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WARNING
ABUSE AND DEPENDENCE
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, Drug Abuse And Dependence].
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 polystyrenesulfonate particles.
CONTEMPLA 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
 |
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.
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].
Prior to treating patients with COTEMPLA XR-ODT, assess:
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].
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.
If paradoxical aggravation of symptoms or other adverse reactions occur, reduce dosage, or, if necessary, discontinue COTEMPLA XR-ODT. If improvement is not observed after appropriate dosage adjustment over a one-month period, discontinue COTEMPLA XR-ODT.
Instruct the patient or caregiver on the following administration instructions:
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.
Store at 20° C to 25° C (68° F to 77° F); excursions permitted from 15° C to 30° C (59° F to 86° F) [see USP Controlled Room Temperature].
Store COTEMPLA XR-ODT blister packages in the reusable travel case after removal from the carton.
Manufactured for Neos Therapeutics Brands, LLC. Grand Prairie, TX 75050. Revised: Mar 2024.
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.
Commonly reported (≥2% of the methylphenidate group and at least twice the rate of the placebo group) adverse reactions from placebo-controlled trials of methylphenidate products include: appetite decreased, weight decreased, nausea, abdominal pain, dyspepsia, dry mouth, vomiting, insomnia, anxiety, nervousness, restlessness, affect lability, agitation, irritability, dizziness, vertigo, tremor, blurred vision, blood pressure increased, heart rate increased, tachycardia, palpitations, hyperhidrosis, and pyrexia.
There is limited experience with COTEMPLA XR-ODT in controlled trials. Based on this limited experience, the adverse reaction profile of COTEMPLA XR-ODT appears similar to other methylphenidate extended release-products.
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, Increased intraocular pressure, 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, Motor and Verbal Tics
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
Table 1: Drugs Having Clinically Important Interactions with Methylphenidate
| 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] |
| Intervention: | Do not administer COTEMPLA-XR ODT concomitantly with MAOIs or within 14 days after discontinuing MAOI treatment. |
| 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. |
| Antihypertensive Drugs | |
| Clinical Impact: | Cotempla XR-ODT may decrease the effectiveness of drug used to treat hypertenstion [see WARNINGS AND PRECAUTIONS] |
| Intervention: | Monitor blood pressure and adjust the dosage of the antihypertensive drug as needed. |
| Halogenated Anesthetics | |
| Clinical Impact: | Concomitant use of halogenated anesthetics and COTEMPLA XR-ODT may increase the risk of sudden blood pressure and heart rate increase during surgery. |
| Intervention: | Avoid use of COTEMPLA XR-ODT in patients being treated with anesthetics on the day of surgery. |
| 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 medicatons, may increase the risk of extrapyramidal symptoms (EPS). |
| Intervention: | Monitor for signs of EPS. |
COTEMPLA XR-ODT contains methylphenidate, a Schedule II controlled substance.
COTEMPLA XR-ODT has a high potential for abuse and misuse which can lead to the development of a substance use disorder, including addiction [see WARNINGS AND PRECAUTIONS]. COTEMPLA XR-ODT can be diverted for non-medical use into illicit channels or distribution.
Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.
Misuse and abuse of methylphenidate may cause increased heart rate, respiratory rate, or blood pressure; sweating; dilated pupils; hyperactivity; restlessness; insomnia; decreased appetite; loss of coordination; tremors; flushed skin; vomiting; and/or abdominal pain. Anxiety, psychosis, hostility, aggression, and suicidal or homicidal ideation have also been observed with CNS stimulants abuse and/or misuse. Misuse and abuse of CNS stimulants, including COTEMPLA XR-ODT, can result in overdose and death [see OVERDOSE], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.
Physical Dependence
COTEMPLA XR-ODT may produce physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.
Withdrawal signs and symptoms after abrupt discontinuation or dose reduction following prolonged use of CNS stimulants including COTEMPLA XR-ODT include dysphoric mood; depression; fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; and psychomotor retardation or agitation.
