ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. The premarketing development program for methylphenidate hydrochloride extended-release capsules included exposures in total of 228 participants in clinical trials (188 pediatric patients with ADHD, 40 healthy adult subjects). These participants received methylphenidate hydrochloride extended-release capsules 20, 40, and/or 60 mg/day. The 188 patients (ages to 15) were evaluated in one controlled clinical study, one controlled, crossover clinical study, and one uncontrolled clinical study. Safety data on all patients are included in the discussion that follows. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.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 meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into smaller number of standardized event categories. In the tables and listings that follow, COSTART 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, 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 Findings in Clinical Trials with Methylphenidate Hydrochloride Extended-release CapsulesAdverse Events Associated with Discontinuation of TreatmentIn the 3-week placebo-controlled, parallel-group trial, two methylphenidate hydrochloride extended-release capsules-treated patients (1%) and no placebo-treated patients discontinued due to an adverse event (rash and pruritus; and headache, abdominal pain, and dizziness, respectively).Adverse Events Occurring at an Incidence of 5% or more among Methylphenidate Hydrochloride Extended-release Capsules-Treated PatientsTable enumerates, for pool of the three studies in pediatric patients with ADHD, at methylphenidate hydrochloride extended-release capsules doses of 20, 40, or 60 mg/day, the incidence of treatment-emergent adverse events. One study was 3-week placebo-controlled, parallel-group trial, one study was controlled, crossover trial, and the third study was an open titration trial. The table includes only those events that occurred in 5% or more of patients treated with methylphenidate hydrochloride extended-release capsules where the incidence in patients treated with methylphenidate hydrochloride extended-release capsules was greater than 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 non-drug factors to the adverse event incidence rate in the population studied.TABLE 1: Incidence of Treatment-Emergent Events1 in Pool of to Week Clinical Trials of Methylphenidate Hydrochloride Extended-release CapsulesBody SystemPreferred TermMethylphenidate Hydrochloride Extended-release Capsules(n=188)Placebo(n=190)GeneralHeadacheAbdominal pain (stomach ache)12%7%8%4%Digestive SystemAnorexia (loss of appetite)9%2%Nervous SystemInsomnia5%2%1: Events, regardless of causality, for which the incidence for patients treated with methylphenidate hydrochloride extended-release capsules were at least 5% and greater than the incidence among placebo-treated patients. Incidence has been rounded to the nearest whole number.Adverse Events with Other Marketed Methylphenidate Hydrochloride ProductsNervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. Other reactions include hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea; dizziness; palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both up and down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss during prolonged therapy. There have been rare reports of Tourettes Syndrome and obsessive-compulsive disorder. Toxic psychosis has been reported. Although definite causal relationship has not been established, the following have been reported in patients taking this drug: instances of abnormal liver function, ranging from transaminase elevation to severe hepatic injury; isolated cases of cerebral arteritis and/or occlusion; leucopenia and/or anemia; transient depressed mood; few instances of scalp hair loss. Very rare reports of neuroleptic malignant syndrome (NMS) have been reported, and, in most of these, patients were concurrently receiving therapies associated with NMS. In single report, ten 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 drug-drug interaction, response to either drug alone, or some other cause.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 above may also occur.Postmarketing ExperienceIn addition to the adverse events listed above, the following have been reported in patients receiving methylphenidate hydrochloride extended-release capsules worldwide. The list is alphabetized: abnormal behavior, aggression, anxiety, bruxism, cardiac arrest, depression, fixed drug eruption, hyperactivity, irritability, libido changes, migraine, obsessive-compulsive disorder, peripheral coldness, Raynauds phenomenon, reversible ischaemic neurological deficit, rhabdomyolysis, serotonin syndrome in combination with serotonergic drugs, sudden death, suicidal behavior (including completed suicide), and thrombocytopenia. Data are insufficient to support an estimation of incidence or establish causation.To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. PharmacodynamicsMethylphenidate hydrochloride is central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. 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. Methylphenidate is racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer.PharmacokineticsThe pharmacokinetics of the methylphenidate hydrochloride extended-release capsule methylphenidate hydrochloride formulation have been studied in healthy adult volunteers and in children with Attention Deficit Hyperactivity Disorder (ADHD).Absorption and DistributionMethylphenidate is readily absorbed. Methylphenidate hydrochloride extended-release capsules have plasma/time concentration profile showing two phases of drug release with sharp, initial slope similar to methylphenidate immediate-release tablet, and second rising portion approximately three hours later, followed by gradual decline (see Figure below).Comparison of Immediate Release (IR) and Methylphenidate Hydrochloride Extended-release Capsules Formulations after Repeated Doses of Methylphenidate Hydrochloride in Children with ADHDMethylphenidate hydrochloride extended-release capsules were administered as repeated once-daily doses of 20 mg or 40 mg to children aged to 12 years with ADHD for one week. After dose of 20 mg, the mean (+-SD) early Cmax was 8.6 (+-2.2) ng/mL, the later Cmax was 10.9 (+-3.9) ng/mL and AUC0-9h was 63.0 (+-16.8) ngoh/mL. The corresponding values after 40 mg dose were 16.8 (+-5.1) ng/mL, 15.1 (+-5.8) ng/mL and 120 (+-39.6) ngoh/mL, respectively. The early peak concentrations (median) were reached about 1.5 hours after dose intake, and the second peak concentrations (median) were reached about 4.5 hours after dose intake. The means for Cmax and AUC following dose of 20 mg were slightly lower than those seen with 10 mg of the immediate-release formulation, dosed at and hours.25% to 30% of the subjects had only one observed peak (Cmax) concentration of methylphenidate.FIGURE 1: Comparison of Immediate Release (IR) and Methylphenidate Hydrochloride Extended-release Capsule Formulations After Repeated Doses of Methylphenidate Hydrochloride in Children with ADHDDose ProportionalityFollowing single oral doses of 10 mg to 60 mg methylphenidate free base as solution given to ten healthy male volunteers, Cmax and AUC increased proportionally with increasing doses. After the 60 mg dose, tmax was reached 1.5 hours post-dose, with mean Cmax of 31.8 ng/mL (range 24.7 ng/mL to 40.9 ng/mL).Following one week of repeated once-daily doses of 20 mg or 40 mg methylphenidate hydrochloride extended-release capsules to children aged to 12 years with ADHD, Cmax and AUC were proportional to the administered dose.Food EffectsIn study in adult volunteers to investigate the effects of high-fat meal on the bioavailability of dose of 40 mg, the presence of food delayed the early peak by approximately hour (range -2 to hours delay). The plasma levels rose rapidly following the food-induced delay in absorption. Overall, high-fat meal increased the Cmax of methylphenidate hydrochloride extended-release capsules by about 30% and AUC by about 17%, on average (see DOSAGE AND ADMINISTRATION).After single-dose, the bioavailability (Cmax and AUC) of methylphenidate in 26 healthy adults was unaffected by sprinkling the capsule contents on applesauce as compared to the intact capsule. This finding demonstrates that 20 mg methylphenidate hydrochloride extended-release capsule, when opened and sprinkled on one tablespoon of applesauce, is bioequivalent to the intact capsule.Metabolism and ExcretionIn humans, methylphenidate is metabolized primarily via deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid). The metabolite has little or no pharmacologic activity.In vitro studies showed that methylphenidate was not metabolized by cytochrome P450 isoenzymes, and did not inhibit cytochrome P450 isoenzymes at clinically observed plasma drug concentrations.The mean terminal half-life (t 1/2 of methylphenidate following administration of methylphenidate hydrochloride extended-release capsules (t 1/2 =6.8h) is longer than the mean terminal (t 1/2 following administration of methylphenidate hydrochloride immediate-release tablets (t 1/2 =2.9h) and methylphenidate hydrochloride sustained-release tablets (t 1/2 =3.4h) in healthy adult volunteers. This suggests that the elimination process observed for methylphenidate hydrochloride extended-release capsules is controlled by the release rate of methylphenidate from the extended-release formulation, and that the drug absorption is the rate-limiting process.Alcohol EffectAn in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the methylphenidate hydrochloride extended-release 60 mg capsule dosage form. At an alcohol concentration of 40% there was an increase in the release rate of methylphenidate in the first hour, resulting in 84% of the methylphenidate being released. The results with the 60 mg capsule are considered to be representative of the other available capsule strengths. Patients should be advised to avoid alcohol while taking methylphenidate hydrochloride extended-release capsules.Special PopulationsGenderThe pharmacokinetics of methylphenidate after single-dose of methylphenidate hydrochloride extended-release capsules were similar between adult men and women.RaceThe influence of race on the pharmacokinetics of methylphenidate after methylphenidate hydrochloride extended-release capsules administration has not been studied.AgeThe pharmacokinetics of methylphenidate after methylphenidate hydrochloride extended-release capsules administration have not been studied in children less than years of age.Renal InsufficiencyThere is no experience with the use of methylphenidate hydrochloride extended-release capsules in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of ritalinic acid. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of methylphenidate hydrochloride extended-release capsules.Hepatic Insufficiency There is no experience with the use of methylphenidate hydrochloride extended-release capsules in patients with hepatic insufficiency.. 1.

