Methylphenidate LA Capsules

Name: Methylphenidate LA Capsules

Methylphenidate LA Capsules Description

Methylphenidate hydrochloride, USP is a central nervous system (CNS) stimulant.

Methylphenidate hydrochloride extended-release capsules (LA) are an extended-release formulation of methylphenidate with a bi-modal release profile. Each bead-filled methylphenidate hydrochloride extended-release capsule (LA) contains half the dose as immediate-release beads and half as enteric- coated, delayed-release beads, thus providing an immediate release of methylphenidate and a second delayed release of methylphenidate. Methylphenidate hydrochloride extended-release 20, 30, 40, and 60 mg capsules (LA) provide in a single dose the same amount of methylphenidate as dosages of 10, 15, or 20, or 30 mg of methylphenidate hydrochloride tablets given twice a day.

The active substance in methylphenidate hydrochloride extended-release capsules (LA) is methyl α- phenyl-2-piperidineacetate hydrochloride, and its structural formula is

Methylphenidate hydrochloride, USP is a 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: sugar spheres (which contain sucrose and starch), hypromellose, cellulose acetate butyrate, hypromellose acetate succinate, acetyltributyl citrate, acetone, talc, and purified water. Opaque gelatin capsules contain: titanium dioxide and gelatin. The 30 and 40 mg capsules contain D&C Red #28 and FD&C Blue #1. The 60 mg capsules contain iron oxide yellow and sodium lauryl sulfate. The capsules are imprinted with black ink which contains black iron oxide, shellac and potassium hydroxide. The 60 mg black imprinting ink also contains ammonium hydroxide and propylene glycol.

Methylphenidate LA Capsules - Clinical Pharmacology

Pharmacodynamics

Methylphenidate hydrochloride, USP, the active ingredient in methylphenidate hydrochloride extended- release capsules (LA), is a central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. 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.

Effects on QT Interval

The effect of dexmethylphenidate hydrochloride extended-release (dexmethylphenidate, the pharmacologically active d-enantiomer of methylphenidate hydrochloride) on the QT interval was evaluated in a double-blind, placebo- and open label active (moxifloxacin)-controlled study following single doses of dexmethylphenidate hydrochloride extended-release 40 mg in 75 healthy volunteers. ECGs 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 <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.

Pharmacokinetics

Absorption

Methylphenidate hydrochloride extended-release capsules (LA) produce a bi-modal plasma concentration-time profile (i.e., 2 distinct peaks approximately 4 hours apart) when orally administered to children diagnosed with ADHD and to healthy adults. The initial rate of absorption for methylphenidate hydrochloride extended-release capsules (LA) is similar to that of methylphenidate hydrochloride tablets as shown by the similar rate parameters between the 2 formulations, i.e., initial lag time (Tlag), first peak concentration (Cmax1), and time to the first peak (Tmax1), which is reached in 1 to 3 hours. The mean time to the interpeak minimum (Tminip), and time to the second peak (Tmax2) are also similar for methylphenidate hydrochloride extended-release capsules (LA) given once daily and methylphenidate hydrochloride tablets given in 2 doses 4 hours apart (see Figure 1 and Table 1), although the ranges observed are greater for methylphenidate hydrochloride extended-release capsules (LA).

Methylphenidate hydrochloride extended-release capsules (LA) given once daily exhibit a lower second peak concentration (Cmax2), higher interpeak minimum concentrations (Cminip), and less peak and trough fluctuations than methylphenidate hydrochloride tablets given in 2 doses given 4 hours apart. This is due to an earlier onset and more prolonged absorption from the delayed-release beads (see Figure 1 and Table 1).

The relative bioavailability of methylphenidate hydrochloride extended-release capsules (LA) given once daily is comparable to the same total dose of methylphenidate hydrochloride tablets given in 2 doses 4 hours apart in both children and in adults.

