Methylphenidate Hydrochloride

Approved Indications

• Attention-Deficit/Hyperactivity Disorder (ADHD)
  • Indicated for the treatment of ADHD in children ≥6 years, adolescents, and adults.
  • Effective for inattentive, hyperactive-impulsive, and combined subtypes.
• Narcolepsy
  • Used to manage excessive daytime sleepiness in patients with narcolepsy.

Clinically Accepted Off-Label Uses

• Treatment-resistant major depressive disorder (as adjunct therapy).
• Fatigue associated with cancer or multiple sclerosis.
• Cognitive impairment in elderly patients (e.g., apathy in dementia).
• Fatigue and apathy in post-stroke rehabilitation (with specialist supervision).

Route: Oral
Formulations: Immediate-release (IR), extended-release (ER), sustained-release (SR)

ADHD – Children (≥6 years) and Adolescents

• IR tablets: Start with 5 mg twice daily (before breakfast and lunch).
  • Titrate weekly by 5–10 mg based on response.
  • Max dose: 60 mg/day in divided doses.
• ER tablets: Start with 18 mg once daily in the morning.
  • Titrate by 18 mg at weekly intervals.
  • Max dose: 72 mg/day.

ADHD – Adults

• IR tablets: Start with 10 mg twice daily.
  • Adjust dose gradually based on clinical response.
  • Max dose: 60 mg/day in divided doses.
• ER tablets: Start with 18–36 mg once daily in the morning.
  • Max dose: 72 mg/day.

Narcolepsy (Adults and Children ≥6 years)

• IR tablets: Start with 10 mg 2–3 times daily.
  • Usual maintenance dose: 20–60 mg/day.
  • Max dose: 80 mg/day.

Renal or Hepatic Impairment

• No specific dose adjustment required, but initiate therapy at the lowest effective dose with close monitoring.

Methylphenidate acts as a central nervous system stimulant. It blocks the reuptake of norepinephrine and dopamine by inhibiting their respective transporters in the presynaptic neurons, particularly in the prefrontal cortex and striatum. This results in increased concentrations of these neurotransmitters in the synaptic cleft, enhancing neurotransmission involved in attention regulation, impulse control, and wakefulness. The pharmacological effects help reduce symptoms of inattention, hyperactivity, and impulsivity in patients with ADHD and promote alertness in those with narcolepsy.

• Absorption: Rapid absorption; oral bioavailability ~30% due to first-pass metabolism.
• Time to Peak Plasma Concentration:
  • IR: 1–3 hours
  • ER: 6–8 hours
• Distribution: Widely distributed; plasma protein binding ~10–33%.
• Metabolism: Primarily via carboxylesterase 1 (CES1A1) in the liver.
• Excretion: Mostly excreted in urine as inactive ritalinic acid; small amount in feces.
• Half-life:
  • IR: ~2–3 hours
  • ER: ~6–10 hours depending on formulation
• Onset of Action: 20–60 minutes.
• Duration:
  • IR: ~3–4 hours
  • ER: up to 12 hours.

Pregnancy

• FDA Pregnancy Category C
• Animal studies have shown fetal risk. Human data are limited.
• Use only if the potential benefit outweighs the risk to the fetus.

Lactation

• Methylphenidate is excreted in breast milk.
• May cause irritability, poor feeding, or sleep disturbance in infants.
• Breastfeeding is not recommended during therapy or should be withheld for 24 hours after the last dose.

• Primary Class: Central Nervous System (CNS) Stimulant
• Pharmacologic Subclass: Dopamine and Norepinephrine Reuptake Inhibitor (DNRI)

• Known hypersensitivity to methylphenidate or excipients.
• Concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuing MAOIs.
• Severe anxiety, agitation, or tension.
• Glaucoma.
• Tourette syndrome or tics (including family history).
• Severe cardiovascular disease, including structural cardiac abnormalities.
• Uncontrolled hypertension.

• Cardiovascular effects: May cause increased blood pressure and heart rate; avoid in patients with serious structural cardiac abnormalities.
• Psychiatric effects: May exacerbate existing psychosis, bipolar disorder, or anxiety.
• Seizures: May lower seizure threshold.
• Growth suppression: Monitor growth in children during long-term use.
• Peripheral vasculopathy: Risk of Raynaud's phenomenon; monitor for signs in fingers and toes.
• Abuse and dependence: High potential for misuse; monitor for signs of abuse or diversion.
• Withdrawal: May cause fatigue, depression, and mood changes upon abrupt discontinuation.

Common Side Effects (≥1%)

• CNS: Insomnia, nervousness, headache, irritability, dizziness.
• GI: Nausea, decreased appetite, abdominal pain, dry mouth.
• Cardiovascular: Increased heart rate, elevated blood pressure, palpitations.
• Other: Weight loss, sweating.

Serious or Rare Side Effects

• Psychosis, mania, hallucinations.
• Cardiac arrhythmias, myocardial infarction, sudden death (especially in predisposed individuals).
• Growth retardation in pediatric patients.
• Seizures.
• Priapism.
• Raynaud’s phenomenon.

• MAO Inhibitors: Contraindicated; risk of hypertensive crisis.
• Antihypertensives: Reduced effectiveness due to stimulant properties.
• CYP2D6 inhibitors (e.g., fluoxetine, paroxetine): May increase methylphenidate levels.
• Tricyclic antidepressants: May increase cardiovascular toxicity.
• Warfarin, phenytoin, phenobarbital: Methylphenidate may increase their serum levels.
• Alcohol: May increase drug release from extended-release formulations, causing dose-dumping and toxicity.
• Enzyme Pathways: Mainly metabolized by carboxylesterase CES1A1, not CYP450.

• FDA (2023): Reinforced monitoring for peripheral vasculopathy (e.g., Raynaud’s phenomenon).
• NICE & AAP (2023): Continue to recommend methylphenidate as a first-line treatment for ADHD in children and adolescents.
• CDC Advisory: Emphasized need for careful monitoring of growth parameters and cardiovascular status during long-term use.

• Temperature: Store at 20°C to 25°C (68°F to 77°F).
• Humidity: Protect from excessive moisture.
• Light Protection: Store in a light-resistant container.
• Handling Precautions:
  • Controlled substance—store securely.
  • Do not crush or chew extended-release tablets.
• Reconstitution: Not applicable.