Focalin XR

SIDE EFFECTS

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

• Abuse and Dependence [see BOX WARNING, WARNINGS AND PRECAUTIONS, Drug Abuse And Dependence]
• Known hypersensitivity to methylphenidate or other ingredients of Focalin XR [see CONTRAINDICATIONS]
• Hypertensive Crisis with Concomitant Use of Monoamine Oxidase Inhibitors [see CONTRAINDICATIONS, DRUG INTERACTIONS]
• Serious Cardiovascular Reactions [see WARNINGS AND PRECAUTIONS]
• Blood Pressure and Heart Rate Increases [see WARNINGS AND PRECAUTIONS]
• Psychiatric Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Priapism [see WARNINGS AND PRECAUTIONS]
• Peripheral Vasculopathy, Including Raynaud’s Phenomenon [see WARNINGS AND PRECAUTIONS]
• Long-Term Suppression of Growth [see WARNINGS AND PRECAUTIONS]

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 The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for ADHD [see Clinical Studies].

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

System Organ Class Adverse 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%
Abbreviation: ADHD, attention deficit hyperactivity disorder.

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

System Organ Class Adverse Reaction	Focalin XR 10 mg/day N = 64	Focalin XR 20 mg/day N = 60	Focalin XR 30 mg/day N = 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%
Abbreviation: ADHD, attention deficit hyperactivity disorder.

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].

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 Class Adverse Reaction	Focalin XR 20 mg N = 57	Focalin XR 30 mg N = 54	Focalin XR 40 mg N = 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

Postmarketing Experience

The following additional adverse reactions have been identified during postapproval use of dexmethylphenidate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal: rhabdomyolysis

Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis

Adverse Reactions Reported With All Ritalin Snd Focalin Formulations

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

Infections and Infestations: nasopharyngitis

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

Immune System Disorders: hypersensitivity reactions, including angioedema and anaphylaxis

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

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

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

Eye Disorders: blurred vision, difficulties in visual accommodation

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

Respiratory, Thoracic, and Mediastinal Disorders: cough

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

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

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

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

Investigations: weight loss (adult ADHD patients)

Additional Adverse Reactions Reported With Other Methylphenidate Products

The list below shows adverse reactions not listed with Ritalin and Focalin formulations that have been reported with other methylphenidate products based on clinical trials data and post-marketing spontaneous reports.

Blood and Lymphatic Disorders: pancytopenia

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

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

Nervous System Disorders: migraine

Eye Disorders: diplopia, mydriasis

Cardiac Disorders: sudden cardiac death, myocardial infarction, bradycardia, extrasystole, supraventricular tachycardia, ventricular extrasystole

Vascular Disorders: peripheral coldness, Raynaud's phenomenon

Respiratory, Thoracic, and Mediastinal Disorders: pharyngolaryngeal pain, dyspnea

Gastrointestinal Disorders: diarrhea, constipation

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

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

Renal and Urinary Disorders: hematuria

Reproductive System and Breast Disorders: gynecomastia

General Disorders: fatigue, hyperpyrexia Urogenital Disorders: priapism

DRUG INTERACTIONS

Clinically Important Drug Interactions With Focalin XR

Table 5 presents clinically important drug interactions with Focalin XR.

Table 5: Clinically Important Drug Interactions With Focalin XR

Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact	Concomitant use of MAOIs and CNS stimulants, including Focalin XR, can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see CONTRAINDICATIONS].
Intervention	Concomitant use of Focalin XR with MAOIs or within 14 days after discontinuing MAOI treatment is contraindicated.
Examples	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Antihypertensive Drugs
Clinical Impact	Focalin XR may decrease the effectiveness of drugs used to treat hypertension [see WARNINGS AND PRECAUTIONS].
Intervention	Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed.
Examples	Potassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, centrally acting alpha-2 receptor agonists
Halogenated Anesthetics
Clinical Impact	Concomitant use of halogenated anesthetics and Focalin XR may increase the risk of sudden blood pressure and heart rate increase during surgery.
Intervention	Avoid use of Focalin XR in patients being treated with anesthetics on the day of surgery.
Examples	halothane, isoflurane, enflurane, desflurane, sevoflurane
Risperidone
Clinical Impact	Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS)
Intervention	Monitor for signs of EPS

Drug Abuse And Dependence

Controlled Substance

Focalin XR contains dexmethylphenidate hydrochloride, a Schedule II controlled substance.

Abuse

CNS stimulants, including Focalin XR, other methylphenidate-containing products, and amphetamines have a high potential for abuse. Abuse is characterized by impaired control over drug use despite harm, and craving.

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

To reduce the abuse of CNS stimulants, including Focalin XR, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants [see HOW SUPPLIED], monitor for signs of abuse while on therapy, and reevaluate the need for Focalin XR use.

Dependence

Tolerance

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

Dependence

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

Read the entire FDA prescribing information for Focalin XR (Dexmethylphenidate Hydrochloride)