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Methylphenidate in:
10mg tablets are white or off-white, circular, flat, bevel-edged tablets, engraved "M" breakline "P" on one face and "10" on the other face.
Methylphenidate tablets are a central nervous system stimulant. Its mode of action in humans is not completely understood, but it is thought to exert its stimulant effect by activating the brainstem arousal system and cortex. The mechanism by which Methylphenidate tablets produces 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.
After oral administration the active substance (methylphenidate hydrochloride) is rapidly and almost completely absorbed. Owing to extensive first-pass metabolism its systemic availability is only 30% (11-51%) of the dose. Ingestion with food accelerates absorption, but has no effect on the amount absorbed. Peak plasma concentrations of about 40nmol/L (11ng/ml) are reached on average 1-2 hours after administration of 0.30 mg/kg. However, peak plasma concentrations vary markedly between patients. The area under the concentration-time curve (AUC), and the peak plasma concentrations, are proportional to the dose.
In blood, methylphenidate and its metabolites are distributed between plasma (57%) and erythrocytes (43%). Binding to plasma proteins of methylphenidate and its metabolites is low (10-33%). The apparent distribution volume is about 13.1L/kg.
Biotransformation of methylphenidate is rapid and extensive. Peak plasma concentrations of the main, de-esterified, metabolite, α-phenyl-2-piperidine acetic acid are attained about 2 hours after administration of methylphenidate, and are 30-50 times higher than those of the unchanged substance. The half-life of α-phenyl-2-piperidine acetic acid is about twice that of methylphenidate, and the mean systemic clearance is 0.17L/h/kg.
Only small amounts of hydroxylated metabolites (eg. hydroxymethylphenidate and hydroxyritalinic acid) are detectable. Therapeutic activity seems to be principally due to the parent compound.
Methylphenidate is eliminated from the plasma with a mean half-life of 2 hours. The apparent mean systemic clearance is 10L/h/kg. After oral administration, 78-97% of the dose is excreted in the urine and 1-3% in the faeces in the form of metabolites within 48-96 hours. Only small quantities (<1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as α-phenyl-2-piperidine acetic acid (60-86%).
There are no apparent differences in the pharmacokinetic behaviour of methylphenidate between hyperactive children and normal adults. The elimination data indicate that in patients with normal renal function renal excretion of unchanged methylphenidate would hardly be diminished in the presence of impaired renal function. However, renal excretion of the metabolite α-phenyl-2-piperidine acetic acid may be reduced.
Attention-Deficit Hyperactivity Disorder (ADHD)
ADHD was previously known as attention-deficit disorder or minimal brain dysfunction in children. Other terms used to describe this behavioural syndrome include: hyperkinetic child syndrome, minimal brain damage, minimal cerebral dysfunction, minor cerebral dysfunction and psycho-organic syndrome of children.
Methylphenidate tablets are indicated as part of a comprehensive treatment program which typically includes psychological, education and social measures to stabilise 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 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. Adequate diagnosis requires both medical and special psychological, education, and social resources. 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 symptoms secondary to environmental factors (child abuse in particular) and/or primary psychiatric disorders, including psychosis.
Appropriate educational placement is essential, and psychosocial intervention is generally necessary. When remedial measures alone are insufficient, the decision to prescribe a stimulant depends on the physician's assessment of the duration and severity of the child's symptoms.
Narcolepsy:
Symptoms include daytime sleepiness, inappropriate sleep episodes, and sudden loss of voluntary muscle tone.
The dosage should be adapted to the patient's needs and responses.
Adults: For the treatment of narcolepsy administer in divided doses 2 or 3 times daily. The average daily dose is 20-30mg. Some patients may require 40-60mg daily. In others 10-15mg daily will be adequate. Patients who are unable to sleep if medication is taken late in the day should take the last dose before 6pm.
Children (6 years & over): For the treatment of ADHD, try to time administration to coincide with the periods of greatest academic, behavioural, social difficulties. Start with 5mg once or twice daily (eg. at breakfast and lunch) with gradual increments of 5-10mg weekly. The total daily dosage should be administered in divided doses. Daily doses above 60mg are not recommended.
