Data Sheet
RITALIN®
10 mg Tablets.
RITALIN® SR
20 mg Tablets.
RITALIN® LA
10mg, 20 mg, 30 mg or 40 mg Capsules
Methylphenidate Hydrochloride
Qualitative and quantitative composition
Active substance: Methylphenidate (INN for alpha-phenyl-2-piperidine acetic acid methyl ester).
Ritalin® tablet contains 10 mg methylphenidate hydrochloride.
Ritalin SR tablet contains 20 mg methylphenidate hydrochloride.
Ritalin LA capsule contains 10mg, 20 mg, 30 mg and 40 mg methylphenidate hydrochloride.
For a full list of excipients, see List of excipients.
Pharmaceutical forms
Ritalin: Table immediate release 10mg Tablets (divisible):
A round flat white table with slightly bevelled edges containing 10mg methylphenidate.
They have a diameter of approx. 7mm and are imprinted CG on one side and A/B, with score on the other.
Ritalin SR: sustained Release 20mg Tablets (non-divisible):
A white to off-white, round, biconvex, bevelled-edge film-coated tablet, containing 20mg of methylphenidate. Branded with CIBA on one side and 16 on the other in black ink. They have a diameter of approx. 7mm.
Ritalin LA 10mg: Modified-release capsule, hard are white to off white beads in a light brown and white capsule with imprint NVR and R10 in tan-coloured ink.
Ritalin LA 20mg: Modified-release capsule, hard are white to off-white beads in a white capsule with imprint NVR and R20 in tan-coloured ink.
Ritalin LA 30 mg: Modified-release capsule, hard are white to off-white beads in a yellow capsule with imprint NVR and R30 in tan-coloured ink.
Ritalin LA 40 mg: Modified-release capsule, hard are white to off-white beads in a light brown capsule with imprint NVR and R40 in tan-coloured ink.
Clinical particulars
Therapeutic indications
Attention-Deficit/Hyperactivity Disorder (ADHD, DSM-IV)
ADHD was previously known as attention-deficit disorder or minimal brain dysfunction. Other terms used to describe this behavioural syndrome include: hyperkinetic disorder, minimal brain damage, minimal cerebral dysfunction, minor cerebral dysfunction and psycho-organic syndrome of children. Ritalin is indicated as part of a comprehensive treatment programme which typically includes psychological, educational, and social measures and is aimed at stabilising children with a behavioural syndrome characterised by moderate to severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis should be made according to DSM-IV criteria or the guidelines in ICD-10. Non-localising (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of central nervous system dysfunction may or may not be warranted.
Special Diagnostic Considerations for ADHD
The specific aetiology of this syndrome is unknown, and there is no single diagnostic test. Proper diagnosis requires medical and neuropsychological, educational, and social investigation. Characteristics commonly reported include: history of short attention span, distractibility, emotional lability, impulsivity, and moderate-to-severe hyperactivity, minor neurological signs, and abnormal EEG. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of one or more of these characteristics. Drug treatment is not indicated in all children with this syndrome. Stimulants are not indicated in children with symptoms secondary to environmental factors (child abuse in particular) and/or primary psychiatric disorder, including psychosis. Appropriate educational placement is essential, and psychosocial intervention is generally necessary. Where remedial measures alone prove insufficient, the decision to prescribe a stimulant must be based on rigorous assessment of the severity of the child's symptoms.
Narcolepsy (Ritalin and Ritalin SR only)
Symptoms include daytime sleepiness, inappropriate sleep episodes, and sudden loss of voluntary muscle tone.
Dosage and method of administration
The dosage of Ritalin should be individualised according to the patient's clinical needs and responses.
In the treatment of ADHD, an attempt should be made to time administration to coincide with the periods of greatest academic, behavioural, and social stress.
Ritalin should be started at a low dose, with increments at weekly intervals. Daily doses above 60 mg are not recommended.
If symptoms do not improve after dose titration over a period of one month, the drug should be discontinued.
