The following Structured Product Label (SPL) was submitted to the FDA by Neos Therapeutics Brands, Llc for the product Cotempla Xr-odt (NDC 70165-300). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding warning: abuse and dependence, 1 indications and usage, 2.1 pretreatment screening, 2.2 general dosing information, 2.3 dose reduction and discontinuation, 2.4 cotempla xr-odt administration, 3 dosage forms and strengths, 4 contraindications, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
CNS stimulants, including COTEMPLA XR-ODT, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Warnings and Precautions (5.1), Drug Abuse and Dependence (9.2, 9.3)] .
COTEMPLA XR-ODT is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 17 years of age [see Clinical Studies (14)].
Prior to initiating treatment with COTEMPLA XR-ODT, assess for the presence of cardiac disease (i.e. perform a careful history, family history of sudden death or ventricular arrhythmia, and physical exam) [see Warnings and Precautions (5.2)] .
Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy. Maintain careful prescription records, educate patients about abuse, and periodically re-evaluate the need for COTEMPLA XR-ODT use [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9)].
COTEMPLA XR-ODT is given orally once daily in the morning.
Advise patients to take COTEMPLA XR-ODT consistently either with food or without food [see Clinical Pharmacology (12.3)] .
The recommended starting dose of COTEMPLA XR-ODT for patients 6 to 17 years of age is 17.3 mg once daily in the morning. The dose may be titrated weekly in increments of 8.6 mg to 17.3 mg. Daily doses above 51.8 mg have not been studied and are not recommended.
The dose should be individualized according to the needs and responses of the patient.
Pharmacological treatment of ADHD may be needed for extended periods. Periodically re-evaluate the long-term use of COTEMPLA XR-ODT and adjust dosage as needed.
If paradoxical aggravation of symptoms or other adverse effects occur, reduce dosage, or, if necessary, discontinue the drug. COTEMPLA XR-ODT should be periodically discontinued to assess the child's condition. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue the drug.
Instruct the patient or caregiver on the following administration instructions:
COTEMPLA XR-ODT is contraindicated in patients with:
CNS stimulants, including COTEMPLA XR-ODT, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy [see Boxed Warning and Drug Abuse and Dependence (9.2, 9.3)] .
Sudden death, stroke and myocardial infarction have occurred in adults treated with CNS stimulants at recommended doses. Sudden death has occurred in pediatric patients with structural cardiac abnormalities and other serious cardiac problems taking CNS stimulants at recommended doses for ADHD. Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, and other serious heart problems. Perform further evaluation on patients who develop exertional chest pain, unexplained syncope, or arrhythmias during COTEMPLA XR-ODT treatment.
CNS stimulants cause an increase in blood pressure (mean increase approximately 2 to 4 mm Hg) and heart rate (mean increase approximately 3 to 6 bpm). Individuals may have larger increases. Monitor all patients for hypertension and tachycardia.
Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate products in both pediatric and adult patients. 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.
CNS stimulants, including COTEMPLA XR-ODT, 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.
CNS stimulants have been associated with weight loss and slowing of growth rate in pediatric patients.
Careful follow-up of weight and height in pediatric patients ages 7 to 10 years who were randomized to either methylphenidate or nonmedication-treatment groups over 14 months, as well as in naturalistic subgroups of newly methylphenidate-treated and nonmedication-treated pediatric patients 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.
Closely monitor growth (weight and height) in pediatric patients treated with CNS stimulants, including COTEMPLA XR-ODT. Patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.
