Methylphenidate Hydrochloride Extended Release Oral Suspension, CII

Name: Methylphenidate Hydrochloride Extended Release Oral Suspension, CII

How supplied

Dosage Forms And Strengths

Extended-release oral suspension (after reconstitution with water): 25 mg per 5 mL (5 mg per mL).

Storage And Handling

QUILLIVANT XR is supplied as powder that, after reconstitution with water, forms an extended-release oral suspension. The product is supplied in a carton. Each carton also contains one bottle, one oral dosing dispenser, and one bottle adapter.

The product must be reconstituted only by the pharmacist and not by the patient or caregiver. After reconstitution, the product is a light beige to tan viscous suspension containing 25 mg per 5 mL (5 mg per mL) of methylphenidate hydrochloride.

Bottles of 300 mg powder (to prepare 60 mL suspension) NDC 24478-190-10
Bottles of 600 mg powder (to prepare 120 mL suspension) NDC 24478-200-20
Bottles of 750 mg powder (to prepare 150 mL suspension) NDC 24478-205-25
Bottles of 900 mg powder (to prepare 180 mL suspension) NDC 24478-210-30

Storage And Handling

Store at 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.]

Dispense in original container.

Disposal

Comply with local laws and regulations on drug disposal of CNS stimulants. Dispose of remaining, unused, or expired QUILLIVANT XR 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 QUILLIVANT XR 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 QUILLIVANT XR in the household trash.

Distributed by: Pfizer, NextWave Pharmaceuticals, Inc. A subsidiary of Pfizer Inc, New York, NY 10017. Revised: Jan 2017

Warnings

Included as part of the PRECAUTIONS section.

Clinical pharmacology

Mechanism Of Action

Methylphenidate HCl is a central nervous system (CNS) stimulant.

Pharmacodynamics

Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer. The mode of therapeutic action in ADHD is not known. Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space.

Pharmacokinetics

Absorption

Following a single, 60 mg oral dose of QUILLIVANT XR in 28 healthy adult subjects in a crossover study under fasting conditions, d-methylphenidate (d-MPH) mean (± SD) peak plasma concentrations of 13.6 (± 5.8) ng/mL occurred at a median time of 5.0 hours after dosing (Figure 2). The relative bioavailability of QUILLIVANT XR compared to Methylphenidate IR oral solution (2×30 mg, q6h) is 95%.

Figure 2. Mean d-Methylphenidate Plasma Concentration-Time Profiles

The single dose pharmacokinetics of d-MPH under fed conditions are summarized (Table 3) from studies in children and adolescents with ADHD, and healthy adults following an oral dose of 60 mg QUILLIVANT XR.

Table 3. d-MPH PK Parameters (mean ±SD) after 60 mg oral dosing of QUILLIVANT XR*

PK Parameter Children† (n=3) Adolescent† (n=4) Adult (n=27)
Tmax (hr)‡ 4.05 (3.98–6.0) 2.0 (1.98–4.0) 4.0 (1.3–7.3)
T1/2(hr) 5.2±0.1 5.0±0.2 5.2±1.0
Cmax (ng/mL) 34.4±14.0 21.1±5.9 17.0±7.7
AUC (hr*ng/mL) 378±175 178±54.2 163.2±80.3
Cl (L/hr/kg) 4.27±0.70 5.06±1.42 5.66±2.15
*Breakfast was given 30 min prior to drug administration
†total MPH measured in children (9–12 years old) and adolescents (13–15 years old), l-MPH <2% of d-MPH in circulation
‡data presented as median (range)

Food Effects

In a study in adult volunteers to investigate the effects of a high-fat meal on the bioavailability of QUILLIVANT XR at a dose of 60 mg, the presence of food reduced the time to peak concentration by approximately 1 hour (fed: 4 hours vs. fasted: 5 hours). Overall, a high-fat meal increased the average Cmax of QUILLIVANT XR by about 28% and the AUC by about 19%. These changes are not considered clinically significant.

Elimination

Following a single 60 mg oral dose of QUILLIVANT XR in 28 healthy adult subjects under fasting conditions, the mean plasma terminal elimination half-life of d-methylphenidate was 5.6 (± 0.8) hours.

