Focalin XR: Package Insert and Label Information

FOCALIN XR- dexmethylphenidate hydrochloride capsule, extended release
Novartis Pharmaceuticals Corporation

WARNING: ABUSE AND DEPENDENCE

CNS stimulants, including Focalin XR, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)].

1 INDICATIONS AND USAGE

Focalin XR is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 Pretreatment Screening

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

Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, monitor for signs of abuse and overdose, and periodically reevaluate the need for Focalin XR use [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)].

2.2 Treatment of Attention Deficit Hyperactivity Disorder

Patients New to Methylphenidate

The recommended starting dosage of Focalin XR for patients who are not currently taking dexmethylphenidate or racemic methylphenidate, or for patients who are on stimulants other than methylphenidate are:

  • Pediatric patients: Start with 5 mg orally once daily in the morning with or without food.
  • Adult patients: Start with 10 mg orally once daily in the morning with or without food.

Patients Currently on Methylphenidate

The recommended starting dose of Focalin XR for patients currently using methylphenidate is half (1/2) the total daily dose of racemic methylphenidate.

Patients currently using Focalin (dexmethylphenidate) immediate-release tablets may be given the same daily dose of Focalin XR.

Titration Schedule

The dose may be titrated weekly in increments of 5 mg in pediatric patients and 10 mg in adult patients. The dose should be individualized according to the needs and response of the patient. Daily doses above 30 mg in pediatrics and 40 mg in adults have not been studied and are not recommended.

Maintenance/Extended Treatment

Pharmacological treatment of ADHD may be needed for extended periods. Periodically reevaluate the long-term use of Focalin XR and adjust dosage as needed.

2.3 Administration Instructions

Focalin XR is administered orally and may be taken whole or the capsule may be opened and the entire contents sprinkled onto applesauce. If the patient is using the sprinkled administration method, the sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. The dose of a single capsule should not be divided. The contents of the entire capsule should be taken, and patients should not take anything less than one capsule per day.

2.4 Dose Reduction and Discontinuation

If paradoxical aggravation of symptoms or other adverse reactions occur, reduce the dosage, or if necessary, discontinue Focalin XR. If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.

3 DOSAGE FORMS AND STRENGTHS

  • 5 mg extended-release capsules – light blue opaque cap and body (imprinted with “NVR” on cap and “D5” on the body)
  • 10 mg extended-release capsules – light caramel opaque cap and body (imprinted with “NVR” on cap and “D10” on the body)
  • 15 mg extended-release capsules – green opaque cap and body (imprinted with “NVR” on cap and “D15” on the body)
  • 20 mg extended-release capsules – white opaque cap and body (imprinted with “NVR” on cap and “D20” on the body)
  • 25 mg extended-release capsules – light blue opaque cap and white opaque body (imprinted with “NVR” on cap and “D25” on the body)
  • 30 mg extended-release capsules – light caramel opaque cap and white opaque body (imprinted with “NVR” on cap and “D30” on the body
  • 35 mg extended-release capsules – light blue opaque cap and light caramel opaque body (imprinted with “NVR” on cap and “D35” on the body
  • 40 mg extended-release capsules – green opaque cap and white opaque body (imprinted with “NVR” on cap and “D40” on the body

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 Potential for Abuse and Dependence

CNS stimulants, including Focalin XR, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Boxed Warning, Drug Abuse and Dependence (9.2, 9.3)].

5.2 Serious Cardiovascular Reactions

Sudden death, stroke and myocardial infarction have been reported in adults with CNS stimulant treatment at recommended doses. Sudden death has been reported in pediatric patients with structural cardiac abnormalities and other serious heart problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems. Further evaluate patients who develop exertional chest pain, unexplained syncope, or arrhythmias during Focalin XR treatment.

5.3 Blood Pressure and Heart Rate Increases

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

5.4 Psychiatric Adverse Reactions

Exacerbation of Preexisting Psychosis

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

Induction of a Manic Episode in Patients with Bipolar Disorder

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

New Psychotic or Manic Symptoms

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

5.5 Priapism

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

5.6 Peripheral Vasculopathy, Including Raynaud’s Phenomenon

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

5.7 Long-Term Suppression of Growth

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

In a 7-week, double-blind, placebo-controlled study of Focalin XR, the mean weight gain was greater for pediatric patients (ages 6 to 17 years) receiving placebo (+0.4 kg) than for patients receiving Focalin XR (-0.5 kg).

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

Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including Focalin XR, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

6 ADVERSE REACTIONS

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

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

6.1 Clinical Trials 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 the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials Experience with Focalin XR in Pediatric Patients with ADHD

The safety data in this section is based on data from a 7-week controlled clinical study of Focalin XR in 100 (103 randomized) pediatric patients with ADHD ages 6 to 17 years (ages 6 to 12, n = 86; ages 13 to 17, n = 17).

This study was a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the time of onset, duration of efficacy, tolerability, safety of Focalin XR 5 mg to 30 mg/day who met DSM-IV criteria for ADHD [see Clinical Studies (14.1)].

Most Common Adverse Reactions (incidence of greater than or equal to 5% and at least twice placebo): dyspepsia, decreased appetite, headache, and anxiety.

Adverse Reactions Leading to Discontinuation: 50 of 684 (7.3%) pediatric patients treated with Focalin (dexmethylphenidate) immediate-release tablets experienced an adverse reaction that resulted in discontinuation. The most common reasons for discontinuation were twitching (described as motor or vocal tics), anorexia, insomnia, and tachycardia (approximately 1% each).

