Pharmacology
CNS Stimulant
Methylphenidate is a mild CNS stimulant.
The mode of action in man is not completely understood, but methylphenidate presumably activates the brain stem arousal system and cortex to produce its stimulant effect.
There is neither specific evidence which clearly establishes the mechanism whereby methylphenidate produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the CNS.
Methylphenidate is rapidly and extensively absorbed from the tablets following oral administration; however, owing to extensive first-pass metabolism, bioavailability is low (approx. 30%) and large individual differences exist (11 to 52%).
In one study, the administration of methylphenidate with food accelerated absorption, but had no effect on the amount absorbed.
Peak plasma concentrations of 10.8 and 7.8 ng/mL were observed, on average, 2 hours after administration of 0.30 mg/kg in children and adults, respectively. However, peak plasma concentrations showed marked variability between subjects. Both the area under the plasma concentration curve (AUC), and the peak plasma concentrations (C(max)) showed dose-proportionality.
Methylphenidate is eliminated from the plasma with a mean half-life of 2.4 hours in children and 2.1 hours in adults. The apparent mean systemic clearance is 10.2 and 10.5 L/hr/kg in children and adults, respectively for a 0.3 mg/kg dose. These data indicate that the pharmacokinetic behavior of methylphenidate in hyperactive children is similar to that in normal adults. The apparent distribution volume of methylphenidate in children was approximately 20 L/kg, with substantial variability (11 to 33 L/kg).
Following oral administration of methylphenidate, 78 to 97% of the dose is excreted in the urine and 1 to 3% in the feces in the form of metabolites within 48 to 96 hours. The main urinary metabolite is ritalinic acid (alpha-phenyl-2-piperidine acetic acid, PPAA); unchanged methylphenidate is excreted in the urine in small quantities (<1%). Peak PPAA plasma concentrations occurred at approximately the same time as peak methylphenidate concentrations, however, levels were several-fold greater than those of the unchanged drug. The half-life of PPAA was approximately twice that of methylphenidate.
In blood, methylphenidate and its metabolites are distributed between plasma (57%) and erythrocytes (43%). Methylphenidate and its metabolites exhibit low plasma protein binding (approx. 15%).
Methylphenidate in the extended-release tablets is more slowly but as extensively absorbed as in the regular tablets. Relative bioavailability of the Ritalin SR tablet, compared to the Ritalin tablet, measured by the urinary excretion of the methylphenidate major metabolite (PPAA), was 105% (49 to 168%) in children and 101% (85% to 152%) in adults. The time to peak rate in children was 4.7 hours (1.3 to 8.2 hours) for the extended-release tablets and 1.9 hours (0.3 to 4.4 hours) for the regular tablets. The elimination half-life and the cumulative urinary excretion of PPAA are not significantly different between the two dosage forms. An average of 67% of the extended-release tablet dose was excreted in children as compared to 86% in adults.
Indications
Attention-Deficit Hyperactivity Disorder (ADHD), previously known as Attention-Deficit Disorder. Other terms being used to describe this behavioral syndrome include: minimal Brain Dysfunction in Children, Hyperkinetic Child Syndrome, Minimal Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction.
Methylphenidate is indicated as an integral part of a total treatment program which typically includes other remedial measures (psychological, educational, social) for a stabilizing effect in children with a behavioral syndrome characterized by the following group of developmentally inappropriate symptoms: moderate-to-severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. The diagnosis of this syndrome should not be made with finality when these symptoms are only of comparatively recent origin. Non-localizing (soft) neurological signs, learning disability, and abnormal EEG may or may not be present, and a diagnosis of CNS dysfunction may or may not be warranted.
Special Diagnostic Considerations:
Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational and social resources.
Characteristics commonly reported include:
Chronic 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 for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors 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 stimulant medication will depend upon the physician's assessment of the chronicity and severity of the child's symptoms.
Narcolepsy.
Contraindications
Anxiety, tension, agitation, thyrotoxicosis, tachyarrhythmias, severe angina pectoris and glaucoma. Hypersensitivity to methylphenidate. Also contraindicated in patients with motor tics or with a family history or diagnosis of Tourette's syndrome.
Warnings
Methylphenidate should not be used in children under 6 years of age, since safety and efficacy in this age group have not been established.
Although a causal relationship has not been established, suppression of growth (i.e. weight gain and/or height) has been reported with the long-term use of stimulants in children. Therefore, patients requiring long-term therapy should be carefully monitored. In addition, the use of "Drug Holidays" is recommended, that is, withholding the drug on weekends and during school holidays in as much as the clinical situation permits.
Methylphenidate should not be used for severe depression of either exogenous or endogenous origin. Clinical experience suggests that in psychotic children, administration of methylphenidate may exacerbate symptoms of behavior disturbance and thought disorder.
