INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
ADAPHEN 5 (TABLETS)
ADAPHEN 10 (TABLETS)
ADAPHEN XL (TABLETS)

SCHEDULING STATUS:
S6

PROPRIETARY NAME
(and dosage form):

ADAPHEN 5 (TABLETS)
ADAPHEN 10 (TABLETS)
ADAPHEN XL (TABLETS)

COMPOSITION
Each tablet contains Methylphenidate 5 mg or 10 mg and sustained release tablets contain 20 mg Methylphenidate hydrochloride.

PHARMACOLOGICAL CLASSIFICATION
A 1.2 Psychoanaleptics (antidepressants)

PHARMACOLOGICAL ACTION
Methylphenidate is a piperidine derivative that is structurally related to amphetamine and exerts a stimulant effect on the central nervous system with more prominent effects on mental than on motor activities.
Pharmacokinetics
Methylphenidate hydrochloride is absorbed after oral administration and reaches peak concentrations in plasma in about 2 hours.
The peak plasma concentrations, however, vary markedly from one patient to another. Due to extensive first-pass metabolism, its systemic availability amounts to only 30% of the dose.
The simultaneous ingestion of food accelerates its absorption, but has no influence on the amount absorbed.
The area under the plasma concentration curve (AUG), as well as the peak plasma concentration, are proportional to the size of the dose administered.
In the blood methylphenidate and its metabolites are distributed 57% in plasma and 43% in the erythrocytes.
The plasma protein-binding of methylphenidate and its metabolites are low (10 —33%) with an apparent distribution volume calculated as 13,1 liter/kg.
Methylphenidate is eliminated from the plasma with mean half-life of 2 hours; the calculated mean systemic clearance is 10 litres/h.kg^-1. 78 to 97% of the administered dose is excreted in the urine and 1 to 3% is excreted in the faeces in the form of metabolites within 48 to 96 hours.
The bulk of the dose (60 to 86%) is excreted in the urine as 2-phenyl-2-piperidyl acetic acid (PPAA) while less than 1% of unchanged methylphenidate appears in the urine. PPAA reaches peak plasma concentrations approximately 2 hours after administration of methylphenidate. The peak plasma concentrations are 30 to 50 times higher than those of the unchanged methylphenidate.
The half-life of PPAA is approximately twice as long as that of methylphenidate, and the mean systemic clearance is 0,17 litres/h.kg^-1.
There are no apparent differences in the pharmacokinetic behaviour of methylphenidate in hyperactive children and normal adults.
Impaired renal function hardly decreases the renal excretion of the unchanged methylphenidate, however, renal excretion of PPAA is reduced.
Pharmacokinetics of ADAPHEN XL Tablets
Due to the slower absorption of methylphenidate from ADAPHEN XL tablets than from the conventional tablets, the fluctuation in plasma concentrations is much smaller. The maximum plasma concentration (Cmax) is approximately 40% lower and is reached about 3 hours later. The total amount absorbed (AUC) is however the same.
The consumption of a high-fat content meal influences the pharmacokinetic parameters of ADAPHEN XL. The total amount absorbed (by 25%) and the maximum plasma concentration (by 27%) are significantly higher, although the rate at absorption (Cmax/AUC ratio) remains the same. Time to reach the maximum concentration (Tmax) is also slightly faster after a high-fat content meal (Tmax is approximately 2,5 hr) as compared to without food (approximately Tmax: 3,0 hr).

INDICATIONS
Attention deficit hyperactivity disorder (ADHD).
Narcolepsy.

CONTRA-INDICATIONS

-	Known hypersensitivity to methylphenidate.
-	Anxiety, tension, agitation, hyperexcitability
-	Tics, tics in siblings.
-	A family history or diagnosis of Tourette’s syndrome
-	Extrapyramidal disorders
-	Hyperthyroidism
-	Cardiovascular disorders including moderate to severe hypertension, cardiac arrhythmias and severe angina pectoris
-	Glaucoma.
-	Methylphenidate should not be given to patients being treated with mono-amine oxidase inhibitors or within 14 days of stopping the treatment thereof.
-	Patients with a history of drug abuse.
-	Pregnancy and lactation.

WARNINGS
Methylphenidate should not be administered to patients suffering from depression or in children less than six years of age. It should not be used for the prevention or treatment of normal fatigue states.
The administration of Methylphenidate may exacerbate the symptoms of behavioural disturbance and thought disorder in psychotic patients.
Methylphenidate should be used with caution in the following patients:

-	Epileptic patients: Clinical experience has shown that a small number of epileptic patients may experience an increase in seizure frequency when treated with methylphenidate. If seizure frequency increases, methylphenidate should be discontinued.
-	Hypertensive patients: Blood pressure should be monitored at appropriate intervals in all patients taking methylphenidate, especially in those with hypertension.
-	Patients with kidney impairment.

