Special Warning : אזהרת שימוש

4.4. Special warnings and precautions for use

General
Treatment with Ritalin is not indicated in all cases of Attention-Deficit/Hyperactivity disorder, and should be considered only after detailed history-taking and evaluation. The decision to prescribe Ritalin should depend on an assessment of the severity of symptoms and in paediatric patients, the appropriateness to the child's age, and not simply on the presence of one or more abnormal behavioural characteristics. Where these symptoms are associated with acute stress reactions, treatment with Ritalin is usually not indicated.

Drug abuse, misuse, addiction, and dependence
Chronic abuse of Ritalin can lead to marked tolerance and psychological dependence with varying degrees of abnormal behaviour. Frank psychotic episodes may occur, especially with parenteral abuse. Clinical data indicate that children given Ritalin are not more likely to abuse drugs as adolescents or adults.
Caution is called for in emotionally unstable patients, such as those with a history of drug dependence or alcoholism, because they may increase the dosage on their own initiative.
Abuse, misuse, and addiction
Before prescribing Ritalin, 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 Ritalin in a safe place, preferably locked, and instruct patients to not give Ritalin to anyone else. Throughout Ritalin treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.
Ritalin has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction. Ritalin can be diverted for non-medical use into illicit channels or distribution.
Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, 
RIT API 11APR24 V14            Page 6 of 23           reference: New Zealand Data Sheet Jan.2024 of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.
Misuse and abuse of methylphenidate hydrochloride may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including Ritalin, can result in overdose and death (see 4.9 Overdosage), and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.
Dependence
Physical Dependence
Ritalin may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.
Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including Ritalin include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.
Tolerance
Ritalin may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

Cardiovascular
Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems: Sudden death has been reported in association with the use of stimulants of the central nervous system at usual doses in patients with structural cardiac abnormalities or other serious problems. A causal relationship with stimulant products has not been established since some of these conditions alone may carry an increased risk of sudden death. Stimulant products generally should not be used in patients with known structural cardiac abnormalities, or other serious cardiac disorders that may increase the risk of sudden death due to sympathomimetic effects of a stimulant drug.
Before initiating Ritalin treatment, patients should be assessed for pre-existing cardiovascular disorders and a family history of sudden death and ventricular arrhythmia (see 4.2 Posology and method of administration).
Cardiovascular Conditions:
Ritalin is contraindicated in patients with severe hypertension (see section 4.3 Contraindications). Ritalin increases heart rate and systolic and diastolic blood pressure.
Therefore, 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 pre-existing hypertension. Severe cardiovascular disorders are contraindicated (see section 4.3 Contraindications).

RIT API 11APR24 V14           Page 7 of 23           reference: New Zealand Data Sheet Jan.2024 Blood pressure should be monitored at appropriate intervals in all patients taking Ritalin, especially those with hypertension. Patients who develop symptoms suggestive of cardiac disease during Ritalin treatment should undergo a prompt cardiac evaluation.
Misuse and Cardiovascular Events:
Misuse of stimulants of the central nervous system, including Ritalin, may be associated with sudden death and other serious cardiovascular adverse events.

Cerebrovascular
Cerebrovascular conditions:
Patients with pre-existing central nervous system (CNS) abnormalities, e.g., cerebral aneurysm and/or other vascular abnormalities such as vasculitis or pre-existing stroke should not be treated with Ritalin. Patients with additional risk factors (history of cardiovascular disease, concomitant medications that elevate blood pressure) should be assessed regularly for neurological/psychiatric signs and symptoms after initiating treatment with Ritalin (see above, paragraph on Cardiovascular Conditions and section 4.5 Interaction with other medicinal products and other forms of interaction).

Psychiatric
Co-morbidity of psychiatric disorders in ADHD is common and should be taken into account when prescribing stimulant products. Prior to initiating treatment with Ritalin, patients should be assessed for pre-existing psychiatric disorders and a family history of psychiatric disorders (see section 4.2 Posology and method of administration).
Treatment of ADHD with stimulant products including Ritalin should not be initiated in patients with acute psychosis, acute mania or acute suicidality. These acute conditions should be treated and controlled before ADHD treatment is considered.
In the case of emergent psychiatric symptoms or exacerbation of pre-existing psychiatric symptoms, Ritalin should not be given to patients unless the benefit outweighs the potential risk.
Exacerbation of Pre-existing 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 Ritalin 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 to 0% of placebo-treated patients.
If such symptoms occur, consider discontinuing treatment.
Aggressive behaviour:


