Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: MYLAN (PTY) LTD, 4 Brewery Street, Isando, 1600, Republic of South Africa
CONTRAMYL XR treatment is not indicated in all children with ADHD and the decision to use it 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.
The safety and efficacy of long-term use of methylphenidate, as in CONTRAMYL XR, has not been systematically evaluated in controlled trials. CONTRAMYL XR treatment should not and need not, be indefinite. CONTRAMYL XR treatment is usually discontinued during or after puberty. Patients on long-term therapy (i.e. over 12 months) must have careful ongoing monitoring according to the guidance in section 4.2 ‘Posology and method of administration’ for cardiovascular status, growth, appetite, development of de novo or worsening of pre-existing psychiatric disorders. Psychiatric disorders to monitor for are described below, and 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.
The medical practitioner who elects to use CONTRAMYL XR for extended periods (over 12 months) in children and adolescents with ADHD should periodically re-evaluate the longterm usefulness of CONTRAMYL XR for the individual patient with trial periods off medicine to assess the patient’s functioning without pharmacotherapy. It is recommended that CONTRAMYL XR is de-challenged at least once yearly to assess the child’s condition (preferably during times of school holidays). Improvement may be sustained when CONTRAMYL XR is either temporarily or permanently discontinued.
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.
CONTRAMYL XR should not be used in the elderly.
Safety and efficacy has not been established in this age group.
CONTRAMYL XR should not be used in children under the age of 6 years. Safety and efficacy in this age group has not been established (see section 4.3).
Patients who are being considered for treatment with stimulant medicines 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, and should receive further specialist cardiac evaluation if initial findings suggest such history or disease. Patients who develop symptoms such as palpitations, exertional chest pain, unexplained syncope, dyspnoea or other symptoms suggestive of cardiac disease during CONTRAMYL XR treatment should undergo a prompt specialist cardiac evaluation.
Analyses of data from clinical trials of methylphenidate, as contained in CONTRAMYL XR, in children and adolescents with ADHD showed that patients using methylphenidate may experience changes in diastolic and systolic blood pressure of over 10 mmHg relative to controls. The short- and long-term clinical consequences of these cardiovascular effects in children and adolescents are not known. The possibility of clinical complications cannot be excluded as a result of the effects observed in the clinical trial data especially when treatment during childhood/adolescence is continued into adulthood.
Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate. See section 4.3 ‘Contraindications’ for conditions in which CONTRAMYL XR treatment is contraindicated.
Cardiovascular status should be carefully monitored. Blood pressure and pulse should be recorded on a centile chart at each adjustment of dose and then at least every 6 months.
Methylphenidate as contained in CONTRAMYL XR should be discontinued in patients under treatment with repeated measures of tachycardia, dysrhythmia or increased systolic blood pressure (> 95th percentile) and referral to a doctor e.g.cardiologist should be considered.
The use of CONTRAMYL XR is contraindicated in certain pre-existing cardiovascular disorders unless specialist paediatric cardiac advice has been obtained (see section 4.3).
cardiac disorders
Sudden death has been reported in association with the use of stimulants of the central nervous system at usual doses in children, some of whom had structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone may carry an increased risk of sudden death, stimulant products (such as CONTRAMYL XR) are not recommended in children or adolescents with known 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 medicine.
Misuse of stimulants of the central nervous system may be associated with sudden death and other serious cardiovascular adverse events.
See section 4.3 ‘Contraindications’ for cerebrovascular conditions in which CONTRAMYL XR treatment is contraindicated. 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 CONTRAMYL XR.
Cerebral vasculitis appears to be a very rare idiosyncratic reaction to methylphenidate, as in CONTRAMYL XR exposure. 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 CONTRAMYL XR and early treatment. The diagnosis should therefore be considered in any patient who develops new neurological symptoms that are consistent with cerebral ischaemia during CONTRAMYL XR therapy. These symptoms could include severe headache, numbness, weakness, paralysis, and impairment of co-ordination, vision, speech, language or memory.
Treatment with CONTRAMYL XR is not contraindicated in patients with hemiplegic cerebral palsy.
Co-morbidity of psychiatric disorders in ADHD is frequent and should be taken into account when prescribing stimulant products, such as CONTRAMYL XR. In the case of emergent psychiatric symptoms or exacerbation of pre-existing psychiatric disorders, CONTRAMYL XR should not be given unless the benefits outweigh the risks to the patient.
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.
In psychotic patients, administration of CONTRAMYL XR may exacerbate symptoms of behavioural disturbance and thought disorder.