Tolerance
COTEMPLA XR-ODT may produce tolerance. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
Included as part of the "PRECAUTIONS" Section
COTEMPLA XR-ODT has a high potential for abuse and misuse. The use of COTEMPLA XR-ODT exposes individuals to the risks of abuse and misuse, which can lead to the development of a substance use disorder, including addiction. COTEMPLA XR-ODT can be diverted for nonmedical use into illicit channels or distribution [see Drug Abuse And Dependence]. Misuse and abuse of CNS stimulants, including COTEMPLA XR-ODT, can result in overdose and death [see OVERDOSE], and this risk is increased with higher doses or unapproved methods of administration, such as snorting or injection.
Before prescribing COTEMPLA XR-ODT, assess each patient’s risk for abuse, misuse, and addiction. Educate patients and their families about these risks and proper disposal of any unused drug. Advise patients to store COTEMPLA XR-ODT in a safe place, preferably locked, and instruct patients to not give COTEMPLA XR-ODT to anyone else. Throughout COTEMPLA XR-ODT treatment, reassess each patient’s risk of abuse, misuse, and addiction and frequently monitor for signs and symptoms of abuse, misuse, and addiction.
Sudden death has occurred in patients with structural cardiac abnormalities or other serious cardiac disease who were treated with CNS stimulants at the recommended ADHD dosages.
Avoid COTEMPLA XR-ODT use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease.
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). Some patients may have larger increases.
Monitor all COTEMPLA XR-ODT-treated patients for hypertension and tachycardia.
CNS stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a pre-existing psychotic disorder.
CNS stimulants may induce a manic or mixed episode in patients. Prior to initiating COTEMPLA XR-ODT treatment, screen patients for risk factors for developing a manic episode (e.g. comorbid or history of depressive symptoms or a family history of suicide, bipolar disorder, or depression).
CNS stimulants, at the recommended dosage, may cause psychotic or manic symptoms (e.g., hallucinations, delusional thinking or mania) in patients without a prior history of psychotic illness or mania. In a pooled analysis of multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or manic symptoms occurred in approximately 0.1% of CNS stimulanttreated patients, compared to 0% of placebo-treated patients. If such symptoms occur, consider discontinuing COTEMPLA XR-ODT.
Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with methylphenidate use in both adult and pediatric male patients. Although priapism was not reported with methylphenidate initiation, it developed after some time on methylphenidate, often subsequent to an increase in dosage. Priapism also occurred during methylphenidate withdrawal (drug holidays or during discontinuation).
COTEMPLA XR-ODT-treated 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, sequelae have included digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy, including Raynaud’s phenomenon, were observed in post-marketing reports and at the therapeutic dosages of CNS stimulants in all age groups throughout the course of treatment. Signs and symptoms generally improved after dosage reduction or discontinuation of the CNS stimulant.
Careful observation for digital changes is necessary during COTEMPLA XR-ODT treatment. Further clinical evaluation (e.g., rheumatology referral) may be appropriate for COTEMPLA XRODT- treated patients who develop signs or symptoms of peripheral vasculopathy.
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 pediatric patients who received methylphenidate for 7 days per week throughout the year had 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 development period.
Closely monitor growth (weight and height) in COTEMPLA XR-ODT-treated pediatric patients. Pediatric patients who are not growing or gaining height or weight as expected may need to have their treatment interrupted.
There have been reports of angle closure glaucoma associated with methylphenidate treatment.
Although the mechanism is not clear, COTEMPLA XR-ODT-treated patients considered at risk for acute angle closure glaucoma (e.g., patients with significant hyperopia) should be evaluated by an ophthalmologist.
There have been reports of an elevation of intraocular pressure (IOP) associated with methylphenidate treatment [see ADVERSE REACTIONS].
Prescribe COTEMPLA XR-ODT to patients with open-angle glaucoma or abnormally increased IOP only if the benefit of treatment is considered to outweigh the risk. Closely monitor COTEMPLA XR-ODT-treated patients with a history of abnormally increased IOP or open angle glaucoma.
CNS stimulants, including methylphenidate, have been associated with the onset or exacerbation of motor and verbal tics. Worsening of Tourette’s syndrome has also been reported [see ADVERSE REACTIONS].
