Methylphenidate transdermal

Detailed information on serious and adverse reactions of particular importance is provided in the Boxed Warning and Warnings and Precautions (5) sections:

• Drug dependence [see BOX WARNING]
• Hypersensitivity to Methylphenidate [see CONTRAINDICATIONS]
• Marked anxiety, tension, or agitation [see CONTRAINDICATIONS]
• Glaucoma [see CONTRAINDICATIONS]
• Tics or a family history of Tourette’s syndrome [see CONTRAINDICATIONS]
• Monoamine Oxidase Inhibitors [see CONTRAINDICATIONS and DRUG INTERACTIONS]
• Serious Cardiovascular Events [see WARNINGS AND PRECAUTIONS]
• Increase in Blood Pressure [see WARNINGS AND PRECAUTIONS]
• Psychiatric Adverse Events [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• Priapism [see WARNINGS AND PRECAUTIONS]
• Peripheral Vasculopathy[see WARNINGS AND PRECAUTIONS]
• Long-Term Suppression of Growth [see WARNINGS AND PRECAUTIONS]
• Chemical Leukoderma [see WARNINGS AND PRECAUTIONS]
• Contact Sensitization [see WARNINGS AND PRECAUTIONS]
• Visual Disturbance [see WARNINGS AND PRECAUTIONS]
• External Heat [see WARNINGS AND PRECAUTIONS]
• Hematologic Monitoring [see WARNINGS AND PRECAUTIONS]

The most commonly reported (frequency ≥ 5% and twice the rate of placebo) adverse reactions in a controlled trial in children aged 6-12 included appetite decreased, insomnia, nausea, vomiting, weight decreased, tic, affect lability, and anorexia. The most commonly reported (frequency ≥ 5% and twice the rate of placebo) adverse reactions in a controlled trial in adolescents aged 13-17 were appetite decreased, nausea, insomnia, weight decreased, dizziness, abdominal pain, and anorexia [see Clinical Trials Experience].

The most common (≥ 2% of subjects) adverse reaction associated with discontinuations in double-blind clinical trials in children or adolescents was application site reactions [see Clinical Trials Experience].

The overall Daytrana development program included exposure to Daytrana in a total of 2,152 participants in clinical trials, including 1,529 children aged 6-12, 223 adolescents aged 13-17, and 400 adults. The 1,752 child and adolescent subjects aged 6-17 years were evaluated in 10 controlled clinical studies, 7 open-label clinical studies, and 5 clinical pharmacology studies. In a combined studies pool of children using Daytrana with a wear time of 9 hours, 212 subjects were exposed for ≥ 6 months and 115 were exposed for ≥ 1 year; 85 adolescents have been exposed for ≥ 6 months. Most patients studied were exposed to Daytrana patch sizes of 12.5 cm2, 18.75 cm2, 25 cm2 or 37.5 cm2, with a wear time of 9 hours.

In the data presented below, the adverse reactions reported during exposure were obtained primarily by general inquiry at each visit, and were recorded by the clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of events into a smaller number of standardized event categories.

Throughout this section adverse reactions reported are events that were considered to be reasonably associated with the use of Daytrana based on comprehensive assessment of the available adverse event information. A causal association for Daytrana often cannot be reliably established in individual cases. Further, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials Experience

In a 7-week double-blind, parallel-group, placebo-controlled study in children with ADHD conducted in the outpatient setting, 7.1% (7/98) of patients treated with Daytrana discontinued due to adverse events compared with 1.2% (1/85) receiving placebo. The most commonly reported (≥ 1% and twice the rate of placebo) adverse reactions leading to discontinuation in the Daytrana group were application site reaction (2%), tics (1%), headache (1%), and irritability (1%).

In a 7-week double-blind, parallel-group, placebo-controlled study in adolescents with ADHD conducted in the outpatient setting, 5.5% (8/145) of patients treated with Daytrana discontinued due to adverse reactions compared with 2.8% (2/72) receiving placebo. The most commonly reported adverse reactions leading to discontinuation in the Daytrana group were application site reaction (2%) and decreased appetite/anorexia (1.4%).