CLINICAL STUDIES SECTION.

CLINICAL STUDIES. Methylphenidate hydrochloride extended-release capsules were evaluated in double-blind, parallel-group, placebo-controlled trial in which 321 untreated or previously treated pediatric patients with DSM-IV diagnosis of Attention Deficit Hyperactivity Disorder (ADHD), to 15 years of age, received single morning dose for up to weeks. Patients were required to have the combined or predominantly hyperactive-impulsive subtype of ADHD; patients with the predominantly inattentive subtype were excluded. Patients randomized to the methylphenidate hydrochloride extended-release capsules group received 20 mg daily for the first week. Their dosage could be increased weekly to maximum of 60 mg by the third week, depending on individual response to treatment.The patients regular school teacher completed the teachers version of the Conners Global Index Scale (TCGIS), scale for assessing ADHD symptoms, in the morning and again in the afternoon on three alternate days of each treatment week. The change from baseline of the overall average (i.e. an average of morning and afternoon scores over days) of the total TCGIS scores during the last week of treatment was analyzed as the primary efficacy parameter. Patients treated with methylphenidate hydrochloride extended-release capsules showed statistically significant improvement in symptom scores from baseline over patients who received placebo (see Figure 2). Separate analyses of TCGIS scores in the morning and afternoon revealed superiority in improvement with methylphenidate hydrochloride extended-release capsules over placebo during both time periods (see Figure 3). This demonstrates that single morning dose of methylphenidate hydrochloride extended-release capsules exerts treatment effect in both the morning and the afternoon.. 1.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. AgitationMethylphenidate hydrochloride extended-release capsules are contraindicated in patients with marked anxiety, tension and agitation, since the drug may aggravate these symptoms.Hypersensitivity to Methylphenidate or Other ExcipientsMethylphenidate hydrochloride extended-release capsules are contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product.Methylphenidate hydrochloride extended-release capsules contain sucrose. Therefore, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency should not take this medicine.GlaucomaMethylphenidate hydrochloride extended-release capsules are contraindicated in patients with glaucoma.TicsMethylphenidate hydrochloride extended-release capsules are contraindicated in patients with motor tics or with family history or diagnosis of Tourettes syndrome (see ADVERSE REACTIONS).Monoamine Oxidase InhibitorsMethylphenidate hydrochloride extended-release capsules are contraindicated during treatment with monoamine oxidase inhibitors, and also within minimum of 14 days following discontinuation of monoamine oxidase inhibitor (hypertensive crises may result).Hypertension and Other Cardiovascular ConditionsMethylphenidate hydrochloride extended-release capsules are contraindicated in patients with severe hypertension, angina pectoris, cardiac arrhythmias, heart failure, recent myocardial infarction, hyperthyroidism or thyrotoxicosis (see WARNINGS).Halogenated AnestheticsThere is risk of sudden blood pressure increase during surgery. If surgery is planned, methylphenidate hydrochloride extended-release capsules should not be taken on the day of the surgery.

DESCRIPTION SECTION.

DESCRIPTION. Methylphenidate hydrochloride extended-release capsules are central nervous system (CNS) stimulant. The extended-release capsules comprise beads each with both immediate-release (IR) and extended-release (ER) components such that 30% of the dose is provided by the IR component and 70% of the dose is provided by the ER component. Methylphenidate hydrochloride extended-release capsules are available in six strengths containing 10 mg (3 mg IR; mg ER), 20 mg (6 mg IR; 14 mg ER), 30 mg (9 mg IR; 21 mg ER), 40 mg (12 mg IR; 28 mg ER), 50 mg (15 mg IR; 35 mg ER), or 60 mg (18 mg IR; 42 mg ER) of methylphenidate hydrochloride for oral administration.Chemically, methylphenidate hydrochloride is d,l (racemic)-threo-methyl -phenyl-2-piperidineacetate hydrochloride. Its empirical formula is C14H19NO2oHCl. Its structural formula is:Methylphenidate hydrochloride, USP is white, odorless, crystalline 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.Methylphenidate hydrochloride extended-release capsules also contain the following inert ingredients: Sugar spheres, povidone, hydroxypropylmethylcellulose and polyethylene glycol, ethyl cellulose, cetyl alcohol, sodium lauryl sulfate, dibutyl sebacate, gelatin, and titanium dioxide.The individual capsules contain the following color agents:10 mg capsules: FD&C Blue No. 2, FDA/E172 Yellow Iron Oxide20 mg capsules: D&C Red No. 28, FD&C Blue No. 1, FD&C Green No. 330 mg capsules: FDA/E172 Black Iron Oxide, FDA/E172 Red Iron Oxide, FDA/E172 Yellow Iron Oxide40 mg capsules: D&C Yellow No. 10, FD&C Red No. 4050 mg capsules: D&C Red No. 28, FD&C Green No. 3, FDA/E172 Black Iron Oxide. The chemical structure for methylphenidate HCl.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Methylphenidate hydrochloride extended-release capsules are administered once daily in the morning, before breakfast.Methylphenidate hydrochloride extended-release capsules may be swallowed whole with the aid of liquids, or alternatively, the capsule may be opened and the capsule contents sprinkled onto small amount (tablespoon) of applesauce and given immediately, and not stored for future use. Drinking some fluids, e.g., water, should follow the intake of the sprinkles with applesauce. The capsules and the capsule contents must not be crushed or chewed (see PRECAUTIONS: Information for Patients). Patients should be advised to avoid alcohol while taking methylphenidate hydrochloride extended-release capsules.Dosage should be individualized according to the needs and responses of the patient.Initial TreatmentThe recommended starting dose of methylphenidate hydrochloride extended-release capsules is 20 mg once daily. Dosage may be adjusted in weekly 10 mg to 20 mg increments to maximum of 60 mg/day taken once daily in the morning, depending upon tolerability and degree of efficacy observed. Daily dosage above 60 mg is not recommended.Maintenance/Extended TreatmentThere is no body of evidence available from controlled trials to indicate how long the patient with ADHD should be treated with methylphenidate hydrochloride extended-release capsules. It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods. Nevertheless, the physician who elects to use methylphenidate hydrochloride extended-release capsules for extended periods in patients with ADHD should periodically re-evaluate the long-term usefulness of the drug for the individual patient with trials off medication to assess the patients functioning without pharmacotherapy. Improvement may be sustained when the drug is either temporarily or permanently discontinued.Dose Reduction and DiscontinuationIf 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 one-month period, the drug should be discontinued.

