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically reevaluate the need for dexmethylphenidate hydrochloride tablets use [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].
Patients New to Methylphenidate
The recommended starting dose of dexmethylphenidate hydrochloride tablets for pediatric patients who are not currently taking racemic methylphenidate, or for patients who are on stimulants other than methylphenidate, is 5 mg daily (2.5 mg twice daily) with or without food.
Patients Currently on Methylphenidate
The recommended starting dose of dexmethylphenidate hydrochloride tablets for pediatric patients currently using methylphenidate is half the total daily dose of racemic methylphenidate.
The dose may be titrated weekly in increments of 2.5 to 5 mg to a maximum of 20 mg daily (10 mg twice daily). The dose should be individualized according to the needs and response of the patient.
Dexmethylphenidate hydrochloride tablets are administered orally twice daily, at least 4 hours apart.
If paradoxical aggravation of symptoms or other adverse reactions occur, reduce the dosage, or if necessary, discontinue dexmethylphenidate hydrochloride tablets. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.
Dexmethylphenidate hydrochloride tablets are available as follows:
Sudden death, stroke, and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in pediatric patients with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during dexmethylphenidate hydrochloride tablets treatment.
CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.
Exacerbation of Pre-Existing Psychosis
CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.
Induction of a Manic Episode in Patients with Bipolar Disorder
CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).
New Psychotic or Manic Symptoms
CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing dexmethylphenidate hydrochloride tablets. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared to 0 in placebo-treated patients.
Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.
CNS stimulants, including dexmethylphenidate hydrochloride tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud's phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.
CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.
Careful follow-up of weight and height in 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 consistently medicated pediatric patients (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development.
Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including dexmethylphenidate hydrochloride tablets, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.
The following are discussed in more detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Clinical Trials Experience with Dexmethylphenidate Hydrochloride Tablets in Pediatric Patients with ADHD
The safety data in this section is based on data related to dexmethylphenidate hydrochloride tablets exposure during the premarketing development program in a total of 696 participants in clinical trials (684 patients, 12 healthy adult subjects). These participants received dexmethylphenidate hydrochloride tablets 5, 10, or 20 mg/day. The 684 ADHD patients (ages 6 to 17 years) were evaluated in 2 controlled clinical studies, 2 clinical pharmacology studies, and 2 open-label long-term safety studies.
Most Common Adverse Reactions (incidence of greater than or equal to 5% and at least twice placebo): abdominal pain, fever, anorexia, and nausea.
Adverse Reactions Leading to Discontinuation: Overall, 50 of 684 (7.3%) pediatric patients treated with dexmethylphenidate hydrochloride 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 two, placebo-controlled, parallel group studies in pediatric patients with ADHD taking dexmethylphenidate hydrochloride tablets doses of 5, 10, and 20 mg/day. The table includes only those reactions that occurred in patients treated with dexmethylphenidate hydrochloride tablets for which the incidence was at least 5% and twice the incidence among placebo-treated patients.
|System Organ Class||Adverse Reactions||Dexmethylphenidate hydrochloride tablets|
|Body as a Whole||Abdominal pain||15%||6%|
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.
Immune System Disorders: hypersensitivity reactions such as angioedema, anaphylactic reactions
Adverse Reactions Reported with all Ritalin and Dexmethylphenidate Hydrochloride Tablets Formulations
The following adverse reactions associated with the use of all Ritalin and dexmethylphenidate hydrochloride tablets formulations were identified in clinical trials, spontaneous reports, and literature. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.
Infections and Infestations: nasopharyngitis
Blood and the Lymphatic System Disorders: leukopenia, thrombocytopenia, anemia
Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis
Metabolism and Nutrition Disorders: decreased appetite, reduced weight gain, and suppression of growth during prolonged use in pediatric patients
Psychiatric Disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood
Nervous System Disorders: headache, dizziness, tremor, dyskinesia including choreoatheetoid movements, drowsiness, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages, and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs
Eye Disorders: blurred vision, difficulties in visual accommodation
Cardiac Disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris
Respiratory, Thoracic, and Mediastinal Disorders: cough
Gastrointestinal Disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia
Hepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury
Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura
Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramps, rhabdomyolysis
Investigations: weight loss (adult ADHD patients)
Additional Adverse Reactions Reported with Other Methylphenidate-Containing Products
The list below shows adverse reactions not listed with Ritalin and dexmethylphenidate hydrochloride tablets formulations [see Adverse Reactions (6.2)] that have been reported with other methylphenidate products based on clinical trials data and postmarketing spontaneous reports.
