Drug Criteria & Outcomes

Drug evaluation: Dexmethylphenidate hydrochloride tablets (Focalin)

Part 1: Mechanism of Action, Pharmacokinetics, Indication, Dosage, Contraindications, Drug Interactions, Adverse Reactions, Warnings and Precautions

By Emily K Pauli, BS, BMS, PharmD Candidate
Harrison School of Pharmacy
Auburn (AL) University

Dexmethylphenidate, d-MPH (Focalin) is a new methylphenidate (d,l-MPH; MPH) formulation of the active enantiomer only. A variety of methylphenidate products are available but only dexmethylphenidate is the purified active enantiomer.

Mechanism of action

Proposed: Dexmethylphenidate (d-MPH) is a central nervous system stimulant that blocks the reuptake of norepinephrine and dopamine and increases the release of monoamines. The actual mechanism of action is not known.

Pharmacokinetics

  • The pharmacokinetic differences (if any) between d-MPH and d,l-MPH are clinically insignificant.

  • Absorption
    — Well absorbed (both d-MPH and d,l-MPH).
    — Time to peak in the fasted state is 1-1.5 hours post-dose for d-MPH; 2 hours for the racemic products (d,l–MPH).
    — Food delays the time to peak by approximately 1.5 hours but does not affect the Cmax or AUC for d-MPH or d,l-MPH.
  • Distribution
    — Plasma levels decline exponentially following oral administration.
    — No data are provided regarding distribution of d-MPH.
    — Protein binding of racemic methylphenidate is minimal (15.2%).
    — Volume of distribution for d,l-MPH is 1.1-6 L/kg.
  • Metabolism
    De-esterification to an inactive metabolite (d-ritalinic acid) for both d-MPH and d,l-MPH.
  • Excretion
    — Elimination half-life is 2.2 hours for d-MPH and d,l-MPH.
    — d-MPH and d,l-MPH do not inhibit cytochrome P450 isozymes.
    — Primarily excreted in the urine (80%) as the inactive metabolite.
    — Specific renal excretion data for d-MPH are unavailable. However, approximately 90% of an oral dose of d,l-MPH appears in the urine, mainly as ritalinic acid (about 80%); less than 1% appears as unchanged methylphenidate.

Indication

  • d-MPH
  • — Treatment of attention deficit hyperactivity disorder (ADHD).
    — Efficacy established in clinical trials in patients 6-17 years of age.
    — Long-term use (greater than six weeks) has not been evaluated with d-MPH.
  • d,l-MPH — Treatment of ADHD in both children and adults.
    — Narcolepsy.
  • — Disease-related fatigue (not FDA-approved).

Dosage

  • d-MPH
    — Administered twice daily and at least four hours apart, irrespective of food.
    — Thirty to 45 minutes prior to a meal; morning and noontime is recommended.
    — Dosing is individualized to the patient and based on response.
    — Dosing is for children 6-17 years old; not established in adults and children younger than 6 years of age.
    — Treatment naïve: Initiate at 5 mg/day (2.5 mg twice daily); weekly adjustment of 2.5-5 mg daily to a maximum dose of 20 mg/day (10 mg twice daily).
    — Treatment non-naïve: Initiate d-MPH at half the dose of other methylphenidate products; weekly adjustments of 2.5-5 mg daily to a maximum of 20 mg/day (10 mg twice daily).
    — When changing from d-MPH tablets to d-MPH XR capsules, patients may be switched to the same daily dose using d-MPH XR (maximum dose: 20 mg/day).
  • Racemic methylphenidate (d,l-MPH)
    — Administered twice daily and at least four hours apart, irrespective of food.
    — Thirty to 45 minutes prior to a meal; morning and noontime is recommended.
    — Dosing is individualized to the patient and based on response.

Adult

Immediate-release

  • 10-60 mg daily; average dose is 20-30 mg daily; administer 2-3 times daily, preferably 30-45 minutes before meals.

