Get your patient on Concerta (Methylphenidate Hydrochloride)

CONCERTA is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6 years of age and older, adolescents, and adults up to the age of 65

[see

14 CLINICAL STUDIES

CONCERTA^®was demonstrated to be effective in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in 4 randomized, double-blind, placebo-controlled studies in children and adolescents and 2 double-blind placebo-controlled studies in adults who met the Diagnostic and Statistical Manual 4^thedition (DSM-IV) criteria for ADHD.

14.1 Children

Three double-blind, active- and placebo-controlled studies were conducted in 416 children aged 6 to 12 years. The controlled studies compared CONCERTA given once daily (18, 36, or 54 mg), methylphenidate given three times daily over 12 hours (15, 30, or 45 mg total daily dose), and placebo in two single-center, 3-week crossover studies (Studies 1 and 2) and in a multicenter, 4-week, parallel-group comparison (Study 3). The primary comparison of interest in all three trials was CONCERTA versus placebo.

Symptoms of ADHD were evaluated by community schoolteachers using the Inattention/Overactivity with Aggression (IOWA) Conners scale. Statistically significant reduction in the Inattention/Overactivity subscale versus placebo was shown consistently across all three controlled studies for CONCERTA. The scores for CONCERTA and placebo for the three studies are presented in Figure 2.

Figure 2.

Mean Community School Teacher IOWA Conners Inattention/Overactivity Scores with CONCERTA once daily (18, 36, or 54 mg) and placebo. Studies 1 and 2 involved a 3-way crossover of 1 week per treatment arm. Study 3 involved 4 weeks of parallel-group treatments with a Last Observation Carried Forward analysis at week 4. Error bars represent the mean plus standard error of the mean.

In Studies 1 and 2, symptoms of ADHD were evaluated by laboratory schoolteachers using the SKAMPSwanson, Kotkin, Agler, M-Fynn, and Pelhamlaboratory school rating scale. The combined results from these two studies demonstrated statistically significant improvements in attention and behavior in patients treated with CONCERTA versus placebo that were maintained through 12 hours after dosing. Figure 3 presents the laboratory schoolteacher SKAMP ratings for CONCERTA and placebo.

Figure 3.

Laboratory School Teacher SKAMP Ratings: Mean (SEM) of Combined Attention (Studies 1 and 2)

14.2 Adolescents

In a randomized, double-blind, multicenter, placebo-controlled trial (Study 4) involving 177 patients, CONCERTA was demonstrated to be effective in the treatment of ADHD in adolescents aged 13 to 18 years at doses up to 72 mg/day (1.4 mg/kg/day). Of 220 patients who entered an open 4-week titration phase, 177 were titrated to an individualized dose (maximum of 72 mg/day) based on meeting specific improvement criteria on the ADHD Rating Scale and the Global Assessment of Effectiveness with acceptable tolerability. Patients who met these criteria were then randomized to receive either their individualized dose of CONCERTA (18 – 72 mg/day, n=87) or placebo (n=90) during a two-week double-blind phase. At the end of this phase, mean scores for the investigator rating on the ADHD Rating Scale demonstrated that CONCERTA was statistically significantly superior to placebo.

14.3 Adults

Two double-blind, placebo-controlled studies were conducted in 627 adults aged 18 to 65 years. The controlled studies compared CONCERTA administered once daily and placebo in a multicenter, parallel-group, 7-week dose-titration study (Study 5) (36 to 108 mg/day) and in a multicenter, parallel-group, 5-week, fixed-dose study (Study 6) (18, 36, and 72 mg/day).

Study 5 demonstrated the effectiveness of CONCERTA in the treatment of ADHD in adults aged 18 to 65 years at doses from 36 mg/day to 108 mg/day based on the change from baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS). Of 226 patients who entered the 7-week trial, 110 were randomized to CONCERTA and 116 were randomized to placebo. Treatment was initiated at 36 mg/day and patients continued with incremental increases of 18 mg/day (36 to 108 mg/day) based on meeting specific improvement criteria with acceptable tolerability. At the final study visit, mean change scores (LS Mean, SEM) for the investigator rating on the AISRS demonstrated that CONCERTA was statistically significantly superior to placebo.

Study 6 was a multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-response study (5-week duration) with 3 fixed-dose groups (18, 36, and 72 mg). Patients were randomized to receive CONCERTA administered at doses of 18 mg (n=101), 36 mg (n=102), 72 mg/day (n=102), or placebo (n=96). All three doses of CONCERTA were statistically significantly more effective than placebo in improving CAARS (Conners' Adult ADHD Rating Scale) total scores at double-blind end point in adult subjects with ADHD.