Blood and Lymphatic Disorders: pancytopenia
Immune System Disorders: hypersensitivity reactions such as auricular swelling
Psychiatric Disorders: affect lability, mania, disorientation, libido changes
Nervous System Disorders: migraine
Eye Disorders: diplopia, mydriasis
Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole, supraventricular tachycardia, ventricular extrasystole
Vascular Disorders: peripheral coldness, Raynaud's phenomenon
Respiratory, Thoracic, and Mediastinal Disorders: pharyngolaryngeal pain, dyspnea
Gastrointestinal Disorders: diarrhea, constipation
Skin and Subcutaneous Tissue Disorders: angioneurotic edema, erythema, fixed drug eruption
Musculoskeletal, Connective Tissue, and Bone Disorders: myalgia, muscle twitching
Renal and Urinary Disorders: hematuria
Reproductive System and Breast Disorders: gynecomastia
General disorders: fatigue
Urogenital disorders: priapism
Table 2 presents clinically important drug interactions with dexmethylphenidate hydrochloride tablets.
|Monoamine Oxidase Inhibitors (MAOI)|
|Clinical Impact||Concomitant use of MAOIs and CNS stimulants, including dexmethylphenidate hydrochloride tablets, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications (4)].|
|Intervention||Concomitant use of dexmethylphenidate hydrochloride tablets with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated.|
|Examples||selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue|
|Clinical Impact||Dexmethylphenidate hydrochloride tablets may decrease the effectiveness of drugs used to treat hypertension [see Warnings and Precautions (5.3)].|
|Intervention||Adjust the dosage of the antihypertensive drug as needed.|
|Examples||Potassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, centrally acting alpha-2 receptor agonists|
|Clinical Impact||Concomitant use of halogenated anesthetics and dexmethylphenidate hydrochloride tablets may increase the risk of sudden blood pressure and heart rate increase during surgery.|
|Intervention||Monitor blood pressure and avoid use of dexmethylphenidate hydrochloride tablets in patients being treated with anesthetics on the day of surgery.|
|Examples||halothane, isoflurane, enflurane, desflurane, sevoflurane|
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including dexmethylphenidate hydrochloride tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy registry for ADHD medications at 1-866-961-2388 or visit https://womensmentalhealth.org/adhd-medications/.
Dexmethylphenidate is the d-threo enantiomer of racemic methylphenidate. Published studies and postmarketing 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 use 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. Plasma levels in adults were comparatively similar to plasma levels in adolescents (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.
Fetal/Neonatal Adverse Reactions
CNS stimulants such as dexmethylphenidate hydrochloride tablets, 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.
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 (AUCs) of dexmethylphenidate in pregnant rats and rabbits were approximately 5 and 1 times, respectively, those in adults dosed with the MRHD of 20 mg/day.
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.
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 between 1.1 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 tablets and any potential adverse effects on the breastfed infant from dexmethylphenidate hydrochloride tablets or from the underlying maternal condition.
The safety and effectiveness of dexmethylphenidate hydrochloride tablets have been established in pediatric patients ages 6 to 17 years in two adequate and well-controlled trials [see Clinical Studies (14)]
The safety and effectiveness of dexmethylphenidate hydrochloride tablets in pediatric patients less than 6 years have not been established.
The long-term efficacy of dexmethylphenidate hydrochloride tablets in pediatric patients has not been established.
Long Term Suppression of Growth
Growth should be monitored during treatment with stimulants, including dexmethylphenidate hydrochloride tablets. 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/m2 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 to 14), 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 of racemic methylphenidate given to children 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 (8 times the MRHD given to children on a mg/m2 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/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
Dexmethylphenidate hydrochloride tablets contain dexmethylphenidate hydrochloride, a Schedule II controlled substance.