If symptoms worsen or other adverse effects occur, the dosage should be reduced or, if necessary, the drug discontinued.
If the effect of the drug wears off too early in the evening, disturbed behaviour and/or inability to go to sleep may recur. A small evening dose of the normal tablet or an afternoon dose of the SR tablet may help to solve this problem. Ritalin should be discontinued periodically to assess the child's condition. Improvement may continue when the drug is temporarily or permanently discontinued.
Drug treatment should not, and need not, be indefinite. It can usually be discontinued during or after puberty. However, ADHD may continue into adulthood and in such cases treatment with Ritalin may continue to be beneficial after puberty.
Children (6 years and over)
Tablets: Start with 5 mg once or twice daily (e.g. at breakfast and lunch) with weekly increments of 5 to 10 mg. The total daily dosage should be administered in divided doses.
SR Tablets: Ritalin SR tablets have a duration of action of about 8 hours. They may therefore be used when a prolonged effect is desired exceeding the duration of action of standard Ritalin tablets. Ritalin SR tablets must be swallowed whole and never crushed or chewed and should be taken after meals, preferably after a substantial breakfast (see Pharmacokinetic properties) for maximum duration of effect. It may be necessary to use a combination of the standard immediate release and SR tablets in some patients to achieve the optimal clinical response. As the duration of action of Ritalin SR is variable from patient to patient, it may not be possible to avoid administration of a Ritalin dose during the middle part of the day in all patients. The total absorption and duration of action of Ritalin 20mg SR are maximized when it is taken with a meal (see Pharmacokinetics).The total daily dose should be similar to that required if the immediate formulation is used. In the fasted state, Ritalin SR 20mg gives similar blood concentration to those expected following two Ritalin 10mg immediate release tablets (with the second being taken four hours after the first).
LA Capsules: Ritalin LA (methylphenidate hydrochloride modified-release capsules) is for oral administration once daily in the morning. The recommended starting dose of Ritalin LA is 20 mg. When in the judgement of the clinician a lower initial dose is appropriate, patients may begin treatment with Ritalin LA 10 mg.
Ritalin LA capsules may be administered with or without food. They may be swallowed as whole capsules or alternatively may be administered by sprinkling the contents over a small amount of food (see specific instructions below).
Ritalin LA capsules and/or their contents should not be crushed, chewed, or divided.
Ritalin LA administration by sprinkling capsule contents on food
The capsules may be carefully opened and the beads sprinkled over soft food (e.g. apple-sauce). The food should not be warm because this could affect the modified-release properties of this formulation. The mixture of drug and food should be consumed immediately in its entirety. The drug and food mixture should not be stored for future use.
Ritalin LA, administered as a single dose, provides comparable overall exposure (AUC) of methylphenidate compared to the same total dose of Ritalin administered b.i.d.
Switching patients to Ritalin LA
The recommended dose of Ritalin LA in patients being switched from the standard formulation or the SR formulation is provided below.
Table 1
| Previous methylphenidate dose | Recommended Ritalin LA dose |
|---|---|
| 5mg methylphenidate b.i.d | 10 mg once daily |
| 10 mg methylphenidate b.i.d. or 20 mg methylphenidate SR |
20 mg once daily |
| 15 mg methylphenidate b.i.d. | 30 mg once daily |
| 20 mg methylphenidate b.i.d. or 40 mg methylphenidate SR |
40 mg once daily |
For other methylphenidate regimens, clinical judgement should be used when selecting the starting dose. Ritalin LA dosage may be adjusted at weekly intervals in 10 mg increments.
Adults
Tablets: The average daily dose is 20 to 30 mg, given in 2 to 3 divided doses.
Some patients may require 40 to 60 mg daily, while for others, 10 to 15 mg daily will be adequate. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6 p.m.