Before initiating COTEMPLA XR-ODT, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome. Regularly monitor COTEMPLA XR-ODT-treated patients for the emergence or worsening of tics or Tourette’s syndrome, and discontinue treatment if clinically appropriate.
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Educate patients and their families about the risks of abuse, misuse, and addiction of COTEMPLA XR-ODT, which can lead to overdose and death, and proper disposal of any unused drug [see WARNINGS AND PRECAUTIONS, Drug Abuse And Dependence and OVERDOSE]. Advise patients to store COTEMPLA XR-ODT in a safe place, preferably locked, and instruct patients to not give COTEMPLA XR-ODT to anyone else.
Instruct patients and their caregivers on the following:
Advise patients that there are potential risks to patients with serious cardiac disease, including sudden death, with COTEMPLA XR-ODT use. Instruct patients to contact a healthcare provider immediately if they develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease [see WARNINGS AND PRECAUTIONS].
Advise patients and their caregivers that COTEMPLA XR-ODT can elevate blood pressure and heart rate [see WARNINGS AND PRECAUTIONS].
Advise patients and their caregivers that COTEMPLA XR-ODT, at recommended doses, can cause psychotic or manic symptoms, even in patients without a prior history or psychotic symptoms or mania [see WARNINGS AND PRECAUTIONS].
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].
Advise patients, families, and caregivers that COTEMPLA XR-ODT can cause slowing of growth and weight loss [see WARNINGS AND PRECAUTIONS].
Advise patients that IOP and glaucoma may occur during treatment with COTEMPLA XR-ODT [see WARNINGS AND PRECAUTIONS].
Advise patients that motor and verbal tics and worsening of Tourette’s Syndrome may occur during treatment with COTEMPLA XR-ODT. Instruct patients to notify their healthcare provider if emergence of new tics or worsening of tics or Tourette’s syndrome occurs [see WARNINGS AND PRECAUTIONS].
Advise patients to avoid alcohol while taking COTEMPLA XR-ODT. Consumption of alcohol while taking COTEMPLA XR-ODT may result in a more rapid release of the dose of methylphenidate [see CLINICAL PHARMACOLOGY].
Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to COTEMPLA XR-ODT during pregnancy [see Use In Specific Populations].
In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas and, in males only, an increase in hepatoblastomas at a daily dose of approximately 60 mg/kg/day. For pediatric patients, this dose is approximately 4 times the maximum recommended human dose of 51.8 (as base) on a mg/m2 basis. Hepatoblastoma is a relatively rare rodent malignant tumor type. There was no increase in total malignant hepatic tumors. The mouse strain used is sensitive to the development of hepatic tumors, and the significance of these results to humans is unknown.
Methylphenidate did not cause any increase in tumors in a lifetime carcinogenicity study carried out in F344 rats; the highest dose used was approximately 45 mg/kg/day, which is approximately 5 times the maximum recommended dose of 51.8 mg (as base) for pediatric patients on a mg/m2 basis.
Methylphenidate was not mutagenic in the in vitro Ames reverse mutation assay or the in vitro mouse lymphoma cell forward mutation assay. Sister chromatid exchanges and chromosome aberrations were increased, indicative of a weak clastogenic response, in an in vitro assay in cultured Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in an in vivo mouse bone marrow micronucleus assay.
Methylphenidate did not impair fertility in male or female mice that were fed diets containing the drug in an 18-week Continuous Breeding study. The study was conducted at doses up to 160 mg/kg/day, approximately 12-fold the maximum recommended human dose of 51.8 (as base) for adolescents on a mg/m2 basis.
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to COTEMPLA XR–ODT during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychostimulants at 1-866-961-2388.
Published studies and postmarketing reports on methylphenidate use during pregnancy are insufficient to inform a drug–associated risk of adverse pregnancy–related outcomes [see Data]. There are risks to the fetus associated with the use of central nervous system (CNS) stimulants during pregnancy [see Clinical Considerations]. No teratogenic effects were observed in embryo–fetal development studies with oral administration of methylphenidate to pregnant rats and rabbits during organogenesis at doses 4 and 18 times, respectively, the maximum recommended human dose (MRHD) of 51.8 mg(as base). However, spina bifida was observed in rabbits at a dose 60 times the MRHD[see Data].
