Methylphenidate Hydrochloride (Page 3 of 10)

5.6 Long-Term Suppression of Growth

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 consistently medicated children (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. Published data are inadequate to determine whether chronic use of amphetamines may cause similar suppression of growth; however, it is anticipated that they likely have this effect as well. Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

5.7 Visual Disturbance

Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.

5.8 Potential for Gastrointestinal Obstruction

Because the methylphenidate hydrochloride extended-release tablet is nondeformable and does not appreciably change in shape in the GI tract, methylphenidate hydrochloride extended-release tablets 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, methylphenidate hydrochloride extended-release tablets should be used only in patients who are able to swallow the tablet whole [see Patient Counseling Information (17)].

5.9 Hematologic Monitoring

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

6 ADVERSE REACTIONS

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

• Drug Dependence [see Box Warning]
• Hypersensitivity to Methylphenidate [see Contraindications (4.1)]
• Agitation [see Contraindications (4.2)]
• Glaucoma [see Contraindications (4.3)]
• Tics [see Contraindications (4.4)]
• Monoamine Oxidase Inhibitors [see Contraindications (4.5) and Drug Interactions (7.1)]
• Serious Cardiovascular Events [see Warnings and Precautions (5.1)]
• Psychiatric Adverse Events [see Warnings and Precautions (5.2)]
• Seizures [see Warnings and Precautions (5.3)]
• Priapism [see Warnings and Precautions (5.4)]
• Long-Term Suppression of Growth [see Warnings and Precautions (5.6)]
• Visual Disturbance [see Warnings and Precautions (5.7)]
• Potential for Gastrointestinal Obstruction [see Warnings and Precautions (5.8)]
• Hematologic Monitoring [see Warnings and Precautions (5.9)]

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 [see Adverse Reactions (6.1)].

The most common adverse reactions associated with discontinuation (≥1%) from either pediatric or adult clinical trials were anxiety, irritability, insomnia, and blood pressure increased [see Adverse Reactions (6.3)].

The development program for methylphenidate hydrochloride extended-release tablets included exposures in a total of 3,906 participants in clinical trials. Children, adolescents, and adults with ADHD were evaluated in 6 controlled clinical studies and 11 open-label clinical studies (see Table 3). Safety was assessed by collecting adverse events, vital signs, weights, and ECGs, and by performing physical examinations and laboratory analyses.

Table 3. Methylphenidate hydrochloride extended-release tablets Exposure in Double-Blind and Open-Label Clinical Studies

Patient Population	N	Dose Range
Children	2,216	18 to 54 mg once daily
Adolescents	502	18 to 72 mg once daily
Adults	1,188	18 to 108 mg once daily

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 methylphenidate hydrochloride extended-release tablets based on the comprehensive assessment of the available adverse event information. A causal association for methylphenidate hydrochloride extended-release tablets 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.

6.1 Commonly Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials

Adverse reactions in either the pediatric or adult double-blind adverse reactions tables may be relevant for both patient populations.

Children and Adolescents Table 4 lists the adverse reactions reported in 1% or more of methylphenidate hydrochloride extended-release tablets treated children and adolescent subjects in 4 placebo-controlled, double-blind clinical trials.

Table 4. Adverse Reactions Reported by ≥1% of Methylphenidate Hydrochloride Extended-Release Tablets -Treated Children and Adolescent Subjects in 4 Placebo-Controlled, Double-Blind Clinical Trials of Methylphenidate Hydrochloride Extended-Release Tablets

* Terms of Initial insomnia (Methylphenidate hydrochloride extended-release tablets =0.6%) and Insomnia (Methylphenidate hydrochloride extended-release tablets =2.2%) are combined into Insomnia
System/Organ Class  Adverse Reaction	Methylphenidate hydrochloride extended-release tablets (n=321) %	Placebo (n=318) %
Gastrointestinal Disorders
Abdominal pain upper	6.2	3.8
Vomiting	2.8	1.6
General Disorders and Administration Site Conditions
Pyrexia	2.2	0.9
Infections and Infestations
Nasopharyngitis	2.8	2.2
Nervous System Disorders
Dizziness	1.9	0
Psychiatric Disorders
Insomnia *	2.8	0.3
Respiratory, Thoracic and Mediastinal Disorders
Cough	1.9	0.9
Oropharyngeal pain	1.2	0.9

The majority of adverse reactions were mild to moderate in severity.

Adults Table 5 lists the adverse reactions reported in 1% or more of methylphenidate hydrochloride extended-release tablets-treated adults in 2 placebo-controlled, double-blind clinical trials.

Table 5. Adverse Reactions Reported by ≥1% of Methylphenidate Hydrochloride Extended- Release Tablets-Treated Adult Subjects in 2 Placebo-Controlled, Double-Blind Clinical Trials *

* Included doses up to 108 mg.
System/Organ Class  Adverse Reaction	Methylphenidate hydrochloride extended-release tablets (n=415) %	Placebo (n=212) %
Cardiac Disorders
Tachycardia	4.8	0
Palpitations	3.1	0.9
Ear and Labyrinth Disorders
Vertigo	1.7	0
Eye Disorders
Vision blurred	1.7	0.5
Gastrointestinal Disorders
Dry mouth	14.0	3.8
Nausea	12.8	3.3
Dyspepsia	2.2	0.9
Vomiting	1.7	0.5
Constipation	1.4	0.9
General Disorders and Administration Site Conditions
Irritability	5.8	1.4
Infections and Infestations
Upper respiratory tract infection	2.2	0.9
Investigations
Weight decreased	6.5	3.3
Metabolism and Nutrition Disorders
Decreased appetite	25.3	6.6
Anorexia	1.7	0
Musculoskeletal and Connective Tissue Disorders
Muscle tightness	1.9	0
Nervous System Disorders
Headache	22.2	15.6
Dizziness	6.7	5.2
Tremor	2.7	0.5
Paresthesia	1.2	0
Sedation	1.2	0
Tension headache	1.2	0.5
Psychiatric Disorders
Insomnia	12.3	6.1
Anxiety	8.2	2.4
Initial insomnia	4.3	2.8
Depressed mood	3.9	1.4
Nervousness	3.1	0.5
Restlessness	3.1	0
Agitation	2.2	0.5
Aggression	1.7	0.5
Bruxism	1.7	0.5
Depression	1.7	0.9
Libido decreased	1.7	0.5
Affect lability	1.4	0.9
Confusional state	1.2	0.5
Tension	1.2	0.5
Respiratory, Thoracic and Mediastinal Disorders
Oropharyngeal pain	1.7	1.4
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis	5.1	0.9

The majority of ADRs were mild to moderate in severity.