Metadate Cd Capsule, Extended Release
FDA Label NDC 0527-6579

METADATE CD has a high potential for abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including METADATE CD, can result in overdose and death [see Overdosage (10)], and this risk is increased with a higher dosage or unapproved methods of administration, such as snorting or injection. 

Before prescribing METADATE CD, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of METADATE CD, and proper disposal of any unused drug. Throughout METADATE CD treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.2)].

METADATE CD is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in pediatric patients 6 years of age and older.

Limitations of Use

The use of METADATE CD is not recommended in pediatric patients younger than 6 years of age because they had higher plasma exposure and a higher incidence of adverse reactions (e.g. weight loss) than patients 6 years and older at the same dosage [see Warnings and Precautions (5.7), Use in Specific Populations (8.4)].

Prior to treating patients with METADATE CD, assess:

• The risk for abuse, misuse, and addiction [see Warnings and Precautions (5.1)].
• For the presence of cardiac disease (e.g., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)].
• The risk for developing a manic episode (e.g., history of depressive symptoms or a family history of suicide, bipolar disorder, or depression) [see Warnings and Precautions (5.4)].
• For a family history for tics or Tourette syndrome and clinically evaluate patients for motor or verbal tics or Tourette syndrome [see Warnings and Precautions (5.10)].

The recommended starting dosage of METADATE CD in pediatric patients 6 years of age and older is 20 mg once daily.  Dosage may be adjusted weekly in 10 mg to 20 mg increments to the maximum recommended dosage of 60 mg per day.

Take METADATE CD orally once daily in the morning, before breakfast [see Clinical Pharmacology (12.3)].

Swallow the extended-release capsules whole with the aid of liquids. Alternatively, open the extended-release capsules and sprinkle the contents onto a small amount (tablespoon) of applesauce and administer immediately and then drink fluids.  Do not store for future use.  Do not crush or chew the extended-release capsules.

If paradoxical aggravation of ADAD symptoms or METADATE CD-associated adverse reactions occur, reduce dosage or, if necessary, discontinue METADATE CD. If ADHD improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue METADATE CD.

METADATE CD (methylphenidate hydrochloride) extended-release capsules are available in the following strengths (see Table 1):

METADATE CD is contraindicated in patients:

• With known hypersensitivity reaction(s) to methylphenidate or other ingredients of METADATE CD.  Angioedema has been reported in patients treated with METADATE CD. Anaphylactic reactions have been reported in patients treated with other methylphenidate products  [see Adverse Reactions (6)].
• Taking a monoamine oxidase inhibitor (MAOI) or within 14 days of discontinuing use of an MAOI because of the risk of hypertensive crisis [see Drug Interactions (7)].
• With hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase insufficiency because METADATE CD contains sucrose.
• With pheochromocytoma or a history of pheochromocytoma. Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with pheochromocytoma or a history of pheochromocytoma who received a CNS stimulant.

METADATE CD has a high potential for abuse and misuse. The use of METADATE CD exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants, including METADATE CD, can result in overdose and death [see Overdosage (10)], and this risk is increased with a higher dosage or unapproved methods of administration, such as snorting or injection.

Before prescribing METADATE CD, 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 and/or their caregivers to store METADATE CD in a safe place, preferably locked, and instruct patients and/or their caregivers to not give METADATE CD to anyone else. Throughout METADATE CD treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

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 dosage.

Prior to treating patients with METADATE CD, assess for the presence of cardiac disease (e.g., perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam). Avoid METADATE CD use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac problems.

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). Some patients may have larger increases.

Monitor all METADATE CD treated patients for hypertension and tachycardia.

Exacerbation of Pre-Existing Psychosis in Patients with a Psychotic Disorder

CNS stimulants, including METADATE CD, may exacerbate symptoms of 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 METADATE CD, may induce a manic or mixed episode in patients with bipolar disorder. Prior to initiating METADATE CD 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 in Patients without a History of a Bipolar or Psychotic Disorder

CNS stimulants, including METADATE CD, at the recommended dosages, 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 CNC stimulant-treated patients, compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing METADATE CD.