The estimated background risk of major birth defects and miscarriage for the indicated population is unkown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general populations, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–, respectively.
Fetal/Neonatal Adverse Reactions
CNS stimulants, such as COTEMPLA XR-ODT, can cause vasoconstriction and thereby decrease placental perfusion. No fetal and/or neonatal adverse reactions have been reported with the use of therapeutic doses of methylphenidate during pregnancy; however, premature delivery and low birth weight infants have been reported in amphetamine-dependent mothers.
Human Data
A limited number of pregnancies have been reported in published observational studies and postmarketing reports describing methylphenidate use during pregnancy. Due to the small number of methylphenidate-exposed pregnancies with known outcomes, these data cannot definitely establish or exclude any drug-associated risk during pregnancy. Methodological limitations of these observational studies include small sample size, concomitant use of other medications, lack of detail regarding dose and duration of exposure to methylphenidate and non-generalizability of the enrolled populations.
Animal Data
In studies conducted in rats and rabbits, methylphenidate was administered orally at doses of up to 75 and 200 mg/kg/day, respectively, during the period of organogenesis. Teratogenic effects (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 60 times the maximum recommended human dose (MRHD) of 51.8 mg (as base) for adolescents on a mg/m2 basis. The no effect level for embryo-fetal development in rabbits was 60 mg/kg/day (18 times the MRHD for adolescent on a mg/m2 basis). There was no evidence of specific teratogenic activity in rats, although increased incidences of fetal skeletal variations were seen at the highest dose level (11 times the MRHD on a mg/m2 basis for adolescent), which was also maternally toxic. The no effect level for embryo-fetal development in rats was 25 mg/kg/day (4 times the MRHD on a mg/m2 basis for adolescent).
Limited published literature, based on breast milk sampling from five mothers, reports that methylphenidate is present in human milk, which resulted in infant doses of 0.16% to 0.7% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7. There are no reports of adverse effects on the breastfed infant and no effects on milk production. Long-term neurodevelopmental effects on infants from stimulant exposure are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for COTEMPLA XR-ODT and any potential adverse effects on the breastfed child from COTEMPLA XR-ODT or from the underlying maternal condition.
Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain.
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 methylphenidate-containing products [see CLINICAL PHARMACOLOGY and Clinical Studies].
The safety and effectiveness of COTEMPLA XR-ODT in pediatric patients below 6 years of age have not been established. The long-term efficacy of methylphenidate in pediatric patients has not been established.
Growth should be monitored during treatment with stimulants, including COTEMPLA XR-ODT. Children who are not growing or gaining weight as expected may need to have their treatment interrupted [see WARNINGS AND PRECAUTIONS].
Rats treated with methylphenidate early in the postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific learning task was observed in females only. The doses at which these findings were observed are at least 6 times the maximum recommended human dose (MRHD) of 51.8 mg (as base) for pediatric patients on a mg/m2 basis.
In the study conducted in young rats, methylphenidate was administered orally at doses of up to 100 mg/kg/day for 9 weeks, starting early in the postnatal period (postnatal day 7) and continuing through sexual maturity (postnatal week 10). When these animals were tested as adults (postnatal weeks 13-14), decreased spontaneous locomotor activity was observed in males and females previously treated with 50 mg/kg/day [approximately 6 times the MRHD of 51.8 mg (as base) on a mg/m2 basis] or greater, and a deficit in the acquisition of a specific learning task was observed in females exposed to the highest dose (12 times the MRHD on a mg/m2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (half the MRHD on a mg/m2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
COTEMPLA XR-ODT has not been studied in patients over the age of 65 years.
Overdose of CNS stimulants is characterized by the following sympathomimetic effects:
Consider the possibility of multiple drug ingestion. The pharmacokinetic profile of COTEMPLA XR-ODT should be considered when treating patients with overdose. Because methylphenidate has a large volume of distribution and is rapidly metabolized, dialysis is not useful. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
COTEMPLA XR-ODT is contraindicated in patients with:
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.