The following are discussed in more detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The following adverse reactions have been identified during post approval use of methylphenidate products. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions are as follows:
Blood and Lymphatic System Disorders: Pancytopenia, Thrombocytopenia, Thrombocytopenic purpura
Cardiac Disorders: Angina pectoris, Bradycardia, Extrasystole, Supraventricular tachycardia, Ventricular extrasystole
Eye Disorders: Diplopia, Mydriasis, Visual impairment
General Disorders: Chest pain, Chest discomfort, Hyperpyrexia
Immune System Disorders: Hypersensitivity reactions such as Angioedema, Anaphylactic reactions, Auricular swelling, Bullous conditions, Exfoliative conditions, Urticarias, Pruritis NEC, Rashes, Eruptions, and Exanthemas NEC
Investigations: Alkaline phosphatase increased, Bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal
Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis
Nervous System Disorders: Convulsion, Grand mal convulsion, Dyskinesia, Serotonin syndrome in combination with serotonergic drugs
Psychiatric Disorders: Disorientation, Hallucination, Hallucination auditory, Hallucination visual, Libido changes, Mania
Urogenital System: Priapism
Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema
Vascular Disorders: Raynaud's phenomenon
| Monoamine Oxidase Inhibitors (MAOI) | |
| Clinical Impact: | Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications (4)] . |
| Intervention: | Do not administer COTEMPLA-XR ODT concomitantly with MAOIs or within 14 days after discontinuing MAOI treatment. |
| Examples: | selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue |
| Gastric pH Modulators | |
| Clinical Impact: | May change the release profile and alter the pharmacodynamics of COTEMPLA-XR ODT. |
| Intervention: | Concomitant use of Cotempla XR-ODT with a gastric pH modulator (i.e., a H2-blocker or a proton pump inhibitor) is not recommended. |
| Examples: | omeprazole, famotidine, sodium bicarbonate |
| Antihypertensive Drugs | |
| Clinical Impact: | Cotempla XR-ODT may decrease the effectiveness of drug used to treat hypertension [see Warnings and Precautions (5.3)]. |
| Intervention: | Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. |
| Examples: | Potassium-sparing and thiazide diuretics, calcium channel blockers, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta blockers, centrally acting alpha-2 receptor agonists |
| Risperidone | |
| Clinical Impact: | Combined use of methylphenidate with risperidone when there is a change, whether an increase or decrease, in dosage of either or both medications, may increase the risk of extrapyramidal symptoms (EPS). |
| Intervention: | Monitor for signs of EPS. |
The safety and effectiveness of COTEMPLA XR-ODT have been established in pediatric patients 6 to 17 years of age in one adequate and well-controlled study in pediatric patients 6 to 12 years, pharmacokinetic data in adolescents, and safety information from other methyphenidate-containing products [see Clinical Pharmacology (12) and Clinical Studies (14)] .
The long-term efficacy of methylphenidate in pediatric patients has not been established. Safety and effectiveness of COTEMPLA XR-ODT in pediatric patients below 6 years of age have not been established.
COTEMPLA XR-ODT has not been studied in patients over the age of 65 years.
COTEMPLA XR-ODT contains methylphenidate, a Schedule II controlled substance.
CNS stimulants including COTEMPLA XR-ODT, other methylphenidate-containing products, and amphetamines have a high potential for abuse. Abuse is characterized by impaired control over drug use, compulsive use, continued use despite harm, and craving.
Signs and symptoms of CNS stimulant abuse include increased heart rate, respiratory rate, blood pressure, and/or sweating, dilated pupils, hyperactivity, restlessness, insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and/or abdominal pain. Anxiety, psychosis, hostility, aggression, suicidal or homicidal ideation have also been observed. Abusers of CNS stimulants may chew, snort, inject, or use other unapproved routes of administration which can result in overdose and death [see Overdosage (10)] .
To reduce the abuse of CNS stimulants including COTEMPLA XR-ODT, assess the risk of abuse prior to prescribing. After prescribing, keep careful prescription records educate patients and their families about abuse and on proper storage and disposal of CNS stimulants [see How Supplied/Storage and Handling (16)] , monitor for signs of abuse while on therapy, and re-evaluate the need for COTEMPLA XR-ODT use.