SR Tablets: Ritalin SR tablets have a duration of action of about 8 hours. They may therefore be used when a prolonged effect is desired exceeding the duration of action of standard Ritalin tablets. Ritalin SR tablets must be swallowed whole and never crushed or chewed and should be taken after meals, preferably after a substantial breakfast (see Pharmacokinetic properties) for maximum duration of effect. It may be necessary to use a combination of the standard immediate release and SR tablets in some patients to achieve the optimal clinical response. As the duration of action of Ritalin SR is variable from patient to patient, it may not be possible to avoid administration of a Ritalin dose during the middle part of the day in all patients. The total absorption and duration of action of Ritalin 20mg SR are maximized when it is taken with a meal (see Pharmacokinetics).The total daily dose should be similar to that required if the immediate formulation is used. In the fasted state, Ritalin SR 20mg gives similar blood concentration to those expected following two Ritalin 10mg immediate release tablets (with the second being taken four hours after the first).
Contraindications
- Hypersensitivity to methylphenidate or to any of the excipients.
- Anxiety, tension.
- Agitation.
- Hyperthyroidism.
- Cardiac arrhythmia.
- Severe angina pectoris.
- Glaucoma.
- Phaeochromocytoma.
- Diagnosis of motor tics or tics in sibling.
- Diagnosis or family history of Tourette's syndrome.
Special warnings and precautions for use
Cardiovascular
Pre-existing Structural Cardiac Abnormalities: Sudden death has been reported in association with the use of stimulants of the central nervous system at usual doses in children with structural cardiac abnormalities. A causal relationship with stimulant products has not been established since some structural cardiac abnormalities alone may carry an increased risk of sudden death. Stimulant products generally should not be used in patients with known structural cardiac abnormalities.
Cardiovascular Conditions: Ritalin generally should not be used in patients with severe hypertension. 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, heart failure, recent myocardial infarction. Cardiac arrhythmia and severe angina pectoris are contraindicated (see Contraindications). Blood pressure should be monitored at appropriate intervals in all patients taking Ritalin, especially those with hypertension.
Misuse and Cardiovascular Events: Misuse of stimulants of the central nervous system may be associated with sudden death and other serious cardiovascular adverse events.
Cerebrovascular
Cerebrovascular conditions: Patients with pre-existing 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 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. 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.
Psychotic symptoms: Psychotic symptoms, including visual and tactile hallucinations have been reported in patients administered usual prescribed doses of stimulant products, including Ritalin (see Adverse effects). Physicians should consider treatment discontinuation.
Aggressive behaviour: Emergent aggressive behaviour or an exacerbation of baseline aggressive behaviour has been reported during stimulant therapy, including Ritalin. However, patients with ADHD may experience aggression as part of their medical condition. Therefore causal association with treatment is difficult to assess. 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 with emergent suicidal ideation and behaviour during treatment for ADHD should be evaluated immediately by their physician. The physician should initiate appropriate treatment of the underlying psychiatric condition and consider a possible change in the ADHD treatment regimen.
Other
Ritalin should not be used in children under 6 years of age, since safety and efficacy in this age group have not been established.
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.
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 their 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.
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.
Moderately reduced weight gain and slight growth retardation have been reported with the long-term use of stimulants in children, although a causal relationship has not been confirmed.
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.
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.
Careful supervision is required during drug withdrawal, since this may unmask depression as well as the effects of chronic overactivity. Some patients may require long-term follow-up.
Interaction with other medicinal products and other forms of interaction
Pharmacodynamic interactions
Ritalin may decrease the effectiveness of drugs used to treat hypertension. Ritalin should be used with caution in patients being treated with drugs that elevate blood pressure including MAO inhibitors (see also paragraph on Cerebrovascular Conditions in Special warnings and precautions for use).
Alcohol may exacerbate the adverse CNS effects of psychoactive drugs, including Ritalin. It is therefore advisable for patients to abstain from alcohol during treatment.
As an inhibitor of dopamine reuptake, Ritalin may be associated with pharmacodynamic interactions when coadministered with direct and indirect dopamine agonists (including DOPA and tricyclic antidepressants) as well as dopamine antagonists (antipsychotics, e.g. haloperidol). The coadministration of Ritalin with antipsychotics is not recommended because of the counteracting mechanism of action.