Following a single dose of 51.8 mg (2x25.9 mg daily) COTEMPLA XR-ODT in healthy adult subjects under fasted conditions, plasma methylphenidate (MPH) reached maximal concentration (Cmax) at a median time of 5 hours after dosing. Compared to an extended release capsule formulation of methylphenidate, methylphenidate mean Cmax and exposure (AUCinf) was about 26% and 6% higher, respectively, after COTEMPLA XR-ODT administration (Figure 2).
Figure 2: Mean d-Methylphenidate Plasma Concentration-Time Profiles After Administration of COTEMPLA XR-ODT or Methylphenidate Hydrochloride Extended-Release Capsule in Healthy Volunteers Under Fasted Conditions
 |
Effect of Food
Administration of 51.8 mg COTEMPLA XR-ODT with food (a high fat meal) decreased the Cmax and increased AUCinf of total MPH by approximately 24% and 16%, respectively. Food shortened the median time to peak concentration (Tmax) by 0.5 hour (fed: 4.5 hours vs. fasted: 5.0 hours).
Effect of Alcohol
There is no in vivo study conducted for the effect of alcohol on drug exposure. An in vitro dissolution study showed alcohol-induced dose dumping potential in the presence of 40% alcohol. Dose dumping was not observed in the presence of lower alcohol concentrations.
Plasma methylphenidate concentrations decline monophasically following oral administration of COTEMPLA XR-ODT. The mean plasma terminal elimination half-life of methylphenidate was about 4 hours in healthy volunteers following a single 51.8 mg dose administration.
Metabolism
In humans, methylphenidate is metabolized primarily via deesterification to alpha-phenylpiperidine acetic acid (ritalinic acid). The metabolite has little or no pharmacological activity.
Excretion
After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main primary metabolite was PPAA, accounting for approximately 80% of the dose.
There is insufficient experience with the use of COTEMPLA XR-ODT to detect gender or ethnic variations in pharmacokinetics.
The pharmacokinetics of methylphenidate after COTEMPLA XR-ODT administration were studied in pediatric patients (6-17 years of age) with ADHD under fasted conditions. After a single oral dose of 51.8 mg COTEMPLA XR-ODT, plasma concentrations of methylphenidate in children (6-12 years of age) were approximately twice the concentrations observed in adults. Exposure levels in adolescent patients (13 -17 years of age) were similar to those in adults. Body weight normalized clearance values were similar across the age groups (Table 2).
Table 2: PK Parameters (Mean ± SD) of d-MPH After 51.8 mg Oral Dosing of COTEMPLA XRODT Under Fasted Conditions
| PK Parameter | Children (n=24) | Adolescent (n=8) | Adult (n=38) |
| Tmax (hr)† | 4.6 (2.0-8.0) | 5.31 (3.5-8.0) | 4.98 (2.5 - 6.5) |
| T½ (hr) | 4.43 ± 1.0 | 3.93 ± 0.33 | 4.00 ± 0.73 |
| Cmax (ng/mL) | 32.7 ± 9.83 | 20.2 ± 5.79 | 20.8 ± 5.22 |
| Cl (L/hr/kg) | 6.21 ± 1.48 | 5.54 ± 1.19 | 5.48 ± 1.46 |
| AUC∞ (hr*ng/mL) | 328.9 ± 90.21 | 187.2 ± 62.05 | 169.1 ± 57.13 |
| † data presented as median range | |||
There is no experience with the use of COTEMPLA XR-ODT in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of PPAA. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of COTEMPLA XR-ODT.
There is no experience with the use of COTEMPLA XR-ODT in patients with hepatic insufficiency.
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).
Table 3: Efficacy Analysis Results: SKAMP-Combined Scores Averaged Over Classroom Day in Patients with ADHD
| Study Number | Treatment Group | Baseline Score at Randomizationa (SD) |
Pre-dose Score on Classroom Dayb (SD) |
LS Meanc (SE) |
Placebo-subtracted Differenced (95% CI) |
| 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) | - | |
| 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. |
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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
 |
| *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
(koh-TEM-pluh - oh dee tee)
(methylphenidate) extended-release, orally disintegrating tablets
What is the most important information I should know about COTEMPLA XR-ODT?