DRUG ABUSE AND DEPENDENCE SECTION.

DRUG ABUSE AND DEPENDENCE. Controlled Substance ClassMethylphenidate hydrochloride extended-release capsules, like other methylphenidate products, are classified as Schedule II controlled substance by federal regulation.Abuse, Dependence, and ToleranceSee WARNINGS for boxed warning containing drug abuse and dependence information.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Methylphenidate Hydrochloride Extended-release Capsules are available in six strengths.Methylphenidate Hydrochloride Extended-release Capsules, 10 mg are green cap and white body, opaque capsules, imprinted with CP over 401 on the cap and 10 mg on the body.They are available as:Bottles of 100: NDC 0115-1736-01Methylphenidate Hydrochloride Extended-release Capsules, 20 mg are blue cap and white body, opaque capsules, imprinted with CP over 402 on the cap and 20 mg on the body.They are available as:Bottles of 100: NDC 0115-1737-01Methylphenidate Hydrochloride Extended-release Capsules, 30 mg are brown cap and white body, opaque capsules, imprinted with CP over 403 on the cap and 30 mg on the body.They are available as:Bottles of 100: NDC 0115-1738-01Methylphenidate Hydrochloride Extended-release Capsules, 40 mg are yellow cap and white body, opaque capsules, imprinted with CP over 404 on the cap and 40 mg on the body.They are available as:Bottles of 100: NDC 0115-1739-01Methylphenidate Hydrochloride Extended-release Capsules, 50 mg are navy blue cap and white body, opaque capsules, imprinted with CP over 405 on the cap and 50 mg on the body.They are available as:Bottles of 100: NDC 0115-1740-01Methylphenidate Hydrochloride Extended-release Capsules, 60 mg are white, opaque capsule imprinted with CP over 406 on the cap and 60 mg on the body.They are available as: Bottles of 100: NDC 0115-1741-01Store at 20 to 25C (68 to 77F); excursions permitted between 15 to 30C (59 to 86F) [see USP Controlled Room Temperature]. Keep out of the reach of children.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. Patients should be instructed to take one dose in the morning before breakfast. The patients should be instructed that the capsule may be swallowed whole, or alternatively, the capsule may be opened and the capsule contents sprinkled onto small amount (tablespoon) of applesauce and given immediately, and not stored for future use. The capsules and the capsule contents must not be crushed or chewed.Patients should be advised to avoid alcohol while taking methylphenidate hydrochloride extended-release capsules. Consumption of alcohol while taking methylphenidate hydrochloride extended-release capsules may result in more rapid release of the dose of methylphenidate. PriapismAdvise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynauds phenomenon]Instruct patients beginning treatment with methylphenidate hydrochloride extended-release capsules about the risk of peripheral vasculopathy, including Raynauds 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 methylphenidate hydrochloride extended-release capsules.Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with methylphenidate and should counsel them in its appropriate use. patient Medication Guide is available for methylphenidate hydrochloride extended-release capsules. The prescriber or healthcare professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. The Medication Guide may also be found in the full prescribing information for methylphenidate hydrochloride extended-release capsules on www.amneal.com or by calling 1-877-835-5472.Drug InteractionsBecause of possible effects on blood pressure, methylphenidate hydrochloride extended-release capsules should be used cautiously with pressor agents.Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), phenylbutazone and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). Downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate.In theory, there is possibility that the clearance of methylphenidate might be affected by urinary pH, either being increased with acidifying agents or decreased with alkalizing agents. This should be considered when methylphenidate is given in combination with agents that alter urinary pH.Halogenated AnestheticsThere is risk of sudden blood pressure increase during surgery. If surgery is planned, methylphenidate hydrochloride extended-release capsules should not be taken the day of the surgery.Carcinogenesis, Mutagenesis, and Impairment of FertilityIn lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and times the maximum recommended human dose of methylphenidate hydrochloride extended-release capsules on mg/kg and mg/m2 basis, respectively. Hepatoblastoma is 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.Methylphenidate did not cause any increases in tumors in lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and times the maximum recommended human dose of methylphenidate hydrochloride extended-release capsules on mg/kg and mg/m2 basis, respectively.In 24-week carcinogenicity study 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 concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate.Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay.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 up to 160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended human dose of methylphenidate hydrochloride extended-release capsules on mg/kg and mg/m2 basis, respectively.PregnancyTeratogenic EffectsPregnancy Category CMethylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 100 times and 40 times the maximum recommended human dose on mg/kg and mg/m2 basis, respectively.A reproduction study in rats revealed no evidence of teratogenicity at an oral dose of 58 mg/kg/day. However, this dose, which caused some maternal toxicity, resulted in decreased postnatal pup weights and survival when given to the dams from day one of gestation through the lactation period. This dose is approximately 30 fold and fold the maximum recommended human dose of methylphenidate hydrochloride extended-release capsules on mg/kg and mg/m2 basis, respectively.There are no adequate and well-controlled studies in pregnant women. Methylphenidate hydrochloride extended-release capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Nursing MothersIt is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if methylphenidate hydrochloride extended-release capsules are administered to nursing woman.Pediatric UseThe safety and efficacy of methylphenidate hydrochloride extended-release capsules in children under years old have not been established. Long-term effects of methylphenidate in children have not been well established (see WARNINGS).. Instruct patients beginning treatment with methylphenidate hydrochloride extended-release capsules about the risk of peripheral vasculopathy, including Raynauds 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 methylphenidate hydrochloride extended-release capsules.. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

OVERDOSAGE SECTION.

OVERDOSAGE. Signs and SymptomsSigns 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.Recommended TreatmentTreatment consists of appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. Gastric contents may be evacuated by gastric lavage as indicated. Before performing gastric lavage, control agitation and seizures if present and protect the airway. Other measures to detoxify the gut include administration of activated charcoal and cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia.Efficacy of peritoneal dialysis or extracorporeal hemodialysis for methylphenidate hydrochloride extended-release capsules overdosage has not been established.The prolonged release of methylphenidate from methylphenidate hydrochloride extended-release capsules should be considered when treating patients with overdose.Poison Control CenterAs with the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting poison control center for up-to-date information on the management of overdosage with methylphenidate.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 10 mg. NDC 0115-1736-01Methylphenidate Hydrochloride Extended-Release Capsules, 10 mg (CII) Rx only100 Capsules. 1.