Figure 1. Mean Plasma Concentration Time- Profile of Methylphenidate After a Single Dose of Methylphenidate Hydrochloride Extended- Release Capsules (LA) 4 0 mg Once a Day and Methylphenidate Hydrochloride Tablets 20 mg Given in Two Doses Four Hours Apart

Table 1. Mean ± SD and Range of Pharmacokinetic Parameters of Methylphenidate After a Single Dose of Methylphenidate Hydrochloride Extended-Release Capsules (LA) and Methylphenidate Hydrochloride Tablets Given in Two Doses 4 Hours Apart
Population Children Adult Males
Formulation Methylphenidate Hydrochloride Tablets Methylphenidate Hydrochloride Extended-Release Capsules (LA) Methylphenidate Hydrochloride Tablets Methylphenidate Hydrochloride Extended-Release Capsules (LA)
Dose
N
10 mg & 10 mg
21
20 mg
18
10 mg & 10 mg
9
20 mg
8
* N = 15
T lag (h) 0.24 ± 0.44
0 to 1
0.28 ± 0.46
0 to 1
1.0 ± 0.5
0.7 to 1.3
0.7 ± 0.2
0.3 to 1.0
T max1 (h) 1.8 ± 0.6
1 to 3
2.0 ± 0.8
1 to 3
1.9 ± 0.4
1.3 to 2.7
2.0 ± 0.9
1.3 to 4.0
Cmax1 (ng/mL) 10.2 ± 4.2
4.2 to 20.2
10.3 ± 5.1
5.5 to 26.6
4.3 ± 2.3
1.8 to 7.5
5.3 ± 0.9
3.8 to 6.9
T minip (h) 4.0 ± 0.2
4 to 5
4.5 ± 1.2
2 to 6
3.8 ± 0.4
3.3 to 4.3
3.6 ± 0.6
2.7 to 4.3
Cminip (ng/mL) 5.8 ± 2.7
3.1 to 14.4
6.1 ± 4.1
2.9 to 21.0
1.2 ± 1.4
0.0 to 3.7
3.0 ± 0.8
1.7 to 4.0
T max2 (h) 5.6 ± 0.7
5 to 8
6.6 ± 1.5
5 to 11
5.9 ± 0.5
5.0 to 6.5
5.5 ± 0.8
4.3 to 6.5
Cmax2 (ng/mL)

AUC(0-∞)
15.3 ± 7.0
6.2 to 32.8
102.4 ± 54.6
10.2 ± 5.9
4.5 to 31.1
86.6 ± 64.0*
5.3 ± 1.4
3.6 to 7.2
37.8 ± 21.9
6.2 ± 1.6
3.9 to 8.3
45.8 ± 10.0
(ng/mL × h-1)
t1/2 (h)
40.5 to 261.6
2.5 ± 0.8
1.8 to 5.3
43.3 to 301.44
2.4 ± 0.7*
1.5 to 4.0
14.3 to 85.3
3.5 ± 1.9
1.3 to 7.7
34.0 to 61.6
3.3 ± 0.4
3.0 to 4.2
Dose Proportionality

After oral administration of methylphenidate hydrochloride extended-release capsules (LA) 20 mg and 40 mg capsules to adults there is a slight upward trend in the methylphenidate area under the curve (AUC) and peak plasma concentrations (Cmax1 and Cmax2).

Distribution

Binding to plasma proteins is low (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.

Metabolism

The absolute oral bioavailability of methylphenidate in children was 22±8% for d-methylphenidate and 5±3% for l-methylphenidate, suggesting pronounced presystemic metabolism. Biotransformation of methylphenidate by the carboxylesterase CES1A1 is rapid and extensive leading to the main, de- esterified metabolite α-phenyl-2-piperidine acetic acid (ritalinic acid). Only small amounts of hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic acid) are detectable in plasma. Therapeutic activity is principally due to the parent compound.

