Methyl Phenidylacetate

Uses

Attention Deficit Disorders (previously known as Minimal Brain Dysfunction in Children). Other terms being used to describe the behavioral syndrome below include: Hyperkinetic Child Syndrome, Minimal Brain Damage, Minimal Cerebral Dysfunction, Minor Cerebral Dysfunction. Methyl Phenidylacetate is used for 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. Nonlocalizing (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.

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 1 or more of these characteristics. Drug treatment is not used 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.

Methyl Phenidylacetate is also used to associated treatment for these conditions: Attention Deficit Hyperactivity Disorder (ADHD), Narcolepsy

How Methyl Phenidylacetate works

While its exact mechanism is unclear, methylphenidate (MPH) has been shown to act as a norepinephrine and dopamine reuptake inhibitor (NDRI), thereby increasing the presence of these neurotransmitters in the extraneuronal space and prolonging their action. There is a dose-related effect of psychostimulants on receptor stimulation, where higher doses are shown to increase norepinephrine (NE) and dopamine (DA) efflux throughout the brain which can result in impaired cognition and locomotor-activating effects. In contrast, low doses are found to selectively activate NE and DE neurotransmission within the prefrontal cortex which is an area of the brain thought to play a prominent role in ADHD pathophysiology, thereby improving clinical efficacy and preventing side effects. The lower doses used to treat ADHD are not associated with the locomotor-activating effects associated with higher doses and instead reduce movement, impulsivity, and increase cognitive function including sustained attention and working memory. Methyl Phenidylacetate's beneficial effects in sustaining attention have also been shown to be mediated by alpha-1 adrenergic receptor activity.

Clinical findings have shown that children with ADHD have an abnormality in the dopamine transporter gene (DAT1), the D4 receptor gene (DRD-4), and/or the D2 receptor gene that may be at least partly overcome by the dopaminergic effects of methylphenidate, suggesting a possible mode of action.

Dosage

Methyl Phenidylacetate dosage

Adults-

Tablets:Administer in divided doses 2 or 3 times daily, preferably 30 to 45 minutes before meals. Average dosage is 20 to 30 mg daily. Some patients may require 40 to 60 mg daily. In 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.

Sustained release tablets:This tablets have a duration of action of approximately 8 hours. Therefore, Methyl Phenidylacetate sustained release tablets may be used in place of Methyl Phenidylacetate tablets when the 8-hour dosage of Methyl Phenidylacetate sustained release tablets corresponds to the titrated 8 hour dosage of Methyl Phenidylacetate. Methyl Phenidylacetate sustained release tablets must be swallowed whole and never crushed or chewed.

Children (6 Years and Over)-

Methyl Phenidylacetate should be initiated in small doses, with gradual weekly increments. Daily dosage above 60 mg is not recommended. If improvement is not observed after appropriate dosage adjustment over a 1-month period, the drug should be discontinued.

Tablets:Start with 5 mg twice daily (before breakfast and lunch) with gradual increments of 5 to 10 mg weekly.

Sustained release tablets:Methyl Phenidylacetatesustained release tablet have a duration of action of approximately 8 hours. Therefore, Methyl Phenidylacetate sustained release tablet may be used in place of Methyl Phenidylacetate tablets when the 8 hour dosage of Methyl Phenidylacetate sustained release tablet corresponds to the titrated 8 hour dosage of Methyl Phenidylacetate. Methyl Phenidylacetatesustained release tablet must be swallowed whole and never crushed or chewed.

If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug. Methyl Phenidylacetate should be periodically discontinued to assess the child's condition. Improvement may be sustained when the drug is either temporarily or permanently discontinued. Drug treatment should not and need not be indefinite and usually may be discontinued after puberty.

Should be taken on an empty stomach. Take 30-45 min before meals. May be taken with or without food. Swallow whole, do not divide/chew/crush.

Side Effects

Abdominal pain, aggression, alopecia, anorexia, arrhythmias, arthralgia, asthenia, changes in BP, cough, depression, diarrhoea, dizziness, dry mouth, dyspepsia, fever, growth restriction, headache, insomnia, irritability, movement disorders, nasopharyngitis, nausea, nervousness, palpitation, pruritus, rash, wt loss, tachycardia, tics, vomiting, confusion, abnormal dreams, constipations, dyspnoea, epistaxis, muscle cramps, suicidal ideation, urinary frequency. Rarely, angina, sweating, visual disturbances, cerebral arteritis, blood disorders, angle-closure glaucoma, seizures, tolerance, MI. Transdermal: Insomnia, decreased appetite; nausea; tic, emotional instability; vomiting, anorexia; nasal congestion, nasopharyngitis; wt loss.

