Bx Rating 24 Hr Methylphenidate Hydrochloride 54 Mg Extended Release Oral Tablet

2.1 Pretreatment Screening

Prior to treating patients with Methylphenidate HCl Extended-Release Tablets, assess:

2.2 Important Administration Instructions

Administer Methylphenidate HCl Extended-Release Tablets orally once daily in the morning with or without food.

Swallow Methylphenidate HCl Extended-Release Tablets whole with liquids. Do not split, crush, or chew the extended-release tablets because doing so will compromise the extended-release characteristics of Methylphenidate HCl Extended-Release Tablets and may compromise the effectiveness or safety of Methylphenidate HCl Extended-Release Tablets. 

2.3 Recommended Methylphenidate HCl Extended-Release Tablets Dosage in Patients New to Methylphenidate

See Table 1 for the recommended once-daily dosage of Methylphenidate HCl Extended-Release Tablets in patients who were not taking a methylphenidate product. In patients who have not achieved an optimal response at a lower dosage, increase the Methylphenidate HCl Extended-Release Tablets dosage in 18 mg increments at weekly intervals. However, if a slower titration is recommended for patients who have not achieved an optimal response taking 18 mg of Methylphenidate HCl Extended-Release Tablets once daily, increase their daily dosage to 27 mg once per day. 

Table 1 : Recommended Methylphenidate HCl Extended-Release Tablets Dosage in Patients New to Methylphenidate

2.4 Recommended Methylphenidate HCl Extended-Release Tablets Dosage in Patients Switching from Another Methylphenidate Product

See Table 2 for the recommended starting dosage of Methylphenidate HCl Extended-Release Tablets in patients switching from an immediate-release methylphenidate product administered twice daily or three times daily (total daily dosage of 10 to 60 mg/day). 

Table 2: Recommended Starting Dosage in Patients Switching from Another Methylphenidate Product

* Only for patients 13-65 years of age.

In patients who have not achieved an optimal response at a lower dosage, increase the Methylphenidate HCl Extended-Release Tablets dosage in 18 mg increments at weekly intervals. The maximum recommended dosage in pediatric patients 6 to 12 years of age is 54 mg/day, and the maximum recommended dosage in patients 13-65 years old is 72 mg/day. 

2.5 Dosage Reduction and Discontinuation

If paradoxical aggravation of ADHD symptoms or Methylphenidate HCl Extended-Release Tablets-associated  adverse reactions occur, reduce the Methylphenidate HCl Extended-Release Tablets dosage or, if necessary, discontinue Methylphenidate HCl Extended-Release Tablets.

If ADHD improvement is not observed after appropriate dosage modification over a one-month period, discontinue Methylphenidate HCl Extended-Release Tablets.

5.1 Abuse, Misuse, and Addiction

Methylphenidate HCl Extended-Release Tablets have a high potential for abuse and misuse. The use of Methylphenidate HCl Extended-Release Tablets exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction [see Drug Abuse and Dependence (9.1, 9.2)]. Misuse and abuse of CNS stimulants, including Methylphenidate HCl Extended-Release Tablets, can result in overdose and death [see  Overdosage (10) ], and this risk is increased with higher dosage or unapproved methods of administration, such as snorting or injection.

Before prescribing Methylphenidate HCl Extended-Release Tablets, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store Methylphenidate HCl Extended-Release Tablets in a safe place, preferably locked, and instruct patients to not give Methylphenidate HCl Extended-Release Tablets to anyone else. Throughout Methylphenidate HCl Extended-Release Tablets treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

5.2 Risks to Patients with Serious Cardiac Disease

Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosage.

Avoid Methylphenidate HCl Extended-Release Tablets use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

5.3 Increased Blood Pressure and Heart Rate

CNS stimulants may cause an increase in blood pressure (mean increase approximately 2 to 4 mm Hg) and heart rate (mean increase approximately 3 to 6 beats per minute) [see Adverse Reactions (6)]. Some patients may have larger increases.

Monitor all Methylphenidate HCl Extended-Release Tablets-treated patients for hypertension and tachycardia.