Treatment-emergent psychotic symptoms (visual/tactile/auditory hallucinations and delusions) or mania in children and adolescents without prior history of psychotic illness or mania can be caused by CONTRAMYL XR at usual doses (see section 4.8). If manic or psychotic symptoms occur, consideration should be given to a possible causal role for CONTRAMYL XR, and discontinuation of treatment may be appropriate.
The emergence or worsening of aggression or hostility can be caused by treatment with stimulants. Patients treated with CONTRAMYL XR should be closely monitored for the emergence or worsening of aggressive behaviour or hostility at treatment initiation, at every dose adjustment and then at least every 6 months and every visit. Medical practitioners should evaluate the need for adjustment of the treatment regimen in patients experiencing behaviour changes bearing in mind that upwards or downwards titration may be appropriate. Treatment interruption can be considered.
Patients with emergent suicidal ideation or behaviour during treatment for ADHD should be evaluated immediately by their medical practitioner. Consideration should be given to the exacerbation of an underlying psychiatric condition and to a possible causal role of CONTRAMYL XR treatment. Treatment of an underlying psychiatric condition may be necessary and consideration should be given to a possible discontinuation of CONTRAMYL XR.
CONTRAMYL XR is associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has been reported. Family history should be assessed and clinical evaluation for tics or Tourette’s syndrome in children should precede use of CONTRAMYL XR. Patients should be regularly monitored for the emergence or worsening of tics during treatment with CONTRAMYL XR.
Monitoring should be at every adjustment of dose and then at least every 6 months or every visit. CONTRAMYL XR should not be used in patients under six years old (see section 4.3 CONTRAINDICATIONS).
CONTRAMYL XR is associated with the worsening of pre-existing anxiety, agitation or tension. Clinical evaluation for anxiety, agitation or tension should precede use of CONTRAMYL XR and patients should be regularly monitored for the emergence or worsening of these symptoms during treatment, at every adjustment of dose and then at least every 6 months or every visit.
Particular care should be taken in using CONTRAMYL XR to treat ADHD in patients with comorbid bipolar disorder (including untreated Type I Bipolar Disorder or other forms of bipolar disorder) because of concern for possible precipitation of a mixed/manic episode in such patients. Prior to initiating treatment with CONTRAMYL XR, patients with co-morbid 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 above ‘Psychiatric Disorders’ and section 4.2). Patients should be monitored for symptoms at every adjustment of dose, then at least every 6 months and at every visit.
Moderately reduced weight gain and growth retardation have been reported with the longterm use of CONTRAMYL XR in children.
The effects of methylphenidate, as contained in CONTRAMYL XR on final height and final weight are unknown.
Growth should be monitored during CONTRAMYL XR treatment: height, weight and appetite should be recorded at least 6 monthly with maintenance of a growth chart. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.
CONTRAMYL XR should be used with caution in patients with epilepsy. CONTRAMYL XR may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and rarely in patients without a history of convulsions and no EEG abnormalities. If seizure frequency increases or new-onset seizures occur, CONTRAMYL XR should be discontinued.
Patients should be carefully monitored for the risk of diversion, misuse and abuse of CONTRAMYL XR.
CONTRAMYL XR should be used with caution in patients with known substance or alcohol dependency because of a potential for abuse, misuse or diversion.
Chronic abuse of CONTRAMYL XR can lead to marked tolerance and psychological dependence with varying degrees of abnormal behaviour. Frank psychotic episodes can occur, especially in response to parenteral abuse.
Patient age, the presence of risk factors for substance use disorder (such as co- morbid oppositional-defiant or conduct disorder and bipolar disorder), previous or current substance abuse should all 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 substance or alcohol dependence, because such patients may increase the dosage on their own initiative.
For some high-risk substance abuse patients, CONTRAMYL XR or other stimulants may not be suitable and non-stimulant treatment should be considered.
Careful supervision is required during CONTRAMYL XR withdrawal, since this 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.
CONTRAMYL XR should not be used to treat severe depression and/or for the prevention or treatment of normal fatigue states.
There is no experience with the use of CONTRAMYL XR in patients with renal or hepatic insufficiency (see section 4.3).
The long-term safety of treatment with methylphenidate, as contained in CONTRAMYL XR, is not fully known. 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.
Because the CONTRAMYL XR tablet is non-deformable and does not appreciably change in shape in the gastrointestinal (GI) tract, it should not ordinarily be administered to patients with pre-existing severe GI 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 in association with the ingestion of medicines in non-deformable prolonged-release formulations.