Metabolism

In humans, methylphenidate is metabolized primarily via deesterification to alpha-phenyl-piperidine acetic acid (PPAA). The metabolite has little or no pharmacologic activity.

Excretion

After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPAA, accounting for approximately 80% of the dose.

Alcohol Effect

An in vitro study was conducted to explore the effect of alcohol on the release characteristics of methylphenidate from QUILLIVANT XR Oral Suspension. At alcohol concentrations of 5% and 10%, there was no effect of alcohol on the release characteristics of methylphenidate. At 20% alcohol concentration, there was on average a 20% increase in drug exposure [see DOSAGE AND ADMINISTRATION].

Specific Populations

Sex

There is insufficient experience with the use of QUILLIVANT XR to detect gender variations in pharmacokinetics.

Race

There is insufficient experience with the use of QUILLIVANT XR to detect ethnic variations in pharmacokinetics.

Age

The pharmacokinetics of methylphenidate after QUILLIVANT XR administration were studied in pediatric patients with ADHD between 9 and 15 years of age. After a single oral dose of 60 mg QUILLIVANT XR, plasma concentrations of methylphenidate in children (9–12 years old; n=3) were approximately twice the concentrations observed in adults. The plasma concentrations in adolescent patients (13–15 years old; n=4) were similar to those in adults.

Renal Impairment

There is no experience with the use of QUILLIVANT XR 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 QUILLIVANT XR.

Hepatic Impairment

There is no experience with the use of QUILLIVANT XR in patients with hepatic insufficiency.

Clinical Studies

The efficacy of QUILLIVANT XR was evaluated in a laboratory classroom study conducted in 45 pediatric patients (ages 6 to 12 years) with ADHD. Patients in the trial met Diagnostic and Statistical Manual of Mental Diseases, 4 edition (DSM-IV®) criteria for ADHD. The study began with an open-label dose optimization period (4 to 6 weeks) with an initial QUILLIVANT XR dose of 20 mg once daily in the morning. The dose could be titrated weekly in increments of 10 or 20 mg until a therapeutic dose or the maximum dose of 60 mg/day was reached. At the end of the dose optimization period, approximately 5% of subjects were receiving 20 mg/day; 39%, 30 mg/day; 31%, 40 mg/day; 10%, 50 mg/day; and 15%, 60 mg/day. Subjects then entered a 2-week randomized, double-blind, crossover treatment with the individually optimized dose of QUILLIVANT XR or placebo. At the end of each week, school teachers and raters evaluated the attention and behavior of the subjects in a laboratory classroom using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale. The primary efficacy endpoint was the SKAMP-Combined score at 4 hours post-dosing. The key secondary efficacy endpoints were the SKAMP-Combined scores at 0.75, 2, 8, 10, and 12 hours post-dosing.

Results from the first double-blind, placebo-controlled week of the study are summarized in Figure 3. SKAMPCombined scores were statistically significantly lower (improved) at all time points (0.75, 2, 4, 8, 10, 12 hours) post-dosing with QUILLIVANT XR compared to placebo.

Figure 3. Absolute SKAMP-Combined Score after treatment with QUILLIVANT XR or Placebo during Period 1.

Patient information

QUILLIVANT XR®
(\kwil-∂-vant\)
(methylphenidate hydrochloride)
for extended-release oral suspension

What is the most important information I should know about QUILLIVANT XR?

QUILLIVANT XR is a federally controlled substance (CII) because it can be abused or lead to dependence. Keep QUILLIVANT XR in a safe place to prevent misuse and abuse. Selling or giving away QUILLIVANT XR may harm others, and is against the law.

Tell your health care provider if you or your child have (or have a family history of) ever abused or been dependent on alcohol, prescription medicines or street drugs.

The following have been reported with use of methylphenidate hydrochloride and other stimulant medicines.

  1. Heart-related problems:
    • sudden death in patients who have heart problems or heart defects
    • stroke and heart attack in adults
    • increased blood pressure and heart rate

    Tell your health care provider if you or your child have any heart problems, heart defects, high blood pressure, or a family history of these problems.

