RADD Prolonged-release tablet Ref.[51222] Active ingredients: Methylphenidate

General

Methylphenidate treatment is not indicated in all children with ADHD, the decision to use RADD must be based on a very thorough assessment of the severity and chronicity of the child’s symptoms in relation to the child’s age and not simply on the presence of one or more abnormal behavioural characteristics.

RADD should not be used for the treatment of attention deficit or hyperactivity secondary to amenable causes, including acute stress reactions.

Use in adults

Safety and efficacy have not been established for the initiation of treatment in adults or the routine continuation of treatment beyond 18 years of age. If treatment withdrawal has not been successful when an adolescent has reached 18 years of age continued treatment into adulthood may be necessary. The need for further treatment of these adults should be reviewed regularly and undertaken annually.

Use in the elderly

Methylphenidate should not be used in the elderly (over 65) as safety and efficacy have not been established.

Use in children under 6 years of age

RADD should not be used in children under the age of 6 years. Safety and efficacy in this age group has not been established.

Long-term use (more than 12 months) in children and adolescents

Controlled studies regarding the safety and efficacy of long-term use of methylphenidate have not been undertaken. RADD treatment should not and need not, be indefinite, with treatment generally being discontinued during or after puberty.

Careful monitoring for cardiovascular status, growth, appetite, development of de novo or worsening of pre-existing psychiatric disorders is essential in this patient group.

Psychiatric disorders to be monitored include (but are not limited to) motor or vocal tics, aggressive or hostile behaviour, agitation, anxiety, depression, psychosis, mania, delusions, irritability, lack of spontaneity, withdrawal and excessive perseveration.

In the event extended use (more than 12 months) is required in children and adolescents with ADHD, periodic re-evaluation of the benefits should be undertaken by stopping therapy and assessing the patient’s functioning without pharmacotherapy.

It is recommended that RADD is de-challenged at least once yearly to assess the child’s condition (preferably during times of school holidays). Improvement may be sustained when the medicinal product is either temporarily or permanently discontinued.

Cardiovascular status

Patients considered for treatment should have a careful history (including assessment for a family history of sudden cardiac or unexplained death or malignant dysrhythmia) and physical exam to assess for the presence of cardiac disease. Should cardiac disease be suspected, further specialist cardiac evaluation is to be undertaken. The development of symptoms suggestive of cardiac disease (e.g. palpitations, exertional chest pain, unexplained syncope, dyspnoea) during RADD treatment require immediate specialist cardiac evaluation.

RADD is contraindicated in patients with hypertension.

ADHD patients whose underlying medical conditions might be compromised by increases in heart rate and/or blood pressure, e.g. heart failure and hypertension, should be closely monitored as methylphenidate increases heart-rate, systolic and diastolic blood pressure. Whilst taking RADD, patient blood pressure should be monitored at appropriate intervals in all patients, especially in those with hypertension (see section 4.3). Patients who develop symptoms suggestive of cardiac disease during RADD treatment should undergo prompt cardiac evaluation.

Sudden death and pre-existing structural cardiac abnormalities or other serious cardiac disorders

Cases of sudden death have been reported in ADHD patients with structural cardiac abnormalities and other serious cardiac disorders, treated with methylphenidate used at usual doses. Although some serious heart problems alone may carry an increased risk of sudden death, RADD is not recommended in patients with 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 RADD (see section 4.3). Before initiating RADD treatment, patients should be assessed for pre-existing cardiovascular disorders such as congenital long QT syndrome, or a family history of sudden death and ventricular dysrhythmia.

Misuse and cardiovascular events

Misuse of stimulants of the central nervous system, such as RADD, may be associated with sudden death and other serious cardiovascular adverse events.

Cerebrovascular disorders

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 RADD. Patients with additional risk factors (such as a history of cardiovascular disease, concomitant medicines that elevate blood pressure) should be assessed at every visit for neurological signs and symptoms after initiating treatment with RADD.

Cerebral vasculitis appears to be a very rare idiosyncratic reaction to methylphenidate exposure (as contained in RADD). There is little evidence to suggest that patients at higher risk can be identified and the initial onset of symptoms may be the first indication of an underlying clinical problem. Early diagnosis, based on a high index of suspicion, may allow the prompt withdrawal of RADD and early treatment. The diagnosis should therefore be considered in any patient who develops new neurological symptoms that are consistent with cerebral ischemia during RADD therapy. These symptoms could include severe headache, numbness, weakness, paralysis, and impairment of coordination, vision, speech, language or memory.

Treatment with RADD is not contraindicated in patients with hemiplegic cerebral palsy.

Tics

RADD is associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported. Family history and clinical evaluation for tics or Tourette’s syndrome should therefore be established prior RADD treatment. Regular monitoring for the emergence or worsening of tics during treatment with RADD is required.

Growth retardation

Long-term treatment with RADD may retard normal growth and weight in children. Careful monitoring is required, patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.