PRECAUTIONS SECTION.

PRECAUTIONS. Hematologic MonitoringPeriodic CBC, differential, and platelet counts are advised during prolonged therapy.Drug TestingMethylphenidate hydrochloride extended-release capsules contain methylphenidate which may result in positive result during drug testing.. Information for Patients. Patients should be instructed to take one dose in the morning before breakfast. The patients should be instructed that the capsule may be swallowed whole, or alternatively, the capsule may be opened and the capsule contents sprinkled onto small amount (tablespoon) of applesauce and given immediately, and not stored for future use. The capsules and the capsule contents must not be crushed or chewed.Patients should be advised to avoid alcohol while taking methylphenidate hydrochloride extended-release capsules. Consumption of alcohol while taking methylphenidate hydrochloride extended-release capsules may result in more rapid release of the dose of methylphenidate. PriapismAdvise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynauds phenomenon]Instruct patients beginning treatment with methylphenidate hydrochloride extended-release capsules about the risk of peripheral vasculopathy, including Raynauds 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 methylphenidate hydrochloride extended-release capsules.Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with methylphenidate and should counsel them in its appropriate use. patient Medication Guide is available for methylphenidate hydrochloride extended-release capsules. The prescriber or healthcare professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. The Medication Guide may also be found in the full prescribing information for methylphenidate hydrochloride extended-release capsules on www.amneal.com or by calling 1-877-835-5472.Drug InteractionsBecause of possible effects on blood pressure, methylphenidate hydrochloride extended-release capsules should be used cautiously with pressor agents.Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), phenylbutazone and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). Downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate.In theory, there is possibility that the clearance of methylphenidate might be affected by urinary pH, either being increased with acidifying agents or decreased with alkalizing agents. This should be considered when methylphenidate is given in combination with agents that alter urinary pH.Halogenated AnestheticsThere is risk of sudden blood pressure increase during surgery. If surgery is planned, methylphenidate hydrochloride extended-release capsules should not be taken the day of the surgery.Carcinogenesis, Mutagenesis, and Impairment of FertilityIn lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at daily dose of approximately 60 mg/kg/day. This dose is approximately 30 times and times the maximum recommended human dose of methylphenidate hydrochloride extended-release capsules on mg/kg and mg/m2 basis, respectively. Hepatoblastoma is 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.Methylphenidate did not cause any increases in tumors in lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 22 times and times the maximum recommended human dose of methylphenidate hydrochloride extended-release capsules on mg/kg and mg/m2 basis, respectively.In 24-week carcinogenicity study 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 concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate.Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or in the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay.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 up to 160 mg/kg/day, approximately 80-fold and 8-fold the highest recommended human dose of methylphenidate hydrochloride extended-release capsules on mg/kg and mg/m2 basis, respectively.PregnancyTeratogenic EffectsPregnancy Category CMethylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 100 times and 40 times the maximum recommended human dose on mg/kg and mg/m2 basis, respectively.A reproduction study in rats revealed no evidence of teratogenicity at an oral dose of 58 mg/kg/day. However, this dose, which caused some maternal toxicity, resulted in decreased postnatal pup weights and survival when given to the dams from day one of gestation through the lactation period. This dose is approximately 30 fold and fold the maximum recommended human dose of methylphenidate hydrochloride extended-release capsules on mg/kg and mg/m2 basis, respectively.There are no adequate and well-controlled studies in pregnant women. Methylphenidate hydrochloride extended-release capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Nursing MothersIt is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if methylphenidate hydrochloride extended-release capsules are administered to nursing woman.Pediatric UseThe safety and efficacy of methylphenidate hydrochloride extended-release capsules in children under years old have not been established. Long-term effects of methylphenidate in children have not been well established (see WARNINGS).. Instruct patients beginning treatment with methylphenidate hydrochloride extended-release capsules about the risk of peripheral vasculopathy, including Raynauds 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 methylphenidate hydrochloride extended-release capsules.. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

SPL MEDGUIDE SECTION.

