7 Do not use Methylphenidate HCl Extended-Release Tablets in patients currently using or within 2 weeks of using an MAO inhibitor ( 7.1 ) Methylphenidate HCl Extended-Release Tablets may increase blood pressure; use cautiously with vasopressors ( 7.2 ) Inhibition of metabolism of coumarin anticoagulants, anticonvulsants, and some antidepressants ( 7.3 ) 7.1 MAO Inhibitors Methylphenidate HCl Extended-Release Tablets should not be used in patients being treated (currently or within the preceding 2 weeks) with MAO inhibitors [see Contraindications (4.5) ].
7.2 Vasopressor Agents Because of possible increases in blood pressure, Methylphenidate HCl Extended-Release Tablets should be used cautiously with vasopressor agents [see Warnings and Precautions (5.1) ] .
7.3 Coumarin Anticoagulants, Antidepressants, and Selective Serotonin Reuptake Inhibitors Human pharmacologic studies have shown that methylphenidate may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (eg, phenobarbital, phenytoin, primidone), and some antidepressants (tricyclics and selective serotonin reuptake inhibitors).
Downward dose adjustment of these drugs may be required when given concomitantly with methylphenidate.
It may be necessary to adjust the dosage and monitor plasma drug concentrations (or, in the case of coumarin, coagulation times), when initiating or discontinuing concomitant methylphenidate.
10 10.1 Signs and Symptoms Signs and symptoms of Methylphenidate HCl Extended-Release Tablets overdosage, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: vomiting, agitation, muscle twitching, convulsion, grand mal convulsion, confusional state, hallucinations (auditory and/or visual), hyperhidrosis, headache, pyrexia, tachycardia, palpitations, heart rate increased, sinus arrhythmia, hypertension, rhabdomyolysis, mydriasis, and dry mouth.
10.2 Recommended Treatment Treatment consists of appropriate supportive measures.
The patient must be protected against self-injury and against external stimuli that would aggravate overstimulation already present.
Gastric contents may be evacuated by gastric lavage as indicated.
Before performing gastric lavage, control agitation and seizures if present and protect the airway.
Other measures to detoxify the gut include administration of activated charcoal and a cathartic.
Intensive care must be provided to maintain adequate circulation and respiratory exchange; external cooling procedures may be required for pyrexia.
Efficacy of peritoneal dialysis or extracorporeal hemodialysis for Methylphenidate HCl Extended-Release Tablets overdosage has not been established.
The prolonged release of methylphenidate from Methylphenidate HCl Extended-Release Tablets should be considered when treating patients with overdose.
10.3 Poison Control Center As with the management of all overdosage, the possibility of multiple-drug ingestion should be considered.
The physician may wish to consider contacting a poison control center for up-to-date information on the management of overdosage with methylphenidate.
11 Methylphenidate HCl Extended-Release Tablets is a central nervous system (CNS) stimulant.
Methylphenidate HCl Extended-Release Tablets is available in four tablet strengths.
Each extended-release tablet for once-a-day oral administration contains 18, 27, 36, or 54 mg of methylphenidate HCl USP and is designed to have a 12-hour duration of effect.
Chemically, methylphenidate HCl is d,l (racemic) methyl α-phenyl-2-piperidineacetate hydrochloride.
Its empirical formula is C 14 H 19 NO 2 •HCl.
Its structural formula is: Methylphenidate HCl USP is a white, odorless 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.
Methylphenidate HCl Extended-Release Tablets also contains the following inert ingredients: black iron oxide, carboxymethylcellulose sodium, colloidal silicon dioxide, corn starch, ethocel, hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sucrose, talc, titanium dioxide and triethyl citrate.
The 18, 36, 54 mg tablets also contain synthetic red iron oxide.
The 27 mg tablets also contain yellow iron oxide.
USP dissolution test is pending.
Chemical Structure 11.1 System Components and Performance Methylphenidate HCl Extended-Release Tablets uses extended-release bead technology to deliver methylphenidate HCl at a controlled rate.
The system, which resembles a conventional tablet in appearance, is comprised of a tablet core containing the extended-release beads and the core is covered with an immediate-release drug overcoat.
In an aqueous environment, such as the gastrointestinal tract, the drug overcoat dissolves within one hour, providing an initial dose of methylphenidate.
The tablet disintegrates and then polymer coatings on the beads control the release of methylphenidate HCl over the 12 hour dosing period.