Due to the prolonged-release design of the tablet, CONTRAMYL XR should only be used in patients who are able to swallow the tablet whole. Even though the tablets have a score line, it is not intended as a break line and the tablets should not be divided and taken at different intervals. Patients should be informed that CONTRAMYL XR must be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed. The medicine is contained within a non-absorbable shell designed to release it at a controlled rate. The tablet shell is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.
The choice of formulation of a methylphenidate-containing product (as in CONTRAMYL XR) will have to be decided by the treating specialist on an individual basis and depends on the intended duration of effect.
CONTRAMYL XR contains methylphenidate, which may induce a false positive laboratory test for amphetamines, particularly with immunoassay screen test.
Prolonged and painful erections have been reported in association with CONTRAMYL XR, mainly in association with a change in the CONTRAMYL XR treatment regimen. Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.
Serotonin syndrome has been reported following coadministration of CONTRAMYL XR with serotonergic medicines (see section 4.5). If concomitant use of CONTRAMYL XR 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, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea). CONTRAMYL XR must be discontinued as soon as possible if serotonin syndrome is suspected.
CONTRAMYL XR contains sucrose. Patients with rare hereditary conditions such as fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take CONTRAMYL XR.
Because of possible effects on blood pressure, CONTRAMYL XR should be used cautiously with pressor medicines.
Human pharmacological studies have shown that methylphenidate may inhibit the metabolism of warfarin anticoagulants, anticonvulsants (e.g. phenobarbitone, phenytoin, primidone) and some antidepressants (tricyclics and selective serotonin reuptake inhibitors). Downward dose adjustments of these medicines may be required when given concomitantly with CONTRAMYL XR. It may be necessary to adjust the dosage and monitor plasma medicine concentrations (or, in the case of warfarin, coagulation times/INR), when initiating or discontinuing concomitant use of CONTRAMYL XR.
Because of possible hypertensive crisis, methylphenidate, as contained in CONTRAMYL XR, is contraindicated in patients being treated (currently or within the preceding 2 weeks) with MAO-inhibitors (see section 4.3).
CONTRAMYL XR may decrease the effectiveness of medicines used to treat hypertension.
Caution is advised in patients being treated with CONTRAMYL XR with any other medicine that can also elevate blood pressure (see also sections under sub-headers ‘Cardiovascular status’ and ‘Cerebrovascular disorders’ in section 4.4).
Because of possible hypertensive crisis, CONTRAMYL XR is contraindicated in patients being treated (currently or within the preceding 2 weeks) with non-selective, irreversible MAO-inhibitors (see section 4.3).
Alcohol may exacerbate the adverse CNS effects of CONTRAMYL XR.
It is therefore desirable for patients to abstain from alcohol during treatment.
There have been reports of serotonin syndrome following coadministration of CONTRAMYL XR with serotonergic medicines.
If concomitant use of CONTRAMYL XR with a serotonergic medicine is warranted, prompt recognition of the symptoms of serotonin syndrome is important (see section 4.4). CONTRAMYL XR must be discontinued as soon as possible if serotonin syndrome is suspected.
There is a risk of sudden blood pressure increase during surgery. If surgery is planned, CONTRAMYL XR treatment should not be used on the day of surgery.
The long-term safety of using CONTRAMYL XR in combination with clonidine or other centrally acting alpha-2 agonists has not been systematically evaluated.
Caution is recommended when administering CONTRAMYL XR with dopaminergic medicines, including antipsychotics. Because a predominant action of methylphenidate, as contained in CONTRAMYL XR, is to increase extracelluar dopamine levels, methylphenidate 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.
There is a limited amount of data from the use of CONTRAMYL XR in pregnant women.
Cases of neonatal cardiorespiratory toxicity, specifically foetal tachycardia and respiratory distress have been reported.
Studies in animals have shown evidence of reproductive toxicity at maternally toxic doses.
CONTRAMYL XR is not recommended for use during pregnancy unless a clinical decision is made that postponing treatment may pose a greater risk to the pregnancy (see section 4.3).
Methylphenidate, as contained in CONTRAMYL XR, is excreted in breast-milk (see section 4.3).
There is one case report of an infant who experienced an unspecified decrease in weight during the period of exposure but recovered and gained weight after the mother discontinued treatment with methylphenidate, as contained in CONTRAMYL XR. A risk to the suckling child cannot be excluded.
A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from CONTRAMYL XR therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
There were no relevant effects observed in the non-clinical studies.