Elimination

In studies with methylphenidate hydrochloride extended-release capsules (LA) and methylphenidate hydrochloride tablets in adults, methylphenidate from methylphenidate hydrochloride tablets is eliminated from plasma with an average half-life of about 3.5 hours, (range 1.3 to 7.7 hours). In children the average half-life is about 2.5 hours, with a range of about 1.5 to 5.0 hours. The rapid half-life in both children and adults may result in unmeasurable concentrations between the morning and mid-day doses with methylphenidate hydrochloride tablets. No accumulation of methylphenidate is expected following multiple once a day oral dosing with methylphenidate hydrochloride extended-release capsules (LA). The half-life of ritalinic acid is about 3 to 4 hours.

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. After oral administration of an immediate release formulation of methylphenidate, 78% to 97% of the dose is excreted in the urine and 1% to 3% in the feces in the form of metabolites within 48 to 96 hours. Only small quantities (<1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as ritalinic acid (60% to 86%), the remainder being accounted for by minor metabolites.

Food Effects

Administration times relative to meals and meal composition may need to be individually titrated.

When methylphenidate hydrochloride extended-release capsules (LA) was administered with a high fat breakfast to adults, methylphenidate hydrochloride extended-release capsules (LA) had a longer lag time until absorption began and variable delays in the time until the first peak concentration, the time until the interpeak minimum, and the time until the second peak. The first peak concentration and the extent of absorption were unchanged after food relative to the fasting state, although the second peak was approximately 25% lower. The effect of a high fat lunch was not examined.

There were no differences in the pharmacokinetics of methylphenidate hydrochloride extended-release capsules (LA) when administered with applesauce, compared to administration in the fasting condition. There is no evidence of dose dumping in the presence or absence of food.

For patients unable to swallow the capsule, the contents may be sprinkled on applesauce and administered (see DOSAGE AND ADMINISTRATION).

Alcohol Effect

Alcohol may exacerbate the adverse CNS effects of psychoactive drugs, including methylphenidate hydrochloride tablets. It is therefore advisable for patients to abstain from alcohol during treatment. An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from the methylphenidate hydrochloride extended-release (LA) 40 mg capsule dosage form. At an alcohol concentration of 40% there was a 98% release of methylphenidate in the first hour. The results with the 40 mg capsule are considered to be representative of the other available capsule strengths.

Special Populations

Age

The pharmacokinetics of methylphenidate hydrochloride extended-release capsules (LA) was examined in 18 children with ADHD between 7 and 12 years of age. Fifteen of these children were between 10 and 12 years of age. The time until the between peak minimum, and the time until the second peak were delayed and more variable in children compared to adults. After a 20-mg dose of methylphenidate hydrochloride extended-release capsules (LA), concentrations in children were approximately twice the concentrations observed in 18 to 35 year old adults. This higher exposure is almost completely due to the smaller body size and total volume of distribution in children, as apparent clearance normalized to body weight is independent of age.

Gender

There were no apparent gender differences in the pharmacokinetics of methylphenidate between healthy male and female adults when administered methylphenidate hydrochloride extended- release capsules (LA).

Renal Insufficiency

Methylphenidate hydrochloride extended-release capsules (LA) have not been studied in renally-impaired patients. Renal insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since less than 1% of a radiolabeled dose is excreted in the urine as unchanged compound, and the major metabolite (ritalinic acid), has little or no pharmacologic activity.

Hepatic Insufficiency

Methylphenidate hydrochloride extended-release capsules (LA) have not been studied in patients with hepatic insufficiency. Hepatic insufficiency is expected to have minimal effect on the pharmacokinetics of methylphenidate since it is metabolized primarily to ritalinic acid by nonmicrosomal hydrolytic esterases that are widely distributed throughout the body.

Indications and Usage for Methylphenidate LA Capsules

Methylphenidate hydrochloride extended-release capsules (LA) are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD).

The efficacy of methylphenidate hydrochloride extended-release capsules (LA) in the treatment of ADHD was established in 1 controlled trial of children aged 6 to 12 who met DSM-IV criteria for ADHD (see CLINICAL PHARMACOLOGY).

