FDA Label for Methylphenidate Hydrochloride

Warning: Abuse And Dependence

CNS stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, other methylphenidate-containing products, and amphetamines, have a 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)].

1     Indications And Usage

Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets are indicated for the treatment of:

• Attention Deficit Hyperactivity Disorders (ADHD) in pediatric patients 6 years and older and adults
• Narcolepsy

2.1     Pretreatment Screening

Prior to treating pediatric patients and adults with central nervous system (CNS) stimulants, including methylphenidate hydrochloride tablets or methylphenidate hydrochloride extended-release tablets, assess for the presence of cardiac disease (i.e., perform a careful history including family history of sudden death or ventricular arrhythmia, and physical examination) [see Warnings and Precautions (5.2)].

Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically reevaluate the need for methylphenidate hydrochloride tablets or methylphenidate hydrochloride extended-release tablets use [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9)].

2.2     General Dosing Information

Methylphenidate Hydrochloride Tablets
Pediatric Patients 6 years and Older: Start with 5 mg orally twice daily (before breakfast and lunch). Increase dosage gradually, in increments of 5 to 10 mg weekly. Daily dosage above 60 mg is not recommended.

Adults: Average dosage is 20 to 30 mg daily. Administer orally in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Maximum total daily dosage is 60 mg. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m.

Methylphenidate Hydrochloride Extended-Release Tablets
Methylphenidate hydrochloride extended-release tablets have a duration of action of approximately 8 hours. Therefore, methylphenidate hydrochloride extended-release tablets may be used in place of methylphenidate hydrochloride tablets when the 8-hour dosage of methylphenidate hydrochloride extended-release tablets corresponds to the titrated 8-hour dosage of methylphenidate hydrochloride tablets. Methylphenidate hydrochloride extended-release tablets must be swallowed whole and never crushed or chewed.

Pharmacological treatment of ADHD may be needed for extended periods. Periodically reevaluate the long-term use of methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, and adjust dosage as needed.

2.3     Dose Reduction And Discontinuation

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

3     Dosage Forms And Strengths

Tablets

• 5 mg, round, white unscored tablet debossed with 5 on one side and a

  Boxed M - methylphenidate hydrochloride tablets 1

   on the other side
• 10 mg, round, white scored tablet debossed with 10 on one side of the tablet and a  on the other side
• 20 mg, round, white scored tablet debossed with 20 on one side of the tablet and a  on the other side

Extended-Release Tablets

• 10 mg extended-release tablets, round, white to off-white tablet, debossed with 1423 on one side and a  on the other side
• 20 mg extended-release tablets, round, white to off-white tablet, debossed with 1451 on one side and a  on the other side

4     Contraindications

• Hypersensitivity to methylphenidate or other components of methylphenidate hydrochloride tablets or methylphenidate hydrochloride extended-release tablets. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate [see Adverse Reactions (6.1)].
• Concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days following discontinuation of treatment with an MAOI, because of the risk of hypertensive crises [see Drug Interactions (7.1)].

5.1     Potential For Abuse And Dependence

CNS stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, other methylphenidate-containing products, and amphetamines, have a 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 Boxed Warning, Drug Abuse and Dependence (9.2, 9.3)].

5.2     Serious Cardiovascular 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 serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets treatment.

5.3     Blood Pressure And Heart Rate Increases

CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately 3 to 6 bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.

5.4     Psychiatric Adverse Reactions

Exacerbation of Preexisting Psychosis
CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.

Induction of a Manic Episode in Patients with Bipolar Disorder
CNS stimulants may induce a manic or mixed mood episode in patients. Prior to initiating treatment, screen patients for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).

New Psychotic or Manic Symptoms
CNS stimulants, at recommended doses, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. If such symptoms occur, consider discontinuing methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulant-treated patients, compared to 0 in placebo-treated patients.

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 a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

5.6     Peripheral Vasculopathy, Including Raynaud’S Phenomenon

CNS stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in postmarketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

5.7     Long-Term Suppression 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 pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated patients over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated pediatric patients (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development.

Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

6     Adverse Reactions

The following are discussed in more detail in other sections of the labeling:

• Abuse and Dependence [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)]
• Known hypersensitivity to methylphenidate or other ingredients of methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets [see Contraindications (4)]
• Hypertensive crisis with Concomitant Use of Monoamine Oxidase Inhibitors [see Contraindications (4), Drug Interactions (7.1)]
• Serious Cardiovascular Reactions [see Warnings and Precautions (5.2)]
• Blood Pressure and Heart Rate Increases [see Warnings and Precautions (5.3)]
• Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)]
• Priapism [see Warnings and Precautions (5.5)]
• Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions (5.6)]
• Long-Term Suppression of Growth [see Warnings and Precautions (5.7)]

The following adverse reactions associated with the use of all methylphenidate hydrochloride tablets, methylphenidate hydrochloride extended-release tablets, and other methylphenidate products were identified in clinical trials, spontaneous reports, and literature. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure.

Adverse Reactions Reported with Methylphenidate Hydrochloride Tablets and Methylphenidate Hydrochloride Extended-Release Tablets

Infections and Infestations: nasopharyngitis

Blood and the Lymphatic System Disorders: leukopenia, thrombocytopenia, anemia

Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis

Metabolism and Nutrition Disorders: decreased appetite, reduced weight gain, and suppression of growth during prolonged use in pediatric patients

Psychiatric Disorders: insomnia, anxiety, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), depressed mood

Nervous System Disorders: headache, dizziness, tremor, dyskinesia including choreoatheetoid movements, drowsiness, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs

Eye Disorders: blurred vision, difficulties in visual accommodation

Cardiac Disorders: tachycardia, palpitations, increased blood pressure, arrhythmias, angina pectoris

Respiratory, Thoracic and Mediastinal Disorders: cough

Gastrointestinal Disorders: dry mouth, nausea, vomiting, abdominal pain, dyspepsia

Hepatobiliary Disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury

Skin and Subcutaneous Tissue Disorders: hyperhidrosis, pruritus, urticaria, exfoliative dermatitis, scalp hair loss, erythema multiforme rash, thrombocytopenic purpura

Musculoskeletal and Connective Tissue Disorders: arthralgia, muscle cramps, rhabdomyolysis

Investigations: weight loss (adult ADHD patients)

Additional Adverse Reactions Reported with Other Methylphenidate-Containing Products

The list below shows adverse reactions not listed for methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets that have been reported with other methylphenidate-containing products.

Blood and Lymphatic Disorders: pancytopenia

Immune System Disorders: hypersensitivity reactions such as auricular swelling, bullous conditions, eruptions, exanthemas

Psychiatric Disorders: affect lability, mania, disorientation and libido changes

Nervous System Disorders: migraine

Eye Disorders: diplopia, mydriasis

Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole

Vascular Disorders: peripheral coldness, Raynaud's phenomenon

Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain, dyspnea

Gastrointestinal Disorders: diarrhea, constipation

Skin and Subcutaneous Tissue Disorders: angioneurotic edema, erythema, fixed drug eruption

Musculoskeletal, Connective Tissue and Bone Disorders: myalgia, muscle twitching

Renal and Urinary Disorders: hematuria

Reproductive System and Breast Disorders: gynecomastia

General Disorders: fatigue, hyperpyrexia

Urogenital Disorders: priapism

7.1     Clinically Important Interactions With Methylphenidate Hydrochloride Tablets And Methylphenidate Hydrochloride Extended-Release Tablets

Table 1 presents clinically important drug interactions with methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets.

8.1     Pregnancy

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

Risk Summary
Published studies and postmarketing reports on methylphenidate use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There may be risks to the fetus associated with the use of CNS stimulants use during pregnancy (see Clinical Considerations).

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 a mg/m² basis. However, spina bifida was observed in rabbits at a dose 52 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre- and postnatal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at doses 6 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 a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

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

Data
Animal Data
In 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 a 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 a 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 adolescents on a 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 a 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 adolescents on a 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 a mg/m² basis).

8.2     Lactation

Risk Summary
Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride tablets or methylphenidate hydrochloride extended-release tablets and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride tablets or methylphenidate hydrochloride extended-release tablets or from the underlying maternal condition.