Case reports suggested a potential interaction of Ritalin with coumarin anticoagulants, some anticonvulsants (e.g. phenobarbital, phenytoin, primidone), phenylbutazone, and tricyclic antidepressants but pharmacokinetic interactions were not confirmed when explored at higher sample sizes. The dosage of these drugs might have to be reduced.
Pharmacokinetic interactions
Ritalin is not metabolized by cytochrome P450 to a clinically relevant extent. Inducers or inhibitors of cytochrome P450 are not expected to have any relevant impact on Ritalin pharmacokinetics. Conversely, the d- and l- enantiomers of methylphenidate in Ritalin did not relevantly inhibit cytochrome P450 1A2, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A.
Ritalin coadministration did not increase plasma concentrations of the CYP2D6 substrate desipramine.
An interaction with the anticoagulant ethylbiscoumacetate in 4 subjects was not confirmed in a subsequent study with a higher sample size (n=12).
Other specific drug-drug interaction studies with Ritalin have not been performed in vivo.
Other
Methylphenidate may induce false positive laboratory tests for amphetamines, particularly with immunoassays screen test.
Pregnancy and lactation
Pregnancy
Studies to establish safe use of methylphenidate in pregnant women have not been conducted. Ritalin should not be given to pregnant women unless the potential benefit outweighs the risk to the foetus (see Preclinical safety data).
Lactation
It is not known whether the active substance of Ritalin and/or its metabolites pass into breast milk, but for safety reasons, breast-feeding mothers should not use Ritalin.
Effects on ability to drive and use machines
Ritalin may cause dizziness and drowsiness. It is therefore advisable to exercise caution when driving, operating machinery, or engaging in other potentially hazardous activities.
Adverse effects
Nervousness and insomnia are very common adverse reactions which occur at the beginning of Ritalin treatment but can usually be controlled by reducing the dosage and/or omitting the afternoon or evening dose.
Decreased appetite is also common but usually transient. Abdominal pain, nausea and vomiting are common, usually occur at the beginning of treatment and may be alleviated by concomitant food intake.
Adverse reactions listed in Table 2 are ranked under headings of frequency, using the following convention: very common ≥ 10%, common ≥ 1% to < 10%; uncommon ≥ 0.1% to < 1%; rare ≥ 0.01% to < 0.1%; very rare < 0.01%.
Table 2
| Blood and the lymphatic system disorders | |
|---|---|
| Very rare: | Leucopenia, thrombocytopenia, anaemia. |
| Immune system disorders | |
| Very rare: | Hypersensitivity reactions. |
| Metabolism and nutrition disorders | |
| Rare: | Moderately reduced weight gain during prolonged use in children. |
| Psychiatric disorders | |
| Very rare: | Hyperactivity, psychosis (sometimes with visual and tactile hallucinations), transient depressed mood. |
| Nervous system disorders | |
| Common: | Headache, drowsiness, dizziness, dyskinesia. |
| Very rare: | Convulsions, choreoathetoid movements, tics or exacerbation of existing tics and Tourette's syndrome, cerebrovascular disorders including vasculitis, cerebral haemorrhages and cerebrovascular accidents. |
| Eye disorders | |
| Rare: | Difficulties in visual accommodation, blurred vision. |
| Cardiac disorders | |
| Common: | Tachycardia, palpitation, arrhythmias, changes in blood pressure and heart rate (usually an increase). |
| Rare: | Angina pectoris. |
| Gastrointestinal disorders | |
| Common: | Abdominal pain, nausea, vomiting, dry mouth. |
| Hepatobiliary disorders | |
| Very rare: | Abnormal liver function, ranging from transaminase elevation to hepatic coma. |
| Skin and subcutaneous tissue disorders | |
| Common: | Rash, pruritus, urticaria, fever, scalp hair loss. |
| Very rare: | Thrombocytopenic purpura, exfoliative dermatitis, erythema multiforme. |
| Musculoskeletal and connective tissue disorders | |
| Common: | Arthralgia. |
| Very rare: | Muscle cramps. |
| General disorders and administration site conditions | |
| Rare: | Slight growth retardation during prolonged use in children. |
Very rare reports of poorly documented neuroleptic malignant syndrome (NMS) have been received. In most of these reports, patients were also receiving other medications. It is uncertain what role Ritalin played in these cases.