MEDICATION GUIDE. Methylphenidate Hydrochloride (meth il fen date hye droe klor ide) Extended-release Capsules, CII Read the Medication Guide that comes with methylphenidate hydrochloride extended-release capsules before you or your child starts taking it and each time you get refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your or your childs treatment with methylphenidate hydrochloride extended-release capsules. What is the most important information should know about methylphenidate hydrochloride extended-release capsulesThe following have been reported with use of methylphenidate hydrochloride and other stimulant medicines. 1. Heart-related problems: sudden death in patients who have heart problems or heart defects stroke and heart attack in adults increased blood pressure and heart rate Tell your doctor if you or your child has any heart problems, heart defects, high blood pressure, or family history of these problems. Your doctor should check you or your child carefully for heart problems before starting methylphenidate hydrochloride extended-release capsules. Your doctor should check your or your childs blood pressure and heart rate regularly during treatment with methylphenidate hydrochloride extended-release capsules. 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 methylphenidate hydrochloride extended-release capsules. 2. Mental (Psychiatric) problems: All Patients new or worse behavior and thought problems new or worse bipolar illness new or worse aggressive behavior or hostility Children and Teenagers new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms Tell your doctor about any mental problems you or your child have, or about family history of suicide, bipolar illness, or depression. Call your doctor right away if you or your child has any new or worsening mental symptoms or problems while taking ethylphenidate hydrochloride extended-release capsules especially seeing or hearing things that are not real, believing things that are not real, or are suspicious. 3. Circulation Problems in fingers and toes Peripheral vasculopathy, including Raynauds phenomenon): fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes.Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride extended-release capsules. What are methylphenidate hydrochloride extended-release capsules Methylphenidate hydrochloride extended-release capsules are central nervous system stimulant prescription medicine. It is used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Methylphenidate hydrochloride extended-release capsules may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.Methylphenidate hydrochloride extended-release capsules should be used as part of total treatment program for ADHD that may include counseling or other therapies.Methylphenidate hydrochloride extended-release capsules are federally controlled substance (CII) because it can be abused or lead to dependence. Keep methylphenidate hydrochloride extended-release capsules in safe place to prevent misuse and abuse. Selling or giving away methylphenidate hydrochloride extended-release capsules may harm others, and is against the law. Tell your doctor if you or your child have (or have family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs.Who should not take methylphenidate hydrochloride extended-release capsules Methylphenidate hydrochloride extended-release capsules should not be taken if you or your child: are very anxious, tense, or agitated have an eye problem called glaucoma have Tics or Tourettes syndrome, or family history of Tourettes syndrome. Tics are hard to control repeated movements or sounds. have severe high blood pressure or heart problem have hyperthyroidism are taking or have taken within the past 14 days an antidepression medicine called monoamine oxidase inhibitor or MAOI. are allergic to anything in methylphenidate hydrochloride extended-release capsules. See the end of this Medication Guide for complete list of ingredients. Methylphenidate hydrochloride extended-release capsules should not be used in children less than years old because it has not been studied in this age group.Methylphenidate hydrochloride extended-release capsules may not be right for you or your child. Before starting methylphenidate hydrochloride extended-release capsules tell your or your childs doctor about all health conditions (or family history of) including:heart problems, heart defects, high blood pressure mental problems including psychosis, mania, bipolar illness, or depression Tics or Tourettes syndrome seizures or have had an abnormal brain wave test (EEG)circulation problem in fingers and toes Tell your doctor if you or your child is pregnant, planning to become pregnant, or breastfeeding.Can methylphenidate hydrochloride extended-release capsules be taken with other medicines Tell your doctor about all of the medicines that you or your child takes including prescription and non-prescription medicines, vitamins, and herbal supplements. Methylphenidate hydrochloride extended-release capsules 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 methylphenidate hydrochloride extended-release capsules.Your doctor will decide whether methylphenidate hydrochloride extended-release capsules can be taken with other medicines.Especially tell your doctor if you or your child takes: anti-depression medicines including MAOIs seizure medicines blood thinner medicines blood pressure medicines cold or allergy medicines that contain decongestants Know the medicines that you or your child takes. Keep list of your medicines with you to show your doctor and pharmacist.Do not start any new medicine while taking methylphenidate hydrochloride extended-release capsules without talking to your doctor first.How should methylphenidate hydrochloride extended-release capsules be taken Take methylphenidate hydrochloride extended-release capsules exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child. Take methylphenidate hydrochloride extended-release capsules once each day in the morning before breakfast. Methylphenidate hydrochloride extended-release capsules are an extended release capsule. It releases medicine into your body throughout the day. Methylphenidate hydrochloride extended-release capsules can be taken with or without food. Swallow methylphenidate hydrochloride extended-release capsules whole with water or other liquids. If you cannot swallow the capsule, open it and sprinkle the medicine over spoonful of applesauce. Swallow the applesauce and medicine mixture without chewing. Follow with drink of water or other liquid. Never chew or crush the capsule or the medicine inside the capsule. Methylphenidate hydrochloride extended-release capsules should not be taken with alcohol. This may result in more rapid release of the dose of methylphenidate hydrochloride extended-release capsules.From time to time, your doctor may stop methylphenidate hydrochloride extended-release capsules treatment for while to check ADHD symptoms. Your doctor may do regular checks of the blood, heart, and blood pressure while taking methylphenidate hydrochloride extended-release capsules. Children should have their height and weight checked often while taking methylphenidate hydrochloride extended-release capsules. Methylphenidate hydrochloride extended-release capsules treatment may be stopped if problem is found during these check-ups. If you or your child takes too much methylphenidate hydrochloride extended-release capsules or overdoses, call your doctor or poison control center right away, or get emergency treatment.What are possible side effects of methylphenidate hydrochloride extended-release capsulesSee What is the most important information should know about methylphenidate hydrochloride extended-release capsules for information on reported heart and mental problems.Other serious side effects include:slowing of growth (height and weight) in childrenseizures, mainly in patients with history of seizureseyesight changes or blurred visionPainful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by doctor immediately.Common side effects include:headachedecreased appetitestomach achenervousnesstrouble sleepingdizzinessTalk to your doctor if you or your child has side effects that are bothersome or do not go away.This is not complete list of possible side effects. Ask your doctor or pharmacist for more information.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store methylphenidate hydrochloride extended-release capsules Store methylphenidate hydrochloride extended-release capsules in safe place at room temperature, 59 to 86F (15 to 30C). Protect from moisture.Keep methylphenidate hydrochloride extended-release capsules and all medicines out of the reach of children.General information about methylphenidate hydrochloride extended-release capsulesMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use methylphenidate hydrochloride extended-release capsules for condition for which it was not prescribed. Do not give methylphenidate hydrochloride extended-release capsules to other people, even if they have the same condition. It may harm them and it is against the law. This Medication Guide summarizes the most important information about methylphenidate hydrochloride extended-release capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about methylphenidate hydrochloride extended-release capsules that was written for healthcare professionals. For more information about methylphenidate hydrochloride extended-release capsules call 1-877-835-5472.What are the ingredients in methylphenidate hydrochloride extended-release capsules Active Ingredient: methylphenidate hydrochloride, USPInactive Ingredients: sugar spheres, povidone, hydroxypropylmethylcellulose and polyethylene glycol, ethyl cellulose, cetyl alcohol, sodium lauryl sulfate, dibutyl sebacate, gelatin, and titanium dioxide.The individual capsules contain the following coloring agents: 10 mg capsules: FD&C Blue No. 2, FDA/E172 Yellow Iron Oxide 20 mg capsules: D&C Red No. 28, FD&C Blue No. 1, FD&C Green No. 330 mg capsules: FDA/E172 Black Iron Oxide, FDA/E172 Red Iron Oxide, FDA/E172 Yellow Iron Oxide40 mg capsules: D&C Yellow No. 10, FD&C Red No. 4050 mg capsules: D&C Red No. 28, FD&C Green No. 3, FDA/E172 Black Iron OxideThis Medication Guide has been approved by the U.S. Food and Drug Administration.For additional copies of the printed Medication Guide, please visit www.amneal.com or call 1-877-835-5472.Manufactured by: Amneal Pharmaceuticals of New York, LLCBrookhaven, NY 11719 Distributed by:Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 12-2021-01Dispense with Medication Guide available at:documents.amneal.com/mg/methylphenidate-hcl-er-cap.pdf. sudden death in patients who have heart problems or heart defects stroke and heart attack in adults increased blood pressure and heart rate. new or worse behavior and thought problems new or worse bipolar illness new or worse aggressive behavior or hostility new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms. Tell your doctor if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in your fingers or toes.. Call your doctor right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride extended-release capsules.. are very anxious, tense, or agitated have an eye problem called glaucoma have Tics or Tourettes syndrome, or family history of Tourettes syndrome. Tics are hard to control repeated movements or sounds. have severe high blood pressure or heart problem have hyperthyroidism are taking or have taken within the past 14 days an antidepression medicine called monoamine oxidase inhibitor or MAOI. are allergic to anything in methylphenidate hydrochloride extended-release capsules. See the end of this Medication Guide for complete list of ingredients. heart problems, heart defects, high blood pressure mental problems including psychosis, mania, bipolar illness, or depression Tics or Tourettes syndrome seizures or have had an abnormal brain wave test (EEG). circulation problem in fingers and toes anti-depression medicines including MAOIs seizure medicines blood thinner medicines blood pressure medicines cold or allergy medicines that contain decongestants Take methylphenidate hydrochloride extended-release capsules exactly as prescribed. Your doctor may adjust the dose until it is right for you or your child. Take methylphenidate hydrochloride extended-release capsules once each day in the morning before breakfast. Methylphenidate hydrochloride extended-release capsules are an extended release capsule. It releases medicine into your body throughout the day. Methylphenidate hydrochloride extended-release capsules can be taken with or without food. Swallow methylphenidate hydrochloride extended-release capsules whole with water or other liquids. If you cannot swallow the capsule, open it and sprinkle the medicine over spoonful of applesauce. Swallow the applesauce and medicine mixture without chewing. Follow with drink of water or other liquid. Never chew or crush the capsule or the medicine inside the capsule. Methylphenidate hydrochloride extended-release capsules should not be taken with alcohol. This may result in more rapid release of the dose of methylphenidate hydrochloride extended-release capsules.. From time to time, your doctor may stop methylphenidate hydrochloride extended-release capsules treatment for while to check ADHD symptoms. Your doctor may do regular checks of the blood, heart, and blood pressure while taking methylphenidate hydrochloride extended-release capsules. Children should have their height and weight checked often while taking methylphenidate hydrochloride extended-release capsules. Methylphenidate hydrochloride extended-release capsules treatment may be stopped if problem is found during these check-ups. If you or your child takes too much methylphenidate hydrochloride extended-release capsules or overdoses, call your doctor or poison control center right away, or get emergency treatment.. slowing of growth (height and weight) in children. seizures, mainly in patients with history of seizures. eyesight changes or blurred vision. Painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develops priapism, seek medical help right away. Because of the potential for lasting damage, priapism should be evaluated by doctor immediately.. headache. decreased appetite. stomach ache. nervousness. trouble sleeping. dizziness. Store methylphenidate hydrochloride extended-release capsules in safe place at room temperature, 59 to 86F (15 to 30C). Protect from moisture.. Keep methylphenidate hydrochloride extended-release capsules and all medicines out of the reach of children.