Signs and symptoms of acute methylphenidate overdosage, resulting principally from overstimulation of the CNS and from excessive sympathomimetic effects, may include the following: nausea, vomiting, diarrhea, restlessness, anxiety, agitation, tremors, hyperflexia, muscle twitching, convulsion (may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, hypertension, hypotension, tachypnea, mydriasis, dryness of mucous membranes, and rhabdomyolysis.
Consult with a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice on the management of overdosage with methylphenidate. Provide supportive care, including close medical supervision and monitoring. Treatment should consist of general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdosage. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures.
COTEMPLA XR-ODT contains methylphenidate, a central nervous system (CNS) stimulant. COTEMPLA XR-ODT is an extended-release orally disintegrating tablet intended for once daily administration. COTEMPLA XR-ODT contains approximately 25% immediate-release and 75% extended-release methylphenidate. Methylphenidate is ionically-bound to the sulfonate of polystyrene sulfonate particles.
COTEMPLA XR-ODT contains 8.6 mg, 17.3 mg or 25.9 mg of methylphenidate which is the same as the amount of methylphenidate (base equivalent) found, respectively, in 10 mg, 20 mg and 30 mg strength methylphenidate hydrochloride products.
The chemical name of methylphenidate is methyl α-phenyl-2-piperidineacetate, and its structural formula is shown in Figure 1.
Figure 1: Methylphenidate Structure
Figure 1 (Cotempla Xr Odt 1)
C 14H 19NO 2 Mol. Wt. 233.31
COTEMPLA XR-ODT also contains the following inactive ingredients: Mannitol, Fructose, Microcrystalline Cellulose, Crospovidone, Methacrylic Acid, Polystyrene Sulfonate, Citric Acid, Colloidal Silicon Dioxide, Grape Flavor, Natural Masking Type Powder, Triethyl Citrate, Magnesium Stearate, Ethylcellulose, Sucralose, Lake Blend Purple, and Polyethylene Glycol.
Methylphenidate is a central nervous system (CNS) stimulant. The mode of therapeutic action in ADHD is not known.
Methylphenidate is a racemic mixture comprised of the d- and 1-isomers. The d-isomer is more pharmacologically active than the l-isomer. 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.
After oral administration of COTEMPLA XR-ODT, circulation levels of l- methylphenidate (MPH) were about 2% of total MPH.
The efficacy of COTEMPLA XR-ODT was evaluated in a laboratory classroom study conducted in 87 pediatric patients (Aged 6 to 12 years) with ADHD. Following washout of previous methylphenidate medication, there was an open-label dose-optimization period (4 weeks) with an initial dose of 17.3 mg of COTEMPLA XR-ODT once daily in the morning. The dose could be titrated on a weekly basis from 17.3 mg, to 25.9 mg, to 34.6 mg, and up to 51.8 mg until an optimal dose or the maximum dose of 51.8 mg/day was reached. At the end of this period, subjects remained on their optimized dose for an additional week. Subjects then entered a 1-week randomized, double-blind, parallel group treatment period with the individually optimized dose of COTEMPLA XR-ODT or placebo. At the end of this week, raters evaluated the attention and behavior of the subjects in a laboratory classroom setting, using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale SKAMP is a validated 13-item teacher-rated scale that assesses manifestations of ADHD in a classroom setting.
The primary efficacy endpoint was the average of the SKAMP-Combined (Attention and Deportment) scores over the test day (not including the baseline score), with assessments conducted at baseline, and 1, 3, 5, 7, 10, 12, and 13 hours post-dosing. The key secondary efficacy endpoints were onset and duration of effect, defined as the first point at which active drug separated from placebo on SKAMP-Combined scores and the last time point at which active drug separated from placebo on SKAMP-Combined scores, respectively.