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

METADATE CD-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

CNS stimulants, including METADATE CD, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon. 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 generally improved after dosage reduction in or discontinuation of the CNS stimulant.

Carefully assess for digital changes during METADATE CD treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for METADATE CD-treated patients who develop signs of symptoms of peripheral vasculopathy.

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 pediatric patients over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate treatment for 7 days per week throughout the year 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.  METADATE CD is not approved for use and is not recommended in pediatric patients below 6 years of age because of a higher incidence of adverse reactions including weight loss [see Use in Specific Populations (8.4)].

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

There have been reports of angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, METADATE CD-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.

There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.2)].

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

CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette syndrome has also been reported [see Adverse Reactions (6.2)].

Before initiating METADATE CD, assess the family history for tics or Tourette syndrome and clinically evaluate patients for tics or Tourette syndrome. Regularly monitor METADATE CD-treated patients for the emergence or worsening of tics or Tourette syndrome, and discontinue METADATE CD if clinically appropriate.

The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling:

• Abuse, Misuse, and Addiction [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)]
• Risks to Patients with Serious Cardiac Disease [see Warnings and Precautions (5.2)]
• Increased Blood Pressure and Heart Rate [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 in Pediatric Patients [see Warnings and Precautions (5.7)]
• Acute Angle Closure Glaucoma [see Warnings and Precautions (5.8)]
• Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.9)]
• Motor and Verbal Tics, and Worsening of Tourette Syndrome [see Warnings and Precautions (5.10)]

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

The safety database is based on three clinical studies of METADATE CD (i.e., Studies 1, 2, and 3) that included 188 METADATE CD-treated pediatric patients 6 years of age and older with ADHD. Pediatric patients received METADATE CD 20 mg, 40 mg, and/or 60 mg once daily:

• Study 1 was a 3-week placebo-controlled clinical study that included 314 pediatric patients (ages 6 to 15 years; METADATE CD n=155)
• Study 2 was a placebo-controlled, crossover clinical study that included 25 pediatric patients (ages 7 to 12 years); and
• Study 3 was an uncontrolled clinical study that included 8 pediatric patients (ages 6 to 10 years).

Adverse Reactions Leading to Discontinuation of Treatment

In Study 1, 1% (2/155) METADATE CD-treated patients and no placebo-treated patients discontinued due to an adverse reaction.  One METADATE CD-treated patient discontinued due to rash and pruritus; and the other METADATE CD-treated patient discontinued due headache, abdominal pain, and dizziness.

Most Common Adverse Reactions

The most common adverse reactions that occurred in 5% or more of METADATE CD-treated and at least twice as great in the METADATE CD-treated patients compared to the placebo-treated patients in a pool of Studies 1, 2 and 3 in pediatric patients 6 to 15 years of age were anorexia and insomnia.

Adverse reactions that occurred in ≥5% of METADATE CD-treated patients with a greater incidence in METADATE CD-treated patients than placebo-treated patients in pooled Studies, 1, 2, and 3 are presented in Table 2:

Table 2: Adverse Reactions¹ in Pediatric Patients Ages 6 to 15 Years with ADHD in Pooled Three to Four Week Trials (Studies 1, 2, and 3)

	METADATE CD (n=188)	Placebo (n=190)
Headache	12%	8%
Anorexia	9%	2%
Abdominal Pain	7%	4%
Insomnia	5%	2%

¹ Adverse reactions that occurred in ≥5% of METADATE CD-treated patients with a greater incidence in METADATE CD-treated patients than placebo-treated patients

The following adverse reactions have been identified during postmarketing use of METADATE CD and other methylphenidate products. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse Reactions with METADATE CD