5.4 Psychiatric Adverse Reactions

Exacerbation of Psychosis in Patients with a Psychotic Disorder

CNS stimulants, including Methylphenidate HCl Extended-Release Tablets, may exacerbate behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.

Induction of a Manic Episode in Patients with Bipolar Disorder

CNS stimulants, including Methylphenidate HCl Extended-Release Tablets, may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating Methylphenidate HCl Extended-Release Tablets treatment, screen patients for risk factors for developing a manic episode (e.g., history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).

New Psychotic or Manic Symptoms in Patients without a History of a Bipolar or Psychotic Disorder

CNS stimulants (including Methylphenidate HCl Extended-Release Tablets), at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania. 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 with 0% of placebo-treated patients. If such symptoms occur, consider discontinuing Methylphenidate HCl Extended-Release Tablets.

5.5 Priapism

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in adult and pediatric male patients [see Adverse Reactions (6) ]. Although priapism was not reported with methylphenidate initiation, priapism occurred in patients treated with methylphenidate after some time, often subsequent to an increase in dosage.  Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation).

Methylphenidate HCl Extended-Release Tablets-treated 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 HCl Extended-Release Tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon [see Adverse Reactions (6.2)]. Signs and symptoms of these cases of peripheral vasculopathy were usually intermittent and mild; however, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms of peripheral vasculopathy  generally improved after CNS stimulant dosage reduction or discontinuation.

During Methylphenidate HCl Extended-Release Tablets treatment, carefully assess for digital changes.  Further clinical evaluation (e.g., rheumatology referral) may be appropriate for Methylphenidate HCl Extended-Release Tablets-treated patients who develop signs or symptoms of peripheral vasculopathy.

5.7 Long-Term Suppression of Growth in Pediatric Patients

Methylphenidate HCl Extended-Release Tablets are not approved for use and are not recommended in pediatric patients below 6 years of age [see Use in Specific Populations (8.4) ]. CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

Pediatric patients 7 to 13 years of age who received methylphenidate for 7 days per week for over 14 months to over 36 months had 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 development period.

Closely monitor growth (weight and height) in Methylphenidate HCl Extended-Release Tablets-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

5.8 Risk of Gastrointestinal Obstruction in Patients with Gastrointestinal Narrowing

Because Methylphenidate HCl Extended-Release Tablets are nondeformable and do not appreciably change in shape in the gastrointestinal (GI) tract, Methylphenidate HCl Extended-Release Tablets should not ordinarily be administered to patients with pre-existing severe pathologic or iatrogenic GI narrowing.  There have been rare reports of obstructive GI symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable modified-release dosage forms. 

Methylphenidate HCl Extended-Release Tablets should be used only in patients who are able to swallow the extended-release tablets whole [see Dosage and Administration (2.2)]. 

5.9 Acute Angle Closure Glaucoma

There have been reports of angle closure glaucoma associated with methylphenidate treatment.

Although the mechanism is not clear, Methylphenidate HCl Extended-Release Tablets-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.

5.10 Increased Intraocular Pressure and Glaucoma

There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6) ].

Prescribe Methylphenidate HCl Extended-Release Tablets to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor Methylphenidate HCl Extended-Release Tablets-treated patients with a history of abnormally increased IOP or open angle glaucoma.

5.11 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome

CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics [see Adverse Reactions (6)]. Worsening of Tourette’s syndrome has also been reported.

Before initiating Methylphenidate HCl Extended-Release Tablets, assess the family history for tics or Tourette’s syndrome and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor Methylphenidate HCl Extended-Release Tablets-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue Methylphenidate HCl Extended-Release Tablets treatment if clinically appropriate.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data below is based on a total of 3,906 patients in clinical studies who received Methylphenidate HCl Extended-Release Tablets. Patients aged 6 up to 65 years old with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies [see Table 3].