A diagnosis of Attention Deficit Hyperactivity Disorder (ADHD; DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that caused impairment and were present before age 7 years. The symptoms must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and be present in 2 or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder. For the Inattentive Type, at least 6 of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes; lack of sustained attention; poor listener; failure to follow through on tasks; poor organization; avoids tasks requiring sustained mental effort; loses things; easily distracted; forgetful. For the Hyperactive-Impulsive Type, at least 6 of the following symptoms must have persisted for at least 6 months: fidgeting/squirming; leaving seat; inappropriate running/climbing; difficulty with quiet activities; "on the go;" excessive talking; blurting answers; can't wait turn; intrusive. The Combined Types requires both inattentive and hyperactive-impulsive criteria to be met.

Special Diagnostic Considerations

Specific etiology of this syndrome is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the child and not solely on the presence of the required number of DSM-IV characteristics.

Need for Comprehensive Treatment Program

Methylphenidate hydrochloride extended-release capsules (LA) are indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all children with this syndrome. Stimulants are not intended for use in the child who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe stimulant medication will depend upon the physician's assessment of the chronicity and severity of the child's symptoms.

Long-Term Use

The effectiveness of methylphenidate hydrochloride extended-release capsules (LA) for long-term use, i.e., for more than 2 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use methylphenidate hydrochloride extended-release capsules (LA) for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Drug Abuse and Dependence

Methylphenidate hydrochloride extended-release capsules (LA), like other products containing methylphenidate, are a Schedule II controlled substance. (See WARNINGS for boxed warning containing drug abuse and dependence information.)

PRINCIPAL DISPLAY PANEL - 30 mg Capsule Bottle Label

NEW NDC

NDC 51862-264-01

CII

30
mg

Once Daily
Methylphenidate
Hydrochloride
Extended-Release Capsules (LA)

PHARMACIST: Please dispense
with Medication Guide
provided separately.

100 Capsules

Rx Only

PRINCIPAL DISPLAY PANEL - 60 mg Capsule Bottle Label

NDC 51862-267-30

CII

60
mg

Once Daily
Methylphenidate
Hydrochloride
Extended-Release Capsules (LA)

PHARMACIST: Please dispense with
Medication Guide provided separately.