]

• CONCERTA should be taken once daily in the morning and swallowed whole with the aid of liquids. CONCERTA should not be chewed or crushed. CONCERTA may be taken with or without food. (
  
  2.2 Recommended Dosage

  CONCERTA should be administered orally once daily in the morning with or without food.

  CONCERTA must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed

  [seePatient Counseling Information (17)]

  .
  )
  
• For children and adolescents new to methylphenidate, the recommended starting dosage is 18 mg once daily. Dosage may be increased by 18 mg/day at weekly intervals and should not exceed 54 mg/day in children and 72 mg/day in adolescents. (
  
  2.3 Patients New to Methylphenidate

  The recommended starting dose of CONCERTA for patients who are not currently taking methylphenidate or stimulants other than methylphenidate is 18 mg once daily for children and adolescents and 18 or 36 mg once daily for adults (seeTable 1).

  Table 1. CONCERTA Recommended Starting Doses and Dose Ranges

  Patient Age	Recommended Starting Dose	Dose Range
  Children 6–12 years of age	18 mg/day	18 mg – 54 mg/day
  Adolescents 13–17 years of age	18 mg/day	18 mg – 72 mg/day not to exceed 2 mg/kg/day
  Adults 18–65 years of age	18 or 36 mg/day	18 mg – 72 mg/day
  )
  
• For adult patients new to methylphenidate, the recommended starting dose is 18 or 36 mg/day. Dosage may be increased by 18 mg/day at weekly intervals and should not exceed 72 mg/day for adults. (
  
  2.3 Patients New to Methylphenidate

  The recommended starting dose of CONCERTA for patients who are not currently taking methylphenidate or stimulants other than methylphenidate is 18 mg once daily for children and adolescents and 18 or 36 mg once daily for adults (seeTable 1).

  Table 1. CONCERTA Recommended Starting Doses and Dose Ranges

  Patient Age	Recommended Starting Dose	Dose Range
  Children 6–12 years of age	18 mg/day	18 mg – 54 mg/day
  Adolescents 13–17 years of age	18 mg/day	18 mg – 72 mg/day not to exceed 2 mg/kg/day
  Adults 18–65 years of age	18 or 36 mg/day	18 mg – 72 mg/day
  )
  
• For patients currently using methylphenidate, dosing is based on current dose regimen and clinical judgment. (
  
  2.4 Patients Currently Using Methylphenidate

  The recommended dose of CONCERTA for patients who are currently taking methylphenidate twice daily or three times daily at doses of 10 to 60 mg/day is provided in Table 2. Dosing recommendations are based on current dose regimen and clinical judgment. Conversion dosage should not exceed 72 mg daily.

  Table 2. Recommended Dose Conversion from Methylphenidate Regimens to CONCERTA

  Previous Methylphenidate Daily Dose	Recommended CONCERTA®Starting Dose
  5 mg Methylphenidate twice daily or three times daily	18 mg every morning
  10 mg Methylphenidate twice daily or three times daily	36 mg every morning
  15 mg Methylphenidate twice daily or three times daily	54 mg every morning
  20 mg Methylphenidate twice daily or three times daily	72 mg every morning

  Other methylphenidate regimens: Clinical judgment should be used when selecting the starting dose.
  )
  

CONCERTA (methylphenidate HCl) Extended-Release Tablets are available in the following dosage strengths: 18 mg tablets are yellow and imprinted with "alza 18," 27 mg tablets are gray and imprinted with "alza 27," 36 mg tablets are white and imprinted with "alza 36," and 54 mg tablets are brownish-red and imprinted with "alza 54."

• Caution should be exercised if administered to nursing mothers (
  
  
  8.3 Nursing Mothers

  It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if CONCERTA is administered to a nursing woman.

  In lactating female rats treated with a single oral dose of 5 mg/kg radiolabeled methylphenidate, radioactivity (representing methylphenidate and/or its metabolites) was observed in milk and levels were generally similar to those in plasma.
  )
  
• Safety and efficacy has not been established in children less than six years old or elderly patients greater than 65 years of age (
  
  
  8.4 Pediatric Use

  The safety and effectiveness of CONCERTA 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.
  and
  
  
  8.5 Geriatric Use

  CONCERTA has not been studied in patients greater than 65 years of age.
  )
  

• Known hypersensitivity to the product (
  
  
  4.1 Hypersensitivity to Methylphenidate

  Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been observed in patients treated with CONCERTA. Therefore, CONCERTA is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product

  [seeAdverse Reactions (6.5)]

  .
  )
  
• Do not use CONCERTA in patients currently using or within 2 weeks of using an MAO inhibitor (
  