• Blood and the lymphatic system disorders: thrombocytopenia
• Cardiac disorders: cardiac arrest, sudden death
• Immune system disorders: angioedema
• Musculoskeletal and connective tissue disorders: rhabdomyolysis
• Psychiatric disorders: abnormal behavior, aggression, anxiety, irritability, obsessive-compulsive disorder, suicidal behavior (including completed suicide), libido changes, serotonin syndrome in combination with serotonergic drugs
• Nervous System Disorder: migraine, reversible ischemic neurological deficit, bruxism
• Skin and subcutaneous tissue disorders: fixed drug eruption
• Vascular disorders: peripheral coldness, Raynaud’s phenomenon

Adverse Reactions with Other Methylphenidate Products

• Blood and the lymphatic system disorders: leukopenia, anemia, pancytopenia
• Cardiac disorders: palpitations; increased blood pressure, tachycardia, angina pectoris, cardiac arrhythmia, myocardial infarction, bradycardia, extrasystole
• Eye disorders: blurred vision, difficulties in visual accommodation, diplopia, increased intraocular pressure, mydriasis
• Gastrointestinal disorders: nausea, abdominal pain, dry mouth, vomiting, dyspepsia, diarrhea, constipation
• General Disorders: fatigue, hyperpyrexia
• Hepatobiliary disorders: abnormal liver function, ranging from transaminase elevation to severe hepatic injury
• Immune system disorders: hypersensitivity, including anaphylaxis, auricular swelling, bullous conditions, eruptions, exanthemas
• Infections and infestations: nasopharyngitis
• Metabolism and nutrition disorders: decreased appetite, reduced weight gain and suppression of growth during prolonged use in pediatric patients
• Musculoskeletal and connective tissue disorders: arthralgia, muscle cramps, myalgia, muscle twitching
• Nervous System Disorder: nervousness, dizziness, headache, dyskinesia, including choreoatheetoid movements, drowsiness, tremor, convulsions, cerebrovascular disorders (including vasculitis, cerebral hemorrhages and cerebrovascular accidents), serotonin syndrome in combination with serotonergic drugs, motor and verbal tics
• Psychiatric disorders: depressed mood, restlessness, agitation, psychosis (sometimes with visual and tactile hallucinations), affect liability, mania, disorientation
• Renal and urinary disorders: hematuria
• Reproductive system and breast disorders: gynecomastia
• Respiratory, thoracic and mediastinal disorders: pharyngolaryngeal pain, dyspnea, cough
• Skin and subcutaneous tissue disorders: scalp hair loss, hyperhidrosis, angioneurotic edema, erythema, exfoliative dermatitis, thrombocytopenic purpura, urticaria, erythema multiforme rash
• Urogenital disorders: priapism
• Vascular disorders: isolated cases of cerebral arteritis and/or occlusion

Table 3 describes clinically significant drug interactions with METADATE CD.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD drugs, including METADATE CD, 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 postmarketing 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 during organogenesis at dosages up to 10 and 15 times, respectively, the maximum recommended human dosage (MRHD) of 60 mg/day given to adolescents on a mg/m² basis. However, spina bifida was observed in rabbits at a dosage 53 times the MRHD given to adolescents. A decrease in pup body weight was observed in a pre-and post-natal development study with oral administration of methylphenidate to rats throughout pregnancy and lactation at dosages 6 times the MRHD given to adolescents (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 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, including METADATE CD, 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 dosages 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 dosage, 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 dosage level (10 times the MRHD of 60 mg/day given to adults 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 dosages of up to 45 mg/kg/day, offspring body weight gain was decreased at the highest dosage (6 times the MRHD of 60 mg/day given to adults 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).

Risk Summary

Limited published literature, based on milk sampling from a small number of methylphenidate-treated lactating women reports that methylphenidate is present in human milk, which resulted in infant dosages 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 METADATE CD and any potential adverse effects on the breastfed infant from METADATE CD or from the underlying maternal condition.

Clinical Considerations

Monitor breastfeeding infants of METADATE CD-treated lactating women for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.

The safety and effectiveness of METADATE CD for the treatment of ADHD have been established in pediatric patients 6 years of age and older.