14 Methylphenidate HCl Extended-Release Tablets was demonstrated to be effective in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in 4 randomized, double-blind, placebo-controlled studies in children and adolescents and 2 double-blind placebo-controlled studies in adults who met the Diagnostic and Statistical Manual 4 th edition (DSM-IV) criteria for ADHD.
14.1 Children Three double-blind, active- and placebo-controlled studies were conducted in 416 children aged 6 to 12 years.
The controlled studies compared Methylphenidate HCl Extended-Release Tablets given once daily (18, 36, or 54 mg), methylphenidate given three times daily over 12 hours (15, 30, or 45 mg total daily dose), and placebo in two single-center, 3-week crossover studies (Studies 1 and 2) and in a multicenter, 4-week, parallel-group comparison (Study 3).
The primary comparison of interest in all three trials was Methylphenidate HCl Extended-Release Tablets versus placebo.
Symptoms of ADHD were evaluated by community schoolteachers using the Inattention / Overactivity with Aggression (IOWA) Conners scale.
Statistically significant reduction in the Inattention / Overactivity subscale versus placebo was shown consistently across all three controlled studies for Methylphenidate HCl Extended-Release Tablets.
The scores for Methylphenidate HCl Extended-Release Tablets and placebo for the three studies are presented in Figure 2.
Figure 2: Mean Community School Teacher IOWA Conners Inattention/Overactivity Scores with Methylphenidate HCl Extended-Release Tablets once-daily (18, 36, or 54 mg) and placebo.
Studies 1 and 2 involved a 3-way crossover of 1 week per treatment arm.
Study 3 involved 4 weeks of parallel-group treatments with a Last Observation Carried Forward analysis at week 4.
Error bars represent the mean plus standard error of the mean.
In Studies 1 and 2, symptoms of ADHD were evaluated by laboratory schoolteachers using the SKAMP Swanson, Kotkin, Agler, M-Fynn, and Pelham laboratory school rating scale.
The combined results from these two studies demonstrated statistically significant improvements in attention and behavior in patients treated with Methylphenidate HCl Extended-Release Tablets versus placebo that were maintained through 12 hours after dosing.
Figure 3 presents the laboratory schoolteacher SKAMP ratings for Methylphenidate HCl Extended-Release Tablets and placebo.
Figure 3: Laboratory School Teacher SKAMP Ratings: Mean (SEM) of Combined Attention (Studies 1 and 2) Figure 2 Figure 3 14.2 Adolescents In a randomized, double-blind, multi-center, placebo-controlled trial (Study 4) involving 177 patients, Methylphenidate HCl Extended-Release Tablets was demonstrated to be effective in the treatment of ADHD in adolescents aged 13 to 18 years at doses up to 72 mg/day (1.4 mg/kg/day).
Of 220 patients who entered an open 4-week titration phase, 177 were titrated to an individualized dose (maximum of 72 mg/day) based on meeting specific improvement criteria on the ADHD Rating Scale and the Global Assessment of Effectiveness with acceptable tolerability.
Patients who met these criteria were then randomized to receive either their individualized dose of Methylphenidate HCl Extended-Release Tablets (18 – 72 mg/day, n=87) or placebo (n=90) during a two-week double-blind phase.
At the end of this phase, mean scores for the investigator rating on the ADHD Rating Scale demonstrated that Methylphenidate HCl Extended-Release Tablets was statistically significantly superior to placebo.
14.3 Adults Two double-blind, placebo-controlled studies were conducted in 627 adults aged 18 to 65 years.
The controlled studies compared Methylphenidate HCl Extended-Release Tablets administered once daily and placebo in a multicenter, parallel-group, 7-week dose-titration study (Study 5) (36 to 108 mg/day) and in a multicenter, parallel-group, 5-week, fixed-dose study (Study 6) (18, 36, and 72 mg/day).
Study 5 demonstrated the effectiveness of Methylphenidate HCl Extended-Release Tablets in the treatment of ADHD in adults aged 18 to 65 years at doses from 36 mg/day to 108 mg/day based on the change from baseline to final study visit on the Adult ADHD Investigator Rating Scale (AISRS).
Of 226 patients who entered the 7-week trial, 110 were randomized to Methylphenidate HCl Extended-Release Tablets and 116 were randomized to placebo.
Treatment was initiated at 36 mg/day and patients continued with incremental increases of 18 mg/day (36 to 108 mg/day) based on meeting specific improvement criteria with acceptable tolerability.
At the final study visit, mean change scores (LS Mean, SEM) for the investigator rating on the AISRS demonstrated that Methylphenidate HCl Extended-Release Tablets was statistically significantly superior to placebo.