If symptoms do not improve after dosage adjustment over one month, Methylphenidate tablets should be discontinued. If symptoms worsen or other adverse effects occur, the dosage should be reduced or if necessary discontinued.
In some children sleeplessness occurs because the effect of the medicine wears off in the evening. Such children may then rebound to their usual level of activity or distraction. An additional short acting dose of Methylphenidate tablets at about 8pm, may solve this problem. Give a trial dose at bedtime to clarify the issue.
Methylphenidate tablets should be discontinued periodically to assess the child's condition. Improvement may continue when Methylphenidate tablets are temporarily or permanently discontinued. Treatment should not, and need not, be indefinite. It can usually be discontinued during or after puberty.
Anxiety, tension, agitation, hyperthyroidism, cardiac arrhythmias, severe angina pectoris and glaucoma. Hypersensitivity to methylphenidate. Also contraindicated in patients with motor tics, tics in siblings or with a family history or diagnosis of Tourette's syndrome.
Methylphenidate tablets should not be used in children under 6 years of age, since safety and efficacy in this age group have not been established.
Methylphenidate tablets should not be used as treatment for severe depression of either exogenous or endogenous origin. Clinical experience suggests that in psychotic children administration of Methylphenidate tablets may exacerbate symptoms of behavioural disturbance and thought disorder.
Chronic abuse of Methylphenidate tablets can lead to marked tolerance and psychic dependence with varying degrees of abnormal behaviour. Frank psychotic episodes may occur, especially in response to parental abuse. Available clinical data indicate that treatment with Methylphenidate tablets during childhood does not increase the likelihood of adult addiction.
Treatment with Methylphenidate tablets is not indicated in all cases of Attention-Deficit Hyperactivity disorders, and should be considered only after complete history-taking and evaluation. The decision to prescribe Methylphenidate tablets should depend on the physician's assessment of the duration and severity of symptoms and their appropriateness to the child's age.
Methylphenidate tablets should not be prescribed just because one or more behavioural characteristics is present. When these symptoms are associated with acute stress reactions, treatment with Methylphenidate t ablets is usually not indicated.
Methylphenidate tablets should be used with caution in patients with epilepsy. Clinical experience has shown that a small number of such patients may experience an increase in seizure frequency when treated with Methylphenidate tablets. If seizure frequency rises, Methylphenidate tablets should be discontinued.
Although a casual relationship has not been confirmed, moderately reduced weight gain and slight retardation of growth have been reported with the long term use of stimulants in children.
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.
Use cautiously in patients with hypertension. Blood pressure should be monitored at appropriate levels in all patients taking Methylphenidate tablets, especially those with hypertension.
Data on the safety and efficacy of long term use of Methylphenidate tablets are not complete. Patients requiring long term therapy should therefore be carefully monitored. Periodic complete and differential blood counts and platelet counts are advised during prolonged therapy.
Careful supervision is required during withdrawal, since this may unmask depression as well as the effects of chronic overactivity. Some patients may require long term follow-up.
Use during pregnancy and lactation
There is no evidence of risk to the foetus, but experience during pregnancy is limited. In animal studies, Methylphenidate tablets did not affect reproductive performance or fertility and had no embryotoxic, fetotoxic or teratogenic effects at about 2-5 times the therapeutic dose in humans. Methylphenidate tablets should not be given to pregnant women unless the potential benefit outweighs the risk to the foetus. It is not known whether the active substance of Methylphenidate tablets and/or its metabolites pass into the breast milk. For safety reasons, breast-feeding mothers should not use Methylphenidate tablets.
Effects on ability to drive or use machines:
Because Methylphenidate tablets may cause dizziness and drowsiness, patients should be cautioned not to drive, operate machinery, or engage in other potentially dangerous activities.