COTEMPLA XR-ODT may cause serious side effects, including:
Keep COTEMPLA XR-ODT in a safe place and properly dispose of any used medicine. See “How should I store COTEMPLA XR-ODT?” for more information.
Tell your healthcare provider if your child has ever abused or been dependent on alcohol, prescription medicines, or street drugs.
Risks for people with serious heart disease. Sudden death has happened in people who have heart defects or other serious heart disease.
Your healthcare provider should check your child carefully for heart problems before starting COTEMPLA XR-ODT. Tell your healthcare provider if your child has any heart problems, heart disease, or heart defects.
Call your healthcare provider or go to the nearest hospital emergency room right away if your child has any signs of heart problems such as chest pain, shortness of breath, or fainting during treatment with COTEMPLA XR-ODT.
Tell your healthcare provider about any mental problems your child has, or about a family history of suicide, bipolar illness, or depression.
Call your healthcare provider right away if your child has any new or worsening mental
symptoms or problems during treatment with COTEMPLA XR-ODT, especially hearing voices, seeing or believing things that are not real, or new manic symptoms.
What is COTEMPLA XR-ODT?
COTEMPLA XR-ODT is a central nervous system (CNS) stimulant prescription medicine used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children 6 to 17 years of age. COTEMPLA XR-ODT may help increase attention and decrease impulsiveness and hyperactivity in children 6 to 17 years of age with ADHD.
It is not known if COTEMPLA XR-ODT is safe and effective in children under 6 years of age.
COTEMPLA XR-ODT is a federally controlled substance (CII) because it contains methylphenidate that can be a target for people who abuse prescription medicines or street drugs. Keep COTEMPLA XR-ODT in a safe place to protect it from theft. Never give your COTEMPLA XR-ODT to anyone else, because it may cause death or harm them. Selling or giving away COTEMPLA XR-ODT may harm others and is against the law.
Do not give COTEMPLA XR-ODT to your child if they are:
Before taking COTEMPLA XR-ODT tell your child’s healthcare provider about all medical conditions, including if your child:
Tell your healthcare provider about all of the medicines that your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
COTEMPLA XR-ODT and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted during treatment with COTEMPLA XR-ODT. Your healthcare provider will decide whether COTEMPLA XR-ODT can be taken with other medicines. Especially tell your healthcare provider if your child takes:
Know the medicines that your child takes. Keep a list of the medicines with you to show your healthcare provider and pharmacist. Do not start any new medicine during treatment with COTEMPLA XR-ODT without talking to your healthcare provider first.
How should COTEMPLA XR-ODT be taken?
Take COTEMPLA XR-ODT as follows:
If your child takes too much COTEMPLA XR-ODT, call your healthcare provider or Poison Help line at 1-800-222-1222 or go to the nearest hospital emergency room right away.
What should I avoid during treatment with COTEMPLA XR-ODT?
You should avoid drinking alcohol during treatment with COTEMPLA XR-ODT.
What are possible side effects of COTEMPLA XR-ODT?
COTEMPLA XR-ODT may cause serious side effects, including:
Tell your healthcare provider if your child has numbness, pain, skin color change, or sensitivity to temperature in their fingers or toes.
Call your healthcare provider right away if your child has any signs of unexplained wounds appearing on fingers or toes during treatment with COTEMPLA XR-ODT.
The most common side effects of methylphenidate products include:
These are not all the possible side effects of COTEMPLA XR-ODT.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1- 800-FDA-1088.
How should I store COTEMPLA XR-ODT?
Keep COTEMPLA XR-ODT and all medicines out of the reach of children.
General information about the safe and effective use of COTEMPLA XR-ODT
Medicines are sometimes prescribed for purposes other than those listed in the Medication Guide. Do not use COTEMPLA XR-ODT for a condition for which it was not prescribed. Do not give COTEMPLA XR-ODT to other people, even if they have the same condition. It may harm them and it is against the law. You can ask your healthcare provider or pharmacist for information about COTEMPLA XR-ODT that is written for healthcare professionals.
What are the ingredients in COTEMPLA XR-ODT?
Active Ingredient: Methylphenidate
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 3350.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