Study 6 was a multicenter, double-blind, randomized, placebo-controlled, parallel-group, dose-response study (5-week duration) with 3 fixed dose groups (18, 36, and 72 mg).
Patients were randomized to receive Methylphenidate HCl Extended-Release Tablets administered at doses of 18 mg (n=101), 36 mg (n=102), 72 mg/day (n=102), or placebo (n=96).
All three doses of Methylphenidate HCl Extended-Release Tablets were statistically significantly more effective than placebo in improving CAARS (Conners’ Adult ADHD Rating Scale) total scores at double-blind end point in adult subjects with ADHD.
16 /STORAGE AND HANDLING Methylphenidate HCl Extended-Release Tablets is available in 18 mg and 27 mg dosage strengths.
The 18 mg tablets are pink and imprinted with “18” and the 27 mg tablets are yellow and imprinted with “27”.
Both dosage strengths are supplied in bottles containing 100 tablets.
18 mg 100 count bottle NDC 42291-601-01 27 mg 100 count bottle NDC 42291-602-01 36 mg 100 count bottle NDC 42291-602-01 54 mg 100 count bottle NDC 42291-603-01 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.
RECENT MAJOR CHANGES
8.5 Geriatric Use Methylphenidate HCl Extended-Release Tablets has not been studied in patients greater than 65 years of age.
DOSAGE FORMS AND STRENGTHS
3 Methylphenidate HCl Extended-Release Tablets is available in the following dosage strengths: 18 mg tablets are pink and imprinted with “18”, 27 mg tablets are yellow and imprinted with “27”, 36 mg tablets are pink and imprinted with “36”, and 54 mg tablets are pink and imprinted with “54”.
Tablets: 18, 27, 36, and 54 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Methylphenidate HCl 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.
INDICATIONS AND USAGE
1 Methylphenidate HCl Extended-Release Tablets is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6 years of age and older, adolescents, and adults up to the age of 65 [see Clinical Studies (14) ] .
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 two 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 six 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 six 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 Type requires both inattentive and hyperactive-impulsive criteria to be met.
Methylphenidate HCl Extended-Release Tablets is a CNS stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6 years of age and older, adolescents, and adults up to the age of 65.
( 1 ) 1.1 Special Diagnostic Considerations Specific etiology of this syndrome is unknown, and there is no single diagnostic test.
Adequate diagnosis requires the use of medical and 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 patient and not solely on the presence of the required number of DSM-IV characteristics.
1.2 Need for Comprehensive Treatment Program Methylphenidate HCl Extended-Release Tablets is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social).
Drug treatment may not be indicated for all patients with ADHD.
Stimulants are not intended for use in patients who exhibit 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 patient’s symptoms.
8.4 Pediatric Use Methylphenidate HCl 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.
8.1 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 HCl 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 HCl 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 HCl Extended-Release Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 HCl 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.
WARNING: DRUG DEPENDENCE Methylphenidate HCl Extended-Release Tablets should be given cautiously to patients with a history of drug dependence or alcoholism.
Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior.
Frank psychotic episodes can occur, especially with parenteral abuse.
Careful supervision is required during withdrawal from abusive use since severe depression may occur.
Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up.
WARNING: DRUG DEPENDENCE See full prescribing information for complete boxed warning.
Methylphenidate HCl Extended-Release Tablets should be given cautiously to patients with a history of drug dependence or alcoholism.
Chronic abusive use can lead to marked tolerance and psychological dependence, with varying degrees of abnormal behavior.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Serious Cardiovascular Events: Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems.
Sudden death, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD.
Stimulant products generally should not be used in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious heart problems.
( 5.1 ) Increase in Blood Pressure: Monitor patients for changes in heart rate and blood pressure and use with caution in patients for whom an increase in blood pressure or heart rate would be problematic.
( 5.1 ) Psychiatric Adverse Events: Use of stimulants may cause treatment-emergent psychotic or manic symptoms in patients with no prior history, or exacerbation of symptoms in patients with preexisting psychiatric illness.
Clinical evaluation for Bipolar Disorder is recommended prior to stimulant use.
Monitor for aggressive behavior.
( 5.2 ) Seizures: Stimulants may lower the convulsive threshold.
Discontinue in the presence of seizures.
( 5.3 ) Priapism: Cases of painful and prolonged penile erections and priapism have been reported with methylphenidate products.
Immediate medical attention should be sought if signs or symptoms of painful or prolonged penile erections or priapism are observed.
(5.4) Peripheral Vasculopathy, including Raynaud’s Phenomenon: Stimulants used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon.