The safety and effectiveness of METADATE CD 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. Therefore, the use of METADATE CD is not recommended in pediatric patients less than 6 years of age.

Long-Term Suppression of Growth

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 Metadate CD. Pediatric patients who are not growing or gaining weight as expected may need to have their METADATE CD treatment interrupted [see Warnings and Precautions (5.6)].

Juvenile Animal Toxicity Data

In a study conducted in young rats, methylphenidate was administered orally at dosages 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 6 times the MRHD 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 dosage (12 times the MRHD on a mg/m² basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m² basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.

METADATE CD has not been studied in patients over the age of 65 years and is not indicated for use in adults.

METADATE CD contains methylphenidate, a Schedule II controlled substance.

METADATE CD has a high potential for abuse 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. 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.

METADATE CD has a high potential for misuse. 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. Misuse, like abuse, is often associated with higher dosages and/or more frequent use of the drug, which may lead to adverse reactions similar to those seen in the context of abuse and substance use disorder.

Misuse and abuse of methylphenidate 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 METADATE CD, can result in overdose and death [see Overdosage (10)], and this risk is increased with higher dosages or unapproved methods of administration, such as snorting or injection.

Physical Dependence

METADATE CD 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 dosage reduction of a drug.

Withdrawal signs and symptoms after abrupt discontinuation or dosage reduction following prolonged use of CNS stimulants including METADATE CD include dysphoric mood; depression; fatigue; vivid; unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance

METADATE CD may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dosage of a drug is required to produce the same effect that was once obtained at a lower dosage).

Clinical Effects of Overdose

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

• Cardiovascular effects including tachyarrhythmias, and hypertension or hypotension. Vasospasm, myocardial infarction, or aortic dissection may precipitate sudden cardiac death. Takotsubo cardiomyopathy may develop.
• CNS effects including psychomotor agitation, confusion, and hallucinations. Serotonin syndrome, seizures, cerebral vascular accidents, and coma may occur.
• Life-threatening hyperthermia (temperatures greater than 104°F) and rhabdomyolysis may develop.

Posterior reversible encephalopathy syndrome (PRES) symptoms including headache, altered mental status, hypertension, seizures, and visual disturbances including blindness have occurred in the setting of CNS stimulant overdose. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Diagnosis of PRES should be confirmed by radiological procedure (e.g., MRI).

Overdose Management

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

Chemically, methylphenidate hydrochloride is d,l (racemic)-threo-methyl α-phenyl-2-piperidineacetate hydrochloride. Its empirical formula is C₁₄H₁₉NO₂•HCl. Methylphenidate hydrochloride, USP is a 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. Its structural formula is:

Structural Formula (Metadate Cd Methylphenidate Hydrochloride Capsule 1)

METADATE CD (methylphenidate hydrochloride) extended-release capsules is a CNS stimulant.  The extended-release capsules for oral administration comprise both immediate-release (IR) and extended-release (ER) beads such that 30% of the dosage is provided by the IR component and 70% of the dosage is provided by the ER component.  METADATE CD is available in six extended-release capsule strengths containing:

• 10 mg of methylphenidate hydrochloride (3 mg IR; 7 mg ER) (equivalent to 10 mg of methylphenidate),
• 20 mg of methylphenidate hydrochloride (6 mg IR; 14 mg ER) (equivalent to 20 mg of methylphenidate),
• 30 mg of methylphenidate hydrochloride (9 mg IR; 21 mg ER) (equivalent to 30 mg of methylphenidate),
• 40 mg of methylphenidate hydrochloride (12 mg IR; 28 mg ER) (equivalent to 40 mg of methylphenidate),
• 50 mg of methylphenidate hydrochloride (15 mg IR; 35 mg ER) (equivalent to 50 mg of methylphenidate)
• 60 mg of methylphenidate hydrochloride (18 mg IR; 42 mg ER) (equivalent to 60 mg of methylphenidate).