RIT API 11APR24 V14           Page 8 of 23           reference: New Zealand Data Sheet Jan.2024 Emergent aggressive behaviour or an exacerbation of baseline aggressive behaviour has been reported during stimulant therapy, including Ritalin. Physicians should evaluate the need for adjustment of treatment regimen in patients experiencing these behavioural changes, bearing in mind that upwards or downwards titration may be appropriate. Treatment interruption can be considered.
Suicidal tendency:
Patients and caregivers of patients should be alerted about the need to monitor for clinical worsening, suicidal behaviour or thoughts or unusual changes in behaviour and to seek medical advice immediately if these symptoms appear. The physician should initiate appropriate treatment of any underlying psychiatric condition and consider a possible discontinuation or change in the ADHD treatment.
Tics:
Ritalin is associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported (see section 4.8 Undesirable effects). Family history should be assessed and clinical evaluation for tics or Tourette’s syndrome in patients should precede use of methylphenidate for ADHD treatment. Ritalin is contraindicated in case of diagnosis or family history of Tourette's syndrome (see section 4.3 Contraindications).
Patients should be regularly monitored for the emergence or worsening of tics during treatment with Ritalin.
Serotonin syndrome:
Serotonin syndrome has been reported following co-administration of methylphenidate with serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs) and serotonin- norepinephrine reuptake inhibitors (SNRIs). The concomitant use of methylphenidate and serotonergic drugs is not recommended as this may lead to the development of serotonin syndrome. The symptoms of serotonin syndrome may include mental status changes (e.g.
agitation, hallucinations, delirium, and coma), autonomic instability (e.g. tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g.
tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). Prompt recognition of these symptoms is important so that treatment with methylphenidate and serotonergic drugs can be immediately discontinued and appropriate treatment instituted (see section 4.5 Interaction with other medicinal products and other forms of interaction).

Acute Angle Closure Glaucoma
There have been reports of acute angle closure glaucoma associated with methylphenidate treatment. Although the mechanism is not clear, Ritalin-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.

Increased Intraocular Pressure and Glaucoma
There have been reports of an elevation of intraocular pressure (IOP) and glaucoma (including open angle glaucoma and angle closure glaucoma) associated with methylphenidate treatment (see section 4.8 Undesirable effects). Close monitoring of Ritalin-treated patients with a history of abnormally increased IOP or glaucoma is recommended.

Priapism
Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. Priapism generally developed after some time on the drug, often subsequent to an increase in dose.
Priapism has also been reported during a period of drug withdrawal (drug holidays or during RIT API 11APR24 V14            Page 9 of 23           reference: New Zealand Data Sheet Jan.2024 discontinuation). Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

Growth retardation
Moderately reduced weight gain and slight growth retardation have been reported with the long-term use of stimulants, including Ritalin, in children (see section 4.8 Undesirable effects).
Growth should be monitored as clinically necessary during treatment with Ritalin, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

Seizures
Ritalin should be used with caution in patients with epilepsy as clinical experience has shown that it can cause an increase in seizure frequency in a small number of such patients. If seizure frequency increases, Ritalin should be discontinued.

Withdrawal
Careful supervision is required during drug withdrawal, since this may unmask depression as well as the effects of chronic over activity. Some patients may require long-term follow-up.

Haematological effects
The long-term safety and efficacy profiles of Ritalin are not fully known. Patients requiring long-term therapy should therefore be carefully monitored and complete and differential blood counts and a platelet count performed periodically. In the event of haematological disorders appropriate medical intervention should be considered (see section 4.8 Undesirable effects).

Paediatric patients (under 6 years of age)
Ritalin should not be used in children under 6 years of age, since safety and efficacy in this age group have not been established.

Non-clinical safety data
In a conventional study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal day 7) and continuing through sexual maturity (postnatal week 10). When the animals were tested as adults (postnatal weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose of 100 mg/kg/day (about 58-fold higher than the MRHD on a mg/kg basis).

Genotoxicity
With methylphenidate, sister chromatid exchange and chromosome aberrations were elevated in one in vitro study in Chinese Hamster Ovary (CHO) cells. However, no genotoxicity effects were seen in several other assays, including no mutagenic effects in three in vitro tests (Ames reverse mutation test, mouse lymphoma forward mutation test, human lymphocyte chromosome aberration test) and no evidence of clastogenic or aneugenic effects in two in vivo mouse bone marrow (micronucleus tests, at doses up to 250 mg/kg. B6C3F1 mice from the same strain that showed liver tumours in the cancer bioassay were used in one of these studies. Additionally, there was no genotoxic potential as assessed by measuring cII mutations in the liver and micronuclei in peripheral reticulocytes in the Big Blue mouse, 
RIT API 11APR24 V14            Page 10 of 23          reference: New Zealand Data Sheet Jan.2024 micronuclei in peripheral blood reticulocytes, HPRT mutations and chromosomal aberrations in peripheral blood lymphocytes of rhesus monkeys. Pig A locus mutations in adolescent rats, micronucleated reticulocyte frequencies in blood and DNA damage in blood, brain, and liver cells of adult male rats treated for 28 consecutive days, and by measuring micronuclei in mouse peripheral blood erythrocytes.

Carcinogenicity
In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas (a benign tumour) and, in males only, an increase in hepatoblastomas (a malignant tumour) at daily doses of approximately 60 mg/kg/day (about 35-fold-higher than the MRHD on a mg/kg basis). Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no overall increase in the number of malignant hepatic tumours. The mouse strain used is particularly sensitive to the development of hepatic tumours. It is thought that hepatoblastomas might be due to non-genotoxic mechanisms such as an increase in hepatic cell proliferation. This is consistent with the increase in liver weights observed in this mouse carcinogenicity study.
Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day (about 26- fold higher than the MRHD on a mg/kg basis).

Effects on Driving