    Your health care provider should check you or your child carefully for heart problems before starting QUILLIVANT XR.

    Your health care provider should check your or your child's blood pressure and heart rate regularly during treatment with QUILLIVANT XR.

    Call your health care provider right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking QUILLIVANT XR.

  2. Mental (Psychiatric) problems:
    • new or worse behavior and thought problems
    • new or worse bipolar illness
    • new psychotic symptoms (such as hearing voices, believing things that are not true, are suspicious) or new manic symptoms

    Tell your health care provider about any mental problems you or your child have, or about a family history of suicide, bipolar illness, or depression.

    Call your health care provider right away if you or your child have any new or worsening mental symptoms or problems while taking QUILLIVANT XR, especially seeing or hearing things that are not real, believing things that are not real, or are suspicious.

  3. Circulation problems in fingers and toes [Peripheral vasculopathy, including Raynaud's phenomenon]:
    • Fingers or toes may feel numb, cool, painful
    • Fingers or toes may change color from pale, to blue, to red

Tell your health care provider if you have or your child has numbness, pain, skin color change, or sensitivity to temperature in the fingers or toes.

Call your health care provider right away if you have or your child has any signs of unexplained wounds appearing on fingers or toes while taking QUILLIVANT XR.

What is QUILLIVANT XR?

QUILLIVANT XR is a central nervous system stimulant prescription medicine. QUILLIVANT XR is a liquid medicine that you take by mouth.

It is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). QUILLIVANT XR may help increase attention and decrease impulsiveness and hyperactivity in people with ADHD.

It is not known if QUILLIVANT XR is safe and effective in children under 6 years of age.

Do not take QUILLIVANT XR if you or your child:

  • are allergic to methylphenidate hydrochloride, or any of the ingredients in QUILLIVANT XR. See the end of this Medication Guide for a complete list of ingredients in QUILLIVANT XR.
  • are taking or have taken within the past 14 days a type of anti-depression medicine called a monoamine oxidase inhibitor (MAOI).

QUILLIVANT XR may not be right for you or your child. Before starting QUILLIVANT XR tell your or your child's health care provider about all health conditions (or a family history of) including:

  • heart problems, heart defects, high blood pressure
  • mental problems including psychosis, mania, bipolar illness, or depression
  • circulation problems in fingers and toes
  • if you are pregnant or plan to become pregnant. It is not known if QUILLIVANT XR will harm your unborn baby. Talk to your health care provider if you are pregnant or plan to become pregnant.
  • if you are breastfeeding or plan to breast feed. QUILLIVANT XR passes into your breast milk. You and your doctor should decide if you will take QUILLIVANT XR or breast feed.

Tell your health care provider about all of the medicines that you or your child take including prescription and nonprescription medicines, vitamins, and herbal supplements. QUILLIVANT XR and some medicines may interact with each other and cause serious side effects. Sometimes the doses of other medicines will need to be adjusted while taking QUILLIVANT XR.

Your health care provider will decide whether QUILLIVANT XR can be taken with other medicines.

Especially tell your health care provider if you or your child takes:

  • anti-depression medicines including MAOIs

Know the medicines that you or your child takes. Keep a list of your medicines with you to show your health care provider and pharmacist.

Do not start any new medicine while taking QUILLIVANT XR without talking to your health care provider first.

How should QUILLIVANT XR be taken?

  • Read the step-by-step instructions for using QUILLIVANT XR extended-release suspension at the end of this Medication Guide.
  • Take QUILLIVANT XR exactly as prescribed. Your health care provider may adjust the dose, if needed, until it is right for you or your child. During dose adjustment, you or your child may still have ADHD symptoms.
  • QUILLIVANT XR should be used with the oral dosing dispenser provided with the product. If the oral dosing dispenser is missing or not provided, please contact your pharmacist for a replacement.
  • Check and make sure that the QUILLIVANT XR bottle contains liquid medicine. If QUILLIVANT XR is in powder form, do not use it. Return it to your pharmacist.
  • Check and make sure that the bottle adapter was fully inserted into the bottle by the pharmacist. If the bottle adapter is not fully inserted, insert the adapter into the bottle.
  • Take QUILLIVANT XR 1 time each day in the morning. QUILLIVANT XR is an extended-release suspension. It releases medicine into your body throughout the day.
  • QUILLIVANT XR can be taken with or without food. Taking QUILLIVANT XR with food may shorten the time it takes for the medicine to start working.
  • From time to time, your health care provider may stop QUILLIVANT XR treatment for a while to check ADHD symptoms.
  • Your health care provider may do regular checks of the blood, heart, and blood pressure while taking QUILLIVANT XR.
  • Children should have their height and weight checked often while taking QUILLIVANT XR. QUILLIVANT XR treatment may be stopped if a problem is found during these check-ups.
  • In case of poisoning call your poison control center at 1-800-222-1222 right away, or go to the nearest hospital emergency room.
  • If a dose is missed, you or your child should talk to your health care provider about dosing.

What should I avoid while taking QUILLIVANT XR?

  • QUILLIVANT XR should not be taken with MAOI medicines. Do not start taking QUILLIVANT XR if you stopped taking an MAOI in the last 14 days.
  • Do not drink alcohol while taking QUILLIVANT XR. This may cause a faster release of your methylphenidate dose.

What are the possible side effects of QUILLIVANT XR?

QUILLIVANT XR may cause serious side effects, including:

  • See "What is the most important information I should know about QUILLIVANT XR? " for information on reported heart and mental problems.

Other serious side effects include:

  • painful and prolonged erections (priapism) have occurred with methylphenidate. If you or your child develop priapism seek medical help right away. Because priapism can cause long lasting damage, it should be checked by a health care provider right away.
  • slowing of growth (height and weight) in children

The most common side effects of QUILLIVANT XR include:

  • decreased appetite
  • indigestion
  • dizziness
  • increased blood pressure
  • trouble sleeping
  • stomach pain
  • irritability
  • nausea
  • weight loss
  • mood swings
  • vomiting
  • anxiety
  • fast heart beat

These are not all the possible side effects of QUILLIVANT XR.

Call your health care provider for medical advice about side effects. You may report side effects to FDA at 1-8l00 -FDA-1088

How should I store QUILLIVANT XR?

  • Store QUILLIVANT XR in a safe place at 59°F to 86°F (15°C to 30°C).
  • Keep QUILLIVANT XR and all medicines out of the reach of children.

General information about the safe and effective use of QUILLIVANT XR

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use QUILLIVANT XR for a condition for which it was not prescribed. Do not give QUILLIVANT XR to other people, even if they have the same condition. It may harm them.

You can ask your pharmacist or health care provider for information about QUILLIVANT XR that was written for health care professionals.

What are the ingredients in QUILLIVANT XR?

Active Ingredient: methylphenidate hydrochloride

Inactive Ingredients: sodium polystyrene sulfonate, povidone, triacetin, polyvinyl acetate, sucrose, anhydrous trisodium citrate, anhydrous citric acid, sodium benzoate, sucralose, poloxamer 188, corn starch, xanthan gum, talc, banana flavor, and silicon dioxide.

Instructions for Use

QUILLIVANT XR®
(\kwil-∂-vant\)
(methylphenidate hydrochloride) for extended-release oral suspension

Read this Instructions for Use before using QUILLIVANT XR and each time you get a refill. There may be new information. This leaflet does not take the place of talking with the health care provider about your or your child's medical condition or treatment.

Step 1. Remove the QUILLIVANT XR bottle and oral dosing dispenser from the box (See Figure A). If the oral dosing dispenser is missing or not provided, please contact your pharmacist for a replacement.

Figure A

Step 2. Check and make sure that the QUILLIVANT XR bottle contains liquid medicine (See Figure B). If QUILLIVANT XR is still in powder form, do not use it. Return it to your pharmacist.

Figure B

Step 3. Shake the bottle well (up and down) for at least 10 seconds before each use (See Figure C).

Figure C

Step 4. Uncap the bottle and check that the bottle adapter has been fully inserted into the bottle (See Figure D).

Figure D

Step 4 (continued). If bottle adapter (See Figure E) has not been inserted by the pharmacist into the bottle, insert adapter into the bottle as shown (See Figure F and Figure G).

Figure E

Figure F

After the bottle adapter has been fully inserted into the bottle (See Figure G), it should not be removed. If the bottle adapter has not been inserted and is missing from the box, contact your pharmacist. The bottle adapter must be fully inserted and should be even with the mouth of the bottle and must remain in place to allow the child resistant cap to work the right way.

Figure G

Step 5. Check the QUILLIVANT XR dose in milliliters (mL) as prescribed by your health care provider. Locate this number on the oral dosing dispenser (See Figure H).

Figure H

Step 6. Insert tip of the oral dosing dispenser into the upright bottle and push the plunger all the way down (See Figure I).

Figure I

Step 7. With the oral dosing dispenser in place, turn the bottle upside down. Pull the plunger to the number of mL you need (the amount of liquid medicine in Step 5 – See Figure J).

Figure J

Step 7 (continued). Measure the number of mL of medicine from the white end of the plunger (See Figure K)

Figure K

Step 8. Remove the oral dosing dispenser from the bottle adapter.

Step 9. Slowly squirt QUILLIVANT XR directly into your or your child's mouth (See Figure L).

Figure L

Step 10. Cap the bottle tightly. Store the bottle upright at 59°F to 86°F (15°C to 30°C) (See Figure M)

Figure M

Step 11. Clean the oral dosing dispenser after each use by placing in the dishwasher, or by rinsing with tap water (See Figure N).

Figure N

These Instructions for Use have been approved by the U.S. Food and Drug Administration.

Side effects

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

  • Known hypersensitivity to methylphenidate products or other ingredients of QUILLIVANT XR [see CONTRAINDICATIONS]
  • Hypertensive Crisis When Used Concomitantly with Monoamine Oxidase Inhibitors [see CONTRAINDICATIONS, DRUG INTERACTIONS]
  • Drug Dependence [see BOX WARNING, WARNINGS AND PRECAUTIONS, Drug Abuse And Dependence]
  • Serious Cardiovascular Reactions [see WARNINGS AND PRECAUTIONS]
  • Blood Pressure and Heart Rate Increases [see WARNINGS AND PRECAUTIONS]
  • Psychiatric Adverse Reactions [see WARNINGS AND PRECAUTIONS]
  • Priapism [see WARNINGS AND PRECAUTIONS]
  • Peripheral Vasculopathy, including Raynaud's phenomenon [see WARNINGS AND PRECAUTIONS]
  • Long-Term Suppression of Growth [see WARNINGS AND PRECAUTIONS]

Clinical Trials 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 QUILLIVANT XR In Children And Adolescents With ADHD

There is limited experience with QUILLIVANT XR in controlled trials. Based on this limited experience, the adverse reaction profile of QUILLIVANT XR appears similar to other methylphenidate extended-release products. The most common (≥2% in the QUILLIVANT XR group and greater than placebo) adverse reactions reported in the Phase 3 controlled study conducted in 45 ADHD patients (ages 6–12 years) were affect lability, excoriation, initial insomnia, tic, decreased appetite, vomiting, motion sickness, eye pain, and rash.

Table 2. Common Adverse Reactions occurring in ≥2% of subjects on QUILLIVANT XR and greater than placebo during the controlled cross-over phase

Adverse reaction QUILLIVANT XR
N= 45
Placebo
N= 45
Affect lability 9% 2%
Excoriation 4% 0
Initial Insomnia 2% 0
Tic 2% 0
Decreased appetite 2% 0
Vomiting 2% 0
Motion sickness 2% 0
Eye pain 2% 0
Rash 2% 0

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

Hepatobiliary Disorders: Severe hepatocellular injury

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

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

Read the entire FDA prescribing information for Quillivant XR (Methylphenidate Hydrochloride Extended Release Oral Suspension, CII )

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