Methylphenidate Hydrochloride

Methylphenidate is a medication used for treating attention deficit hyperactivity disorder (ADHD). It stimulates the central nervous system (CNS or brain) in a manner that is similar to amphetamines; however, its actions are milder than amphetamines. Amphetamines stimulate the brain by increasing the level of neurotransmitters, dopamine and norepinephrine, in the brain (neurotransmitters are chemicals produced by nerves that are released and attach to other nearby nerves as a means of communication among nerves). The exact mechanism of action of the drug in people with ADHD is unknown. Methylphenidate is the active ingredient in Ritalin and Concerta and is also available as pills and in a patch. FDA approved Methylphenidate suspension in September 2012.

Piperidine-derivative stimulant; 118 pharmacologic actions qualitatively similar to those of amphetamines.a

Absorption

Bioavailability

Well absorbed following oral administration.118 125 126 127 129 130 152 Low oral bioavailability (10–52%) suggests substantial first-pass metabolism.129 147

Oral solution and chewable tablets are bioequivalent to conventional tablets.145 152

Extended-release tablets are absorbed more slowly but to the same extent as conventional tablets.a 151 158

Relative bioavailability of Ritalin LA extended-release capsules given once daily is similar to that of conventional tablets administered at the same total daily dosage in 2 divided doses given 4 hours apart.129

Peak plasma concentrations and AUC were slightly lower for Metadate CD extended-release capsules (20 mg once daily) than for conventional tablets (10 mg twice daily).125 126

Relative bioavailability of Aptensio XR extended-release capsules given once daily is comparable to that of conventional tablets administered 3 times daily.168

Relative bioavailability of the extended-release oral suspension (single 60-mg dose) is 95% that of immediate-release oral solution (given as two 30-mg doses 6 hours apart).157

Relative bioavailability of extended-release trilayer core tablets administered at a dosage of 18 mg once daily is similar to that of conventional tablets administered at a dosage of 5 mg 3 times daily (given every 4 hours).118

Alcohol increases the rate of drug release in vitro from the extended-release capsules but not from extended-release trilayer core tablets (Concerta); 98 or 84% of the drug was released from Ritalin LA 40-mg or Metadate CD 60-mg capsules within the first hour at an alcohol concentration of 40%,125 149 and 96% was released from Aptensio XR 80-mg capsules within 2 hours at an alcohol concentration up to 40%.168 Results are considered representative for available strengths of the respective preparations.125 149 162 168

For timing of peak plasma concentrations for oral formulations, see Table 4.

Peak plasma methylphenidate concentrations for transdermal systems are attained in about 10 hours (single-dose application) or 8 hours (repeated applications of systems worn for up to 9 hours).147 Average lag of 2 hours until d-methylphenidate is detectable in plasma after single-dose application; with repeated administration, low concentrations of the drug are detected earlier because of carryover effect.147

When applied to inflamed skin, time to peak plasma concentrations decreases (to 4 hours) and peak plasma concentration and AUC increase by threefold compared with application to intact skin.147 When heat is applied to transdermal system after application, peak plasma concentration occurs 0.5 hour earlier, and median peak plasma concentration and AUC are 2-fold and 2.5-fold higher, respectively, compared to application without heat.147

Possible increased transdermal absorption following repeated administration.147 Steady state likely to be achieved by approximately day 14 of dosing.147

Because of substantially greater first-pass metabolism following oral compared with transdermal administration, a lower transdermal dose of methylphenidate may result in greater systemic exposure to d-methylphenidate than a higher (on a mg/kg basis) oral dose of the drug.147 Little, if any, l-methylphenidate is systemically available following oral administration; however, systemic exposure to l-methylphenidate following transdermal administration is almost as great as that to d-methylphenidate.147

Duration

Effects persist for 3–6 hours for conventional tablets, about 3–8 hours for extended-release tablets, and about 8–12 hours for extended-release trilayer core tablets, extended-release capsules, and extended-release oral suspension.118 125 126 127 129 130 157 168