Depression/Fatigue

RADD should not be used to treat depression and/or for the prevention or treatment of normal fatigue states.

Psychiatric disorders

Co-morbidity of psychiatric disorders in ADHD is common and should be taken into account when prescribing RADD. Prior to initiating treatment with RADD, patients should be assessed for pre-existing psychiatric disorders and a family history of psychiatric disorders. Treatment of ADHD with RADD 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 disorders, RADD should not be prescribed (see section 4.3).

Development or worsening of psychiatric disorders should be monitored at every adjustment of dose, then at least every 6 months, and at every visit; discontinuation of treatment may be appropriate.

Emergence of new psychotic or manic symptoms

Treatment-emergent psychotic symptoms (visual/tactile/auditory hallucinations and delusions) or mania in patients without prior history of psychotic illness or mania can be caused by RADD at normal doses. In the event manic or psychotic symptoms occur, consideration should be given to a possible causal role for RADD, and discontinuation of treatment may be appropriate.

Aggressive or hostile behaviour

Patients beginning treatment with RADD should be monitored for the appearance or worsening of aggressive behaviour or hostility. Aggression is frequently associated with ADHD, however, emergence or worsening of aggression has been reported during treatment with RADD. Patients should be monitored at treatment initiation, at every dose adjustment and then at least every 6 months or every visit. Medical practitioners should evaluate the need for adjustment of the treatment regimen in patients experiencing behavioural changes, bearing in mind that upwards or downwards titration may be appropriate. Treatment interruption can be considered.

RADD should be given with caution in the following conditions

Exacerbation of pre-existing psychotic or manic symptoms

Administration of RADD may exacerbate symptoms of behaviour disturbances and thought disorder in psychotic patients.

Abuse, misuse and dependence

RADD should be given cautiously to patients with a history of narcotic dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behaviour. Frank psychotic episodes can occur, especially with parenteral abuse. Patient age, the presence of risk factors for substance use disorder (such as comorbid oppositional-defiant or conduct disorder and bipolar disorder), and previous or current substance abuse should be taken into account when deciding on a course of treatment for ADHD.

Caution is called for in emotionally unstable patients, such as those with a history of drug or alcohol dependence, because such patients may increase the dosage on their own initiative. For some high-risk substance abuse patients, RADD may not be suitable.

Seizures

RADD should be used with caution in patients with epilepsy.

Evidence indicates lowering of the convulsive threshold in patients with prior history of seizures, prior EEG abnormalities in absence of seizures, and in patients without a history of convulsions and no EEG abnormalities. If seizure frequency increases or new-onset seizures occur, treatment should be discontinued.

Suicidal tendency

Patients with emergent suicidal ideation or behaviour during treatment for ADHD should be evaluated immediately by their doctor. Consideration should be given to the exacerbation of an underlying psychiatric condition and to a possible causal role of RADD treatment. Treatment of an underlying psychiatric condition may be necessary, and consideration should be given to a possible discontinuation of RADD.

Anxiety, agitation or tension

Worsening of pre-existing anxiety, agitation or tension is associated with RADD treatment. Clinical evaluation for anxiety, agitation or tension prior RADD treatment should be undertaken with regular monitoring. RADD is contraindicated in patients suffering from these conditions (see section 4.3).

Forms of bipolar disorder

Particular care should be taken in the treatment of ADHD in patients with comorbid bipolar disorder (including untreated Type I Bipolar Disorder or other forms of bipolar disorder) due to the risk of possible precipitation of a mixed/manic episode in such patients. Prior to initiating treatment with RADD, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Close ongoing monitoring is essential in these patients. (see section 4.2). Patients should be monitored for symptoms at every adjustment of dose, then at least every 6 months and at every visit.

Visual adverse reactions

Symptoms of visual disturbances have been reported. Difficulties with accommodation and blurring of vision have been reported.

Haematological effects

The long-term safety of treatment with methylphenidate, as in RADD is 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 leukopenia, thrombocytopenia, anaemia or other alterations, including those indicative of serious renal or hepatic disorders, discontinuation of treatment should be considered

Potential for gastrointestinal obstruction

RADD must be swallowed whole with the aid of liquids. Tablets should not be chewed, divided or crushed. RADD is contained within a non-absorbable shell designed to release the medicine at a prolonged rate. The tablet shell together with insoluble core components are eliminated from the body. Patients should not be concerned if they occasionally notice something that resembles a tablet in their stools.

As RADD is non-deformable and does not appreciably change shape in the GI tract, RADD should not be administered to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic) or in patients with dysphagia or significant difficulty in swallowing tablets. There have been reports of obstructive symptoms in patients with known strictures. Due to the prolonged release design of the tablet, RADD should only be administered to patients who are able to swallow the tablet whole.