Table 1 enumerates adverse reactions for the placebo-controlled, parallel-group study in children and adolescents with ADHD at flexible Focalin XR doses of 5–30 mg/day. The table includes only those events that occurred in 5% or more of patients treated with Focalin XR and for which the incidence in patients treated with Focalin XR was at least twice the incidence in placebo-treated patients.

Table 1: Common Adverse Reactions in Pediatric Patients (6 to 17 years of age) with ADHD
Abbreviation: attention deficit hyperactivity disorder.
System Organ ClassAdverse Reaction Focalin XR N = 53 Placebo N = 47
Gastrointestinal Disorders 38% 19%
Dyspepsia 8% 4%
Metabolism and Nutrition Disorders 34% 11%
Decreased Appetite 30% 9%
Nervous System Disorders 30% 13%
Headache 25% 11%
Psychiatric Disorders 26% 15%
Anxiety 6% 0%

Table 2 below enumerates the incidence of dose-related adverse reactions that occurred during a fixed-dose, double-blind, placebo-controlled trial in pediatric patients with ADHD taking Focalin XR up to 30 mg daily versus placebo. The table includes only those reactions that occurred in patients treated with Focalin XR for which the incidence was at least 5% and greater than the incidence among placebo-treated patients.

Table 2: Dose-Related Adverse Reactions in Pediatric Patients (6 to 17 years of age) with ADHD
Abbreviation: attention deficit hyperactivity disorder.
System Organ ClassAdverse Reaction Focalin XR 10 mg/dN = 64 Focalin XR 20 mg/dN = 60 Focalin XR 30 mg/dN = 58 Placebo N = 63
Gastrointestinal Disorders 22% 23% 29% 24%
Vomiting 2% 8% 9% 0%
Metabolism and Nutritional Disorders 16% 17% 22% 5%
Anorexia 5% 5% 7% 0
Psychiatric Disorders 19% 20% 38% 8%
Insomnia 5% 8% 17% 3%
Depression 0 0 3% 0
Mood Swings 0% 0% 3% 2%
Other Adverse Reactions
Irritability 0% 2% 5% 0%
Nasal Congestion 0% 0% 5% 0%
Pruritus 0% 0% 3% 0%

Clinical Trials Experience with Focalin XR in Adult Patients with ADHD

The safety data in this section is based on data from a 5-week controlled clinical study of Focalin XR in 218 adult patients (221 randomized) with ADHD ages 18 to 60 years. In this study, 101 adult patients were treated for at least 6 months.

This study was a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of Focalin XR 20 mg, 30 mg, or 40 mg daily who met DSM-IV criteria for ADHD [see Clinical Studies (14.3)].

Most Common Adverse Reactions (incidence of greater than or equal to 5% and at least twice placebo): dry mouth, dyspepsia, headache, anxiety, and pharyngolaryngeal pain.

Adverse Reactions Leading to Discontinuation: During the double-blind phase of the study, 10.7% of the Focalin XR-treated patients and 7.5% of the placebo-treated patients discontinued due to adverse reactions. Three patients (1.8%) in the Focalin XR discontinued due to insomnia and jittery, respectively and two patients (1.2%) in the Focalin XR discontinued due to anorexia and anxiety, respectively.

Table 3 enumerates adverse reactions for the placebo-controlled, parallel-group study in adults with ADHD at fixed Focalin XR doses of 20, 30, and 40 mg/day. The table includes only those events that occurred in 5% or more of patients in a Focalin XR dose group and for which the incidences in patients treated with Focalin XR appeared to increase with dose.

Table 3: Dose-Related Adverse Reactions in Adult Patients (18 to 60 years of age) with ADHD
System Organ ClassAdverse Reaction Focalin XR 20 mgN = 57 Focalin XR 30 mgN = 54 Focalin XR 40 mgN = 54 Placebo N = 53
Gastrointestinal Disorders 28% 32% 44% 19%
Dry Mouth 7% 20% 20% 4%
Dyspepsia 5% 9% 9% 2%
Nervous System Disorders 37% 39% 50% 28%
Headache 26% 30% 39% 19%
Psychiatric Disorders 40% 43% 46% 30%
Anxiety 5% 11% 11% 2%
Respiratory, Thoracic and Mediastinal Disorders 16% 9% 15% 8%
Pharyngolaryngeal Pain 4% 4% 7% 2%

Two other adverse reactions occurring in clinical trials with Focalin XR at a frequency greater than placebo, but which were not dose related were: feeling jittery (12% and 2%, respectively) and dizziness (6% and 2%, respectively).

Table 4 summarizes changes in vital signs and weight that were recorded in the adult study (N = 218) of Focalin XR in the treatment of ADHD.

Table 4: Changes (Mean ± SD) in Vital Signs and Weight by Randomized Dose During Double-Blind Treatment–Adults
Focalin XR 20 mg(N = 57) Focalin XR 30 mg(N = 54) Focalin XR 40 mg(N = 54) Placebo (N = 53)
Pulse (bpm) 3.1 ± 11.1 4.3 ± 11.7 6.0 ± 10.1 -1.4 ± 9.3
Diastolic BP (mmHg) -0.2 ± 8.2 1.2 ± 8.9 2.1 ± 8.0 0.3 ± 7.8
Weight (kg) -1.4 ± 2.0 -1.2 ± 1.9 -1.7 ± 2.3 -0.1 ± 3.9

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