Methylphenidate Hydrochloride (Page 4 of 7)

8.5 Geriatric Use

Clinical trials of Methylphenidate Hydrochloride Extended-Release Capsules did not include any patients aged 65 years and over. In general, dose selection for an elderly patient start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Methylphenidate Hydrochloride Extended-Release Capsules contains methylphenidate a Schedule II controlled substance.

9.2 Abuse

CNS stimulants including Methylphenidate Hydrochloride Extended-Release Capsules, other methylphenidate-containing products, and amphetamines have a high potential for abuse. Abuse is characterized by impaired control over drug use despite harm, and craving.

Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, suicidal or homicidal ideation have also been observed. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which can result in overdose and death [see Overdosage (10)].

To reduce the abuse of CNS stimulants including Methylphenidate Hydrochloride Extended-Release Capsules, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records, educate patients and their families about abuse and on proper storage and disposal of CNS stimulants, monitor for signs of abuse while on therapy, and re-evaluate the need for Methylphenidate Hydrochloride Extended-Release Capsules use.

9.3 Dependence

Tolerance

Tolerance (a state of adaptation in which exposure to a drug results in a reduction of the drug’s desired and/or undesired effects over time) can occur during chronic therapy with CNS stimulants including Methylphenidate Hydrochloride Extended-Release Capsules.

Dependence

Physical dependence (a state of adaptation manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist) can occur in patients treated with CNS stimulants including Methylphenidate Hydrochloride Extended-Release Capsules. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include extreme fatigue and depression.

10 OVERDOSAGE

10.1 Signs and Symptoms

Signs and symptoms of acute methylphenidate overdose, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: nausea, vomiting, diarrhea, restlessness, anxiety, agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, hypotension, tachypnea, mydriasis, dryness of mucous membranes, and rhabdomyolysis.

10.2 Management of Overdose

Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice on the management of overdosage with methylphenidate. Provide supportive care, including close medical supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosages. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures.

Gastric contents may be evacuated by gastric lavage as indicated. Before performing gastric lavage, control agitation and seizures if present and protect the airway. Other measures to detoxify the gut include administration of activated charcoal and a cathartic. Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for pyrexia.

11 DESCRIPTION

Methylphenidate Hydrochloride Extended-Release Capsules contains methylphenidate hydrochloride, a central nervous system (CNS) stimulant. Methylphenidate Hydrochloride Extended-Release Capsules contain multi layered beads, which are composed of an immediate-release layer which contains approximately 40% of the methylphenidate dose, and a controlled release layer which contains approximately 60% of the methylphenidate dose. Methylphenidate Hydrochloride Extended-Release Capsules is available in seven capsule strengths. Each extended-release capsule for once-a-day oral administration contains 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, or 60 mg of methylphenidate HCl USP, which is equivalent to 8.6 mg, 13.0 mg, 17.3 mg, 25.9 mg, 34.6 mg, 43.2 mg, or 51.9 mg of methylphenidate free base, respectively. Chemically, methylphenidate HCl is d,l (racemic) methyl α-phenyl-2-piperidineacetate hydrochloride. Its molecular formula is C14 H19 NO2 ∙HCl. Its structural formula is:

Chemical Structure

Methylphenidate hydrochloride USP is a white to off-white, odorless, fine crystalline powder. Its solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77.

Inactive Ingredients: ammonio methacrylate copolymer, type B; colloidal silicon dioxide (added if necessary); gelatin; hypromelloses; methacrylic acid copolymer, type C; polyethylene glycol; sugar spheres; talc; titanium oxide; and triethyl citrate.

Each strength capsule also contains colorant ingredients in the capsule shell as follows:

10 mg: FD&C Blue No. 1
15 mg: D&C Red No. 28, D&C Yellow No. 10, FD&C Red No. 40
20 mg: D&C Red No. 33, D&C Yellow No. 10
30 mg: FD&C Blue No. 1, FD&C Red No. 3
40 mg: D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40
50 mg: D&C Yellow No. 10, FD&C Green No. 360 mg: Black Iron Oxide

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Methylphenidate HCl is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD is not known.