Toxicity

Symptoms of overdose include 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. LD₅₀=190mg/kg (orally in mice)

Precaution

Patient with history of seizure disorder, alcohol or drug abuse. HTN and other CV disorders that might be exacerbated by increases in BP or heart rate; pre-existing psychosis or bipolar disorder. Childn. Pregnancy and lactation.

Food Interaction

• Avoid alcohol. Co-administration with alcohol may cause a "dose-dumping" effect with some extended-release formulations of methylphenidate. It may also potentiate the CNS effects of methylphenidate.
• Take with or without food. Patients may take methylphenidate with food to alleviate GI upset.

[Moderate] GENERALLY AVOID: Alcohol may exacerbate the adverse central nervous system effects of psychoactive drugs, including methylphenidate.

GENERALLY AVOID: Consumption of alcohol while taking certain sustained-release formulations of methylphenidate may cause rapid release of the drug, resulting in increased systemic levels of methylphenidate.

In vitro studies have been conducted using Metadate CD 60 mg and Ritalin LA 40 mg capsules, as well as Concerta 18 mg tablet.

At an alcohol concentration of 40%, an increase in the release rate of methylphenidate was observed in the first hour for Metadate CD and Ritalin LA, resulting in 84% and 98% of the methylphenidate being released, respectively.

In contrast, there was no increased release of methylphenidate in the first hour for Concerta.

These results are considered to be representative of the other available strengths of the corresponding product.

MANAGEMENT: Patients treated with methylphenidate should be advised to avoid alcohol or medications that contain alcohol.

Methyl Phenidylacetate Hypertension interaction

[Major] The use of CNS stimulants is contraindicated in patients with significant cardiovascular impairment such as uncompensated heart failure, severe coronary disease, severe hypertension (including that associated with hyperthyroidism or pheochromocytoma), cardiac structural abnormalities, serious arrhythmias, etc.

Sudden death has been reported in adults and children taking CNS stimulant treatment.

Additionally, stroke, myocardial infarction, chest pain, syncope, arrhythmias and other symptoms have been reported in adults under treatment.

A careful assessment of the cardiovascular status should be done in patients being considered for treatment.

This includes family history, physical exam and further cardiac evaluation (EKG and echocardiogram).

Patients who develop symptoms should have a detailed cardiac evaluation and if needed, treatment should be suspended.

[Major] CNS stimulant medications have shown to increase blood pressure, and their use might be contraindicated in patients with severe hypertension.

Caution should be used when administering to patients with preexisting high blood pressure and other cardiovascular conditions.

All patients under treatment should be regularly monitored for changes in blood pressure and heart rate.

[Major] Methyl Phenidylacetate (racemic) and dexmethylphenidate (the more pharmacologically active d-enantiomer) exhibit sympathomimetic activity and may elevate blood pressure and pulse rate.

Therapy with these agents should be administered cautiously in patients with hypertension.

Blood pressure should be monitored periodically during therapy.

Methyl Phenidylacetate Drug Interaction

Major: bupropionModerate: escitalopram, fluoxetine, sertralineUnknown: aripiprazole, amphetamine / dextroamphetamine, amphetamine / dextroamphetamine, diphenhydramine, duloxetine, omega-3 polyunsaturated fatty acids, lamotrigine, pregabalin, quetiapine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, lisdexamfetamine, alprazolam, cetirizine

Methyl Phenidylacetate Disease Interaction

Major: agitation, cardiac disease, glaucoma, hypertension, liver disease, psychiatric disorders, substance abuse, tics, hypertension, seizures disordersModerate: bipolar disorders, psychotic disorders, renal dysfunction, seizure disorders, hematologic toxicity, GI narrowing

Volume of Distribution

Concerta: Plasma methylphenidate concentrations in adults decline bi-exponentially following oral administration.

Biphentin: The apparent distribution volume of methylphenidate in children is approximately 20 L/kg, with substantial variability (11 to 33 L/kg).