Overdose
Signs and symptoms
Signs and symptoms of acute overdosage, mainly due to overstimulation of the central and sympathetic nervous systems, may include: vomiting, agitation, tremor, hyperreflexia, muscle twitching, convulsions (possibly followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitation, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.
Management
When treating overdose, practitioners should bear in mind that a second release of methylphenidate from Ritalin LA (methylphenidate hydrochloride modified-release capsules) occurs at approximately four hours after administration.
Management consists in providing supportive measures, and symptomatic treatment of life-threatening events, e.g. hypertensive crisis, cardiac arrhythmias, convulsions. For the most current guidance for treatment of symptoms of overdose, the practitioner should consult a certified Poison Control Center or current toxicological publication.
Supportive measures include preventing self-injury and protecting the patient from external stimuli that would exacerbate the overstimulation already present. If the overdose is oral and the patient is conscious, the stomach could be evacuated by induction of vomiting, followed by administration of activated charcoal. Airway protected gastric lavage is necessary in hyperactive or unconscious patients, or those with depressed respiration. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required to reduce hyperpyrexia.
The efficacy of peritoneal dialysis or extracorporeal haemodialysis for Ritalin overdosage has not been established.
Pharmacological properties
Pharmacodynamic properties
Pharmacotherapeutic group: psychostimulants - ATC code: NO6B AO4.
Ritalin is a racemate consisting of a 1:1 mixture of d-methylphenidate (d-MPH) and l-methylphenidate (l-MPH).
Ritalin is a mild CNS stimulant with more prominent effects on mental than on motor activities. Its mode of action in man is not completely understood, but its stimulant effects are thought to be due to an inhibition of dopamine reuptake in the striatum, without triggering the release of dopamine.
The mechanism by which Ritalin exerts its mental and behavioural effects in children is not clearly established, nor is there conclusive evidence showing how these effects relate to the condition of the central nervous system.
The l-enantiomer is thought to be pharmacologically inactive.
Pharmacokinetic properties
Absorption
Tablets
After oral administration the active substance (methylphenidate hydrochloride) is rapidly and almost completely absorbed. Owing to extensive first-pass metabolism, the absolute bioavailability was 22±8 % for the d-enantiomer and 5±3 % for the l-enantiomer. Ingestion with food has no relevant effect on absorption. Peak plasma concentrations of about 40 nmol/L (11 ng/mL) are reached on average 1 to 2 hours after administration. Peak plasma concentrations vary markedly between patients. The area under the concentration-time curve (AUC), and the peak plasma concentration (Cmax) are proportional to the dose.
SR Tablets
In the fasted state, absorption of methylphenidate from Ritalin 20 mg SR tablets is 37 % slower than with the standard tablets and results in smaller fluctuations of the plasma concentration. Cmax is lower (by 40 %) and is attained later (at 3 hours) but the total amount absorbed (AUC) is the same. After a high-fat meal, both AUC (by 25 %) and Cmax (by 27 %) are significantly higher, although the rate of absorption (Cmax/AUC ratio) remains the same. Time to Cmax (Tmax) is also slightly faster after a high-fat meal (median Tmax: 2.5 hours) as compared to without food (median Tmax: 3 hours).
LA Capsules
Following oral administration of Ritalin LA (modified-release capsules) to children diagnosed with ADHD and adults, methylphenidate is rapidly absorbed and produces a bi-modal plasma concentration-time profile (i.e. two distinct peaks approximately four hours apart). The relative bioavailability of Ritalin LA given once daily is comparable to the same total dose of Ritalin or methylphenidate tablets given twice a day in children and in adults.