Clinical Considerations
Monitor 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 tablets and methylphenidate hydrochloride extended-release tablets for the treatment of ADHD have been established in pediatric patients 6 to 17 years.

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

The long-term efficacy of methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets in pediatric patients has not been established.

Long-Term Suppression of Growth
Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.7)].

Juvenile Animal Toxicity Data
Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 4 times the MRHD of 60 mg/day given to children on a mg/m² basis.

In a study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal Day 7) and continuing through sexual maturity (postnatal Week 10). When these animals were tested as adults (postnatal Weeks 13 to 14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day (approximately 4 times the MRHD of 60 mg/day given to children on a mg/m² basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m² basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD given to children on a mg/m² basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

8.5     Geriatric Use

Methylphenidate hydrochloride has not been studied in the geriatric population.

9.1     Controlled Substance

Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets contain methylphenidate hydrochloride, a Schedule II controlled substance.

9.2     Abuse

CNS stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, have a high potential for abuse. Abuse is characterized by impaired control over drug use despite harm, and craving.

Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which may result in overdose and death [see Overdosage (10)].

To reduce the abuse of CNS stimulants including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants [see How Supplied/Storage and Handling (16)], monitor for signs of abuse while on therapy, and reevaluate the need for methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets use.

9.3     Dependence

Tolerance
Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug’s desired and/or undesired effects over time) can occur during chronic therapy with CNS stimulants, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets.

Dependence
Physical dependence (which is manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) may occur in patients treated with CNS stimulants including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

10     Overdosage

Human Experience
Signs and symptoms of acute overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following: nausea, vomiting, diarrhea, restlessness, anxiety, agitation, tremors, hyperreflexia, muscle twitching, convulsions (which may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, hypotension, tachypnea, mydriasis, dryness of mucous membranes, and rhabdomyolysis.

Overdose Management
Consult with a Certified Poison Control Center (1-800-222-1222) for the latest recommendations.

11     Description

Methylphenidate hydrochloride tablets contain methylphenidate hydrochloride, a CNS stimulant. They are available as tablets of 5 mg, 10 mg, and 20 mg strength for oral administration.

Methylphenidate hydrochloride extended-release tablets contain methylphenidate hydrochloride, a CNS stimulant. They are available as extended-release tablets of 10 mg and 20 mg strength for oral administration. Methylphenidate hydrochloride is methyl α-phenyl-2-piperidineacetate hydrochloride, and its structural formula is:

Chemical Structure - methylphenidate hydrochloride tablets 6

Methylphenidate hydrochloride USP is a white, odorless, fine 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 g/mol.

Methylphenidate hydrochloride tablets contain the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and talc.

Methylphenidate hydrochloride extended-release tablets contain the following inactive ingredients: hydroxypropyl methylcellulose 2208, magnesium stearate, microcrystalline cellulose, and talc.

Note: Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets are color-additive free.

12.1     Mechanism Of Action

Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD and narcolepsy is not known.

12.2     Pharmacodynamics

Methylphenidate is a 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 increase the release of these monoamines into the extraneuronal space.

Cardiac Electrophysiology
A formal QT study has not been conducted in patients taking methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets.

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

12.3     Pharmacokinetics

Absorption
Methylphenidate hydrochloride in the extended-release tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the extended-release tablet compared to the immediate-release tablet, measured by the urinary excretion of methylphenidate’s major metabolite (α-phenyl-2-piperidine acetic acid) was 105% (49% to 168%) in children and 101% (85% to 152%) in adults. The time to peak rate in children was 1.9 hours (0.3 to 4.4 hours) for the methylphenidate hydrochloride tablets and 4.7 hours (1.3 to 8.2 hours) for the methylphenidate hydrochloride extended-release tablets. An average of 67% of extended-release tablet dose was excreted in children as compared to 86% in adults.

Effect of Food
After a high-fat meal, both area under the curve (AUC) (by 25%) and C_max (by 27%) are higher. Time to C_max (T_max) is faster after a high-fat meal (median T_max: 2.5 hours) as compared to without food (median T_max: 3 hours).