Chronic abuse of methylphenidate can lead to marked tolerance and psychic dependence with varying degrees of abnormal behaviour. Frank psychotic episodes may occur. Methylphenidate may be abused by predisposed patients, e.g. in emotionally unstable individuals or those with a history of drug dependence or alcoholism. It should therefore be used only under very strict medical supervision.

DOSAGE AND DIRECTIONS FOR USE
ADAPHEN is part of a comprehensive treatment programme for attention deficit hyperactivity disorder which includes psychological, educational and social remedial measures.
The dosage should be individually adapted to the patient’s requirements and to the indication.
Adults
In the treatment of narcolepsy, the usual dosage is 20 mg to 30 mg daily, taken preferably 30 to 45 minutes before a meal. The effective dose may range from 10 mg to 60 mg in divided doses.
To obviate the risk of insomnia, the last dose should be taken not later than 6 pm.
XL TABLETS: ADAPHEN XL tablets has a duration of action of approximately 8 hours. Therefore, ADAPHEN XL tablets may be used in place of ADAPHEN tablets when the 8-hour dosage of ADAPHEN XL corresponds to the titrated 8-hour dosage of ADAPHEN. ADAPHEN XL must be swallowed whole and never crushed or chewed.
The recommended dosage is 20 mg one to three times daily at eight-hour intervals.
Children 6 years and older
The starting dose should be 5 mg before breakfast and 5 mg before lunch, the daily dosage subsequently being raised by 5 mg to 10 mg each week to a level not higher than 60 mg per day.
The total daily dosage should be administered in divided doses.
The dosage can also be expressed in terms of body weight; usual doses are 0.25 mg per kg daily, doubled each week to 2 mg per kg.
XL TABLETS: ADAPHEN XL tablets has a duration of action of approximately 8 hours. Therefore, ADAPHEN XL tablets may be used in place of ADAPHEN tablets when the 8-hour dosage of ADAPHEN XL corresponds to the titrated 8-hour dosage of ADAPHEN. ADAPHEN XL must be swallowed whole and never crushed or chewed.
The recommended dosage is 20 mg one to three times daily at eight-hour intervals. If a paradoxical increase in the symptoms occurs, the dosage should be reduced or the medication withdrawn.
Methylphenidate’s administration should coincide with periods of greatest academic, behavioural, and social difficulties for the patient.
Note: If improvement of symptoms is not observed after appropriate dosage adjustment over a one-month period, the medicine should be discontinued.
In case of aggravation of symptoms or other adverse effects, the dosage should be reduced or, if necessary, the medicine discontinued.
In some children sleeplessness occurs because the effect of the medicine deteriorates in the evening. Such children may then rebound to their usual level of activity or distraction. This problem may be dealt with by adminestering an additional short-acting dose of the stimulant at about 8 pm. A trial dose at bedtime is necessary to clarify the issue.
ADAPHEN should be periodically discontinued to assess the child’s condition. Improvement may be sustained when the medicine is either temporarily or permanently discontinued.
Treatment with ADAPHEN should not and need not be indefinite and usually may be discontinued during or after puberty.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Central and peripheral nervous system
Common adverse reactions are nervousness, insomnia and a decreased appetite. Nervousness and insomnia usually occur at the beginning of the treatment and may be controlled by reducing the dose and omitting the medicine in the afternoon or evening. The decrease in appetite is usually a transient feature.
The following adverse reactions may also occur:

-	Night terrors.
-	Headache, irritability, euphoria, drowsiness, dizziness and dyskinesia.
-	Difficulties in accommodation and blurring of vision.

The following side-effects occur less frequently:

-	Hyperactivity.
-	Convulsions, muscle cramps, choreo-athetoid movements, tics, or exacerbation of pre-existing tics
-	Tourette’s syndrome.
-	Toxic psychosis (some with visual and tactile hallucinations), depressed mood, cerebral arteritis and/or occlusion.