CNS stimulants including dexmethylphenidate hydrochloride tablets, other methylphenidate-containing products, and amphetamines have a high potential for abuse. Abuse is characterized by impaired control over drug use despite harm and craving.
Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, suicidal or homicidal ideation have also been observed. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which may result in overdose and death [see Overdosage (10)].
To reduce the abuse of CNS stimulants including dexmethylphenidate hydrochloride tablets, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants [see How Supplied/Storage and Handling (16)], monitor for signs of abuse while on therapy, and re-evaluate the need for dexmethylphenidate hydrochloride tablets use.
Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug's desired and/or undesired effects over time) can occur during chronic therapy with CNS stimulants, including dexmethylphenidate hydrochloride tablets.
Physical dependence (which is manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) can occur in patients treated with CNS stimulants including dexmethylphenidate hydrochloride tablets. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.
Signs and symptoms of acute methylphenidate overdosage, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis, dryness of mucous membranes, and rhabdomyolysis.
Dexmethylphenidate Hydrochloride Tablets contain dexmethylphenidate hydrochloride, a CNS stimulant. Dexmethylphenidate hydrochloride is the d-threo enantiomer of racemic methylphenidate hydrochloride. Dexmethylphenidate Hydrochloride Tablets are available as 2.5 mg, 5 mg, and 10 mg strength tablets for oral administration.
Chemically, dexmethylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, (R,R')-(+)-. Its molecular formula is C14H19NO2∙HCl. Its structural formula is:
Note: *=asymmetric carbon centers
Dexmethylphenidate hydrochloride is a white to off-white powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77 g/mol.
Inactive Ingredients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, pregelatinized starch, magnesium stearate, and FD&C Blue No.1 aluminum lake (2.5 mg tablets), D&C Yellow Lake #10 (5 mg tablets); the 10 mg tablet contains no dye.
Dexmethylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD is not known.
Dexmethylphenidate is the more pharmacologically active d-enantiomer of racemic methylphenidate. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.
A formal QT study has not been conducted in patients taking dexmethylphenidate hydrochloride tablets; however, a large QT effect is not expected. At the recommended maximum total daily dosage of 40 mg, dexmethylphenidate hydrochloride tablets do not prolong the QTc interval to any clinically relevant extent.
Dexmethylphenidate hydrochloride is readily absorbed following oral administration of dexmethylphenidate hydrochloride tablets. In patients with ADHD, plasma dexmethylphenidate concentrations increase rapidly, reaching a maximum in the fasted state at about 1 to 1.5 hours postdose. No differences in the pharmacokinetics of dexmethylphenidate hydrochloride tablets were noted following single and repeated twice daily dosing, thus indicating no significant drug accumulation in children with ADHD.
After single dose administration of dexmethylphenidate hydrochloride tablets to pediatric patients, dexmethylphenidate exposure (Cmax and AUC0-inf) showed dose-proportional increase in the range of 2.5 mg to 10 mg. Comparable plasma dexmethylphenidate levels were achieved following single dl-threo-methylphenidate HCl doses given as capsules in twice the total mg amount (equimolar with respect to dexmethylphenidate hydrochloride tablets).
Approximately 90% of the dose is absorbed after oral administration of radiolabeled racemic methylphenidate. However, due to first pass metabolism, the mean absolute bioavailability of dexmethylphenidate, when administered in various formulations, was 22% to 25%.
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 declined exponentially following oral administration of dexmethylphenidate hydrochloride tablets. Intravenous dexmethylphenidate was eliminated with a mean clearance of 0.40 ± 0.12 L/hr/kg. The mean terminal elimination half-life of dexmethylphenidate was approximately 2.2 hours.
In humans, dexmethylphenidate is metabolized primarily via de-esterification to d-α-phenyl-piperidine acetic acid (also known as d-ritalinic acid). This metabolite has little or no pharmacological activity. There is little or no in vivo interconversion to the l-threo-enantiomer.
After oral dosing of radiolabeled racemic methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite of racemic dl-methylphenidate was dl-ritalinic acid, accountable for approximately 80% of the dose. Urinary excretion of parent compound accounted for 0.5% of an intravenous dose.