Use with serotonergic medicinal products

Serotonin syndrome has been reported following coadministration of methylphenidate with serotonergic medicines such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). The concomitant use of RADD and serotonergic medicines is not recommended as this may lead to the development of serotonin syndrome. If concomitant use of RADD with a serotonergic medicine is warranted, prompt recognition of the symptoms of serotonin syndrome is important. These symptoms may include mental-status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular abnormalities (e.g. tremor, myoclonus, hyperreflexia, incoordination, rigidity), seizures and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). RADD must be discontinued as soon as possible if serotonin syndrome is suspected and appropriate treatment instituted.

Withdrawal

Careful supervision is required during RADD withdrawal, as withdrawal may unmask depression as well as chronic over-activity. Some patients may require long-term follow up. Careful supervision is required during withdrawal from abusive use since severe depression may occur.

Drug screening

Methylphenidate may induce a false positive laboratory test for amphetamines, particularly with immunoassay screen test.

Renal or hepatic insufficiency

There is no experience with the use of RADD in patients with renal or hepatic insufficiency.

Priapism

Prolonged and painful erections have been reported in association with methylphenidate, mainly in association with a change in the treatment regimen. Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.

Lactose

RADD contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take RADD.

It is not known how methylphenidate may affect plasma concentrations of concomitantly administered medicines. Therefore, caution is recommended when combining methylphenidate with other medicines, especially those with a narrow therapeutic window.

Pharmacokinetic interactions

Methylphenidate is not metabolised by cytochrome P450 to a clinically relevant extent. Inducers or inhibitors of cytochrome P450 are not expected to have any relevant impact on methylphenidate pharmacokinetics. Conversely, the d- and l- enantiomers of methylphenidate do not relevantly inhibit cytochrome P450 1A2, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A.

However, studies indicate that methylphenidate (as contained in RADD) may inhibit the metabolism of warfarin, anticonvulsants (e.g. phenobarbitone, phenytoin, primidone), and some antidepressants (tricyclic and selective serotonin reuptake inhibitors). It may be necessary to adjust the dosage of these medicines that are already being taken and monitor plasma medicines concentrations (or, in the case of warfarin, coagulation times), when initiating or discontinuing concomitant use of RADD.

RADD coadministration did not increase plasma concentrations of the CYP2D6 substrate desipramine.

The stimulant effects of RADD are inhibited by chlorpromazine, haloperidol and lithium. Disulfiram may inhibit the metabolism and excretion of RADD.

Pharmacodynamic interactions

Use with centrally acting alpha-2 agonists (e.g. clonidine or dexmedetomidine).

Although no causality for the combination has been established, reports of serious adverse effects, including sudden death, in concomitant use with clonidine or dexmedetomidine have been recorded.

Use with alcohol

Alcohol may exacerbate the adverse CNS effects of RADD. It is therefore desirable for patients to abstain from alcohol during treatment (see section 4.4).

Anti-hypertensive medicines

Methylphenidate may decrease the effectiveness of medicines used to treat hypertension.

Use with medicines that elevate blood pressure

Caution is advised in concomitant use with any other medicine that can also elevate blood pressure (see section 4.4).

Due to possible hypertensive crisis, RADD is contraindicated in patients being treated (currently or within the preceding 2 weeks) with non-selective, irreversible MAO-inhibitors (see section 4.3).

Urinary alkalinisers

The urinary excretion of methylphenidate is reduced by urinary alkalinisers, which may enhance or prolong their effects, excretion is increased by urinary acidifiers.

Use with anaesthetics

There is a risk of sudden blood pressure and heart rate increase during surgery. If surgery is planned, RADD treatment should not be used on the day of surgery.

Use with dopaminergic medicines

Caution is recommended when administering RADD with dopaminergic medicines, including antipsychotics. Because a predominant action of methylphenidate is to increase extracellular dopamine levels, RADD may be associated with pharmacodynamic interactions when co-administered with direct and indirect dopamine agonists (including DOPA and tricyclic antidepressants) or with dopamine antagonists including antipsychotics.

Use with serotonergic medicines

The concomitant use of RADD and serotonergic medicines drugs is not recommended as this may lead to the development of serotonin syndrome (see section 4.4).

Methylphenidate has been shown to increase extracellular serotonin and norepinephrine and appears to have weak potency in binding serotonin transporter.

Medicine/Laboratory test

RADD may induce false positive laboratory tests for amphetamines, particularly with immunoassays screen test.

Pregnancy

RADD should not be used during pregnancy as safety has not been established (see section 4.3).

Cases of neonatal cardiorespiratory toxicity, specifically foetal tachycardia and respiratory distress have been reported. Teratogenicity has been shown in laboratory animals.

Breastfeeding

Methylphenidate is excreted in human milk, RADD should not be used during breastfeeding (see section 4.3).

Fertility

No relevant effects observed in non-clinical studies.

RADD may cause changes to vision (including blurring, altered visual depth perception), sedation and dizziness, patients should be advised to avoid driving or operating heavy machinery until they know how RADD affects them.

Tabulated list of adverse effects:

^* post-marketing side effect

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reaction Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8

Not applicable.