Methylphenidate Hydrochloride (Page 3 of 5)

8.2 Lactation

Risk Summary

Limited published literature, based on milk sampling from seven mothers reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight- adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for methylphenidate hydrochloride oral solution and any potential adverse effects on the breastfed infant from methylphenidate hydrochloride oral solution or from the underlying maternal condition.

Clinical Considerations

8.4 Pediatric Use

The safety and effectiveness of methylphenidate hydrochloride oral solution for the treatment of ADHD have been established in pediatric patients six years of age and older. The safety and effectiveness of methylphenidate hydrochloride oral solution in pediatric patients under six years of age have not been established. The long-term efficacy of methylphenidate in pediatric patients has not been established.

Long-Term Suppression of Growth

Growth should be monitored during treatment with stimulants, including methylphenidate hydrochloride oral solution. Pediatric patients who are not growing or gaining weight as expected may need to have their treatment interrupted [see Warnings and Precautions (5.6)].

Juvenile Animal Toxicity Data

² basis) or greater, and a deficit in the acquisition of a specific learning task was seen in females exposed to the highest dose (8 times the MRHD given to children on a mg/m² basis). The no effect level for juvenile neurobehavioral development in rats (5 mg/kg/day) is less than the MRHD given to children on a mg/m² basis. The clinical significance of the long-term behavioral effects observed in rats is unknown.

8.5 Geriatric Use

Methylphenidate hydrochloride oral solution has not been studied in the geriatric population.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Methylphenidate hydrochloride oral solution contains methylphenidate hydrochloride, a Schedule II controlled substance.

9.2 Abuse

CNS stimulants, including methylphenidate hydrochloride oral solution, other methylphenidate-containing products, and amphetamines have a high potential for abuse. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Both abuse and misuse may lead to addiction, and some individuals may develop addiction even when taking methylphenidate hydrochloride oral solution as prescribed.

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, and suicidal or homicidal ideation have also been observed. Individuals who abuse CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which may result in overdose and death [see Overdosage (10)].

To reduce the abuse of methylphenidate hydrochloride oral solution, 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 [see How Supplied/Storage and Handling (16)], monitor for signs of abuse while on therapy, and re-evaluate the need for methylphenidate hydrochloride oral solution use.

9.3 Dependence

Physical Dependence

Methylphenidate hydrochloride oral solution may produce physical dependence from continued therapy. Physical dependence is a state of adaptation manifested by a withdrawal syndrome produced by abrupt cessation, rapid dose reduction, or administration of an antagonist. Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.

Tolerance

10 OVERDOSAGE

Human Experience

Signs and symptoms of acute methylphenidate overdosage, resulting principally from overstimulation of the central nervous system and from excessive sympathomimetic effects, may include the following nausea, vomiting, diarrhea, restlessness, anxiety, agitation, tremors, hyperreflexia, muscle twitching, convulsions (which 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.

Overdose Management

11 DESCRIPTION

Methylphenidate hydrochloride oral solution contains methylphenidate hydrochloride a CNS stimulant. It is available as an oral solution in 5 mg/5 mL and 10 mg/5 mL strengths for oral administration. Chemically, methylphenidate hydrochloride is (d,l (racemic) methyl α-phenyl-2-piperidineacetate hydrochloride and its structural formula is:

Methylphenidate hydrochloride USP is a white to off white, 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.
Each mL of methylphenidate hydrochloride oral solution 5 mg/5 mL contains 1 mg of methylphenidate hydrochloride USP.
Each mL of methylphenidate hydrochloride oral solution 10 mg/5 mL contains 2 mg of methylphenidate hydrochloride USP.
Methylphenidate hydrochloride oral solution also contains the following inactive ingredients: glycerin, polyethylene glycol 1450, concord grape flavor N&A, diluted hydrochloric acid (10%), and purified water.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Methylphenidate hydrochloride 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-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space.

Cardiac Electrophysiology
A formal QT study has not been conducted in subjects taking methylphenidate hydrochloride oral solution.

The effect of dexmethylphenidate, the pharmacologically active d-enantiomer of methylphenidate hydrochloride oral solution, on the QT interval was evaluated in a double-blind, placebo- and open-label active (moxifloxacin)-controlled study following single doses of 40 mg dexmethylphenidate hydrochloride extended-release capsule in 75 healthy volunteers. Electrocardiograms were collected up to 12 hours postdose. Frederica’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). The maximum mean prolongation of QTcF intervals was less than 5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time-matched comparisons versus placebo. This was below the threshold of clinical concern and there was no evident exposure response relationship.

12.3 Pharmacokinetics

Absorption
Following a single dose administration of 20 mg methylphenidate hydrochloride oral solution and 20 mg tablet of methylphenidate hydrochloride in healthy volunteers under fasted conditions, time to peak plasma concentration (T_max ) of methylphenidate was at 1 to 2 hours after dosing, and:

• The mean peak plasma concentration (C_max ) of methylphenidate was 9.1 ng/mL and 9.8 ng/mL, respectively.
• The mean area under concentration curve (AUC) of methylphenidate was 46.7 hour*ng/mL and 50.0 hour*ng/mL, respectively.

Effect of Food
Ingestion of a high-fat meal with methylphenidate hydrochloride oral solution increased methylphenidate mean C_max and AUC by about 13% and 25%, respectively. Time to C_max (T_max ) was delayed by approximately 1 hour.

Distribution
Plasma protein binding is 10% to 33%. The volume of distribution was 2.65 ± 1.11 L/kg for d-methylphenidate and 1.80 ± 0.91 L/kg for l-methylphenidate.

Elimination
The mean terminal half-life (t½) of methylphenidate was 2.7 hours following administration of 20 mg methylphenidate hydrochloride oral solution. The systemic clearance is 0.40 ± 0.12 L/h/kg for d-methylphenidate and 0.73 ± 0.28 L/h/kg for l-methylphenidate.

Metabolism
Methylphenidate is metabolized primarily by deesterification to alpha-phenyl-piperidine acetic acid (ritalinic acid), which has little or no pharmacologic activity.

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

Specific Populations
Male and Female Patients, Racial Groups, and Age
The effect of gender, race, and age on the pharmacokinetics of methylphenidate after methylphenidate hydrochloride oral solution administration have not been studied.

Patients with Renal Impairment
Methylphenidate hydrochloride oral solution has not been studied in in patients with renal impairment. Since renal clearance is not an important route of methylphenidate clearance, renal impairment is expected to have little effect on the pharmacokinetics of methylphenidate hydrochloride oral solution.

Patients with Hepatic Impairment
Methylphenidate hydrochloride oral solution has not been studied in patients with hepatic impairment. Since methylphenidate is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body, hepatic impairment is expected to have minimal effect on the pharmacokinetics of methylphenidate hydrochloride oral solution.