Food

Chewable tablets: Administration with high-fat meal delays time to peak plasma concentration by approximately 1 hour and increases AUC by about 20%; magnitude of food effect is comparable to that observed with conventional tablets.152

Oral solution: Administration with high-fat meal delays time to peak plasma concentration by approximately 1 hour and increases peak plasma concentration and AUC by about 13 and 25%, respectively.145

Extended-release oral suspension: Administration with high-fat meal reduces time to peak concentration by approximately 1 hour and increases peak plasma concentration and AUC by approximately 28 and 19%, respectively; not considered clinically important.157

Extended-release capsules (Aptensio XR, Ritalin LA, Metadate CD): High-fat meal may alter absorption characteristics; opening the capsules and sprinkling the contents on applesauce does not alter bioavailability.125 129 168

Extended-release trilayer core tablets: High-fat meal does not alter pharmacokinetics.118

Distribution

Extent

Extent of distribution in humans is unknown.a

Plasma Protein Binding

About 10–33%.149

Elimination

Metabolism

Metabolized primarily by de-esterification by carboxylesterase 1A1 to form d-ritalinic acid, which has little or no pharmacologic activity.118 125 129 145 147 149 152

Elimination Route

Excreted as metabolites (principally as ritalinic acid), mostly in urinea 118 125 and a small amount in feces.129

Clearance increases with increasing weight; thus, patients with higher body weight may have lower exposures to total methylphenidate at similar doses.118

Half-life

For methylphenidate elimination half-lives reported for various methylphenidate formulations, see Table 5.

• Appears to block norepinephrine and dopamine reuptake into the presynaptic neuron and increases their release into the extraneuronal space.118 125 129 Mechanism of action involved in the central effect not determined.a

• Pharmacologic actions include CNS stimulation (e.g., increased motor activity, mental alertness, diminished sense of fatigue, brighter spirits, mild euphoria), respiratory stimulation, and weak sympathomimetic activity;a also produces an anorexigenic effect.114

• At usual therapeutic dosages, exhibits only moderate effects on the peripheral circulatory system.a

• Racemic mixture; the d-enantiomer is the more pharmacologically active enantiomer.118 125 129

• No clinically important changes in corrected QT (QTc) interval observed in healthy individuals following 40-mg dose of extended-release dexmethylphenidate hydrochloride (the more active enantiomer).114 149 151 158

4.1 Hypersensitivity to Methylphenidate

Hypersensitivity reactions, such as angioedema and anaphylactic reactions, have been observed in patients treated with Methylphenidate Hydrochloride extended-release tablets. Therefore, Methylphenidate Hydrochloride extended-release tablets are contraindicated in patients known to be hypersensitive to methylphenidate or other components of the product [see Adverse Reactions  (6.6)] .

4.2 Agitation

Methylphenidate Hydrochloride extended-release tablets are contraindicated in patients with marked anxiety, tension, and agitation, since the drug may aggravate these symptoms.

4.3 Glaucoma

Methylphenidate Hydrochloride extended-release tablets are contraindicated in patients with glaucoma.

4.4 Tics

Methylphenidate Hydrochloride extended-release tablets are contraindicated in patients with motor tics or with a family history or diagnosis of Tourette's syndrome [see Adverse Reactions  (6.4)] .

4.5 Monoamine Oxidase Inhibitors

Methylphenidate Hydrochloride extended-release tablets are contraindicated during treatment with monoamine oxidase (MAO) inhibitors, and also within a minimum of 14 days following discontinuation of a MAO inhibitor (hypertensive crises may result) [see Drug Interactions  (7.1)] .

8.1 Pregnancy

Pregnancy Category C

Methylphenidate has been shown to have teratogenic effects in rabbits when given in doses of 200 mg/kg/day, which is approximately 100 times and 40 times the maximum recommended human dose on a mg/kg and mg/m 2 basis, respectively.