SPL UNCLASSIFIED SECTION.

INDICATION AND USAGE. Attention Deficit Hyperactivity Disorder (ADHD)Methylphenidate hydrochloride extended-release capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).The efficacy of methylphenidate hydrochloride extended-release capsules in the treatment of ADHD was established in one controlled trial of children aged to 15 who met DSM-IV criteria for ADHD (see CLINICAL PHARMACOLOGY).A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in two or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least six of the following symptoms must have persisted for at least months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least six of the following symptoms must have persisted for at least months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; on the go; excessive talking; blurting answers; cant wait turn; intrusive. The Combined Types requires both inattentive and hyperactive-impulsive criteria to be met.Special Diagnostic ConsiderationsSpecific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon complete history and evaluation of the child and not solely on the presence of the required number of DSM-IV characteristics.Need For Comprehensive Treatment ProgramMethylphenidate hydrochloride extended-release capsules are indicated as an integral part of total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physicians assessment of the chronicity and severity of the childs symptoms.Long-Term UseThe effectiveness of methylphenidate hydrochloride extended-release capsules for long-term use, i.e. for more than weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use methylphenidate hydrochloride extended-release capsules for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

WARNINGS SECTION.

WARNINGS. Serious Cardiovascular EventsSudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart ProblemsChildren and AdolescentsSudden 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 stimulant drug (see CONTRAINDICATIONS).AdultsSudden deaths, 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 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 (see CONTRAINDICATIONS).Hypertension and Other Cardiovascular ConditionsStimulant medications cause modest increase in average blood pressure (about mmHg to mmHg) and average heart rate (about bpm to 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 pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia (see CONTRAINDICATIONS).Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have careful history (including assessment for 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 prompt cardiac evaluation.Psychiatric Adverse EventsPre-Existing PsychosisAdministration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with pre-existing psychotic disorder.Bipolar IllnessParticular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of mixed/manic episode in such patients. Prior to initiating treatment with stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include detailed psychiatric history, including family history of suicide, bipolar disorder, and depression.Emergence of New Psychotic or Manic SymptomsTreatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without prior history of psychotic illness or mania can be caused by stimulants at usual doses. If such symptoms occur, consideration should be given to possible causal role of the stimulant, and discontinuation of treatment may be appropriate. In 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 in placebo-treated patients.AggressionAggressive behavior or hostility is often observed in children and adolescents with ADHD, and has been reported in clinical trials and the postmarketing 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.Long-Term Suppression of GrowthCareful follow-up of weight and height in children ages 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 children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e. treatment for days per week throughout the year) have temporary slowing in growth rate (on average, total of about cm less growth in height and 2.7 kg less growth in weight over years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether chronic use of amphetamines may cause 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.SeizuresThere 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 history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued.PriapismProlonged 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 period of drug withdrawal (drug holidays or discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.Peripheral Vasculopathy, including Raynauds phenomenon Stimulants, including methylphenidate hydrochloride extended-release capsules, used to treat ADHD are associated with peripheral vasculopathy, including Raynauds 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 Raynauds 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.Visual DisturbanceDifficulties with accommodation and blurring of vision have been reported with stimulant treatment.Use in Children Under Six Years of AgeMethylphenidate hydrochloride extended-release capsules should not be used in children under six years, since safety and efficacy in this age group have not been established.Drug Dependence Methylphenidate hydrochloride extended-release capsules should be given cautiously to patients with history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.

BOXED WARNING SECTION.

WARNING: ABUSE AND DEPENDENCE. CNS stimulants, including methylphenidate hydrochloride extended-release capsules, other methylphenidate-containing products and amphetamines, have high potential for abuse and dependence. Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)].. WARNING: ABUSE AND DEPENDENCESee full prescribing information for complete boxed warning.CNS stimulants, including methylphenidate hydrochloride extended-release capsules, other methylphenidate containing products and amphetamines, have high potential for abuse and dependence (5.1, 9.2, 9.3)Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy (5.1, 9.2). CNS stimulants, including methylphenidate hydrochloride extended-release capsules, other methylphenidate containing products and amphetamines, have high potential for abuse and dependence (5.1, 9.2, 9.3). Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy (5.1, 9.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at daily dose of approximately 60 mg/kg per day. This dose is approximately times the maximum recommended human dose (MRHD) of 60 mg/day given to children on mg/m2 basis. Hepatoblastoma is 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. Methylphenidate did not cause any increases in tumors in lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately times the MRHD (children) on mg/m2 basis. In 24-week carcinogenicity study 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 concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 mg/kg to 74 mg/kg per day of methylphenidate. MutagenesisMethylphenidate 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 vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of FertilityMethylphenidate 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 up to 160 mg/kg per day, approximately 10 times the maximum recommended human dose of 60 mg/day given to adolescents on mg/m2 basis.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Methylphenidate hydrochloride extended-release capsules, 10 mg are green cap and white body, opaque capsules, imprinted with CP over 401 on the cap and 10 mg on the body.Methylphenidate hydrochloride extended-release capsules, 20 mg are blue cap and white body, opaque capsules, imprinted with CP over 402 on the cap and 20 mg on the body.Methylphenidate hydrochloride extended-release capsules, 30 mg are brown cap and white body, opaque capsules, imprinted with CP over 403 on the cap and 30 mg on the body.Methylphenidate hydrochloride extended-release capsules, 40 mg are yellow cap and white body, opaque capsules, imprinted with CP over 404 on the cap and 40 mg on the body.Methylphenidate hydrochloride extended-release capsules, 50 mg are navy blue cap and white body, opaque capsules, imprinted with CP over 405 on the cap and 50 mg on the body.Methylphenidate hydrochloride extended-release capsules, 60 mg are white opaque capsule imprinted with CP over 406 on the cap and 60 mg on the body.. Methylphenidate hydrochloride extended-release capsules, 10 mg are green cap and white body, opaque capsules, imprinted with CP over 401 on the cap and 10 mg on the body.. Methylphenidate hydrochloride extended-release capsules, 20 mg are blue cap and white body, opaque capsules, imprinted with CP over 402 on the cap and 20 mg on the body.. Methylphenidate hydrochloride extended-release capsules, 30 mg are brown cap and white body, opaque capsules, imprinted with CP over 403 on the cap and 30 mg on the body.. Methylphenidate hydrochloride extended-release capsules, 40 mg are yellow cap and white body, opaque capsules, imprinted with CP over 404 on the cap and 40 mg on the body.. Methylphenidate hydrochloride extended-release capsules, 50 mg are navy blue cap and white body, opaque capsules, imprinted with CP over 405 on the cap and 50 mg on the body.. Methylphenidate hydrochloride extended-release capsules, 60 mg are white opaque capsule imprinted with CP over 406 on the cap and 60 mg on the body.. Extended-release capsules: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table presents clinically important drug interactions with methylphenidate hydrochloride.Table 3: Clinically Important Drug Interactions with Methylphenidate HydrochlorideMonoamine Oxidase Inhibitors (MAOI)Clinical Impact:Concomitant use of MAOIs and CNS stimulants, including methylphenidate hydrochloride, 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 methylphenidate hydrochloride with monoamine oxidase inhibitors (MAOIs) or within 14 days after discontinuing MAOI treatment is contraindicated.Antihypertensive DrugsClinical Impact:Methylphenidate hydrochloride 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.RisperidoneClinical Impact:Combined use of methylphenidate with risperidone when there is change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS).Intervention:Monitor for signs of EPS.. Antihypertensive drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. (7). Antihypertensive drugs: Monitor blood pressure. Adjust dosage of antihypertensive drug as needed. (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Methylphenidate hydrochloride has not been studied in patients over the age of 65 years.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Methylphenidate hydrochloride extended-release capsules are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients to 15 years of age.. Methylphenidate hydrochloride is central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients to 15 years of age. (1).