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 30 times and 2.5 times the maximum recommended human dose on a mg/kg and mg/m² basis, respectively). There is 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 carcinogenicity 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. On the basis of experience since marketing methylphenidate hydrochloride, there is no evidence that the incidence is higher in patients receiving methylphenidate hydrochloride.
Nervousness and insomnia are the most common adverse reactions. They occur at the beginning of treatment, and can usually be controlled by reducing the dosage and omitting the afternoon or evening dose. Decreased appetite is also common but usually transient.
Estimates from clinical trails and spontaneous ADR reports, classified as follows:
| Classification | Frequency(%) |
|---|---|
| Frequent | >10% |
| Occasional | >1% to 10% |
| Rare | >0.001% to 1% |
| Isolated cases | <0.001% |
Central and peripheral nervous system
Occasional: headache, drowsiness, dizziness, dyskinesia.
Rare: difficulties in visual accommodation and blurred vision.
Isolated cases: hyperactivity, convulsions, muscle cramps, choreoathetoid movements, tics or exacerbation of existing tics and Tourette's syndrome, toxic psychosis (sometimes with visual and tactile hallucinations), transient depressed mood, cerebral arteritis and/or occlusion.
Very rare reports of poorly documented neuroleptic malignant syndrome (NMS) have been received. In most of these reports patients were also receiving other medication. It is uncertain what role methylphenidate hydrochloride played in these cases.
Gastrointestinal tract:
Occasional: abdominal pain, nausea, vomiting. These usually occur at the beginning of treatment and may be alleviated by concomitant food intake. Dry mouth.
Very Rare: abnormal liver function, ranging from transaminase elevation to hepatic coma.
Cardiovascular system:
Occasional: tachycardia, palpitation, arrhythmias, changes in blood pressure and heart rate (usually an increase).
Rare: angina pectoris
Skin and/or hypersensitivity reactions:
Occasional: rash, pruritus, urticaria, fever, arthralgia, alopecia.
Isolated cases: thrombocytopenic purpura, exfoliative dermatitis, erythema multiforme.
Blood:
Isolated cases; leucopenia, thrombocytopenia, anaemia.
Others:
Rare: moderately reduced weight gain and minor retardation of growth during prolonged therapy in children.
Methylphenidate tablets should be used cautiously in patients being tested with pressor agents and MAO inhibitors. Human pharmacological studies have shown that Methylphenidate tablets may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbitone, phenytoin, primidone), phenylbutazone, and tricyclic antidepressants (imipramine, desipramine). The dosage of these medicines may have to be reduced.
Methylphenidate tablets may weaken the antihypertensive effect of guanethidine.
Alcohol may exacerbate the CNS adverse reactions of psychoactive agents, including Methylphenidate tablets. It is therefore advisable for patients to abstain from alcohol during treatment.
Signs and Symptoms:
Signs and symptoms of acute overdosage, mainly due to overstimulation of the central 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.
Treatment:
Treatment consists in providing supportive measures. Protect the patient from self-injury and external stimuli that would aggravate overstimulation already present. If the signs and symptoms are not too severe and the patient is conscious, the stomach can be evacuated by induction of vomiting or gastric lavage. If intoxication is severe, a carefully titrated dose of a short-acting barbiturate should be given before preforming gastric lavage.
Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia. The efficacy of peritoneal dialysis or extracorporeal haemodialysis for overdosage of Methylphenidate tablets has not been established.
Store below 30°C. Protect from light and moisture.
Controlled Drug B2.
10mg tablets: Blister packs of 100 tablets
Methylphenidate Hydrochloride is 2-Piperidineacetic acid, α -phenyl-, methyl ester, hydrochloride. It has a molecular formula and weight of C14H19NO2.HCl and 269.77 respectively.
Other ingredients of the tablets are: microcrystalline cellulose, lactose, pregelatinised maize starch and stearic acid powder.
Douglas Pharmaceuticals Ltd
PO Box 45-027
Auckland 8
New Zealand
Ph: (09) 835-0660
Fax: (09) 835-0665
22 September 1999