12.2 Pharmacodynamics

Methylphenidate is a racemic mixture comprised of the d- and l- isomers. The d- isomer is more pharmacologically active than the l- isomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

12.3 Pharmacokinetics

Absorption

Following oral administration of Methylphenidate Hydrochloride Extended-Release Capsules in adults, plasma methylphenidate concentrations increase rapidly, reaching an initial maximum at about 2 hours, followed by gradual descending concentrations over the next 4 to 6 hours, after which a gradual increase begins, reaching a second peak at approximately 8 hours (Figure 1). The relative bioavailability of Methylphenidate Hydrochloride Extended-Release Capsules given once daily as compared to a methylphenidate immediate-release oral product given three times daily in adults is comparable. The relative bioavailability is 102%.

The pharmacokinetic profiles and parameters of methylphenidate are similar when Methylphenidate Hydrochloride Extended-Release Capsules is administered either as a whole capsule or sprinkled onto applesauce in subjects under fasting conditions (see Table 2 and Figure 1).

Table 2: The Single Dose Pharmacokinetics of d,l-Methylphenidate * ER Capsule and Sprinkle following an Oral Dose of 80 mg Methylphenidate Hydrochloride Extended-Release Capsules under Fasted Conditions in Healthy Adults
Pharmacokinetic ParametersCapsuleSprinkle
*
d,l (racemic) methylphenidate HCl
Cmax , AUC (0-t) AUC (0-inf) presented as mean ± SD
data presented as median (range)
Cmax (ng/mL)23.47 ± 11.4 21.78 ± 9.5
AUC(0-t) (ng.hr/mL)262.7 ± 135 262.9 ± 128
AUC(0-inf ) (ng.hr/mL)258.1 ± 94.2 258.0 ± 84.4
Tmax (hr) 2.0 2.0
Half-life (hr) 5.09 5.43
Relative bioavailability 102% 101%

Figure 1: Mean d,l -Methylphenidate Plasma Concentration-Time Profiles following 80 mg Administered as Capsule and Sprinkle Dose in Healthy Adults

Figure 1
(click image for full-size original)

Metabolism and Excretion

In humans, methylphenidate is metabolized primarily via deesterification to alpha-phenyl-piperidine acetic acid (PPAA). The metabolite has little or no pharmacologic activity.

After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose.

Food Effects

Administration of Methylphenidate Hydrochloride Extended-Release Capsules with high fat meal showed a decreased or diminished second peak. A high-fat meal also increased the average Cmax of methylphenidate by about 28% and the AUC by about 19%. In the clinical trials of Methylphenidate Hydrochloride Extended-Release Capsules, it was administered without regard to meals.

Alcohol Effect

At an alcohol concentration up to 40%, there was 96% release of methylphenidate from Methylphenidate Hydrochloride Extended-Release Capsules 80 mg within two hours. The results with the 80 mg capsule are considered to be representative of the other available capsules strengths.

Studies in Specific Populations

Gender

There is insufficient experience with the use of Methylphenidate Hydrochloride Extended-Release Capsules to detect gender variations in pharmacokinetics.

Race

There is insufficient experience with the use of Methylphenidate Hydrochloride Extended-Release Capsules to detect ethnic variations in pharmacokinetics.

Age

The pharmacokinetics of methylphenidate after Methylphenidate Hydrochloride Extended-Release Capsules administration was studied in pediatric patients with ADHD between 6 and 12 years of age. Following administration of Methylphenidate Hydrochloride Extended-Release Capsules, the bi-phasic plasma methylphenidate concentration profile was qualitatively similar in healthy adult volunteers and pediatric patients with ADHD. The bi-phasic profile in both groups is characterized by an early peak due to rapid absorption of the immediate-release component followed by a delayed, secondary peak due to the controlled-release component of Methylphenidate Hydrochloride Extended-Release Capsules.

Renal Insufficiency

There is no experience with the use of Methylphenidate Hydrochloride Extended-Release Capsules in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of ritalinic acid metabolite. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of Methylphenidate Hydrochloride Extended-Release Capsules.

Hepatic Insufficiency

There is no experience with the use of Methylphenidate Hydrochloride Extended-Release Capsules in patients with hepatic insufficiency.

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