Extended-release

  • Starting dose of Concerta extended-release tablet for new patients is 18 mg once a day in the morning; adjust weekly in 18-mg increments to a maximum of 54 mg per day. Patients converting from immediate-release (IR) or sustained-release (SR) methylphenidate may follow the dosage conversion recommendation shown in Table 1.
  • For methylphenidate extended-release capsules (Metadate CD) the starting dose is 20 mg once daily in the morning before breakfast; increase by 20 mg at weekly intervals to a maximum dose of 60 mg/day taken once daily in the morning.

Pediatric

Immediate-release

  • Usual dose is 5 mg twice daily; increased at weekly intervals by 5-10 mg; maximum recommended dose is 60 mg.

Extended-release

  • For methylphenidate extended-release capsules, the starting dose is 20 mg once daily in the morning before breakfast; increased by 20 mg at weekly intervals to a maximum dose of 60 mg/day taken once daily in the morning.

Dosage forms of comparable methylphenidate products

  • Immediate-release
    — Dexmethylphenidate (Focalin)
    — Ritalin HCl
    — Methylphenidate HCl
    — Methylin
  • Extended-release
    — Ritalin LA/Ritalin SR
    — Metadate CD/Metadate ER
    — Concerta
    — Methylin ER
    — Methylphenidate ER
    — Dexmethylphenidate (Focalin XR)

Contraindications

  • Same contraindications for d-MPH and d,l-MPH
    — Agitation (patients with marked anxiety, tension, and agitation): d-MPH and d,l-MPH may aggravate the symptoms.
    — Hypersensitivity to any methylphenidate product or component of d-MPH.
    — Glaucoma.
  • — Tics: Motor tics, family history, or diagnosis of Tourette’s syndrome; in rare cases MPH has caused Tourette’s syndrome.
    — Current or recent (within 14 days) treatment with monoamine oxidase inhibitors: Hypertensive crisis may result.

Drug interactions (based on d,l-MPH)

  • Same interactions and frequency of interactions for d-MPH and d,l-MPH
    — May decrease the effects of antihypertensive treatments.
    — May inhibit metabolism of coumarins, anticonvulsants (phenobarbital, phenytoin, primidone), tricyclic antidepressants, selective serotonin reuptake inhibitors; lower doses of these drugs.

Adverse reactions

  • Same for d-MPH and d,l-MPH
  • — Paradoxical aggravation: Reduce the dose or discontinue d-MPH.
    — The most common reasons (1% for each) for discontinuation were: motor or vocal tics, anorexia, insomnia, and tachycardia.
    — Adverse events with an incidence of 5% or more include: abdominal pain (15%), fever (5%), anorexia (6%), and nausea (9%)
    — Adverse events reported with use of other MPH products include: angina, arrhythmias, dizziness, headache, drowsiness, dyskinesia, psychosis, changes in blood pressure, cerebral arteriti, or occlusion.
    — Although no established casual relationship has been established, the following events have been reported: leukopenia, anemia, elevated liver associated enzymes, hepatic coma, transient depression, alopecia, and neuroleptic malignant syndrome.

Warnings and precautions

  • Unless otherwise noted, these are the same for both d-MPH and d,l-MPH.
  • Depression.
  • Fatigue.
  • Long-term use and growth suppression: Safety of long-term use (more than six weeks) has not been established with d-MPH
    — Still controversial that d,l-MPH MAY cause growth suppression after long-term treatment.
  • May exacerbate psychosis.
  • May lower the seizure threshold: Discontinue if seizures occur.
  • Use cautiously in hypertensive patients or in patients with conditions that increase heart rate or blood pressure (heart failure, myocardial infarction, hyperthyroidism).
  • Give cautiously in patients with a history of substance abuse or dependence.
  • Pregnancy Category C.
  • Unknown if excreted in breast milk.
  • Safety and efficacy is not established in children younger than 6 years of age.
    Look-/sound-alike drugs for dexmethylphenidate (Focalin):
    — Methylin, Ritalin
    — Metadate, methylphenidate