METADATE CD contains the following inactive ingredients: Dibutyl sebacate, ethylcellulose aqueous dispersion, gelatin, hydroxypropyl methylcellulose, polyethylene glycol, povidone, sugar spheres, and titanium dioxide.

The extended-release capsules contain the following color agents:

• 10 mg: FD&C Blue No. 2, FDA/E172 Yellow Iron Oxide
• 20 mg: FD&C Blue No. 2
• 30 mg: FD&C Blue No. 2, FDA/E172 Red Iron Oxide
• 40 mg: FDA/E172 Yellow Iron Oxide
• 50 mg: FD&C Blue No. 2, FDA/E172 Red Iron Oxide

Methylphenidate hydrochloride is a central nervous system (CNS) stimulant. The mode of therapeutic action of METADATE CD in the treatment of ADHD in pediatric patients 6 years of age and older 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.

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. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of METADATE CD have not been fully characterized.

Following one week of 20 mg/day or 40 mg/day of METADATE CD to pediatric patients aged 7 to12 years old with ADHD, C_max and AUC of methylphenidate were approximately proportional to the administered dosage.

Absorption

Following administration of METADATE CD in pediatric patients aged 7 to 12 years old with ADHD, the plasma concentration time profile of methylphenidate showed two phases of drug release with a sharp, initial slope similar to a methylphenidate immediate-release tablet (median T_max1 about 1.5 hours post dosage), and a second rising portion approximately three hours later (median T_max2 about 4.5 hours post dosage)*, followed by a gradual decline (Figure 1). The means for C_max and area under the curve (AUC) following a dosage of 20 mg of METADATE CD were slightly lower than those seen with 10 mg of the immediate-release methylphenidate, dosed at 0 and 4 hours.

*25-30% of the patients had only one observed peak (C_max) concentration of methylphenidate.

Figure 1: Methylphenidate Pharmacokinetics After Repeat Dosages of an Immediate Release (IR) Methylphenidate Product and METADATE CD in Pediatric Patients 7 to 12 Years of Age with ADHD

Figure 1 (Metadate Cd Methylphenidate Hydrochloride Capsule 2)

Effect of Food: Ingestion of a high-fat meal with METADATE CD administration increased the mean C_max and AUC of methylphenidate by about 30% and 17%, respectively. The presence of food delayed the early peak by approximately 1 hour (range -2 to 5 hours delay) [see Dosage and Administration (2.1)].

The bioavailability (C_max and AUC) of methylphenidate was unaffected by sprinkling the METADATE CD extended-release capsule contents on applesauce as compared to the intact capsule.

Distribution

Plasma 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.

Elimination

The mean terminal half-life (t½) of methylphenidate following administration of METADATE CD (t½=6.8 hours) is longer than the mean terminal t½ following administration of methylphenidate hydrochloride immediate-release tablets (t½=2.9 hours) and methylphenidate hydrochloride extended-release tablets (t½=3.4 hours) in healthy adult volunteers.

Metabolism: In 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.

Excretion: After 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 dosage.

Specific Populations

• Male and Female Patients: The pharmacokinetics of methylphenidate after a single dosage of METADATE CD were similar between adult males and females.
• Patients with Renal Impairment: METADATE CD has not been studied in patients with renal impairment. Since renal clearance is not an important route of methylphenidate clearance, and the major metabolite (ritalinic acid), has little or no pharmacologic activity, renal impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate after METADATE CD administration.
• Patients with Hepatic Impairment: METADATE CD has not been studied in patients with hepatic impairment. Hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate because it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.
• Racial or Ethnic Groups: The influence of race on the pharmacokinetics of methylphenidate after METADATE CD administration has not been studied.

Drug Interaction Studies

Alcohol: An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the METADATE CD 60 mg extended-release capsules. 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 strengths [see Drug Interactions (7)].

In vitro studies showed that methylphenidate did not inhibit cytochrome P450 isoenzymes at clinically observed plasma drug concentrations.

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 dosage of approximately 60 mg/kg per day. This dosage is approximately 2 times the maximum recommended human dosage (MRHD) of 60 mg/day given to children on a mg/m² basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown.