  
  4.2 Monoamine Oxidase Inhibitors

  CONCERTA is contraindicated during treatment with monoamine oxidase (MAO) inhibitors, and also within a minimum of 14 days following discontinuation of a MAO inhibitor (hypertensive crises may result)

  [seeDrug Interactions (7.1)]

  .
  )
  

• Risks to Patients with Serious Cardiac Disease: Avoid in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease. (
  
  
  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 CONCERTA use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.
  )
  
• Increase in Blood Pressure and Heart Rate: Monitor blood pressure and pulse. (
  
  
  5.3 Increased Blood Pressure and Heart Rate

  CNS stimulants may 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 CONCERTA-treated patients for hypertension and tachycardia.
  )
  
• Psychiatric Adverse Reactions: Prior to initiating CONCERTA, screen patients for risk factors for developing a manic episode. If new psychotic or manic symptoms occur, consider discontinuing CONCERTA. (
  
  
  5.4 Psychiatric Adverse Reactions

  Exacerbation of Pre-existing Psychosis

  CNS stimulants 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 may induce a manic or mixed episode in patients. Prior to initiating CONCERTA 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 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 CONCERTA.
  )
  
• Seizures: Stimulants may lower the convulsive threshold. Discontinue in the presence of seizures. (
  
  
  5.5 Seizures

  There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued.
  )
  
• Priapism: If abnormally sustained or frequent and painful erections occur, patients should seek immediate medical attention (
  
  
  5.6 Priapism

  Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients

  [seeAdverse Reactions (6.5)]

  . 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).

  CONCERTA-treated patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.
  )
  
• Peripheral Vasculopathy, including Raynaud's Phenomenon: Careful observation for digital changes is necessary during CONCERTA treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for patients who develop signs or symptoms of peripheral vasculopathy (
  
  
  5.7 Peripheral Vasculopathy, including Raynaud's Phenomenon

  CNS stimulants, including CONCERTA, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are 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 or discontinuation of the CNS stimulant.

  Careful observation for digital changes is necessary during CONCERTA treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for CONCERTA-treated patients who develop signs or symptoms of peripheral vasculopathy.
  )
  
• Long-Term Suppression of Growth in Pediatric Patients Closely monitor growth (height and weight) in pediatric patients. Pediatric patients not growing or gaining height or weight as expected may need to have their treatment interrupted. (
  
  
  5.8 Long-Term Suppression of Growth in Pediatric Patients

  CONCERTA is not approved for use and is not recommended in pediatric patients below 6 years of age

  [seeUse in Specific Populations (8.4)]

  .

  CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

  Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated children over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate 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. Closely monitor growth (weight and height) in CONCERTA-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.
  )
  
• Gastrointestinal obstruction with preexisting GI narrowing. (
  
  
  5.9 Potential for Gastrointestinal Obstruction

  Because the CONCERTA tablet is nondeformable and does not appreciably change in shape in the GI tract, CONCERTA should not ordinarily be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or Meckel's diverticulum). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable controlled-release formulations. Due to the controlled-release design of the tablet, CONCERTA should be used only in patients who are able to swallow the tablet whole

  [seePatient Counseling Information (17)]

  .
  )
  
• Hematologic monitoring: Periodic CBC, differential, and platelet counts are advised during prolonged therapy. (
  
  
  5.10 Hematologic Monitoring

  Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
  )
  
• Acute Angle Closure Glaucoma
  
  
  :
  CONCERTA -treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist. (
  
  
  5.11 Acute Angle Closure Glaucoma

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

  Although the mechanism is not clear, CONCERTA-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.
  )
  
• Increased Intraocular Pressure and Glaucoma: Prescribe CONCERTA to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor patients with a history of increased IOP or open angle glaucoma. (
  
  
  5.12 Increased Intraocular Pressure and Glaucoma

  There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment

  [seeAdverse Reactions (6.5)].

  Prescribe CONCERTA to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor CONCERTA-treated patients with a history of abnormally increased IOP or open angle glaucoma.
  )
  
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome: Before initiating CONCERTA, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor patients for the emergence or worsening of tics or Tourette's syndrome. Discontinue treatment if clinically appropriate. (
  
  
  5.13 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

  [seeAdverse Reactions (6.2,6.5)]

  . Worsening of Tourette's syndrome has also been reported

  .

