Data from FDA - Curated by EPG Health - Last updated 28 July 2017

Indication(s)

1 INDICATIONS AND USAGE 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)]. COTEMPLA XR-ODT is a central nervous system (CNS) stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients 6 to 17 years of age. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS COTEMPLA XR-ODT is contraindicated in patients with: Known hypersensitivity to methylphenidate or other components of COTEMPLA XR-ODT. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate products [see Adverse Reactions (6.2)]. Concomitant treatment with monoamine oxidase inhibitors (MAOIs), and also within a minimum of 14 days following discontinuation of treatment with a monoamine oxidase inhibitor because of the risk of hypertensive crisis [see Drug Interactions (7.1)]. Known hypersensitivity to methylphenidate or product components. (4) Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or use of an MAOI within the preceding 14 days. (4)
Adverse reactions
6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Known hypersensitivity to methylphenidate or other ingredients of Cotempla XR-ODT [see Contraindications (4)] Hypertensive crisis when used concomitantly with monoamine oxidase inhibitors [see Contraindications (4) and Drug Interactions (7.1)] Drug dependence [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)] Serious cardiovascular reactions [see Warnings and Precautions (5.2)] Blood pressure and heart rate increases [see Warnings and Precautions (5.3)] Psychiatric adverse reactions [see Warnings and Precautions (5.4)] Priapism [see Warnings and Precautions (5.5)] Peripheral vasculopathy, including Raynaud's phenomenon [see Warnings and Precautions (5.6)] Long-term suppression of growth [see Warnings and Precautions (5.7)] Based on accumulated data from other methylphenidate products, the most common (>5% and twice the rate of placebo) adverse reactions are appetite decreased, insomnia, nausea, vomiting, dyspepsia, abdominal pain, weight decreased, anxiety, dizziness, irritability, affect lability, tachycardia, and blood pressure increased. (6) To report SUSPECTED ADVERSE REACTIONS, contact Neos Therapeutics, Inc. at 1-888-319-1789 or http://www.COTEMPLAXRODT.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience 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. Clinical Trials Experience with Other Methylphenidate Products in Children, Adolescents, and Adults with ADHD 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. Clinical Trials Experience with COTEMPLA XR-ODT in Children with ADHD 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. 6.2 Postmarketing Experience 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

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Recommended starting dose for pediatric patients 6 to 17 years of age is 17.3 mg given orally once daily in the morning. Dosage may be increased weekly in increments of 8.6 mg to 17.3 mg per day. Daily dosage above 51.8 mg is not recommended. (2.2) Patients are advised to take COTEMPLA XR-ODT consistently either with food or without food. (2.2) 2.1 Pretreatment Screening 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)]. 2.2 General Dosing Information 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. 2.3 Dose Reduction and Discontinuation 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. 2.4 COTEMPLA XR-ODT Administration Instruct the patient or caregiver on the following administration instructions: Do not remove the tablet from the blister pack until just prior to dosing. Take the tablet immediately after opening the blister pack. Do not store the tablet for future use. Use dry hands when opening the blister pack. Remove the tablet by peeling back the foil on the blister pack. Do not push the tablet through the foil. As soon as the blister is opened, remove the tablet and place on the patient's tongue. Place the whole tablet on the tongue and allow it to disintegrate without chewing or crushing. The tablet will disintegrate in saliva so that it can be swallowed. No liquid is needed to take the tablet.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry 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. Risk Summary 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 unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations 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. Data 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). 8.2 Lactation Risk Summary 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. Clinical Considerations Monitor breastfeeding infants for adverse reactions, such as agitation, insomnia, anorexia, and reduced weight gain. 8.4 Pediatric Use 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. Long Term Suppression Growth 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 (5.7)]. Juvenile Animal Toxicity Data 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. 8.5 Geriatric Use COTEMPLA XR-ODT has not been studied in patients over the age of 65 years.

Interactions

7 DRUG INTERACTIONS 7.1 Clinically Important Interactions with COTEMPLA XR-ODT 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 (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

More information

Category Value
Authorisation number NDA205489
Agency product number 207ZZ9QZ49
Orphan designation No
Product NDC 70165-300,70165-200,70165-100
Date Last Revised 28-06-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1926849
Storage and handling 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. Disposal Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired COTEMPLA XR-ODT by a medicine take-back program or by an authorized collector registered with the Drug Enforcement Administration. If no take-back program or authorized collector is available, mix COTEMPLA XR-ODT with an undesirable, nontoxic substance to make it less appealing to children and pets. Place the mixture in a container such as a sealed plastic bag and discard COTEMPLA XR-ODT in the household trash.
Marketing authorisation holder Neos Therapeutics, LP
Warnings 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 (5.1), Drug Abuse and Dependence (9.2, 9.3)]. WARNING: ABUSE AND DEPENDENCE See full prescribing information for complete boxed warning. CNS stimulants, including COTEMPLA XR-ODT, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence (5.1, 9.2, 9.3) Assess the risk of abuse prior to prescribing, and monitor for signs of abuse and dependence while on therapy (5.1, 9.2)