Skin Irritation and Application Site Reactions

Daytrana is a dermal irritant. In addition to the most commonly reported adverse reactions presented in Table 2, the majority of subjects in those studies had minimal to definite skin erythema at the patch application site. This erythema generally caused no or minimal discomfort and did not usually interfere with therapy or result in discontinuation from treatment. Erythema is not by itself a manifestation of contact sensitization. However, contact sensitization should be suspected if erythema is accompanied by evidence of a more intense local reaction (edema, papules, vesicles) that does not significantly improve within 48 hours or spreads beyond the patch site [see WARNINGS AND PRECAUTIONS].

Most Commonly Reported Adverse Reactions

Table 2 lists treatment-emergent adverse reactions reported in ≥ 1% Daytrana-treated children or adolescents with ADHD in two 7 week double-blind, parallel-group, placebo-controlled studies conducted in the outpatient setting. Overall, in these studies, 75.5% of children and 78.6% of adolescents experienced at least 1 adverse event.

Table 2 Number (%) of Subjects with Commonly Reported Adverse Reactions (≥ 1% in the Daytrana Group) in 7-Week Placebo-controlled Studies in Either Children or Adolescents -Safety Population

In a long-term open-label study of up to 12 months duration in 326 children wearing Daytrana 9 hours daily, the most common (≥ 10%) adverse reactions were decreased appetite, headache, and weight decreased. A total of 30 subjects (9.2%) were withdrawn from the study due to adverse events and 22 additional subjects (6.7%) discontinued treatment as the result of an application site reaction. Other than application site reactions, affect lability (5 subjects, 1.5%) was the only additional adverse reaction leading to discontinuation reported with a frequency of greater than 1%.

In a long-term open-label study of up to 6 months duration in 162 adolescents wearing Daytrana 9 hours daily, the most common (≥ 10%) adverse reactions were decreased appetite and headache. A total of 9 subjects (5.5%) were withdrawn from the study due to adverse events and 3 additional subjects (1.9%) discontinued treatment as the result of an application site reaction. Other adverse reactions leading to discontinuation that occurred with a frequency of greater than 1% included affect lability and irritability (2 subjects each, 1.2%).

Postmarketing Experience

In addition, the following adverse reactions have been identified during the postapproval use of Daytrana. 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 Daytrana exposure.

Cardiac Disorders: palpitations

Eye Disorders: visual disturbances, blurred vision, mydriasis, accommodation disorder

General Disorders and Administration Site Disorders: fatigue, application site reactions such as bleeding, bruising, burn, burning, dermatitis, discharge, discoloration, discomfort, dryness, eczema, edema, erosion, erythema, excoriation, exfoliation, fissure, hyperpigmentation, hypopigmentation, induration, infection, inflammation, irritation, pain, papules, paresthesia, pruritus, rash, scab, swelling, ulcer, urticaria, vesicles, and warmth

Immune System Disorders: hypersensitivity reactions including generalized erythematous and urticarial rashes, allergic contact dermatitis, angioedema, and anaphylaxis

Investigations: blood pressure increased

Nervous System Disorders: convulsion, dyskinesia, lethargy, somnolence, serotonin syndrome in combination with serotonergic drugs

Psychiatric Disorders: transient depressed mood, hallucination, nervousness, libido changes

Skin and Subcutaneous Tissue Disorders: alopecia

Adverse Reactions With Oral Methylphenidate Products

Nervousness and insomnia are the most common adverse reactions reported with other methylphenidate products. In children, loss of appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and tachycardia may occur more frequently; however, any of the other adverse reactions listed below may also occur.

Cardiac: angina, arrhythmia, pulse increased or decreased

Immune: hypersensitivity reactions including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme with histopathological findings of necrotizing vasculitis, and thrombocytopenic purpura

Metabolism/Nutrition: anorexia, weight loss during prolonged therapy

Nervous System: drowsiness, rare reports of Tourette’s syndrome, toxic psychosis

Vascular: blood pressure increased or decreased, cerebral arteritis and/or occlusion

Although a definite causal relationship has not been established, the following have been reported in patients taking methylphenidate:

Blood/lymphatic: leukopenia and/or anemia

Hepatobiliary: abnormal liver function, ranging from transaminase elevation to severe hepatic injury

Psychiatric: transient depressed mood

Skin/Subcutaneous: scalp hair loss

Neuroleptic Malignant Syndrome: Very rare reports of neuroleptic malignant syndrome (NMS) have been received, and, in most of these, patients were concurrently receiving therapies associated with NMS. In a single report, a ten-year-old boy who had been taking methylphenidate for approximately 18 months experienced an NMS-like event within 45 minutes of ingesting his first dose of venlafaxine. It is uncertain whether this case represented a drug-drug interaction, a response to either drug alone, or some other cause.