LABOR & DELIVERY SECTION.

8.2 Lactation. Risk SummaryLimited 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 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 mothers clinical need for methylphenidate hydrochloride and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride or from the underlying maternal condition. Clinical ConsiderationsMonitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia and reduced weight gain.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Methylphenidate hydrochloride is central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD is not known.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at daily dose of approximately 60 mg/kg per day. This dose is approximately times the maximum recommended human dose (MRHD) of 60 mg/day given to children on mg/m2 basis. Hepatoblastoma is 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. Methylphenidate did not cause any increases in tumors in lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately times the MRHD (children) on mg/m2 basis. In 24-week carcinogenicity study 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 concentration of methylphenidate as in the lifetime carcinogenicity study; the high-dose groups were exposed to 60 mg/kg to 74 mg/kg per day of methylphenidate. MutagenesisMethylphenidate 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 vitro chromosomal aberration assay using human lymphocytes. Sister chromatid exchanges and chromosome aberrations were increased, indicative of weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay. Impairment of FertilityMethylphenidate 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 up to 160 mg/kg per day, approximately 10 times the maximum recommended human dose of 60 mg/day given to adolescents on mg/m2 basis.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of methylphenidate hydrochloride for the treatment of ADHD have been established in pediatric patients to 15 years of age. The safety and effectiveness of methylphenidate hydrochloride in pediatric patients younger than years of age have not been established. Long-term efficacy of methylphenidate hydrochloride in pediatric patients have not been established.Long-Term Suppression of GrowthGrowth should be monitored during treatment with stimulants, including methylphenidate hydrochloride. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.6)].Juvenile Animal Toxicity DataIn study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 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 times the MRHD on mg/m2 basis) or greater and deficit in the acquisition of specific learning task was seen in females exposed to the highest dose (12 times the MRHD on mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was mg/kg/day (half the MRHD on mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Methylphenidate is racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following one week of once-daily doses of 20 mg or 40 mg methylphenidate hydrochloride extended-release capsules to children aged to 12 years old with ADHD, Cmax and AUC of methylphenidate were approximately proportional to the administered doses.AbsorptionFollowing administration of methylphenidate hydrochloride extended-release capsules in children aged to 12 years old with ADHD, the plasma concentration time profile of methylphenidate showed two phases of drug release with sharp, initial slope similar to methylphenidate immediate-release tablet (median Tmax1about 1.5 hours post dose) and second rising portion approximately three hours later (median Tmax2about 4.5 hours post dose), followed by gradual decline (Figure 1). The means for Cmax and area under the curve (AUC) following dose of 20 mg were slightly lower than those seen with 10 mg of the immediate-release formulation, dosed at and hours. 25% to 30% of the subjects had only one observed peak (Cmax) concentration of methylphenidate. Figure 1: Comparison of Immediate Release (IR) and Methylphenidate Hydrochloride Extended-Release Capsules Formulations After Repeated Doses of Methylphenidate Hydrochloride in Pediatric Patients to 12 Years of Age with ADHDEffect of FoodIngestion of high-fat meal with methylphenidate hydrochloride extended-release capsules increased the mean Cmax and AUC of methylphenidate by about 30% and 17%, respectively. The presence of food delayed the early peak by approximately hour (range -2 to hours delay) [see Dosage and Administration (2.1)].The bioavailability (Cmax and AUC) of methylphenidate was unaffected by sprinkling the methylphenidate hydrochloride extended-release capsule contents on applesauce as compared to the intact capsule.Effect of AlcoholAt an alcohol concentration of 40%, there was an increase in the release rate of methylphenidate in the first hour, resulting in 84% of the methylphenidate being released. The results with the 60 mg capsule are considered to be representative of the other available capsule strengths [see Drug Interactions (7)].DistributionPlasma protein binding is 10% to 33%. The volume of distribution was 2.65 +- 1.11 L/kg for d- methylphenidate and 1.80 +- 0.91 L/kg for l- methylphenidate.EliminationThe mean terminal half-life (t 1/2 of methylphenidate following administration of methylphenidate hydrochloride extended-release capsules (t 1/2 =6.8 hours) is longer than the mean terminal 1/2 following administration of methylphenidate hydrochloride immediate-release tablets (t 1/2 =2.9 hours) and methylphenidate hydrochloride extended-release tablets (t 1/2 =3.4 hours) in healthy adult volunteers.MetabolismIn vitro studies showed that methylphenidate was not metabolized by cytochrome P450 isoenzymes. Methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity.ExcretionAfter oral administration of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was ritalinic acid, accounting for approximately 80% of the dose.Specific PopulationsMale and Female PatientsThe pharmacokinetics of methylphenidate after single-dose of methylphenidate hydrochloride extended-release capsules were similar between adult men and women.Racial or Ethnic GroupsThe influence of race on the pharmacokinetics of methylphenidate after methylphenidate hydrochloride extended-release capsules administration has not been studied.Pediatric PatientsThe pharmacokinetics of methylphenidate after methylphenidate hydrochloride extended-release capsules administration has not been studied in children less than years of age.Patients with Renal ImpairmentMethylphenidate hydrochloride has not been studied in patients with renal insufficiency. Since renal clearance is not an important route of methylphenidate clearance and the major metabolite (ritalinic acid), has little or no pharmacologic activity, renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate hydrochloride.Patients with Hepatic ImpairmentMethylphenidate hydrochloride extended-release capsules has not been studied in patients with hepatic insufficiency. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body. Drug Interaction StudiesIn vitro studies showed that methylphenidate did not inhibit cytochrome P450 isoenzymes at clinically observed plasma drug concentrations.. 1.

