Special Warning : אזהרת שימוש

5 WARNINGS AND PRECAUTIONS
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 [see Drug Abuse and Dependence (9.2)]. Misuse and abuse of CNS stimulants, including CONCERTA, can result in overdose and death [see Overdosage (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.



5.2 Serious Cardiovascular Events
Sudden Death and Preexisting Structural Cardiac Abnormalities or Other Serious Heart Problems
Children and Adolescents
Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems.
Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug.

Adults
Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with such abnormalities should also generally not be treated with stimulant drugs.

Hypertension and Other Cardiovascular Conditions
Stimulant medications cause a modest increase in average blood pressure (about 2 to 4 mm Hg) and average heart rate (about 3 to 6 bpm) [see Adverse Reactions (6.5)], and individuals may have larger increases. While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure.
Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with preexisting hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.

Assessing Cardiovascular Status in Patients Being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.



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.

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.

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.

5.6 Priapism
Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidateuse in both adult and pediatric male patients [see Adverse Reactions (6.6)].
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.


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.

5.8 Long-Term Suppression of Growth in Pediatric Patients
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.

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 [see Patient Counseling Information (17)].



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

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.

5.12 Increased Intraocular Pressure and Glaucoma
There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see Adverse Reactions (6.6)].

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.


6      ADVERSE REACTIONS
The following are discussed in more detail in other sections of the labeling: 
•     Abuse, Misuse, and Addiction [see Boxed Warning, Warnings and Precautions (5.1)] •     Hypersensitivity to Methylphenidate [see Contraindications (4.1)] •     Tics [see Contraindications (4.2)]
•     Monoamine Oxidase Inhibitors [see Contraindications (4.3) and Drug Interactions (7.1)] •     Serious Cardiovascular Events [see Warnings and Precautions (5.2)] •     Increased Blood Pressure and Heart Rate [see Warnings and Precautions (5.3)] •     Psychiatric Adverse Reactions [see Warnings and Precautions (5.4)] •     Seizures [see Warnings and Precautions (5.5)]
•     Priapism [see Warnings and Precautions (5.6)]
•     Peripheral Vasculopathy, including Raynaud’s Phenomenon [see Warnings and Precautions (5.7)]
•     Long-Term Suppression of Growth in Pediatric Patients [see Warnings and Precautions (5.8)] •     Potential for Gastrointestinal Obstruction [see Warnings and Precautions (5.9)] •     Hematologic Monitoring [see Warnings and Precautions (5.10)]


•     Acute Angle Closure Glaucoma [see Warnings and Precautions (5.11)] •     Increased Intraocular Pressure and Glaucoma [see Warnings and Precautions (5.12)] 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 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 Table 3). Safety was assessed by collecting adverse events, vital signs, weights, and ECGs, and by performing physical examinations and laboratory analyses.

Table 3. CONCERTA Exposure in Double-Blind and Open-Label Clinical Studies Patient Population        N              Dose Range
Children                  2216           18 to 54 mg once daily
Adolescents               502            18 to 72 mg once daily
Adults                    1188           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 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.

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 CONCERTA-treated children and adolescent subjects in 4 placebo-controlled, double-blind clinical trials.

Table 4. Adverse Reactions Reported by ≥1% of CONCERTA-Treated Children and Adolescent Subjects in 4 Placebo-Controlled, Double-Blind Clinical Trials of CONCERTA CONCERTA              Placebo
System/Organ Class
(n=321)             (n=318)
Adverse Reaction
%                    %
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 *Terms of Initial insomnia (CONCERTA=0.6%) and Insomnia (CONCERTA=2.2%) are combined into Insomnia.


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

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

Table 5. Adverse Reactions Reported by ≥1% of CONCERTA-Treated Adult Subjects in 2 Placebo-Controlled, Double-Blind Clinical Trials*
CONCERTA           Placebo
System/Organ Class                                  (n=415)          (n=212) Adverse Reaction                                     %                % Cardiac Disorders

CONCERTA    Placebo
System/Organ Class                                       (n=415)   (n=212) Adverse Reaction                                         %         %
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 * Included doses up to 108 mg.
The majority of ADRs were mild to moderate in severity.


6.2 Other Adverse Reactions Observed in CONCERTA Clinical Trials
This section includes adverse reactions reported by CONCERTA-treated subjects in double-blind trials that do not meet the criteria specified for Table 4 or Table 5 and all adverse reactions reported by CONCERTA-treated subjects who participated in open-label and postmarketing clinical trials.