Distribution
Binding to plasma proteins is low (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.

Elimination
The systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate.

Metabolism
Methylphenidate is metabolized primarily by de-esterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity.

Excretion
After oral administration, 78% to 97% of the dose is excreted in the urine and 1% to 3% in feces in the form of metabolites within 48 to 96 hours. Most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60% to 86%). The cumulative urinary excretion of alpha-phenyl-2-piperidine acetic acid are not significantly different for methylphenidate hydrochloride extended-release tablets.

Studies in Specific Populations
Male and Female Patients
In a clinical study involving adult subjects who received methylphenidate hydrochloride extended-release tablets, plasma concentrations of methylphenidate hydrochloride’s major metabolite appeared to be greater in females than in males. No gender differences were observed for methylphenidate hydrochloride’s plasma concentration in the same subjects.

Racial or Ethnic Groups
There is insufficient experience with the use of methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets to detect ethnic variations in pharmacokinetics.

Patients with Renal Impairment
Methylphenidate hydrochoride has not been studied in renally-impaired patients. Renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity.

Patients with Hepatic Impairment
Methylphenidate hydrochoride has not been studied in patients with hepatic impairment. 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.

13.1     Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis
In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas, and in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times the MRHD of 60 mg/day given to children on mg/m² basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors and the significance of these results to humans is unknown.

Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 4 times the MRHD (children) on a mg/m² basis.

In a 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.

Mutagenesis
Methylphenidate 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 a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay.

Impairment of Fertility
No human data on the effect of methylphenidate on fertility are available. 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 10 times the MRHD of 60 mg/day given to adolescents on a mg/m² basis.

16     How Supplied/Storage And Handling

Methylphenidate Hydrochloride Tablets USP
5 mg tablets available as a round, white unscored tablet debossed with 5 on one side and a

Boxed M - methylphenidate hydrochloride tablets 7

Bottles of 100........................NDC 0406-1142-01

10 mg tablets available as a round, white scored tablet debossed with 10 on one side of the tablet and a  on the other side

Bottles of 100........................NDC 0406-1144-01

20 mg tablets available as a round, white scored tablet debossed with 20 on one side of the tablet and a  on the other side

Bottles of 100........................NDC 0406-1146-01

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Protect from light.

Dispense in tight, light-resistant container with child-resistant closure.

Methylphenidate Hydrochloride Extended-Release Tablets USP
10 mg extended-release tablets available as a round, white to off-white tablet, debossed with 1423 on one side and a  on the other side

Bottles of 100........................NDC 0406-1445-01

20 mg extended-release tablets available as a round, white to off-white tablet, debossed with 1451 on one side and a  on the other side

Bottles of 100........................NDC 0406-1473-01

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Protect from moisture.

Dispense in tight, light-resistant container with child-resistant closure.

Note: Methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets are color-additive free.

Disposal
Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets by a medicine take-back program or by an authorized collector registered with the Drug Enforcement Administration. If no take-back program or authorized collector is available, mix methylphenidate hydrochloride tablets or methylphenidate hydrochloride extended-release tablets with an undesirable, nontoxic substance to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and discard methylphenidate hydrochloride tablets or methylphenidate hydrochloride extended-release tablets in the household trash.

17     Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Controlled Substance Status/High Potential for Abuse and Dependence
Advise patients that methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets are controlled substances, and they can be abused and lead to dependence. Instruct patients that they should not give methylphenidate hydrochloride tablets or methylphenidate hydrochloride extended-release tablets to anyone else. Advise patients to store methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets in a safe place, preferably locked, to prevent abuse. Advise patients to comply with laws and regulations on drug disposal. Advise patients to dispose of remaining, unused, or expired methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets by a medicine take-back program if available [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.1, 9.2, 9.3), How Supplied/Storage and Handling (16)].

Serious Cardiovascular Risks
Advise patients that there is a potential serious cardiovascular risk including sudden death, myocardial infarction, stroke, and hypertension with methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2)].

Blood Pressure and Heart Rate Increases
Instruct patients that methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets can cause elevations of their blood pressure and pulse rate [see Warnings and Precautions (5.3)].

Psychiatric Risks
Advise patients that methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, at recommended doses, can cause psychotic or manic symptoms, even in patients without prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)].

Priapism
Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct them to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.5)].

Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, including Raynaud’s Phenomenon]
Instruct patients about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red. Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.

Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients [see Warnings and Precautions (5.6)].

Suppression of Growth
Advise patients that methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets may cause slowing of growth and weight loss [see Warnings and Precautions (5.7)].

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to ADHD medications, including methylphenidate hydrochloride tablets and methylphenidate hydrochloride extended-release tablets, during pregnancy [see Use in Specific Populations (8.1)].

Mallinckrodt, the “M” brand mark, the Mallinckrodt Pharmaceuticals logo and

Boxed M - methylphenidate hydrochloride tablets 12

© 2019 Mallinckrodt.

Manufactured and Distributed by:
SpecGx LLC
Webster Groves, MO 63119 USA

Rev 11/2019

Mallinckrodt™
Pharmaceuticals

An electronic copy of the medication guide for Methylphenidate Hydrochloride Tablets USP can be obtained from www.mallinckrodt.com/Medguide/L20M46.pdf or by calling 1-800-778-7898 for alternate delivery options.

An electronic copy of the medication guide for Methylphenidate Hydrochloride Extended-Release Tablets USP can be obtained from www.mallinckrodt.com/Medguide/L20M47.pdf or by calling 1-800-778-7898 for alternate delivery options.

Medication Guide

Principal Display Panel - Methylphenidate Hydrochloride Tablet Usp  (5 Mg Bottle Of 100)

NDC 0406-1142-01                    100 TABLETS

Methylphenidate Hydrochloride
Tablets USP

CII    Rx only

5 mg

Each tablet contains: Methylphenidate Hydrochloride USP......5 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Mallinckrodt™

L0M125
Rev 08/2017

Methylphenidate Hydrochloride Tablet USP (5 mg bottle of 100) - methylphenidate hydrochloride tablets 13

Principal Display Panel - Methylphenidate Hydrochloride Tablet Usp  (10 Mg Bottle Of 100)

NDC 0406-1144-01                    100 TABLETS

Methylphenidate Hydrochloride
Tablets USP

CII    Rx only

10 mg

Each tablet contains: Methylphenidate Hydrochloride USP......10 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Mallinckrodt™

L0M127
Rev 08/2017

Methylphenidate Hydrochloride Tablet USP (10 mg bottle of 100) - methylphenidate hydrochloride tablets 14

Principal Display Panel - Methylphenidate Hydrochloride Tablet Usp  (20 Mg Bottle Of 100)

NDC 0406-1146-01                    100 TABLETS

Methylphenidate Hydrochloride
Tablets USP

CII    Rx only

20 mg

Each tablet contains: Methylphenidate Hydrochloride USP......20 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Mallinckrodt™

L0M129
Rev 08/2017

Methylphenidate Hydrochloride Tablet USP (20 mg bottle of 100) - methylphenidate hydrochloride tablets 15

Principal Display Panel - Methylphenidate Hydrochloride Er Tablet Usp  (10 Mg Bottle Of 100)

NDC 0406-1445-01                    100 TABLETS

Methylphenidate Hydrochloride
Extended-Release Tablets USP

CII    Rx only

10 mg

Each tablet contains: Methylphenidate Hydrochloride USP......10 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Mallinckrodt™

L0M131
Rev 08/2017

Methylphenidate Hydrochloride ER Tablet USP (10 mg bottle of 100) - methylphenidate hydrochloride tablets 16

Principal Display Panel - Methylphenidate Hydrochloride Er Tablet Usp  (20 Mg Bottle Of 100)

NDC 0406-1473-01                    100 TABLETS

Methylphenidate Hydrochloride
Extended-Release Tablets USP

CII    Rx only

20 mg

Each tablet contains: Methylphenidate Hydrochloride USP......20 mg

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

Mallinckrodt™

L0M132
Rev 08/2017

Methylphenidate Hydrochloride ER Tablet USP (20 mg bottle of 100) - methylphenidate hydrochloride tablets 17