Table 3 : Methylphenidate HCl Extended-Release Tablets -treated Patients in Double-Blind and Open-Label Clinical Studies

The most common adverse reactions (≥5%) in double-blind clinical trials were:

The most common adverse reactions associated with Methylphenidate HCl Extended-Release Tablets discontinuation (≥1%) from the pediatric and adult clinical trials were anxiety, irritability, insomnia, and increased blood pressure.

Most Common Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials: Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations.

Adverse Reactions in Pediatric Patients Aged 6 years and Older

Table 4 displays adverse reactions reported in 2% or more of Methylphenidate HCl Extended-Release Tablets-treated pediatric patients ages 6 and older with ADHD in 4 placebo-controlled, double-blind clinical trials. 

Table 4: Most Common Adverse Reactions¹ in Pediatric Patients 6 Years of Age and Older with ADHD in 4 Placebo-Controlled, Double-Blind Clinical Trials

¹ Reported in ≥ 2% of Methylphenidate HCl Extended-Release Tablets-treated patients

² Initial insomnia (Methylphenidate HCl Extended-Release Tablets=0.6%) and insomnia (Methylphenidate HCl Extended-Release Tablets=2.2%) terms were combined into Insomnia.

Adverse Reactions in Adults

Table 5 lists the adverse reactions reported in 2% or more of Methylphenidate HCl Extended-Release Tablets-treated adults with ADHD in 2 placebo-controlled, double-blind clinical trials.

Table 5: Most Common Adverse Reactions¹ in Adults with ADHD in 2 Placebo-Controlled, Double-Blind Clinical Trials

¹ Reported in ≥ 2% of Methylphenidate HCl Extended-Release Tablets-treated patients

² Included dosages up to 108 mg/day (1.5 times the maximum recommended dosage).

Other Adverse Reactions Observed in Clinical Trials of Methylphenidate HCl Extended-Release Tablets

The following adverse reactions occurred in less than 2% of Methylphenidate HCl Extended-Release Tablets-treated patients ages 6 to 65 years of age in the double-blind and open-label clinical ADHD trials.

Discontinuation Due to Adverse Reactions

In the 2 placebo-controlled studies in adults with ADHD, 25 (6%) Methylphenidate HCl Extended-Release Tablets-treated patients and 6 (3%) placebo-treated patients discontinued due to an adverse reaction. In the Methylphenidate HCl Extended-Release Tablets group, adverse reactions leading to discontinuation with an incidence of >0.5% were anxiety (1.7%), irritability (1.4%), increased blood pressure (1%), and nervousness (0.7%). In the placebo group, adverse reactions leading to discontinuation with an incidence of >0.5% were increased blood pressure (0.9%) and depressed mood (0.9%).

In the 11 open-label studies in patients 6 to 65 years of age with ADHD, 266 (7%) Methylphenidate HCl Extended-Release Tablets-treated patients discontinued due to an adverse reaction including insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%).

Blood Pressure and Heart Rate Increases

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Methylphenidate HCl Extended-Release Tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency:

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD drugs, including Methylphenidate HCl Extended-Release Tablets, during pregnancy. Healthcare providers are encouraged to advise patients to register by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-medications/.

Risk Summary

Published studies and post-marketing reports on methylphenidate use during pregnancy have inconsistent findings about a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the fetus associated with the use of central nervous system (CNS) stimulants 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 throughout organogenesis at doses up to 4 and 16 times, respectively, the maximum recommended human dose (MRHD) of 72 mg/day given to adults on a mg/m² basis. However, spina bifida was observed in rabbits at a dose 54 times the MRHD given to adults. A slight decrease in body weight was observed in pregnant rats at the highest dose of 30 mg/kg/day (4 times the MRHD given to adults).

In a pre- and postnatal development study in which rats were treated with oral administration of methylphenidate throughout pregnancy and lactation, a decrease in pup body weight, alterations in sensory and neuromotor performance, and deficits in learning and memory were observed in both sexes at the highest dose (4 times the MRHD given to adults on a mg/m² basis) (see Data).

The background risk of major birth defects and miscarriage in those with ADHD is unknown. All pregnancies have a background risk of birth defects, 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 HCl 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 a therapeutic dosage 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 up to 30 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 54 times the maximum recommended human dose (MRHD) of 72 mg/day given to adults on a mg/m² basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (16 times the MRHD given to adults on a mg/m² basis).