A reproduction study in rats revealed no evidence of harm to the fetus at oral doses up to 30 mg/kg/day, approximately 15-fold and 3-fold the maximum recommended human dose of Methylphenidate Hydrochloride extended-release tablets on a mg/kg and mg/m 2 basis, respectively. The approximate plasma exposure to methylphenidate plus its main metabolite PPAA in pregnant rats was 1–2 times that seen in trials in volunteers and patients with the maximum recommended dose of Methylphenidate Hydrochloride extended-release tablets based on the AUC.

The safety of methylphenidate for use during human pregnancy has not been established. There are no adequate and well-controlled studies in pregnant women. Methylphenidate Hydrochloride extended-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.2 Labor and Delivery

The effect of Methylphenidate Hydrochloride extended-release tablets on labor and delivery in humans is unknown.

8.3 Nursing Mothers

It is not known whether methylphenidate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if Methylphenidate Hydrochloride extended-release tablets is administered to a nursing woman.

In lactating female rats treated with a single oral dose of 5 mg/kg radiolabeled methylphenidate, radioactivity (representing methylphenidate and/or its metabolites) was observed in milk and levels were generally similar to those in plasma.

8.4 Pediatric Use

Methylphenidate Hydrochloride extended-release tablets should not be used in children under six years, since safety and efficacy in this age group have not been established. Long-term effects of methylphenidate in children have not been well established.

8.5 Geriatric Use

Methylphenidate Hydrochloride extended-release tablets have not been studied in patients greater than 65 years of age.

Methylphenidate Hydrochloride extended-release tablets are available in 18, 27, 36, 54, and 72 mg strengths.  The 18 mg tablets are yellow with “TL706” imprinted in black ink, 27 mg tablets are gray with “TL707”imprinted in black ink, 36 mg tablets are white with “TL708”imprinted in black ink, 54 mg tablets are pink with “TL709" imprinted in black ink, and 72 mg tablets are blue with “TL710” imprinted in black ink. The tablets are supplied in bottles containing 100 tablets.

Storage and Handling

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from humidity.

See Medication Guide

17.1 Information for Patients

Priapism

Advise patients, caregivers, and family members of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.4)]. 

Circulation Problems in Fingers and Toes [Peripheral Vasculopathy, including Raynaud’s Phenomenon]

Instruct patients beginning treatment with Methylphenidate Hydrochloride extended release tablets about the risk of peripheral vasculopathy, including Raynaud’s phenomenon, and associated signs and symptoms: fingers or toes may feel numb, cool, painful, and/or may change color from pale, to blue, to red.

Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to temperature in fingers or toes.

Instruct patients to call their physician immediately with any signs of unexplained wounds appearing on fingers or toes while taking Methylphenidate Hydrochloride extended release tablets.

Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

General Considerations

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with methylphenidate and should counsel them in its appropriate use. A patient Medication Guide is available for Methylphenidate Hydrochloride extended-release tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

Administration Instructions

Patients should be informed that Methylphenidate Hydrochloride extended-release tablets should be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.

Driving or Operating Heavy Machinery

Stimulants may impair the ability of the patient to operate potentially hazardous machinery or vehicles. Patients should be cautioned accordingly until they are reasonably certain that Methylphenidate Hydrochloride extended-release tablets do not adversely affect their ability to engage in such activities.

Trigen Laboratories, LLC

Bridgewater, NJ 08807

www.trigenlab.com

1-888-987-4436

200114  Rev. 02/2017

PRINCIPAL DISPLAY PANEL - 18 mg Tablet Label

NDC 13811-706-10
100 tablets

Methylphenidate Hydrochloride Extended-release Tablets
CII

18 mg

Each tablet contains 18 mg
Methylphenidate Hydrochloride
in an extended-release formulation.

Rx only

Please see the Medication Guide
provided by your pharmacist.