The fluctuations between peak and trough plasma methylphenidate concentrations are smaller for Ritalin LA given once a day compared to Ritalin tablets given twice a day.
Food Effects
Ritalin LA may be administered with or without food. There were no differences in the bioavailability of Ritalin LA when administered with either a high-fat breakfast or applesauce, compared to administration in the fasting condition. There is no evidence of dose dumping in the presence or absence of food.
For patients unable to swallow the capsule, the contents may be sprinkled on soft food such as apple-sauce and administered (see Dosage and method of administration).
Distribution
In blood, methylphenidate and its metabolites are distributed between plasma (57 %) and erythrocytes (43 %). Binding to plasma proteins is low (10 to 33 %). The volume of distribution was 2.65±1.11 L/kg for d-MPH and 1.80±0.91 L/kg for l-MPH.
Biotransformation
Biotransformation of methylphenidate by the carboxylesterase CES1A1 is rapid and extensive. Peak plasma concentrations of the main, deesterified, metabolite - alpha-phenyl-2-piperidine acetic-acid (ritalinic acid) - are attained about 2 hours after administration and are 30 to 50 times higher than those of the unchanged substance. The half-life of alpha-phenyl-2-piperidine acetic acid is about twice that of methylphenidate, and its mean systemic clearance is 0.17 L/h/kg. Only small amounts of hydroxylated metabolites (e.g. hydroxymethylphenidate and hydroxyritalinic acid) are detectable. Therapeutic activity seems to be principally due to the parent compound.
Elimination
Methylphenidate is eliminated from the plasma with a mean half-life of 2 hours. The systemic clearance is 0.40±0.12 L/h/kg for d-MPH and 0.73±0.28 L/h/kg for l-MPH. After oral administration, 78 to 97 % of the dose is excreted in the urine and 1 to 3 % in the faeces in the form of metabolites within 48 to 96 hours. Only small quantities (< 1 %) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as alpha-phenyl-2-piperidine acetic acid (60 to 86 %).
The elimination half-life and the cumulative urinary excretion of alpha-phenyl-2-piperidine acetic acid are not significantly different for SR tablets.
Characteristics in patients
There are no apparent differences in the pharmacokinetics of methylphenidate between hyperactive children and healthy adult volunteers. Elimination data from patients with normal renal function suggest that renal excretion of unchanged methylphenidate would hardly be diminished in the presence of impaired renal function. However, renal excretion of the metabolite alpha-phenyl-2-piperidine acetic acid may be reduced.
Preclinical safety data
Pregnancy-embryonal/fetal development
Methylphenidate is considered to be possibly teratogenic in rabbits. Spina bifida with malrotated hind limbs was observed in two separate litters at a dose of 200 mg/kg/day. This dose was approximately 116-fold higher than the maximum recommended human dose (MRHD) of 60 mg. A second study was conducted with a high dose of 300 mg/kg, which was considered maternally toxic. No spina bifida was seen, however, in 12 litters (92 foetuses) surviving.
Methylphenidate is not teratogenic in rats. Development foetal toxicity was noted at a high dose of 75 mg/kg (44-fold higher than the MRHD) and consisted of an increase of the instance of foetuses with delayed ossification of the skull and hyoid bones as well as foetuses with short supernumerary ribs (see Pregnancy and lactation).
Carcinogenesis-mutagenesis
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). 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, and the significance of these results to humans is unknown.
Similar studies in F344 rats showed no evidence of carcinogenicity.
Sister chromatid exchange and chromosome aberrations were elevated in an in vitro test on cultured ovary cells of Chinese hamster but no mutagenic effects were observed in two further in vitro tests (Ames reverse mutation test, mouse lymphoma forward mutation test). In an in vivo study of the effect of methylphenidate on mouse bone marrow cells (micronucleus test), in which doses up to 250 mg/kg were given, there was no evidence of clastogenic or aneugenic effects. The strain used for this in vivo assay was the B6C3F1 mouse, the same strain that produced a positive response in the mouse carcinogenecity study.