Methylphenidate did not cause any increases in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dosage 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-dosage groups were exposed to 60 to 74 mg/kg per 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 cells. Methylphenidate was negative in vivo in males and females in the mouse bone marrow micronucleus assay.

Impairment of Fertility

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 dosages up to 160 mg/kg per day, approximately 10 times the maximum recommended human dosage of 60 mg/day given to adolescents on a mg/m² basis.

METADATE CD was evaluated in a double-blind, parallel-group, placebo-controlled 3-week trial (Study 1) in which 321 untreated or previously treated pediatric patients 6 to 15 years of age with a DSM-IV diagnosis of attention deficit hyperactivity disorder (ADHD).  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 METADATE CD group received 20 mg daily in the morning for the first week.  Their METADATE CD dosage could be increased weekly to a maximum of 60 mg by the third week, depending on individual response to treatment.

The patient’s regular school teacher completed the teachers’ version of the Conners’ Global Index Scale (TCGIS), a scale for assessing ADHD symptoms, in the morning and again in the afternoon on three alternate days of each treatment week.  The primary efficacy endpoint was determined by the average of the total scores for the 10-item TCGIS completed by the classroom teacher in the morning and again in the afternoon on the three observation days during the last week of double-blind therapy. Patients in the METADATE CD group showed a statistically significant improvement in symptom scores from baseline over patients in the placebo group (See Figure 2).  Separate analyses of TCGIS scores in the morning and afternoon revealed superiority in improvement in the METADATE CD group over the placebo group during both time periods (See Figure 3).

Figure 2: Least Squares Mean Change from Baseline in TCGIS Total Score in Pediatric Patients 6 to 15 years of Age with ADHD (Study 1)

Figure 2 (Metadate Cd Methylphenidate Hydrochloride Capsule 3)

Last observation carried forward analysis at week 3; Error bars represent the standard error of the mean.

Figure 3: Least Squares Mean Change from Baseline in TCGIS Total Score in Pediatric Patients 6 to 15 years of Age with ADHD in Study 1: Morning (AM) and Afternoon (PM)

Figure 3 (Metadate Cd Methylphenidate Hydrochloride Capsule 4)

Last observation carried forward analysis at week 3; Error bars represent the standard error of the mean.

How Supplied

METADATE CD (methylphenidate hydrochloride) extended-release capsules are available in six strengths (see Table 4):

Storage and Handling

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

Advise the patient and/or their caregivers to read the FDA-approved patient labeling (Medication Guide).

Abuse, Misuse, and Addiction

Educate patients and their families about the risks of abuse, misuse, and addiction of METADATE CD, which can lead to overdose and death, and proper disposal of any unused drug [see Warnings and Precautions (5.1)], Drug Abuse and Dependence (9.2), Overdosage (10)]. Advise them to store METADATE CD in a safe place, preferably locked, and instruct them to not give METADATE CD to anyone else.

Risks to Patients with Serious Cardiac Disease

Advise patients and/or their caregivers that there are potential risks to patients with serious cardiac disease, including sudden death, with METADATE CD use. Instruct them to contact a healthcare provider immediately if the patient develops symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see Warnings and Precautions (5.2)].

Increased Blood Pressure and Heart Rate

Instruct patients and their caregivers that METADATE CD can cause elevations of their blood pressure and heart rate [see Warnings and Precautions (5.3)].

Psychiatric Adverse Reactions

Advise patients and their caregivers that METADATE CD, at the recommended dosage, can cause psychotic or manic symptoms, even in patients without a prior history of psychotic symptoms or mania [see Warnings and Precautions (5.4)].

Priapism

Advise male patients and/or their caregivers of the possibility of priapism. Instruct them to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.5)].

Peripheral Vasculopathy, Including Raynaud’s Phenomenon

Instruct patients and/or their caregivers about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms; to report to their healthcare provider immediately with any signs of unexplained wounds appearing on fingers or toes while taking METADATE CD [see Warnings and Precautions (5.6)].