Methyl Phenidylacetate (immediate release): The apparent distribution volume of methylphenidate in children was approximately 20 L/kg, with substantial variability (11-33 L/kg). The volume of distribution after an intravenous dose (Vss) is 2.23 L/kg for the racemate in healthy adult volunteers.

Elimination Route

Concerta®: Methyl Phenidylacetate is readily absorbed. Following oral administration of Concerta, plasma methylhphenidate concentrations reach an initial maximum at about 1 hour followed by gradual ascending concentrations over the next 5-9 hours. Mean times to reach peak plasma concentrations across all doses of Concerta occurred between 6-10 hours. Once daily dosing minimizes the fluctuations between peak and trough concentrations associated with multiple doses of immediate-release methylphenidate treatments. Depending on the doses provided, Cmax was found to range from 6.0-15.0ng/mL, Tmax ranged from 8.1-9.4h, and AUC ranged from 50.4-121.5 ng·h/mL in children.

When provided as Concerta®, methylphenidate is released through the patented Osmotic Controlled-Release Oral Delivery (OROS) system where 22% of the dose is provided as an immediate release and 78% is provided through a gradual release. OROS is comprised of an osmotically active trilayer core surrounded by a semipermeable membrane with an immediate-release drug overcoat. Within an aqueous environment, such as the stomach, the drug overcoat, which consists of 22% of the dose, dissolves within one hour, providing an initial immediate-release formulation of methylphenidate. Water then permeates through the membrane into the tablet core where the osmotically active polymer excipients expand, allowing methylphenidate to release slowly through the orifice over a period of 6-7 hours. Concerta also provides a sustained 10-12 hour effect, allowing for once-daily dosing.

Biphentin®: Methyl Phenidylacetate is rapidly and extensively absorbed following oral administration, with peak blood levels obtained in 1-3 hours.

When provided as Biphentin®, methylphenidate is released through a multi-layer release delivery system (MLRTM) where 40% of the dose is provided as an immediate release and 60% is provided through a gradual release. Biphentin was designed to be an alternative to separate doses of immediate-release (IR) methylphenidate by providing a biphasic concentration-time profile when given as a single dose. The MLRTM release system allows for a sustained effect for 10-12 hours, allowing for once-daily dosing that covers the major times that ADHD impairment might occur (such as school, homework periods, during the workday, etc).

Methyl Phenidylacetate (immediate release): Methyl Phenidylacetate hydrochloride 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 (11-52%). In one study, the administration of methylphenidate hydrochloride 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. Peak plasma concentrations showed marked variability between subjects. Both the area under the concentration-time curve (AUC), and the peak plasma concentrations (Cmax) showed dose-proportionality.

Half Life

Concerta: The half-life of methylphenidate in adults following oral administration of Concerta® was approximately 3.5 h.

Biphentin: Methyl Phenidylacetate is eliminated from plasma with a mean half-life of 2.4 hours in children and 2.1 hours in adults.

Methyl Phenidylacetate (immediate release): Methyl Phenidylacetate is eliminated from the plasma with a mean half-life of 2.4 hours in children and 2.1 hours in adults.

Clearance

The apparent mean systemic clearance after an oral dose is 10.2 and 10.5 L/h/kg in children and adults, respectively for a 0.3 mg/kg dose, and 0.565 L/h/kg after an intravenous dose of the racemate in healthy adult volunteers.

Elimination Route

After oral administration of an immediate release formulation of methylphenidate, 78%-97% of the dose is excreted in the urine and 1%-3% in the feces 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 ritalinic acid (60%-86%), the remainder being accounted for by minor metabolites.

Pregnancy & Breastfeeding use

Pregnancy Category C. Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Contraindication

History of marked anxiety, tension, agitation; glaucoma; hyperthyroidism; anorexia; phaeochromocytoma; tics or family history or diagnosis of Tourette's syndrome. Pre-existing CV disorders (e.g. severe HTN, heart failure, angina, MI, arrhythmia); aneurysm; vascular abnormalities. Concomitant or within 14 days of MAOI use.

Acute Overdose

Symptoms: Vomiting, tremor, agitation, muscle twitching, hyperpyrexia, hallucinations, euphoria, confusions, delirium, sweating, flushing, headache, HTN, dryness of mucous membranes, tachycardia, mydriasis, palpitations.

Management: Symptomatic and supportive treatment.

Storage Condition

Store between 20-25° C. Protect from light and moisture.

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