Careful observation for digital changes is necessary during treatment with ADHD stimulants.
(5.5) Visual Disturbance: Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
(5.7) Long-Term Suppression of Growth: Monitor height and weight at appropriate intervals in pediatric patients.
(5.6) Gastrointestinal obstruction with preexisting GI narrowing.
(5.8) Hematologic monitoring: Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
(5.9) 5.1 Serious Cardiovascular Events Sudden Death and Preexisting Structural Cardiac Abnormalities or Other Serious Heart Problems Children and Adolescents Sudden death has been reported in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems.
Although some serious heart problems alone carry an increased risk of sudden death, stimulant products generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug.
Adults Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD.
Although the role of stimulants in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems.
Adults with such abnormalities should also generally not be treated with stimulant drugs.
Hypertension and other Cardiovascular Conditions Stimulant medications cause a modest increase in average blood pressure (about 2 to 4 mm Hg) and average heart rate (about 3 to 6 bpm) [see Adverse Reactions (6.5) ] , and individuals may have larger increases.
While the mean changes alone would not be expected to have short-term consequences, all patients should be monitored for larger changes in heart rate and blood pressure.
Caution is indicated in treating patients whose underlying medical conditions might be compromised by increases in blood pressure or heart rate, e.g., those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.
Assessing Cardiovascular Status in Patients being Treated with Stimulant Medications Children, adolescents, or adults who are being considered for treatment with stimulant medications, should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram).
Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.
5.2 Psychiatric Adverse Events Preexisting Psychosis Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder.
Bipolar Illness Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in such patients.
Prior to initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.
Emergence of New Psychotic or Manic Symptoms Treatment-emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in patients without a prior history of psychotic illness or mania can be caused by stimulants at usual doses.
If such symptoms occur, consideration should be given to a possible causal role of the stimulant, and discontinuation of treatment may be appropriate.
In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3482 exposed to methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared to 0 in placebo-treated patients.
Aggression Aggressive behavior or hostility is often observed in patients with ADHD, and has been reported in clinical trials and the postmarketing experience of some medications indicated for the treatment of ADHD.
Although there is no systematic evidence that stimulants cause aggressive behavior or hostility, patients beginning treatment for ADHD should be monitored for the appearance of or worsening of aggressive behavior or hostility.
5.3 Seizures There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a history of seizures and no prior EEG evidence of seizures.
In the presence of seizures, the drug should be discontinued.
5.4 Priapism Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products, including Methylphenidate HCI Extended-Release Tablets in both pediatric and adult patients [see Adverse Reactions (6.6)].
Priapism was not reported with drug initiation but developed after some time on the drug, often subsequent to an increase in dose.
Priapism has also appeared during a period of drug withdrawal (drug holidays or during discontinuation).
Patients who develop abnormally sustained or frequent and painful erections should seek immediate medical attention.
5.5 Peripheral Vasculopathy, including Raynaud’s Phenomenon Stimulants, including Methylphenidate HCl Extended-Release Tablets, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s phenomenon.
Signs and symptoms are usually intermittent and mild; however, very rare sequelae include digital ulceration and/or soft tissue breakdown.
Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports at different times and at therapeutic doses in all age groups throughout the course of treatment.
Signs and symptoms generally improve after reduction in dose or discontinuation of drug.
Careful observation for digital changes is necessary during treatment with ADHD stimulants.
Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.
5.6 Long-Term Suppression of Growth Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either methylphenidate or non-medication treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and non-medication treated children over 36 months (to the ages of 10 to 13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of development.
Published data are inadequate to determine whether chronic use of amphetamines may cause similar suppression of growth; however, it is anticipated that they likely have this effect as well.
Therefore, growth should be monitored during treatment with stimulants, and patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.
5.7 Visual Disturbance Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.
5.8 Potential for Gastrointestinal Obstruction Because the Methylphenidate HCl Extended-Release Tablet is nondeformable and does not appreciably change in shape in the GI tract, Methylphenidate HCl Extended-Release Tablets should not ordinarily be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, 'short gut' syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or Meckel's diverticulum).
There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in nondeformable controlled-release formulations.
Due to the controlled-release design of the tablet, Methylphenidate HCl Extended-Release Tablets should only be used in patients who are able to swallow the tablet whole [see Patient Counseling Information (17) ] .
5.9 Hematologic Monitoring Periodic CBC, differential, and platelet counts are advised during prolonged therapy.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION See Medication Guide 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 HCl Extended-Release Tabletsabout 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 HCl 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 HCl 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.
The complete text of the Medication Guide is reprinted at the end of this document.