  Before initiating CONCERTA, assess the family history and clinically evaluate patients for tics or Tourette's syndrome. Regularly monitor CONCERTA-treated patients for the emergence or worsening of tics or Tourette's syndrome, and discontinue treatment if clinically appropriate.
  )
  

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

• Abuse, Misuse, and Addiction
  
  
  [see
  
  

  WARNING: ABUSE, MISUSE, AND ADDICTION

  CONCERTA 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 CONCERTA, can result in overdose and death

  [seeOverdosage (10)]

  , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

  Before prescribing CONCERTA, assess each patient's risk for abuse, misuse, and addiction. Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug. Throughout CONCERTA treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction

  [seeWarnings and Precautions (5.1)andDrug Abuse and Dependence (9.2)].

  WARNING: ABUSE, MISUSE, AND ADDICTION

  See full prescribing information for complete boxed warning.

  CONCERTA 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 CONCERTA, can result in overdose and death (5.1,9.2,10):

  • Before prescribing CONCERTA, assess each patient's risk for abuse, misuse, and addiction.
  • Educate patients and their families about these risks, proper storage of the drug, and proper disposal of any unused drug.
  • Throughout treatment, reassess each patient's risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

  ,
  
  

  5.1 Abuse, Misuse, and Addiction

  CONCERTA has a high potential for abuse and misuse. The use of CONCERTA exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. CONCERTA can be diverted for non-medical use into illicit channels or distribution

  [seeDrug Abuse and Dependence (9.2)]

  . Misuse and abuse of CNS stimulants, including CONCERTA, can result in overdose and death

  [seeOverdosage (10)]

  , and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.

  Before prescribing CONCERTA, 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 CONCERTA in a safe place, preferably locked, and instruct patients to not give CONCERTA to anyone else. Throughout CONCERTA treatment, reassess each patient's risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.

  ]
  
  
• Hypersensitivity to Methylphenidate
  
  
  [see
  
  

  4.1 Hypersensitivity to Methylphenidate

  Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been observed in patients treated with CONCERTA. Therefore, CONCERTA is contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product

  [seeAdverse Reactions (6.5)]

  .

  ]
  
  
• Monoamine Oxidase Inhibitors
  
  
  [see
  
  

  4.2 Monoamine Oxidase Inhibitors

  CONCERTA is contraindicated during treatment with monoamine oxidase (MAO) inhibitors, and also within a minimum of 14 days following discontinuation of a MAO inhibitor (hypertensive crises may result)

  [seeDrug Interactions (7.1)]

  .

  and
  
  

  7.1 MAO Inhibitors

  CONCERTA should not be used in patients being treated (currently or within the preceding 2 weeks) with MAO inhibitors

  [seeContraindications (4.2)]

  .

  ]
  
  
• Risks to Patients with Serious Cardiac Disease
  
  
  [see
  
  

  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 CONCERTA use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.

  ]
  
  
• Increased Blood Pressure and Heart Rate
  
  
  [see
  
  

  5.3 Increased Blood Pressure and Heart Rate

  CNS stimulants may 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 CONCERTA-treated patients for hypertension and tachycardia.

  ]
  
  
• Psychiatric Adverse Reactions
  
  
  [see
  
  

  5.4 Psychiatric Adverse Reactions

  Exacerbation of Pre-existing Psychosis

  CNS stimulants 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 may induce a manic or mixed episode in patients. Prior to initiating CONCERTA 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 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 CONCERTA.

  ]
  
  
• Seizures
  
  
  [see
  
  

  5.5 Seizures

  There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures, the drug should be discontinued.

  ]
  
  
• Priapism
  
  
  [see
  
  

  5.6 Priapism

  Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients

  [seeAdverse Reactions (6.5)]

  . 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).

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

  ]
  
  
• Peripheral Vasculopathy, including Raynaud's Phenomenon
  
  
  [see
  
  

  5.7 Peripheral Vasculopathy, including Raynaud's Phenomenon

  CNS stimulants, including CONCERTA, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud's phenomenon. Signs and symptoms are 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 or discontinuation of the CNS stimulant.

  Careful observation for digital changes is necessary during CONCERTA treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for CONCERTA-treated patients who develop signs or symptoms of peripheral vasculopathy.

  ]
  
  
• Long-Term Suppression of Growth in Pediatric Patients
  
  
  [see
  
  

  5.8 Long-Term Suppression of Growth in Pediatric Patients

  CONCERTA is not approved for use and is not recommended in pediatric patients below 6 years of age

  [seeUse in Specific Populations (8.4)]

  .

  CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.

  Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or nonmedication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated children over 36 months (to the ages of 10 to 13 years), suggests that pediatric patients who received methylphenidate 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. Closely monitor growth (weight and height) in CONCERTA-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

  ]
  
  
• Potential for Gastrointestinal Obstruction
  
  
  [see
  
  

  5.9 Potential for Gastrointestinal Obstruction

  Because the CONCERTA tablet is nondeformable and does not appreciably change in shape in the GI tract, CONCERTA should not ordinarily be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or Meckel's diverticulum). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable controlled-release formulations. Due to the controlled-release design of the tablet, CONCERTA should be used only in patients who are able to swallow the tablet whole

  [seePatient Counseling Information (17)]

  .

  ]
  
  
• Hematologic Monitoring
  
  
  [see
  
  

  5.10 Hematologic Monitoring

  Periodic CBC, differential, and platelet counts are advised during prolonged therapy.

  ]
  
  
• Acute Angle Closure Glaucoma
  
  
  [see
  
  

  5.11 Acute Angle Closure Glaucoma

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

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

  ]
  
  
• Increased Intraocular Pressure and Glaucoma
  
  
  [see
  
  

  5.12 Increased Intraocular Pressure and Glaucoma

  There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment

  [seeAdverse Reactions (6.5)].

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

  ]
  
  
• Motor and Verbal Tics, and Worsening of Tourette's Syndrome
  
  
  [see
  
  

  5.13 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

  [seeAdverse Reactions (6.2,6.5)]

  . Worsening of Tourette's syndrome has also been reported

  .

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

  ]
  
  

The most common adverse reaction in double-blind clinical trials (>5%) in pediatric patients (children and adolescents) was abdominal pain upper. The most common adverse reactions in double-blind clinical trials (>5%) in adult patients were decreased appetite, headache, dry mouth, nausea, insomnia, anxiety, dizziness, weight decreased, irritability, and hyperhidrosis

The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased

The development program for CONCERTA included exposures in a total of 3906 participants in clinical trials. Children, adolescents, and adults with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies (see

Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.

The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of CONCERTA based on the comprehensive assessment of the available adverse event information. A causal association for CONCERTA often cannot be reliably established in individual cases. Further, 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 majority of adverse reactions were mild to moderate in severity.

• CONCERTA may increase blood pressure; use cautiously with vasopressors (
  
  
  7.2 Vasopressor Agents

  Because of possible increases in blood pressure, CONCERTA should be used cautiously with vasopressor agents

  [seeWarnings and Precautions (5.3)]

  .
  )
  
• Inhibition of metabolism of coumarin anticoagulants, anticonvulsants, and some antidepressants (
  
  
  7.3 Coumarin Anticoagulants, Antidepressants, and Selective Serotonin Reuptake Inhibitors

  Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (eg, phenobarbital, phenytoin, primidone), and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). Downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate. It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate.
  )
  

CONCERTA
^®is a central nervous system (CNS) stimulant. CONCERTA is available in four tablet strengths. Each extended-release tablet for once-a-day oral administration contains 18, 27, 36, or 54 mg of methylphenidate HCl USP and is designed to have a 12-hour duration of effect. Chemically, methylphenidate HCl is d,l (racemic) methyl α-phenyl-2-piperidineacetate hydrochloride. Its empirical formula is C
₁₄H
₁₉NO
₂∙HCl. Its structural formula is:

Methylphenidate HCl 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.

CONCERTA also contains the following inert ingredients: butylated hydroxytoluene, carnauba wax, cellulose acetate, hypromellose, lactose, phosphoric acid, poloxamer, polyethylene glycol, polyethylene oxides, povidone, propylene glycol, sodium chloride, stearic acid, succinic acid, synthetic iron oxides, titanium dioxide, and triacetin.

Methylphenidate HCl is a central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

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 30 times and 4 times the maximum recommended human dose of CONCERTA on a mg/kg and mg/m
²basis, respectively. 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 dose used was approximately 45 mg/kg/day, which is approximately 22 times and 5 times the maximum recommended human dose of CONCERTA on a mg/kg and mg/m
²basis, respectively.

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.

CONCERTA
^®was demonstrated to be effective in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in 4 randomized, double-blind, placebo-controlled studies in children and adolescents and 2 double-blind placebo-controlled studies in adults who met the Diagnostic and Statistical Manual 4
^thedition (DSM-IV) criteria for ADHD.

CONCERTA
^®(methylphenidate HCl) Extended-release Tablets are available in 18 mg, 27 mg, 36 mg, and 54 mg dosage strengths. The 18 mg tablets are yellow and imprinted with "alza 18". The 27 mg tablets are gray and imprinted with "alza 27". The 36 mg tablets are white and imprinted with "alza 36". The 54 mg tablets are brownish-red and imprinted with "alza 54". All four dosage strengths are supplied in bottles containing 100 tablets.

Methylphenidate HCl is a central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.