Blood and Lymphatic System Disorders: Leukopenia

Eye Disorders: Accommodation disorder, Dry eye
Vascular Disorders: Hot flush

Gastrointestinal Disorders: Abdominal discomfort, Abdominal pain, Diarrhea 
General Disorders and Administrative Site Conditions: Asthenia, Fatigue, Feeling jittery, Thirst

Infections and Infestations: Sinusitis

Investigations: Alanine aminotransferase increased, Blood pressure increased, Cardiac murmur, Heart rate increased

Musculoskeletal and Connective Tissue Disorders: Muscle spasms

Nervous System Disorders: Lethargy, Psychomotor hyperactivity, Somnolence 
Psychiatric Disorders: Anger, Hypervigilance, Mood altered, Mood swings, Panic attack, Sleep disorder, Tearfulness, Tic

Reproductive System and Breast Disorders: Erectile dysfunction

Respiratory, Thoracic and Mediastinal Disorders: Dyspnea
Skin and Subcutaneous Tissue Disorders: Rash, Rash macular

Vascular Disorders: Hypertension

6.3 Discontinuation Due to Adverse Reactions
Adverse reactions in the 4 placebo-controlled studies of children and adolescents leading to discontinuation occurred in 2 CONCERTA patients (0.6%) including depressed mood (1, 0.3%) and headache and insomnia (1, 0.3%), and 6 placebo patients (1.9%) including headache and insomnia (1, 0.3%), irritability (2, 0.6%), headache (1, 0.3%), psychomotor hyperactivity (1, 0.3%), and tic (1, 0.3%).


In the 2 placebo-controlled studies of adults, 25 CONCERTA patients (6.0%) and 6 placebo patients (2.8%) discontinued due to an adverse reaction. Those events with an incidence of >0.5% in the CONCERTA patients included anxiety (1.7%), irritability (1.4%), blood pressure increased (1.0%), and nervousness (0.7%). In placebo patients, blood pressure increased and depressed mood had an incidence of >0.5% (0.9%).

In the 11 open-label studies of children, adolescents, and adults, 266 CONCERTA patients (7.0%) discontinued due to an adverse reaction. Those events with an incidence of >0.5% included insomnia (1.2%), irritability (0.8%), anxiety (0.7%), decreased appetite (0.7%), and tic (0.6%).

6.4 Tics
In a long-term uncontrolled study (n=432 children), the cumulative incidence of new onset of tics was 9% after 27 months of treatment with CONCERTA.

In a second uncontrolled study (n=682 children) the cumulative incidence of new-onset tics was 1% (9/682 children). The treatment period was up to 9 months with mean treatment duration of 7.2 months.

6.5 Blood Pressure and Heart Rate Increases
In the laboratory classroom clinical trials in children (Studies 1 and 2), both CONCERTA once daily and methylphenidate three times daily increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 4 mm Hg during the day, relative to placebo. In the placebo-controlled adolescent trial (Study 4), mean increases from baseline in resting pulse rate were observed with CONCERTA and placebo at the end of the double-blind phase (5 and 3 beats/minute, respectively). Mean increases from baseline in blood pressure at the end of the double-blind phase for CONCERTA and placebo-treated patients were 0.7 and 0.7 mm Hg (systolic) and 2.6 and 1.4 mm Hg (diastolic), respectively. In one placebo- controlled study in adults (Study 6), dose-dependent mean increases of 3.9 to 9.8 bpm from baseline in standing pulse rate were observed with CONCERTA at the end of the double-blind treatment vs.
an increase of 2.7 beats/minute with placebo. Mean changes from baseline in standing blood pressure at the end of double-blind treatment ranged from 0.1 to 2.2 mm Hg (systolic) and -0.7 to 2.2 mm Hg (diastolic) for CONCERTA and was 1.1 mm Hg (systolic) and -1.8 mm Hg (diastolic) for placebo. In a second placebo-controlled study in adults (Study 5), mean changes from baseline in resting pulse rate were observed for CONCERTA and placebo at the end of the double-blind treatment (3.6 and –1.6 beats/minute, respectively). Mean changes from baseline in blood pressure at the end of the double–blind treatment for CONCERTA and placebo-treated patients were – 1.2 and –0.5 mm Hg (systolic) and 1.1 and 0.4 mm Hg (diastolic), respectively [see Warnings and Precautions (5.3)].


6.6 Postmarketing Experience
The following additional adverse reactions have been identified during postapproval use of CONCERTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency:

Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura

Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystoles, Supraventricular tachycardia, Ventricular extrasystoles

Eye Disorders: Diplopia, Increased intraocular pressure, Mydriasis, Visual impairment 
General Disorders: Chest pain, Chest discomfort, Drug effect decreased, Hyperpyrexia, Therapeutic response decreased

Hepatobiliary disorders: Hepatocellular injury, Acute hepatic failure 
Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritus NEC, Rashes, Eruptions, and Exanthemas NEC

Investigations: Blood alkaline phosphatase increased, Blood bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal

Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis

Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs, Motor and Verbal Tics

Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Mania, Logorrhea, Libido changes

Reproductive System and Breast Disorders: Priapism

Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema
Vascular Disorders: Raynaud’s phenomenon

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected 
adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il.

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