Long-Term Suppression of Growth in Pediatric Patients

Advise patients and/or their caregivers that METADATE CD may cause slowing of growth and weight loss in pediatric patients [see Warnings and Precautions (5.7)].

Increased Intraocular Pressure and Glaucoma

Advise patients and/or their caregivers what increased intraocular pressure and glaucoma may occur during METADATE CD treatment [see Warnings and Precautions (5.9)].

Motor and Verbal Tics, and Worsening of Tourette Syndrome

Advise patients and/or their caregivers that motor and verbal tics and worsening of Tourette syndrome may occur during METADATE CD treatment. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette syndrome occurs [see Warnings and Precautions (5.10)].

Alcohol Use

Advise patients to avoid alcohol while taking METADATE CD. Consumption of alcohol while taking METADATE CD may result in a more rapid release of the dosage of methylphenidate [see Drug Interactions (7)].

Pregnancy Registry

Advise patients and/or their caregivers that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to METADATE CD during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise METADATE CD-treated breastfeeding women to monitor their infants for agitation, poor sleeping patterns, changes in feeding, and reduced weight gain [see Use in Specific Populations (8.2)].

Administration Instructions

Instruct patients and their caregivers that the METADATE CD extended-release capsules and the contents of the extended-release capsules must not be crushed or chewed. Instruct patients and their caregivers to either (1) swallow whole the extended-release capsules, or (2) alternatively, open the extended-release capsules and sprinkle the contents onto a small amount (tablespoon) of applesauce and take immediately and not to store for future use [see Dosage and Administration (2.3)].

Distributed by:
Lannett Company, Inc.
Philadelphia, PA 19136

METADATE CD is a registered trademark of the Lannett Company, Inc.

NDC 0527-6579-30

Once Daily

CII

Metadate CD ^®
[methylphenidate HCl, USP]
Extended-Release Capsules

10 mg

A Medication Guide is required for every prescription
dispensed. Please use accompanying Medication Guide.

Rx Only
30 Capsules

10 mg 100 Count (Metadate Cd Methylphenidate Hydrochloride Capsule 5)

NDC 0527-6580-30

Once Daily

CII

Metadate CD ^®
[methylphenidate HCl, USP]
Extended-Release Capsules

20 mg

A Medication Guide is required for every prescription
dispensed. Please use accompanying Medication Guide.

Rx Only
30 Capsules

20 mg (Metadate Cd Methylphenidate Hydrochloride Capsule 6)

NDC 0527-6581-30

Once Daily

CII

Metadate CD ^®
[methylphenidate HCl, USP]
Extended-Release Capsules

30 mg

A Medication Guide is required for every prescription
dispensed. Please use accompanying Medication Guide.

Rx Only
30 Capsules

30 mg (Metadate Cd Methylphenidate Hydrochloride Capsule 7)

NDC 0527-6582-30

Once Daily

CII

Metadate CD ^®
[methylphenidate HCl, USP]
Extended-Release Capsules

40 mg

A Medication Guide is required for every prescription
dispensed. Please use accompanying Medication Guide.

Rx Only
30 Capsules

40 mg (Metadate Cd Methylphenidate Hydrochloride Capsule 8)

NDC 0527-6583-30

Once Daily

CII

Metadate CD ^®
[methylphenidate HCl, USP]
Extended-Release Capsules

50 mg

A Medication Guide is required for every prescription
dispensed. Please use accompanying Medication Guide.

Rx Only
30 Capsules

50 mg (Metadate Cd Methylphenidate Hydrochloride Capsule 9)

NDC 0527-6584-30

Once Daily

CII

Metadate CD ^®
[methylphenidate HCl, USP]
Extended-Release Capsules

60 mg

A Medication Guide is required for every prescription
dispensed. Please use accompanying Medication Guide.

Rx Only
30 Capsules

60 mg (Metadate Cd Methylphenidate Hydrochloride Capsule 10)