Administration Instructions Patients should be informed that Methylphenidate HCl Extended-Release Tablets should be swallowed whole with the aid of liquids.
Tablets should not be chewed, divided, or crushed.
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 HCl Extended-Release Tablets does not adversely affect their ability to engage in such activities.
DOSAGE AND ADMINISTRATION
2 Methylphenidate HCl Extended-Release Tablets should be taken once daily in the morning and swallowed whole with the aid of liquids.
Methylphenidate HCl Extended-Release Tablets should not be chewed or crushed.
Methylphenidate HCl Extended-Release Tablets may be taken with or without food.
( 2.1 ) For children and adolescents new to methylphenidate, the recommended starting dosage is 18 mg once daily.
Dosage may be increased by 18 mg/day at weekly intervals and should not exceed 54 mg/day in children and 72 mg/day in adolescents.
( 2.2 ) For adult patients new to methylphenidate, the recommended starting dose is 18 or 36 mg/day.
Dosage may be increased by 18 mg/day at weekly intervals and should not exceed 72 mg/day for adults.
( 2.2 ) For patients currently using methylphenidate, dosing is based on current dose regimen and clinical judgment.
( 2.3 ) 2.1 General Dosing Information Methylphenidate HCl Extended-Release Tablets should be administered orally once daily in the morning with or without food.
Methylphenidate HCl Extended-Release Tablets must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed [see Patient Counseling Information (17) ] .
2.2 Patients New to Methylphenidate The recommended starting dose of Methylphenidate HCl Extended-Release Tablets for patients who are not currently taking methylphenidate or stimulants other than methylphenidate is 18 mg once daily for children and adolescents and 18 or 36 mg once daily for adults (see Table 1).
Methylphenidate HCl Extended-Release Tablets Recommended Starting Doses and Dose Ranges Patient Age Recommended Starting Dose Dose Range Children 6-12 years of age 18 mg/day 18 mg – 54 mg/day Adolescents 13-17 years of age 18 mg/day 18 mg – 72 mg/day not to exceed 2 mg/kg/day Adults 18-65 years of age 18 or 36 mg/day 18 mg – 72 mg/day 2.3 Patients Currently Using Methylphenidate The recommended dose of Methylphenidate HCl Extended-Release Tablets for patients who are currently taking methylphenidate twice daily or three times daily, at doses of 10 to 60 mg/day is provided in Table 2.
Dosing recommendations are based on current dose regimen and clinical judgment.
Conversion dosage should not exceed 72 mg daily.
Recommended Dose Conversion from Methylphenidate Regimens to Methylphenidate HCl Extended-Release Tablets Previous Methylphenidate Daily Dose Recommended Methylphenidate HCl Extended-Release Tablets Starting Dose 5 mg Methylphenidate twice daily or three times daily 18 mg every morning 10 mg Methylphenidate twice daily or three times daily 36 mg every morning 15 mg Methylphenidate twice daily or three times daily 54 mg every morning 20 mg Methylphenidate twice daily or three times daily 72 mg every morning Other methylphenidate regimens: Clinical judgment should be used when selecting the starting dose.
2.4 Dose Titration Doses may be increased in 18 mg increments at weekly intervals for patients who have not achieved an optimal response at a lower dose.
Daily dosages above 54 mg in children and 72 mg in adolescents have not been studied and are not recommended.
Daily dosages above 72 mg in adults are not recommended.
A 27 mg dosage strength is available for physicians who wish to prescribe between the 18 mg and 36 mg dosages.
2.5 Maintenance/Extended Treatment There is no body of evidence available from controlled trials to indicate how long the patient with ADHD should be treated with Methylphenidate HCl Extended-Release Tablets.
It is generally agreed, however, that pharmacological treatment of ADHD may be needed for extended periods.
The effectiveness of Methylphenidate HCl Extended-Release Tablets for long-term use, i.e., for more than 7 weeks, has not been systematically evaluated in controlled trials.
The physician who elects to use Methylphenidate HCl Extended-Release Tablets for extended periods in patients with ADHD should periodically re-evaluate the long-term usefulness of the drug for the individual patient with trials off medication to assess the patient’s functioning without pharmacotherapy.
Improvement may be sustained when the drug is either temporarily or permanently discontinued.
2.6 Dose Reduction and Discontinuation If paradoxical aggravation of symptoms or other adverse events occur, the dosage should be reduced, or, if necessary, the drug should be discontinued.
If improvement is not observed after appropriate dosage adjustment over a one-month period, the drug should be discontinued.