Musculoskeletal: rhabdomyolysis

Apply a patch as soon as you remember, and do not wear the patch for longer than 9 hours. You may need to shorten the wearing time to less than 9 hours if you apply a patch later than usual and you have sleep problems. Do not apply two patches at the same time to make up the missed dose.

Your pharmacist can provide more information about methylphenidate transdermal.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 4.01. Revision date: 2/12/2013.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

Do not expose the skin patch to heat while you are wearing it. This includes heat from a heating pad, hot tub, electric blanket, or a heated water bed. Heat can cause the skin patch to release too much medicine at one time.

Avoid placing a patch on skin that is oily, irritated, or damaged. Avoid a skin area that will be rubbed by a waistband or tight clothing.

This medication may cause blurred vision and can impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert and able to see clearly.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For methylphenidate, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to methylphenidate or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of methylphenidate transdermal in the pediatric population. However, use is not recommended in children younger than 6 years. Safety and efficacy have not been established in this age group.

Geriatric

Appropriate studies on the relationship of age to the effects of methylphenidate transdermal have not been performed in geriatric patients.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking methylphenidate, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using methylphenidate with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Brofaromine
• Clorgyline
• Furazolidone
• Iproniazid
• Isocarboxazid
• Lazabemide
• Linezolid
• Moclobemide
• Nialamide
• Pargyline
• Phenelzine
• Procarbazine
• Rasagiline
• Safinamide
• Selegiline
• Toloxatone
• Tranylcypromine

Using methylphenidate with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Bupropion
• Donepezil

Using methylphenidate with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Carbamazepine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using methylphenidate with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use methylphenidate, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of methylphenidate. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol abuse, history of or
• Drug abuse or dependence, history of—Dependence may be more likely to develop.

• Bipolar disorder (manic-depressive illness), or a family history of or
• Blood vessel problems (eg, peripheral vasculopathy) or
• Hypertension (high blood pressure) or
• Priapism (painful or prolonged erection of the penis) or
• Psychosis (mental illness), history of or
• Raynaud phenomenon or
• Seizures, history of or
• Tachycardia (increased heart rate)—Use with caution. May make these conditions worse.

• Coronary artery disease or
• Depression, or a family history of or
• Heart attack, recent or
• Heart disease (eg, cardiomyopathy) or
• Heart failure or
• Heart rhythm problems, or a family history of or
• Stroke, history of or
• Vitiligo (skin disease), or family history of—Use with caution. May make side effects become worse.

Along with its needed effects, a medicine 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:

• Aggressive and violent behavior
• arm, back, or jaw pain
• black, tarry stools
• blistering, peeling, or loosening of the skin
• blood in the urine
• bloody nose
• chest pain or discomfort
• chest tightness or heaviness
• chills
• cold
• confusion
• cough or hoarseness
• cracks in the skin
• crying
• depersonalization
• diarrhea
• dizziness
• dysphoria
• euphoria
• fainting
• fast, pounding, or irregular heartbeat or pulse
• fever
• flu-like symptoms
• heavier menstrual periods
• joint or muscle pain
• loss of heat from the body
• nausea
• nervousness
• paranoia
• pinpoint red spots on the skin
• quick to react or overreact emotionally
• rapidly changing moods
• red, irritated eyes
• red, swollen skin
• scaly skin
• seeing, hearing, or feeling things that are not there
• severe or sudden headache
• skin rash or itching
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• sudden loss of coordination
• sudden slurring of speech
• sweating
• twitching, twisting, or uncontrolled repetitive movements of the tongue, lips, face, arms, or legs
• unusual bleeding or bruising
• unusual tiredness or weakness

• