Aptensio XR

Using this medicine improperly can cause death or serious side effects on the heart.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Methylphenidate may be habit-forming. Never share this medicine with another person, especially someone with a history of drug abuse or addiction. Selling or giving away this medicine is against the law.

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

To prevent sleep problems, take this medicine in the morning.

Some brands of methylphenidate should be taken at least 30 minutes before a meal. Extended-release methylphenidate can be taken with or without food. Follow the directions on your medicine label

Do not crush, chew, or break an extended-release tablet. Swallow it whole. Breaking the pill may cause too much of the drug to be released at one time.

To make swallowing easier, you may open the capsule and sprinkle the medicine into a spoonful of pudding or applesauce. Swallow right away without chewing. Do not save the mixture for later use.

The chewable tablet must be chewed before you swallow it.

Measure liquid medicine with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.

Shake the oral suspension (liquid) well just before you measure a dose.

While using methylphenidate, your doctor will need to check your progress at regular visits. Your heart rate, blood pressure, height and weight may also need to be checked often.

If you need surgery, tell the surgeon ahead of time that you are using methylphenidate. You may need to stop using the medicine for a short time.

Store at room temperature away from moisture and heat.

Keep track of the amount of medicine used from each new bottle. Methylphenidate is a drug of abuse and you should be aware if anyone is using your medicine improperly or without a prescription.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of methylphenidate could be fatal.

Take the missed dose as soon as you remember. Skip the missed dose if it is later than 6:00 p.m. Do not take extra medicine to make up the missed dose.

Do not use methylphenidate if you have used an MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, tranylcypromine, and others.

You should not use methylphenidate if you are allergic to it, or if you have:

• glaucoma;

• a personal or family history of tics (muscle twitches) or Tourette's syndrome; or

• severe anxiety, tension, or agitation (stimulant medicine can make these symptoms worse).

Stimulants have caused stroke, heart attack, and sudden death in certain people. Tell your doctor if you have:

• heart problems or a congenital heart defect;

• high blood pressure; or

• a family history of heart disease or sudden death.

To make sure this medicine is safe for you, tell your doctor if you or anyone in your family has ever had:

• depression, mental illness, bipolar disorder, psychosis, or suicidal thoughts or actions;

• motor tics (muscle twitches) or Tourette's syndrome;

• blood circulation problems in the hands or feet;

• seizures or epilepsy;

• problems with the esophagus, stomach, or intestines;

• an abnormal brain wave test (EEG); or

• a history of drug or alcohol addiction.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It is not known whether methylphenidate passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Methylphenidate is not approved for use by anyone younger than 6 years old.

General Dosing Information

The recommended starting dose of Aptensio XR for patients 6 years and above is 10 mg once daily in the morning with or without food. Advise patients to establish a routine pattern with regard to meals. The dose should be individualized according to the needs and response of the patient.

The dose may be titrated weekly in increments of 10 mg. Daily doses above 60 mg have not been studied and are not recommended.

Aptensio XR may be taken whole or the capsule may be opened and the entire contents sprinkled onto applesauce. If the patient is using the sprinkled administration method, the sprinkled applesauce should be consumed immediately; it should not be stored. Patients should take the applesauce with sprinkled beads in its entirety without chewing. The dose of a single capsule should not be divided. The contents of the entire capsule should be taken, and patients should not take anything less than one capsule per day.

Pharmacological treatment of ADHD may be needed for extended periods. Healthcare providers should periodically re-evaluate the long-term use of Aptensio XR, and adjust dosage as needed.

Dose Reduction and Discontinuation

If paradoxical aggravation of symptoms or other adverse reactions 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.

Important Information Prior to Initiating Treatment

Prior to treating pediatric patients and adults with CNS stimulants including Aptensio XR, 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, monitor for signs of abuse and overdose, and periodically re-evaluate the need for Aptensio XR use [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9)].

• 10 mg Extended-Release Capsules – light turquoise blue cap/white body (imprinted with “Aptensio XR” on cap and “10 mg” on the body)
• 15 mg Extended-Release Capsules – orange cap/white body (imprinted with “Aptensio XR” on cap and “15 mg” on the body)
• 20 mg Extended-Release Capsules – yellow cap/white body (imprinted with “Aptensio XR” on cap and “20 mg” on the body)
• 30 mg Extended-Release Capsules – blue violet cap/white body (imprinted with “Aptensio XR” on cap and “30 mg” on the body)
• 40 mg Extended-Release Capsules – pink cap/white body (imprinted with “Aptensio XR” on cap and “40 mg” on the body)
• 50 mg Extended-Release Capsules – green cap/white body (imprinted with “Aptensio XR” on cap and “50 mg” on the body)
• 60 mg Extended-Release Capsules – gray cap/white body (imprinted with “Aptensio XR” on cap and “60 mg” on the body)

• Hypersensitivity to methylphenidate or other components of the product. Hypersensitivity reactions such as angioedema and anaphylactic reactions have been reported in patients treated with methylphenidate products [see Adverse Reactions (6.1)].
• Concomitant treatment with monoamine oxidase inhibitors, and also within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor, because of the risk of hypertensive crisis [see Drug Interactions (7.1)].

The following are discussed in more detail in other sections of the labeling:

• Drug Dependence [see Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence (9.2, 9.3)]
• Hypersensitivity to Methylphenidate [see Contraindications (4)]
• Monoamine Oxidase Inhibitors [see Contraindications (4) and Drug Interactions (7.1)]
• Serious Cardiovascular Events [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)]

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: decreased appetite, decreased weight, nausea, abdominal pain, dyspepsia, dry mouth, vomiting, insomnia, anxiety, nervousness, restlessness, affect lability, agitation, irritability, dizziness, vertigo, tremor, blurred vision, increased blood pressure, increased heart rate, tachycardia, palpitations, hyperhidrosis, and pyrexia.

Clinical Trials Experience with Aptensio XR in Pediatric Patients with ADHD

The safety data in this section is based on data from two one-week controlled clinical studies of Aptensio XR in pediatric patients with ADHD, one in children ages 6 to 12 years (RP-BP-EF001, hereafter "Study 1"), and one in children and adolescents ages 6 to 17 years (RP-BP-EF002, hereafter "Study 2").

Two Aptensio XR clinical studies evaluated a total of 256 patients with ADHD. Two hundred and forty-three (243) patients participated in the double-blind phase of these two clinical studies.

Study 1 was a randomized, double-blind, single center, placebo-controlled, flexible-dose, cross-over study to evaluate the time of onset, duration of efficacy, tolerability and safety of Aptensio XR 15 mg, 20 mg, 30 mg, or 40 mg administered for one week in 26 pediatric patients aged 6 to 12 years who met DSM-IV criteria for ADHD [see Clinical Studies (14)].

Most Common Adverse Reactions (incidence of  ≥ 5% and at a rate at least twice placebo): abdominal pain, pyrexia and headache.

Adverse Reactions Leading to Discontinuation: No subjects discontinued due to adverse reactions during the double-blind phase of this study.

Study 2 was a randomized, double-blind, multicenter, placebo-controlled, parallel group, fixed-dose study of 10 mg, 15 mg, 20 mg, and 40 mg of Aptensio XR administered for one week in 221 pediatric patients (6 to 17 years of age) who met DSM-IV criteria for ADHD [see Clinical Studies (14)].

Most Common Adverse Reactions (incidence of  ≥ 5% and at a rate of at least twice placebo): abdominal pain, decreased appetite, headache and insomnia.

Adverse Reactions Leading to Discontinuation: Two patients (4.4%) in the Aptensio XR 40 mg group discontinued due to insomnia, nausea and rapid heart rate, respectively during the double-blind phase of the study.

Table 1: Common Adverse Reactions Occurring in ≥ 2% of Pediatric Patients (6 to 17 years of age) with ADHD Taking Aptensio XR and at a Rate Greater than Placebo (Study 2)

Post-Marketing 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, Pruritus NEC, Rashes, Eruptions, and Exanthemas NEC
Investigations: Alkaline phosphatase increased, Bilirubin increased, Hepatic enzyme increased, Platelet count decreased, White blood cell count abnormal, severe hepatic injury
Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, Myalgia, Muscle twitching, Rhabdomyolysis
Nervous System: Convulsion, Grand mal convulsion, Dyskinesia, serotonin syndrome in combination with serotonergic drugs
Psychiatric Disorders: Disorientation, Libido changes
Skin and Subcutaneous Tissue Disorders: Alopecia, Erythema 

Clinically Important Interactions with Aptensio XR

Monoamine Oxidase Inhibitors (MAOIs)

Do not administer Aptensio XR concomitantly or within 14 days after discontinuing MAOI treatment. 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)].

Applies to methylphenidate: oral capsule extended release, oral powder for suspension extended release, oral solution, oral tablet, oral tablet chewable, oral tablet extended release, oral tablet extended release chewable

Other dosage forms:

• transdermal patch extended release

Along with its needed effects, methylphenidate (the active ingredient contained in Aptensio XR) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking methylphenidate:

• Fast heartbeat

• Chest pain
• fever
• joint pain
• skin rash or hives

• Black, tarry stools
• blood in the urine or stools
• blurred vision or other changes in vision
• crusting, dryness, or flaking of the skin
• muscle cramps
• pinpoint red spots on the skin
• scaling, severe redness, soreness, or swelling of the skin
• seizures
• uncontrolled vocal outbursts or tics (uncontrolled and repeated body movements)
• unusual bleeding or bruising

• Confusion
• depression
• feeling like surroundings are not real
• numbness of the hands
• painful or difficult urination
• pale skin
• paleness or cold feeling in the fingertips and toes
• red, irritated eyes
• red, swollen, or scaly skin
• seeing, hearing, or feeling things that are not there
• severe or sudden headache
• sores, ulcers, or white spots on the lips or in the mouth
• sudden loss of coordination
• sudden slurring of speech
• tingling or pain in the fingers or toes when exposed to cold
• unusual behavior
• unusual tiredness or weakness
• weight loss
• yellow skin or eyes

Get emergency help immediately if any of the following symptoms of overdose occur while taking methylphenidate:

• Agitation
• anxiety
• bigger, dilated, or enlarged pupils of the eyes
• confusion as to time, place, or person
• dark-colored urine
• diarrhea
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• dry eyes, mouth, nose, or throat
• false or unusual sense of well-being
• fast, slow, irregular, pounding, or racing heartbeat or pulse
• holding false beliefs that cannot be changed by fact
• increased sensitivity of the eyes to light
• loss of consciousness
• muscle pain or stiffness
• muscle twitching
• nervousness
• overactive reflexes
• pounding in the ears
• rapid, shallow breathing
• sweating
• tremors
• unusual excitement, nervousness, or restlessness

Some side effects of methylphenidate may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Headache
• loss of appetite
• nervousness
• stomach pain
• stuffy nose
• trouble sleeping
• unusually warm skin

• Anger
• decreased appetite
• dizziness
• drowsiness
• fear
• irritability
• muscle aches
• nausea
• runny nose
• scalp hair loss
• talking, feeling, and acting with excitement
• vomiting

Methylphenidate has been assigned to pregnancy category C by the FDA. Adequate animal reproductive studies to establish the safe use of methylphenidate during pregnancy have not been conducted. There are no controlled data in human pregnancy. However, in the Michigan Medicaid Birth Defects Study involving 229,101 pregnancies from 1985 to 1992, there was one major cardiovascular birth defect reported out of 13 newborns who were exposed to methylphenidate during the first trimester. (One was expected.) (Written communication, Franz Rosa, MD, Food and Drug Administration, 1994) Methylphenidate is only recommended for use during pregnancy when benefit outweighs risk.

Summary of Use during Lactation

In dosages prescribed for medical indications, limited evidence indicates that methylphenidate levels in milk are very low and might not affect nursing infants adversely. The effects of methylphenidate in milk on the neurological development of the infant have not been well studied. It is possible that large dosages of methylphenidate might interfere with milk production, especially in women whose lactation is not well established.

Drug Levels

Maternal Levels. Three mothers were taking methylphenidate in an average dosage of 52 mg daily (range 35 to 80 mg daily) for attention deficit hyperactivity disorder. The average milk level was 19 mcg/L which resulted in an infant dosage of 2.9 mcg/kg daily or 0.7% of the maternal weight-adjusted dosage.[1]

The same authors reported a nursing mother who was taking methylphenidate, but it is unclear if this patient is one of those reported above. The mother was taking 40 mg twice daily, 5 days/week for 5.5 weeks prior to testing, but for 7 consecutive days immediately before collecting blood and milk samples after a morning dose of 40 mg. The average milk level of methylphenidate over the 24 hours after the dose was 15.4 mcg/L. The infant was calculated to receive 2.3 mcg/kg daily which was 0.2% of the maternal weight-adjusted dosage.[2]

A woman who was 11 months postpartum was taking oral immediate-release methylphenidate 5 mg in the morning and 10 mg at noon. The drug was undetectable (<0.3 mcg/L) before the morning dose and 21 hours after the noon dose. Three other levels ranged from1.7 to 3.8 mcg/L. The authors estimated that a fully breastfed infant would receive a dose of 0.38 mcg/kg daily or 0.16% of the maternal weight-adjusted dosage.[3]

A woman was taking 72 mg daily of slow-release methylphenidate. The drug was undetectable (assay limit not stated) in breastmilk at 6 to 12 months postpartum.[4]

Infant Levels. Methylphenidate blood levels were measured in 2 breastfed infants. These were 2 of 3 infants whose mothers were taking an average of 52 mg daily of methylphenidate. The drug was undetectable (<1 mcg/L) in the infants' blood; however, the corresponding maternal dosages and times of blood collection were not stated in the abstract.[1]

A 6.4-month-old partially breastfed infant had been breastfed for 5.5 weeks by a mother taking methylphenidate 40 mg twice daily. The drug was undetectable (<1 mcg/L)in the infant's plasma 5.3 hours after the mother's dose and having been breastfed 4 times since the dose.[2] This patient might have been one of those in the report above by the same authors.

An infant was born to a mother with attention deficit-hyperactivity disorder who took a tapering dose of methylphenidate before and during pregnancy. The drug was stopped 10 days prior to delivery, but restarted after 5 weeks postpartum. Methylphenidate was undetectable (assay limit not stated) in the infant's blood between 6 and 2 months of age when the mother was taking a dose of 72 mg of slow-release methylphenidate daily. The extent of breastfeeding was not stated.[4]

Effects in Breastfed Infants

Seven of 8 infants, whose mothers were taking either dextroamphetamine (average dosage 25 mg daily) or methylphenidate (average dosage 52 mg daily) were clinically evaluated. The infants had no drug-related adverse reactions and were developing normally for their ages which averaged 4.4 months.[1]

One 6.4-month-old infant was mostly breastfed by a mother who had been taking methylphenidate 40 mg twice daily 5 days/week for 5.5 weeks. The mother reported that the infant was sleeping, eating and gaining weight normally.[2] This patient might have been one of those in the report above by the same authors.

An infant was being breastfed (extent not stated) by a mother who began taking sertraline 50 mg daily and methylphenidate after 5 weeks postpartum. Dosage was started at 10 mg daily with an immediate-release product and gradually increased to 72 mg daily of an extended-release product. At 14 weeks of age, the infant was developing normally no feeding difficulties. Examinations at 6 months and 1 year of age found no developmental problems in the child.[4]

Effects on Lactation and Breastmilk

Methylphenidate reduces serum prolactin,[5] but no studies have been located as of the revision date on the effect of methylphenidate on milk production. The maternal prolactin level in a mother with established lactation may not affect her ability to breastfeed.

A 15-year-old girl had been receiving methylphenidate 54 mg daily in an osmotic release tablet (OROS) for 2 years. Sertraline was started for depression at 50 mg daily and increased to 100 mg daily along with haloperidol 0.5 mg daily. After 12 weeks of therapy, inattentativeness at school and headaches prompted a change from the OROS product to a modified-release methylphenidate product (brand not specified) at 30 mg daily, then increasing to 50 mg daily. Three days after the increase in dosage, the girl had spontaneous milk flow from both breasts and subsequently had an elevated serum prolactin of 67.7 mcg/L. Methylphenidate and haloperidol were discontinued, but sertraline was continued. One week later, galactorrhea resolved completely. Fifteen days after drug discontinuation, the girl's prolactin level was in the normal range at 19.4 mcg/L.[6]

References

1. Hackett LP, Ilett KF, Kristensen JH et al. Infant dose and safety of breastfeeding for dexamphetamine and methylphenidate in mothers with attention deficit hyperactivity disorder. Ther Drug Monit. 2005;27:220-1. Abstract.

2. Hackett LP, Kristensen JH, Hale TW, Paterson R, Ilett KF. Methylphenidate and breast-feeding. Ann Pharmacother. 2006;40:1890-1. PMID: 16940409

3. Spigset O, Brede WR, Zahlsen K. Excretion of methylphenidate in breast milk. Am J Psychiatry. 2007;164:348. PMID: 17267805

4. Bolea-Alamanac BM, Green A, Verma G et al. Methylphenidate use in pregnancy and lactation: a systematic review of evidence. Br J Clin Pharmacol. 2014;77:96-101. PMID: 23593966

5. Upadhyaya HP, Brady KT, Liao J et al. Neuroendocrine and behavioral responses to dopaminergic agonists in adolescents with alcohol abuse. Psychopharmacology (Berl). 2003;166:95-101. PMID: 12520313

6. Ekinci O, Gunes S, Ekinci N. Galactorrhea probably related with switching from osmotic-release oral system methylphenidate (MPH) to modified-release MPH: An adolescent case. Clin Psychopharmacol Neurosci. 2017;15:282-4. PMID: 28783939