There was no evidence of changes in morphological development in rats, although a reduction in maternal body weight was observed at the highest dose of 30 mg/kg/day (4 times the MRHD of 72 mg/day given to adults (on a mg/m² basis). The no effect level for maternal body weight in rats is 5 mg/day (equal to the MRHD for adults on a mg/m² basis); and the no effect level for embryo-fetal development is 30 mg/kg/day (4 times the MRHD for adults on a mg/m² basis).

When methylphenidate was administered to rats throughout pregnancy and lactation at doses of up to 30 mg/kg/day, decreases in offspring body weight, alterations in sensory and neuromotor performance, and deficits in learning and memory were observed in both sexes at the highest dose (4 times the MRHD of 72 mg/day, given to adults on a mg/m² basis). The no effect level for pre- ­and post-natal development in rats was 12.5 mg/kg/day (2 times the MRHD given to adults on a mg/m² basis).

8.2 Lactation

Risk Summary

Limited published literature, based on breast milk sampling from a small number of methylphenidate-treated lactating women, reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted methylphenidate dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant or effects on milk production. Long-term neurodevelopmental effects on infants from CNS stimulant exposure are unknown.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Methylphenidate HCl Extended-Release Tablets and any potential adverse effects on the breastfed child from Methylphenidate HCl Extended-Release Tablets or from the underlying maternal condition.

Clinical Considerations

Monitor breastfeeding infants of Methylphenidate HCl Extended-Release Tablets-treated lactating women for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

8.4 Pediatric Use

The safety and effectiveness of Methylphenidate HCl Extended-Release Tablets for the treatment of ADHD have been established in pediatric patients 6 years of age and older. The safety and effectiveness of Methylphenidate HCl Extended-Release Tablets have not been established in pediatric patients below the age of 6 years.

In studies evaluating extended-release methylphenidate products, patients 4 to <6 years of age had higher systemic methylphenidate exposures than those observed in older pediatric patients at the same dosage. Pediatric patients 4 to <6 years of age also had a higher incidence of adverse reactions, including weight loss.

CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients. Growth (weight and height) should be monitored in pediatric patients during treatment with CNS stimulants, including Methylphenidate HCl Extended-Release Tablets. Pediatric patients who are not growing or gaining weight as expected may need to have their Methylphenidate HCl Extended-Release Tablets 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 54 mg/day given to pediatric patients 6 to 12 years of age 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 54 mg/day given to pediatric patients 6 to 12 years of age 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 (9 times the MRHD given to pediatric patients 6 to 12 years of age on a mg/m² basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.4 times the MRHD given to pediatric patients 6 to 12 years of age on a mg/m² basis). The clinical significance of the long-­term behavioral effects observed in rats is unknown.

8.5 Geriatric Use

Methylphenidate HCl Extended-Release Tablets are not indicated for use in patients greater than 65 years of age. 

9.1 Controlled Substance

Methylphenidate HCl Extended-Release Tablets contain methylphenidate, a Schedule II controlled substance.

9.2 Abuse

Methylphenidate HCl Extended-Release Tablets have a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see Warnings and Precautions (5.1)].

Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Misuse and abuse of Methylphenidate HCl Extended-Release Tablets may cause increased heart rate, respiratory rate, or blood pressure; 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 with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including Methylphenidate HCl Extended-Release Tablets, can result in overdose and death [see Overdosage (10) ], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

Studies of Abuse Potential with Methylphenidate HCl Extended-Release Tablets

In two placebo- and active-controlled, crossover human abuse potential (HAP) studies, the relative abuse potential of single oral doses of Methylphenidate HCl Extended-Release Tablets were compared to single oral doses of immediate-release methylphenidate (IR MPH) and placebo in subjects with a history of recreational CNS stimulant use. In these studies, the response for each of the abuse-related subjective measures was defined as the maximum effect within the first 8 hours after treatment administration. When evaluating these results, consider that 22% of the total methylphenidate amount in Methylphenidate HCl Extended-Release Tablets (methylphenidate hydrochloride) extended-release tablets are available for immediate release and the remaining 78% is available for extended-release over 24 hours.