PREGNANCY SECTION.

8.1 Pregnancy. There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including methylphenidate hydrochloride, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388.Risk SummaryPublished studies and post-marketing reports on methylphenidate use during pregnancy have not identified 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).No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on mg/m2 basis. However, spina bifida was observed in rabbits at dose 53 times the MRHD given to adolescents. decrease in pup body weight was observed in pre-and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses times the MRHD given to adolescents (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Clinical ConsiderationsFetal/Neonatal Adverse ReactionsCNS stimulants, such as methylphenidate hydrochloride, 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.Animal DataIn embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the MRHD given to adolescents on mg/m2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adults on mg/m2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adults on mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre-and postnatal development in rats was 15 mg/kg/day (~2 times the MRHD given to adolescents on mg/m2 basis).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including methylphenidate hydrochloride, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388.Risk SummaryPublished studies and post-marketing reports on methylphenidate use during pregnancy have not identified 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).No effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on mg/m2 basis. However, spina bifida was observed in rabbits at dose 53 times the MRHD given to adolescents. decrease in pup body weight was observed in pre-and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses times the MRHD given to adolescents (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Clinical ConsiderationsFetal/Neonatal Adverse ReactionsCNS stimulants, such as methylphenidate hydrochloride, 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.Animal DataIn embryo-fetal development studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52 times the MRHD of 60 mg/day given to adolescents on mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (15 times the MRHD given to adolescents on mg/m2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (10 times the MRHD of 60 mg/day given to adults on mg/m2 basis), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (3 times the MRHD on mg/m2 basis). When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dose (6 times the MRHD of 60 mg/day given to adults on mg/m2 basis), but no other effects on postnatal development were observed. The no effect level for pre-and postnatal development in rats was 15 mg/kg/day (~2 times the MRHD given to adolescents on mg/m2 basis).. 8.2 Lactation. Risk SummaryLimited 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 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 mothers clinical need for methylphenidate hydrochloride and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride or from the underlying maternal condition. Clinical ConsiderationsMonitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia and reduced weight gain.. 8.4 Pediatric Use. The safety and effectiveness of methylphenidate hydrochloride for the treatment of ADHD have been established in pediatric patients to 15 years of age. The safety and effectiveness of methylphenidate hydrochloride in pediatric patients younger than years of age have not been established. Long-term efficacy of methylphenidate hydrochloride in pediatric patients have not been established.Long-Term Suppression of GrowthGrowth should be monitored during treatment with stimulants, including methylphenidate hydrochloride. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.6)].Juvenile Animal Toxicity DataIn study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 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 times the MRHD on mg/m2 basis) or greater and deficit in the acquisition of specific learning task was seen in females exposed to the highest dose (12 times the MRHD on mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was mg/kg/day (half the MRHD on mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.. 8.5 Geriatric Use. Methylphenidate hydrochloride has not been studied in patients over the age of 65 years.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Serious Cardiovascular Reactions: Sudden death has been reported in association with CNS stimulant treatment at recommended doses in pediatric patients with structural cardiac abnormalities or other serious heart problems. In adults, sudden death, stroke and myocardial infarction have been reported. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious heart problems. (5.2)Blood Pressure and Heart Rate Increases: Monitor blood pressure and pulse. Consider the benefits and risks in patients for whom an increase in blood pressure or heart rate would be problematic. (5.3)Psychiatric Adverse Reactions: Use of CNS stimulants may cause psychotic or manic symptoms in patients with no prior history or exacerbation of symptoms in patients with pre-existing psychiatric illness. Evaluate for bipolar disorder prior to methylphenidate hydrochloride extended-release capsules use. (5.4)Priapism: Cases of painful and prolonged penile erections and priapism have been reported with methylphenidate products. Immediate medical attention should be sought if signs or symptoms of painful or prolonged penile erections or priapism are observed. (5.5)Peripheral Vasculopathy, including Raynauds Phenomenon: Stimulants used to treat ADHD are associated with peripheral vasculopathy, including Raynauds phenomenon. Careful observation for digital changes is necessary during treatment with ADHD stimulants. (5.6)Long-Term Suppression of Growth: Monitor height and weight at appropriate intervals in pediatric patients. (5.7) Serious Cardiovascular Reactions: Sudden death has been reported in association with CNS stimulant treatment at recommended doses in pediatric patients with structural cardiac abnormalities or other serious heart problems. In adults, sudden death, stroke and myocardial infarction have been reported. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious heart problems. (5.2). Blood Pressure and Heart Rate Increases: Monitor blood pressure and pulse. Consider the benefits and risks in patients for whom an increase in blood pressure or heart rate would be problematic. (5.3). Psychiatric Adverse Reactions: Use of CNS stimulants may cause psychotic or manic symptoms in patients with no prior history or exacerbation of symptoms in patients with pre-existing psychiatric illness. Evaluate for bipolar disorder prior to methylphenidate hydrochloride extended-release capsules use. (5.4). Priapism: Cases of painful and prolonged penile erections and priapism have been reported with methylphenidate products. Immediate medical attention should be sought if signs or symptoms of painful or prolonged penile erections or priapism are observed. (5.5). Peripheral Vasculopathy, including Raynauds Phenomenon: Stimulants used to treat ADHD are associated with peripheral vasculopathy, including Raynauds phenomenon. Careful observation for digital changes is necessary during treatment with ADHD stimulants. (5.6). Long-Term Suppression of Growth: Monitor height and weight at appropriate intervals in pediatric patients. (5.7) 5.1 Potential forAbuse and Dependence. CNS stimulants, including methylphenidate hydrochloride, other methylphenidate-containing products and amphetamines, have high potential for abuse and dependence. Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy [see Drug Abuse and Dependence (9.2, 9.3)].. 5.2 SeriousCardiovascular Reactions. 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 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 methylphenidate hydrochloride treatment.. 5.3 Blood Pressureand Heart Rate Increases. CNS stimulants cause an increase in blood pressure (mean increase approximately mmHg to mmHg) and heart rate (mean increase approximately bpm to bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.. 5.4 PsychiatricAdverse Reactions. Exacerbation of Pre-Existing PsychosisCNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with pre-existing psychotic disorder. Induction of Manic Episode in Patients with Bipolar DisorderCNS stimulants may induce manic or mixed episode in patients. Prior to initiating treatment, screen patients for risk factors for developing manic episode (e.g., comorbid or history of depressive symptoms or family history of suicide, bipolar disorder, or depression). New Psychotic or Manic SymptomsCNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing methylphenidate hydrochloride. In 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 in placebo-treated patients. 5.5 Priapism. 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 period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.. 5.6 PeripheralVasculopathy, including Raynauds Phenomenon. CNS stimulants, including methylphenidate hydrochloride, used to treat ADHD are associated with peripheral vasculopathy, including Raynauds 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 Raynauds 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.. 5.7 Long-TermSuppression of Growth. CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.Careful follow-up of weight and height in children ages 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 children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e. treatment for days per week throughout the year) have temporary slowing in growth rate (on average, total of about cm less growth in height and 2.7 kg less growth in weight over 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 methylphenidate hydrochloride. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.