Methylphenidate can cause dizziness, drowsiness and visual disturbances including difficulties with accommodation, diplopia and blurred vision (see section 4.8). It may have a moderate influence on the ability to drive and use potentially hazardous machinery machines.
Patients should be cautioned accordingly until they are reasonably certain that CONTRAMYL XR does not adversely affect their ability to engage in such activities.
Tabulated list of adverse reactions:
| Body System | Undesirable effect | ||
|---|---|---|---|
| Frequent | Less frequent | Not known | |
| Infections and infestations | Nasopharyngitis, upper respiratory tract infection, sinusitis | ||
| Blood and lymphatic system disorders | Anaemia, leucopenia, thrombocytopenia, thrombocytopenic purpura | Pancytopenia | |
| Immune system disorders | Hypersensitivity reactions such as angioedema, anaphylactic reactions, auricular swelling, bullous conditions, exfoliative conditions, urticarias, pruritus, rashes and eruptions | ||
| Metabolism and nutritional disorders | Anorexia, decreased appetite, moderately reduced weight and height gain during prolonged use in children | ||
| Psychiatric disorders | Insomnia, nervousness, affect lability, aggression, agitation, anxiety, depression, irritability, abnormal behaviour, mood swings, tics, initial insomnia, depressed mood, depression, libido decreased, tension, bruxism, panic attack | Psychotic disorders, auditory, visual and tactile hallucination, anger, suicidal ideation, mood altered, restlessness, tearfulness, worsening of pre-existing tics of Tourette’s syndrome, logorrhoea, hypervigilance, sleep disorder, mania, disorientation, libido disorder, confusional state, suicidal attempt (including completed suicide), transient depressed mood, abnormal thinking, apathy, repetitive behaviours, overfocussing | Delusion, thought disturbance, abuse and dependence |
| Nervous system disorders | Headache, dizziness, dyskinesia, psychomotor hyperactivity, somnolence, paraesthaesia, tension headache | Sedation, tremor, lethargy, convulsion, choreo-athetoid movements, reversible ischaemic neurological deficit, neuroleptic malignant syndrome | Cerebrovascular disorder (including vasculitis, cerebral haemorrhages, cerebrovascular accidents, cerebral arteritis, cerebral occlusion), Grand mal convulsion, migraine, dysphemia |
| Eye disorders | Accommodation disorder | Blurred vision, dry eye, difficulties in visual accommodation, visual impairment, diplopia | Mydriasis |
| Ear and labyrinth disorders | Vertigo | ||
| Cardiac disorders | Dysrhythmia, tachycardia, palpitations | Chest pain, angina pectoris, cardiac arrest; myocardial infarction | Supraventricular tachycardia, bradycardia, ventricular extrasystoles, extrasystoles |
| Vascular disorders | Hypertension | Hot flush, cerebral arteritis and/or occlusion, peripheral coldness, Raynaud’s phenomenon | |
| Respiratory, thoracic and mediastinal disorders | Cough, oropharyngeal pain | Dyspnoea | |
| Gastrointestinal disorders | Abdominal pain upper, diarrhoea, nausea, abdominal discomfort, vomiting, dry mouth, dyspepsia | Constipation | |
| Hepatobiliary disorders | Hepatic enzyme elevations, abnormal liver function, including hepatic coma | ||
| Skin and subcutaneous tissue disorders | Alopecia, pruritus, rash, urticaria | Bullous conditions, exfoliative conditions; hyperhidrosis, macular rash; erythema, Erythema multiforme, exfoliative dermatitis, fixed medicine eruption | |
| Musculoskeletal and connective tissue disorders | Arthralgia, muscle tightness, muscle spasms | Myalgia, muscle twitching, muscle cramps | Trismus |
| Renal and urinary disorders | Haematuria, pollakiuria | Incontinence | |
| Reproductive system and breast disorders | Erectile dysfunction | Gynaecomastia | Priapism, erection increased and prolonged erection (see section 4.4) |
| General disorders and administration site conditions | Pyrexia, growth retardation during prolonged use in children, fatigue, irritability, feeling jittery, asthenia, thirst | Sudden cardiac death | Chest discomfort, hyperpyrexia |
| Investigations | Changes in blood pressure and heart rate (usually an increase), decreased weight, increased alanine aminotransferase | Cardiac murmur, increased hepatic enzyme, increased blood alkaline phosphatase, increased blood bilirubin, decreased platelet count, abnormal white blood cell count | |
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA on the SAHPRA website at: https://medsafety.sahpra.org.za/#download1, via email at: adr@sahpra.org.za or via telephone at: 0125010311.
Not applicable.
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