Methylphenidate should not be used for the prevention or treatment of normal fatigue states.
There is some clinical evidence that methylphenidate may lower the convulsive threshold in patients with prior history of seizures, with prior EEG abnormalities in absence of seizures and, very rarely, in patients with no prior EEG evidence nor history of seizures. Safe concomitant use of anticonvulsants and methylphenidate has not been established. In the presence of seizures, the drug should be discontinued.
Use cautiously in patients with hypertension. Blood pressure should be monitored at appropriate intervals in all patients taking methylphenidate, especially those with hypertension.
Pregnancy:
Adequate animal reproduction studies to establish safe use of methylphenidate during pregnancy have not been conducted. Therefore, until more information is available, the use of methylphenidate in pregnancy is not recommended.
Lactation:
It is not known whether the active substance of methylphenidate and/or its metabolites pass into breast milk. For safety reasons, mothers taking methylphenidate should refrain from breast feeding their infants.
Drug Dependence:
Methylphenidate should be given cautiously to emotionally unstable patients, such as those with a history of drug dependence or alcoholism, because such patients may increase dosage on their own initiative.
Chronically abusive use can lead to marked tolerance and psychic dependence with varying degrees of abnormal behavior. Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during drug withdrawal, since severe depression as well as the effects of chronic overactivity can be unmasked. Long-term follow-up may be required because of the patient's basic personality disturbances.
Available clinical data indicate that treatment with methylphenidate during childhood and/or adolescence does not seem to result in increased predisposition for addiction.
Precautions
Patients with an element of agitation may react adversely; discontinue therapy if necessary.
Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
Drug treatment is not indicated in all cases of Attention Deficit Hyperactivity Disorders and should be considered only in light of the complete history and evaluation of the child. The decision to prescribe methylphenidate should depend on the physician's assessment of the chronicity and severity of the child's symptoms and their appropriateness for his/her age. Prescription should not depend solely on the presence of one or more of the behavioral characteristics. When these symptoms are associated with acute stress reactions, treatment with methylphenidate is usually not indicated.
Long-term effects of methylphenidate in children have not been well established.
Occupational Hazards:
Because methylphenidate may affect performance, patients should be cautioned against engaging in hazardous activities such as operation of automobiles or dangerous machinery.
Drug Interactions:
Methylphenidate may decrease the hypotensive effect of guanethidine. Use cautiously with pressor agents and MAO inhibitors.
Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone and tricyclic antidepressants (imipramine, desipramine). Downward dosage adjustments of these drugs may be required when given concomitantly with methylphenidate.
Adverse Effects
Nervousness and insomnia are the most common adverse reactions reported with methylphenidate but are usually controlled by reducing dosage and omitting the drug in the afternoon or evening. Decreased appetite is also common but usually transient.
Central and Peripheral Nervous System:
Dizziness, drowsiness, headache, and dyskinesia may occur. Isolated cases of the following have been reported: hyperactivity, convulsions, muscle cramps, choreo-athetoid movements, tics, or exacerbation of pre-existing tics, Tourette's syndrome, and psychotic episodes including hallucinations which subsided when methylphenidate was discontinued. Psychic dependence in emotionally unstable persons has occurred rarely with chronic treatment. Although a definite causal relationship has not been established, isolated cases of transient depressed mood have been reported.
Symptoms of visual disturbances have been encountered in rare cases. Difficulties with accommodation and blurring of vision have been reported.
Gastrointestinal:
Nausea and abdominal pain may occur at the start of treatment and may be alleviated if taken with food.
Cardiovascular:
Palpitations, blood pressure and pulse changes (both up and down), tachycardia, angina and cardiac arrhythmias.
Skin and/or Hypersensitivity:
Rash, pruritus, urticaria, fever, arthralgia, and alopecia. Isolated cases of exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura.
Hematologic:
Isolated cases of leukopenia, thrombocytopenia and anemia.
Other:
Weight loss during prolonged therapy.
In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed above may also occur. Minor retardation of growth may also occur during prolonged therapy in children (see Warnings).
Overdose
Symptoms:
Signs and symptoms of acute overdosage, resulting principally from CNS overstimulation and from excessive sympathomimetic effects, may include the following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, mydriasis and dryness of mucous membranes.
Treatment:
Appropriate supportive measures. The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present. If signs and symptoms are not too severe and the patient is conscious, gastric contents may be evacuated by induction of emesis or gastric lavage. In the presence of severe intoxication, use a carefully titrated dosage of short-acting barbiturate before performing gastric lavage.
Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for hyperpyrexia.
Efficacy of peritoneal dialysis or extracorporeal hemodialysis for methylphenidate overdosage has not been established.
Dosage
Dosage should be individualized according to the needs and responses of the patient.