30 Capsules

Rx Only

METHYLPHENIDATE HYDROCHLORIDE (LA) 
methylphenidate hydrochloride capsule, extended release
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:51862-263
Route of Administration ORAL DEA Schedule CII    
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Methylphenidate Hydrochloride (Methylphenidate) Methylphenidate Hydrochloride 20 mg
Inactive Ingredients
Ingredient Name Strength
SUCROSE  
STARCH, CORN  
HYPROMELLOSE, UNSPECIFIED  
CELLULOSE ACETATE  
HYPROMELLOSE ACETATE SUCCINATE 12070923 (3 MM2/S)  
ACETYLTRIBUTYL CITRATE  
ACETONE  
TALC  
WATER  
TITANIUM DIOXIDE  
GELATIN, UNSPECIFIED  
FERROSOFERRIC OXIDE  
SHELLAC  
POTASSIUM HYDROXIDE  
Product Characteristics
Color WHITE Score no score
Shape CAPSULE Size 18mm
Flavor Imprint Code A;200
Contains     
Packaging
# Item Code Package Description
1 NDC:51862-263-01 100 CAPSULE, EXTENDED RELEASE in 1 BOTTLE, PLASTIC
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078458 08/03/2016
METHYLPHENIDATE HYDROCHLORIDE (LA) 
methylphenidate hydrochloride capsule, extended release
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:51862-264
Route of Administration ORAL DEA Schedule CII    
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Methylphenidate Hydrochloride (Methylphenidate) Methylphenidate Hydrochloride 30 mg
Inactive Ingredients
Ingredient Name Strength
SUCROSE  
STARCH, CORN  
HYPROMELLOSE, UNSPECIFIED  
CELLULOSE ACETATE  
HYPROMELLOSE ACETATE SUCCINATE 12070923 (3 MM2/S)  
ACETYLTRIBUTYL CITRATE  
ACETONE  
TALC  
WATER  
TITANIUM DIOXIDE  
GELATIN, UNSPECIFIED  
FERROSOFERRIC OXIDE  
SHELLAC  
POTASSIUM HYDROXIDE  
FD&C BLUE NO. 1  
D&C RED NO. 28  
Product Characteristics
Color WHITE, BLUE (Light Blue) Score no score
Shape CAPSULE Size 18mm
Flavor Imprint Code A;201
Contains     
Packaging
# Item Code Package Description
1 NDC:51862-264-01 100 CAPSULE, EXTENDED RELEASE in 1 BOTTLE, PLASTIC
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078458 08/03/2016
METHYLPHENIDATE HYDROCHLORIDE (LA) 
methylphenidate hydrochloride capsule, extended release
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:51862-265
Route of Administration ORAL DEA Schedule CII    
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Methylphenidate Hydrochloride (Methylphenidate) Methylphenidate Hydrochloride 40 mg
Inactive Ingredients
Ingredient Name Strength
SUCROSE  
STARCH, CORN  
HYPROMELLOSE, UNSPECIFIED  
CELLULOSE ACETATE  
HYPROMELLOSE ACETATE SUCCINATE 12070923 (3 MM2/S)  
ACETYLTRIBUTYL CITRATE  
ACETONE  
TALC  
WATER  
TITANIUM DIOXIDE  
GELATIN, UNSPECIFIED  
FERROSOFERRIC OXIDE  
SHELLAC  
POTASSIUM HYDROXIDE  
FD&C BLUE NO. 1  
D&C RED NO. 28  
Product Characteristics
Color WHITE, BLUE (Dark Blue) Score no score
Shape CAPSULE Size 19mm
Flavor Imprint Code A;202
Contains     
Packaging
# Item Code Package Description
1 NDC:51862-265-01 100 CAPSULE, EXTENDED RELEASE in 1 BOTTLE, PLASTIC
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078458 08/03/2016
METHYLPHENIDATE HYDROCHLORIDE (LA) 
methylphenidate hydrochloride capsule, extended release
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:51862-267
Route of Administration ORAL DEA Schedule CII    
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Methylphenidate Hydrochloride (Methylphenidate) Methylphenidate Hydrochloride 60 mg
Inactive Ingredients
Ingredient Name Strength
SUCROSE  
STARCH, CORN  
HYPROMELLOSE, UNSPECIFIED  
CELLULOSE ACETATE  
HYPROMELLOSE ACETATE SUCCINATE 12070923 (3 MM2/S)  
ACETYLTRIBUTYL CITRATE  
ACETONE  
TALC  
WATER  
TITANIUM DIOXIDE  
GELATIN, UNSPECIFIED  
FERROSOFERRIC OXIDE  
SHELLAC  
POTASSIUM HYDROXIDE  
FERRIC OXIDE YELLOW  
AMMONIA  
PROPYLENE GLYCOL  
Product Characteristics
Color YELLOW (light yellow/dark yellow) Score no score
Shape CAPSULE Size 22mm
Flavor Imprint Code A602
Contains     
Packaging
# Item Code Package Description
1 NDC:51862-267-30 30 CAPSULE, EXTENDED RELEASE in 1 BOTTLE, PLASTIC
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078458 02/20/2017
Labeler - Mayne Pharma (867220261)
Establishment
Name Address ID/FEI Operations
Catalent Pharma Solutions, LLC 829672745 MANUFACTURE(51862-263, 51862-264, 51862-265, 51862-267), ANALYSIS(51862-263, 51862-264, 51862-265, 51862-267)
Establishment
Name Address ID/FEI Operations
Quality Packaging Specialists International, LLC 078440982 PACK(51862-263, 51862-264, 51862-265, 51862-267), LABEL(51862-263, 51862-264, 51862-265, 51862-267)
Revised: 05/2017   Mayne Pharma
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