The SKAMP-Combined scores test day average was statistically significantly lower (improved) with COTEMPLA XR-ODT compared to placebo (difference of -11 (95% CI: -13.9, -8.2)) (Table 3).
| Study Number | Treatment Group | Baseline Score at Randomization a (SD) | Pre-dose Score on Classroom Day b (SD) | LS Mean c (SE) | Placebo-subtracted Difference d (95% CI) |
|---|---|---|---|---|---|
| SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.
a Visit 7 baseline score (Visit 7 occurred prior to the 1-week randomized, double-blind, parallel group treatment period). b Visit 8 baseline score (Visit 8 occurred at the end of the 1-week randomized, double-blind, parallel group treatment period). c Visit 8 LS mean over hours 1, 3, 5, 7, 10, 12, and 13. d Difference (drug minus placebo) in least-squares means. | |||||
| Study 1 | Cotempla XR-ODT
(17.3-51.8 mg/day) | 21.1 (9.56) | 26.8 (11.52) | 14.3 (1.07) | -11.0 (-13.9, -8.2) |
| Placebo | 20.4 (9.09) | 19.1 (11.04) | 25.3 (1.16) | -- | |
The SKAMP-Combined scores were also statistically significantly lower (improved) at time points (1, 3, 5, 7, 10, 12 hours) post-dosing with COTEMPLA XR-ODT compared to placebo (Figure 3).
Figure 3: LS Mean SKAMP Combined Score After Treatment with COTEMPLA XR-ODT or Placebo During Classroom Day in Patients with ADHD
Figure 3 (Cotempla Xr Odt 3)
*SE = Standard Error
The database was not large enough to assess whether there were differences in effects in age, gender, or race subgroups.
COTEMPLA XR-ODT Extended Release Orally Disintegrating Tablets are available in three strengths:
They are available as follows:
| NDC 70165-100-30 | 8.6 mg tablets: carton containing 5 blister cards of 6 tablets each, for a total of 30 tablets with a reusable travel case. |
| NDC 70165-200-30 | 17.3 mg tablets: carton containing 5 blister cards of 6 tablets each, for a total of 30 tablets with a reusable travel case. |
| NDC 70165-300-30 | 25.9 mg tablets: carton containing 5 blister cards of 6 tablets each, for a total of 30 tablets with a reusable travel case. |
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Contains:
NDC 70165-100-30
30 Tablets (5 x 6-count blister cards)
Travel Case
Rx Only
Cotempla XR-ODT™CII
Methylphenidate Extended-Release
Orally Disintegrating Tablets
Do not crush or chew tablets
Each tablet contains 8.6 mg of methylphenidate
(equivalent to that in a 10 mg strength
methylphenidate hydrochloride product)
8.6
mg
NEOS™
Therapeutics
PHARMACIST: Dispense the enclosed Medication Guide to each patient.
Principal Display Panel (8.6 mg Tablet Blister Pack Carton)
Contains:
NDC 70165-200-30
30 Tablets (5 x 6-count blister cards)
Travel Case
Rx Only
Cotempla XR-ODT™CII
Methylphenidate Extended-Release
Orally Disintegrating Tablets
Do not crush or chew tablets
Each tablet contains 17.3 mg of methylphenidate
(equivalent to that in a 20 mg strength
methylphenidate hydrochloride product)
17.3
mg
NEOS™
Therapeutics
PHARMACIST: Dispense the enclosed Medication Guide to each patient.
Principal Display Panel (17.3 mg Tablet Blister Pack Carton)
Contains:
NDC 70165-300-30
30 Tablets (5 x 6-count blister cards)
Travel Case
Rx Only
Cotempla XR-ODT™CII
Methylphenidate Extended-Release
Orally Disintegrating Tablets
Do not crush or chew tablets
Each tablet contains 25.9 mg of methylphenidate
(equivalent to that in a 30 mg strength
methylphenidate hydrochloride product)
25.9
mg
NEOS™
Therapeutics
PHARMACIST: Dispense the enclosed Medication Guide to each patient.
Principal Display Panel (25.9 mg Tablet Blister Pack Carton)
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