Special Warning : אזהרת שימוש

5         WARNINGS AND PRECAUTIONS
5.1         Potential for Abuse and Dependence
CNS stimulants, including Metadex 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 dexmethylphenidate 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 Metadex 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 Metadex 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 a l 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 dexmethylphenidate , the mean weight gain was greater for pediatric patients (ages 6 to 17 years) receiving placebo (+ 0.4 kg) than for patients receiving dexmethylphenidate (- 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 we l 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 Metadex XR, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.


5.8     5.8 Effects on ability to drive and use machines
Metadex XR may cause dizziness, drowsiness, blurred vision or other CNS side effects.
Patients experiencing such side effects should refrain from driving, operating machinery or engaging in other potentially hazardous activities.


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 Metadex 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 dexmethylphenidate in Pediatric Patients With ADHD The safety data in this section is based on data from a 7-week controlled clinical study of dexmethylphenidate 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 dexmethylphenidate 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 (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 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 dexmethylphenidate doses of 5–30 mg/day. The table includes only those events that occurred in 5% or more of patients treated with dexmethylphenidate and for which the incidence in patients treated with dexmethylphenidate 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                                               dexmethylph   Placebo enidate
Adverse Reaction                                                   N = 53        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 dexmethylphenidate up to 30 mg daily versus placebo. The table includes only those reactions that occurred in patients treated with dexmethylphenidate 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                     dexmethylph dexmethylph dexmethylph     Placebo enidate     enidate     enidate
Adverse Reaction                       10 mg/day 20 mg/day 30 mg/day N = 64    N = 60    N = 58              N = 63
Gastrointestinal Disorders                22%       23%       29%                 24% Vomiting                                  2%        8%        9%                  0% Metabolism and Nutritional                16%       17%       22%                 5% Disorders
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 dexmethylphenidate in Adult Patients With ADHD The safety data in this section is based on data from a 5-week controlled clinical study of dexmethylphenidate 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 dexmethylphenidate 20 mg, 30 mg, or 40 mg daily who met DSM-IV criteria for ADHD [see Clinical Studies (14.2)].
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 dexmethylphenidate -treated patients and 7.5% of the placebo- treated patients discontinued due to adverse reactions. Three patients (1.8%) in the dexmethylphenidate discontinued due to insomnia and jittery, respectively and two patients (1.2%) in the dexmethylphenidate discontinued due to anorexia and anxiety, respectively.
Table 3 enumerates adverse reactions for the placebo-contro led, parallel-group study in adults with ADHD at fixed dexmethylphenidate doses of 20, 30, and 40 mg/day. The table includes only those events that occurred in 5% or more of patients in a dexmethylphenidate dose group and for which the incidences in patients treated with dexmethylphenidate appeared to increase with dose.

Table 3: Dose-Related Adverse Reactions in Adult Patients (18 to 60 years of age) With ADHD dexmethylph dexmethylph dexmethylph     Placebo enidate     enidate     enidate
System Organ Class                       20 mg        30 mg        40 mg Adverse Reaction                         N = 57       N = 54       N = 54        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
16%           9%           15%           8%
Mediastinal Disorders
Pharyngolaryngeal pain                       4%         4%           7%            2% 
Two other adverse reactions occurring in clinical trials with dexmethylphenidate 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 dexmethylphenidate in the treatment of ADHD.

Table 4: Changes (Mean ± SD) in Vital Signs and Weight by
Randomized Dose During Double-Blind Treatment–Adults dexmethylph dexmethylph dexmethylph       Placebo enidate 20  enidate 30  enidate 40 mg         mg              mg         (N = 53)
(N = 57)   (N = 54)        (N = 54)
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 
6.2     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 and dexmethylphenidate Formulations The fol-lowing adverse reactions associated with the use of all Ritalin and dexmethylphenidate 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 dexmethylphenidate 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

Effects on Driving