Comment
The US Food and Drugs Administration examined data from the Surveillance, Epidemiology and End Results (SEER) database for the years 1973 to 1991 and found that the estimated incidence of hepatoblastoma in the general population was not greater than 1 in 10 million person years.
A total of 174 cases of hepatoblastoma were reported by the SEER for the period 1973 to 1995. Age-adjusted incidence rate was very low (IR=0,0382 per 100,000 person-years). The majority of the cases (149 out of 174) were diagnosed among the age group 0 to 4 years old, which is in accordance with the natural history of the disease. For the age group 5 to 24 years old the rates of hepatoblastoma were very low with few or no cases reported.
On the basis of experience since marketing Ritalin, there is no evidence that the incidence is higher in patients receiving Ritalin.
Juvenile neurobehavioural development
Repeated oral administration of methylphenidate to young rats identified decreased spontaneous locomotor activity at 50 mg/kg/day (29-fold higher than the MRHD), due to an exaggerated pharmacological activity of methylphenidate. A deficit in the acquisition of a specific learning task was also observed, only in females and at the highest dose of 100 mg/kg/day (58-fold higher than the MRHD). The clinical relevance of these findings is unknown.
Unlike these preclinical findings, long-term administration of methylphenidate in children with ADHD is well tolerated and improves the school performance. Thus the clinical experience does not suggest that these learning and behavioural results in rats are clinically relevant.
Pharmaceutical particulars
List of excipients
Ritalin tablet [10 mg]: calcium phosphate, lactose, wheat starch, gelatine, magnesium stearate, and talc.
Ritalin SR tablet [20 mg]: lactose, cetostearyl alcohol, magnesium stearate, hydroxypropyl methylcellulose, polyoxyl 40 hydrogenated castor oil, titanium dioxide (E 171), talc, carnauba wax, and fine black ink.
Ritalin LA capsule [10mg, 20 mg, 30 mg and 40 mg]: ammonio methacrylate copolymer, black iron oxide (E 172) (10 and 40 mg capsules only), gelatine, methacrylic acid copolymer, macrogol, red iron oxide (E 172) (10 and 40 mg capsules only), sugar spheres, talc, titanium dioxide (E 171), triethyl citrate, and yellow iron oxide (E 172) (10, 30 and 40 mg capsules only).
Incompatibilities
Not applicable.
Shelf-life
Ritalin tablet [10 mg]: 2 years.
Ritalin SR tablet [20 mg]: 2 years.
Ritalin LA capsule [10mg, 20 mg, 30 mg and 40 mg]: 3 years.
Special precautions for storage
Ritalin tablet [10 mg]
Do not store above 25°C.
Store in the original package in order to protect from moisture.
Ritalin should be kept out of the reach and sight of children.
Ritalin SR tablet [20 mg]
Do not store above 30°C.
Store in the original package in order to protect from moisture.
Ritalin should be kept out of the reach and sight of children.
Ritalin LA capsules [10mg, 20 mg, 30 mg and 40 mg]
Do not store above 25°C.
Keep the bottle tightly closed in order to protect from moisture.
Ritalin should be kept out of the reach and sight of children.
Nature and contents of container
Ritalin tablet [10 mg]: blister packs containing 30 tablets
Ritalin SR tablet [20 mg]: blister packs containing 100 tablets.
Ritalin LA capsules [10mg, 20 mg, 30 mg and 40 mg]: HDPE bottles containing 30 capsules
Medicine classification
Controlled Drug B2
Name and address
Novartis New Zealand Limited
Private Bag 65904
Mairangi Bay
Auckland 0754
Building G, 5 Orbit Drive
Rosedale
Auckland 0632
Telephone: 09 361 8100
Date of preparation
08 June 2009
(Ref: BPI 10 July 2008)