Gastro-intestinal tract
Abdominal pain, nausea and vomiting usually occur at the beginning of treatment and may be reduced by concomitant food intake.
Sweating and dry mouth.
Cardiovascular system
Tachycardia, palpitation, arrhythmia, changes in blood pressure and heart rate (usually an increase), angina pectoris.
Skin and/or hypersensitivity reactions
Rash, pruritis, urticaria, thrombocytopenic purpura, exfoliative dermatitis and erythema multiforme.
Fever, arthralgia and alopecia.
Blood
Leucopenia, thrombocytopenia and anaemia.
Other
Altered libido and impotence.
Special Precautions
Prolonged methylphenidate therapy may cause reduced mass gain and retardation of growth in stature in children.
During withdrawal of the medication, mental depression as well as the effects of chronic over-activity can be exposed. Careful supervision is thus required during withdrawal of methylphenidate. Long-term follow-up may be needed for some patients. Treatment with methylphenidate is not indicated in all cases of hyperkinetic behavioural disorders and should be considered only in light of the complete history and evaluation of the child.
Prescription of ADAPHEN should not depend solely on the presence of isolated behavioural characteristics; the decision to prescribe ADAPHEN should depend on the physician’s assessment of the chronicity and severity of the child’s symptoms and their appropriateness to his or her age.
ADAPHEN is usually not indicated when the symptoms are associated with acute stress reactions.
ADAPHEN may cause dizziness and drowsiness. It is therefore advisable to exercise caution when driving, operating machines or engaging in other potentially hazardous activities.
Safety and efficacy data pertaining to the long-term use of ADAPHEN are not complete and patients requiring long-term therapy should therefore be carefully monitored. Periodic complete blood counts, differential and platelet count are advisable during prolonged therapy.

Interactions
Methylphenidate may decrease the antihypertensive effect of guanethidine and it should be used cautiously with pressor agents including beta-blockers.
Methylphenidate may inhibit the metabolism of the following medications and downward dosage adjustment of these medications may be required when they are given concomitantly:

-	Coumarin anticoagulants
-	Anticonvulsants (phenobarbitone, phenytoin, primidone)
-	Phenylbutazone and tricyclic antidepressants (imipramine, desipramine).

Alcohol may exacerbate the CNS adverse reactions of psychoactive drugs, including methylphenidate. It is advisable for patients to abstain from alcohol during treatment. Urinary excretion may be reduced by urinary alkalinisers, which may enhance or prolong the effect of methylphenidate; excretion may be increased by urinary acidifiers.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Signs and symptoms
Agitation, cardiac arrhythmias, confusion, delirium, panic states, dryness of mouth or mucous membranes, euphoria, fever, hallucinations, headache, hyperreflexia, increased blood pressure, chest pain, respiratory depression, increased sweating. flushing, muscle twitching, mydriasis, palpitations, seizures/convulsions (may be followed by coma), tachycardia, trembling or tremors, vomiting, circulatory collapse and coma.
Individual patient response may vary widely and toxic manifestations may occur at relatively low doses.
Treatment
Treatment consists of appropriate supportive measures with the possible utilization of the following:
The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present.
If the signs and symptoms are not too severe and the patient is conscious, gastric contents may be emptied by emesis or gastric lavage.
For a severe overdose, a short-acting barbiturate should be administered using carefully titrated dosage before performing gastric lavage.
Maintain adequate circulatory and respiratory function.
External cooling procedures may be required for hyperpyrexia.
Efficacy of peritoneal dialysis or extracorporeal haemodialysis for overdosage of methylphenidate has not been established.

IDENTIFICATION
ADAPHEN 5: Round, purple tablets, imprinted “DAN 5”and “5882”.
ADAPHEN 10: Scored, round, green tablets, imprinted “DAN 10”and “5883”.
ADAPHEN XL: Oval, white to off-white mottled tablets, imprinted “DAN”and “A51”.
Note: Upon exposure to higher temperatures than the recommended storage instructions, a slight discolouration of the 5 mg tablets (purple to pinkish purple) and of the 10 mg (slight yellowing of the green colour) may occur.

PRESENTATION
ADAPHEN 5: White plastic containers with a white cap containing 30 tablets.
ADAPHEN 10: White plastic containers with a white cap containing 30 tablets.
ADAPHEN XL: White HDPE containers with a white screw cap with an integral plug
with or without child resistant closure in pack size of 30’s.

STORAGE INSTRUCTIONS
Store below 25° C in a well closed container. Protect from light and moisture.
KEEP OUT OF REACH OF CHILDREN

REGISTRATION NUMBER
ADAPHEN 5: 33/1.2/0442
ADAPHEN 10: 33/1.2/0443
ADAPHEN XL: 36/1.2/0040

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Triomed (Pty) Ltd.
Building 12
Healthcare Park
Woodlands Drive
Woodmead
Sandton
2148

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
27 May 2004

574939/040701

New addition to this site: January 2006
Source: Pharmaceutical Industry
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