Studies in Special Populations
Male and Female Patients
Pharmacokinetic parameters were similar for boys and girls (mean age 10 years).
In a single dose study conducted in adults, the mean dexmethylphenidate AUC0-inf values (adjusted for body weight) following single two 10 mg doses of dexmethylphenidate hydrochloride tablets were 25% to 35% higher in adult female volunteers (n = 6) compared to male volunteers (n = 9). Both tmax and t1/2 were comparable for males and females.
Racial or Ethnic Groups
There is insufficient experience with the use of dexmethylphenidate hydrochloride tablets to detect ethnic variations in pharmacokinetics.
The pharmacokinetics of dexmethylphenidate after dexmethylphenidate hydrochloride tablets administration have not been studied in children less than 6 years of age. When single doses of dexmethylphenidate hydrochloride tablets were given to children between the ages of 6 to 12 years and healthy adult volunteers, Cmax of dexmethylphenidate was similar, however, pediatric patients showed somewhat lower AUCs compared to the adults.
Patients with Renal Impairment
There is no experience with the use of dexmethylphenidate hydrochloride tablets in patients with renal impairment. Since renal clearance is not an important route of methylphenidate clearance, renal impairment is expected to have little effect on the pharmacokinetics of dexmethylphenidate hydrochloride tablets.
Drug Interaction Studies
Methylphenidate is not metabolized by cytochrome P450 (CYP) isoenzymes to a clinically relevant extent. Inducers or inhibitors of CYPs are not expected to have any relevant impact on methylphenidate pharmacokinetics. Conversely, the d- and l-enantiomers of methylphenidate did not relevantly inhibit CYP1A2, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A. Clinically, methylphenidate coadministration did not increase plasma concentrations of the CYP2D6 substrate desipramine.
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/m2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors and the significance of these results to humans is unknown.Racemic methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) of 60 mg/day of racemic methylphenidate on a mg/m2 basis.
In a 24-week carcinogenicity study with racemic methylphenidate in the transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no evidence of carcinogenicity. Male and female mice were fed diets containing the same concentrations as in the lifetime carcinogenicity study; the high-dose group was exposed to 60 to 74 mg/kg/day of racemic methylphenidate.
Dexmethylphenidate was not mutagenic in the in vitro Ames reverse mutation assay, in the in vitro mouse lymphoma cell forward mutation assay, or in the in vivo mouse bone marrow micronucleus test. In an in vitro assay using cultured Chinese Hamster Ovary (CHO) cells treated with racemic methylphenidate, sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response.
Impairment of Fertility
No human data on the effect of methylphenidate on fertility are available.
Fertility studies have not been conducted with dexmethylphenidate. Racemic methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week continuous breeding study. The study was conducted at doses of up to 160 mg/kg/day, approximately 10 times the maximum recommended human dose of 60 mg/day of racemic methylphenidate given adolescents on a mg/m2 basis.
The efficacy of dexmethylphenidate hydrochloride tablets for the treatment of ADHD was established in two double-blind, parallel-group, placebo controlled trials in untreated or previously treated patients (ages 6 to 17 years old) who met DSM-IV criteria for ADHD inattentive, hyperactive-impulsive, or combined inattentive/hyperactive-impulsive subtypes. The sample was predominantly younger (ages 6 to 12 years); thus, the findings are most pertinent to this age group.
In Study 1, patients were randomized to receive either dexmethylphenidate hydrochloride tablets (5, 10, or 20 mg/day total dose), racemic methylphenidate HCl (10, 20, or 40 mg/day total dose), or placebo in a multicenter, 4-week, parallel group study in 132 pediatric patients. Patients received study medication twice daily separated by a 3.5 to 5.5 hours interval. Treatment was initiated with the lowest dose, and doses could be doubled at weekly intervals, depending on clinical response and tolerability, up to the maximum dose. The primary outcome was change from baseline to week 4 of the average score (an average of 2 ratings during the week) of the teacher's version of the SNAP-ADHD Rating Scale. This 18 item scale measures ADHD symptoms of inattention and hyperactivity/impulsivity, rated on a scale of 0 (Not at All) to 3 (Very Much). Patients treated with dexmethylphenidate hydrochloride tablets showed a statistically significant improvement in symptom scores from baseline over patients who received placebo (Table 3).