The clinical significance of the differences in response between Methylphenidate HCl Extended-Release Tablets and IR MPH on subjective measures of abuse potential as reported in these HAP studies is unknown.

9.3 Dependence

Physical Dependence

Methylphenidate HCl Extended-Release Tablets may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. 

Withdrawal signs and symptoms after abrupt discontinuation or dosage reduction following prolonged use of CNS stimulants including Methylphenidate HCl Extended-Release Tablets included dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance

Methylphenidate HCl Extended-Release Tablets may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

10.1 Clinical Effects of Overdose

Overdose of CNS stimulants is characterized by the following sympathomimetic effects:

10.2 Overdose Management

Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of Methylphenidate HCl Extended-Release Tablets should be considered when treating patients with overdose. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

12.1 Mechanism of Action

Methylphenidate is a central nervous system (CNS) stimulant.  The mode of therapeutic action of methylphenidate in the treatment of ADHD is not known.  Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.

12.2 Pharmacodynamics

Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of Methylphenidate HCl Extended-Release Tablets have not been fully characterized.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

14.1 Overview of Clinical Trials

Methylphenidate HCl Extended-Release Tablets were demonstrated to be effective in the treatment of ADHD in patients who met the Diagnostic and Statistical Manual 4^th edition (DSM-IV) criteria for ADHD in the following trials:

14.2 Clinical Trials in Pediatric Patients 6 to 12 Years

Three double-blind, active- and placebo-controlled trials were conducted in 416 pediatric patients 6 to 12 years of age with ADHD: (1) two single-center, crossover trials (patients received each treatment for one week) (Studies 1 and 2) and (2) a multicenter, 4-week, parallel-group comparison trial (Study 3). In these trials, patients were randomized to receive:

The primary comparison of interest in all three trials was the Methylphenidate HCl Extended-Release Tablets group versus the placebo group.

ADHD symptoms were evaluated by community schoolteachers using the Inattention/Overactivity with Aggression (IOWA) Conners scale.

A statistically significant reduction in the Inattention/Overactivity subscale (0 to 15) in the Methylphenidate HCl Extended-Release Tablets group versus the placebo group was shown in all three trials. The scores for Methylphenidate HCl Extended-Release Tablets and placebo for the three trials are presented in Figure 2.

Figure 2.  Mean Community School Teacher Inattention/Overactivity Subscores in the IOWA Conners Scale in Pediatric Patients 6 to 12 Years with ADHD 

14.3 Clinical Trials in Pediatric Patients 13 to 17 Years

In a randomized-withdrawal, double-blind, multicenter, placebo-controlled trial (Study 4) with 177 pediatric patients 13 to 17 years of age with ADHD, Methylphenidate HCl Extended-Release Tablets demonstrated effectiveness with a dosage up to 72 mg/day (1.4 mg/kg/day):

At the end of the double blind phase, mean scores for the investigator rating on the ADHD Rating Scale demonstrated that the Methylphenidate HCl Extended-Release Tablets group was statistically significantly superior to the placebo group.

14.4 Clinical Trials in Adults up to 65 Years Old

Two randomized double-blind, placebo-controlled multicenter, parallel-group trials were conducted in 627 adults aged 18 to 65 years with ADHD who received Methylphenidate HCl Extended-Release Tablets or placebo once daily:

In Study 5, Methylphenidate HCl Extended-Release Tablets demonstrated efficacy based on the change from baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS). At the final study visit, mean change scores (LS Mean, SEM) for the investigator rating on the AISRS demonstrated that the Methylphenidate HCl Extended-Release Tablets group was statistically significantly superior to the placebo group.

In Study 6, all three Methylphenidate HCl Extended-Release Tablets dosages were statistically significantly more effective than placebo in improving Conners’ Adult ADHD Rating Scale (CAARS) total scores after five weeks of treatment.

Storage and Handling

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