|Study Number||Treatment Group||Primary Efficacy Measure: Teacher SNAP-ADHD Total Score*|
|Mean Baseline Score (SD)||Mean Change from Baseline Week 4 Score (SD)|
|ADHD: Attention Deficit Hyperactivity Disorder; SD: standard deviation; n = number of patients available at the assessment time point.|
|Study 1||Dexmethylphenidate hydrochloride tablets 5 to 20 mg/day† (n=44)||1.4 (0.7) (n=42)||-0.7 (0.7) (n=42)|
|Placebo (n=42)||1.6 (0.7) (n=41)||-0.2 (0.7) (n=39)|
Study 2 was a multicenter, placebo-controlled, double-blind, 2-week treatment withdrawal study in 75 children (ages 6 to 12 years) who were responders during a 6-week, open-label initial treatment period. Children took study medication twice a day separated by a 3.5 to 5.5 hour interval. The primary outcome was proportion of treatment failures at the end of the 2-week withdrawal phase, where treatment failure was defined as a rating of 6 (much worse) or 7 (very much worse) on the Investigator Clinical Global Impression - Improvement (CGI-I). Patients continued on dexmethylphenidate hydrochloride tablets showed a statistically significant lower rate of failure over patients who received placebo (Table 4).
|Study Number||Treatment Group||Primary Efficacy Measure: Proportion of Treatment Failure*|
|Number of Treatment Failures/Number of Randomized Patients||Percentage|
|ADHD: Attention Deficit Hyperactivity Disorder|
|Study 2||Dexmethylphenidate hydrochloride tablets 5 to 20 mg/day†||6/35||17.1%|
Dexmethylphenidate Hydrochloride Tablets are available as follows:
Blue, round, biconvex tablet, debossed with "11" on one side and "RP" on the other side.
|Bottles of 100||NDC 42858-011-01|
Yellow, round, biconvex tablet, debossed with "14" on one side and "RP" on the other side
|Bottles of 100||NDC 42858-225-01|
White, round, biconvex tablet, debossed with "17" on one side and "RP" on the other side
|Bottles of 100||NDC 42858-410-01|
Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].
Protect from light and moisture.
Keep this and all medication out of the reach of children.
Dispense in a tight, light-resistant container as defined in the USP, using a child-resistant closure.
Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired dexmethylphenidate hydrochloride tablets by a medicine take-back program or by an authorized collector registered with the Drug Enforcement Administration. If no take-back program or authorized collector is available, mix dexmethylphenidate hydrochloride tablets with an undesirable, nontoxic substance to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and discard dexmethylphenidate hydrochloride tablets in the household trash.
Advise patients to read the FDA-approved patient labeling (Medication Guide).
Controlled Substance Status/High Potential for Abuse and Dependence
Advise patients that dexmethylphenidate hydrochloride tablets are a controlled substance, and can be abused and lead to dependence. Instruct patients that they should not give dexmethylphenidate hydrochloride tablets to anyone else. Advise patients to store dexmethylphenidate hydrochloride tablets in a safe place, preferably locked, to prevent abuse. Advise patients to comply with laws and regulations on drug disposal. Advise patients to dispose of remaining, unused, or expired dexmethylphenidate hydrochloride tablets by a medicine take-back program if available [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.1, 9.2, and 9.3), How Supplied/Storage and Handling (16)].
Serious Cardiovascular Risks
Advise patients that there is a potential serious cardiovascular risk including sudden death, myocardial infarction, stroke, and hypertension with dexmethylphenidate hydrochloride tablets use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2)].
Blood Pressure and Heart Rate Increases
Instruct patients that dexmethylphenidate hydrochloride tablets can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions (5.3)].
Advise patients that dexmethylphenidate hydrochloride tablets, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)].
Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct them to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.5)].
Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, Including Raynaud's Phenomenon]
Instruct patients beginning treatment with dexmethylphenidate hydrochloride tablets about the risk of peripheral vasculopathy, including Raynaud's phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.
Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking dexmethylphenidate hydrochloride tablets. Further clinical evaluation (e.g. rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6)].
Suppression of Growth
Advise patients that dexmethylphenidate hydrochloride tablets may cause slowing of growth and weight loss [see Warnings and Precautions (5.7)].
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ADHD medications, including dexmethylphenidate hydrochloride tablets, during pregnancy [see Use in Specific Population (8.1)].
Rhodes Pharmaceuticals L.P.
Coventry, RI 02816
Purdue Pharmaceuticals L.P.
Stamford, CT 06901
DEXMETHYLPHENIDATE HYDROCHLORIDE TABLETS, CII
(dex meth ill FEN i date) (hye" droe klor'ide)
|This Medication Guide has been approved by the U.S. Food and Drug Administration||Revised: 11/2019|
|What is the most important information I should know about dexmethylphenidate hydrochloride tablets?
Dexmethylphenidate hydrochloride tablets are a federal controlled substance (CII) because it can be abused or lead to dependence. Keep dexmethylphenidate hydrochloride tablets in a safe place to prevent misuse and abuse. Selling or giving away dexmethylphenidate hydrochloride tablets may harm others, and is against the law.
Tell your doctor if you or your child have abused or been dependent on alcohol, prescription medicines, or street drugs.
The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines.
|1. Heart-related problems:
|Tell your doctor if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems.
Your doctor should check you or your child carefully for heart problems before starting dexmethylphenidate hydrochloride tablets.
Your doctor should check you or your child's blood pressure and heart rate regularly during treatment with dexmethylphenidate hydrochloride tablets.
Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking dexmethylphenidate hydrochloride tablets.
|2. Mental (Psychiatric) problems:
|Tell your doctor about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression.
Call your doctor right away if you or your child have any new or worsening mental symptoms or problems while taking dexmethylphenidate hydrochloride tablets, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious.
|What are dexmethylphenidate hydrochloride tablets?
|Who should not take dexmethylphenidate hydrochloride tablets:
Dexmethylphenidate hydrochloride tablets should not be taken if you or your child:
|Dexmethylphenidate hydrochloride tablets may not be right for you or your child. Before starting dexmethylphenidate hydrochloride tablets tell your or your child's doctor about all health conditions (or a family history of) including:
Dexmethylphenidate hydrochloride tablets and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking dexmethylphenidate hydrochloride tablets.
Your doctor will decide whether dexmethylphenidate hydrochloride tablets can be taken with other medicines.
Especially tell your doctor if you or your child takes:
|How should dexmethylphenidate hydrochloride tablets be taken?
|What are the possible side effects of dexmethylphenidate hydrochloride tablets?
Dexmethylphenidate hydrochloride tablets may cause serious side effects, including:
|Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.|
|How should I store dexmethylphenidate hydrochloride tablets?
|General information about the safe and effective use of dexmethylphenidate hydrochloride tablets.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or doctor for information about dexmethylphenidate hydrochloride tablets that is written for healthcare professionals. Do not use dexmethylphenidate hydrochloride tablets for a condition for which it was not prescribed. Do not give dexmethylphenidate hydrochloride tablets to other people, even if they have the same symptoms that you have. It may harm them and it is against the law.
|What are the ingredients in dexmethylphenidate hydrochloride tablets?
Active ingredient: dexmethylphenidate hydrochloride
Inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, pregelatinized starch, magnesium stearate, and FD&C Blue No.1 aluminum lake (2.5 mg tablets), D&C Yellow Lake #10 (5 mg tablets); the 10 mg tablet contains no dye.
Rhodes Pharmaceuticals L.P.
Coventry, RI 02816
For more information, call 1-888-827-0616.
Dispense the accompanying
Medication Guide to each patient.
Dispense the accompanying
Medication Guide to each patient.
dexmethylphenidate hydrochloride tablet
dexmethylphenidate hydrochloride tablet
dexmethylphenidate hydrochloride tablet
|Labeler - Rhodes Pharmaceuticals L.P. (831928986)|
|Purdue Pharmaceuticals L.P.||132080875||MANUFACTURE(42858-011, 42858-225, 42858-410)|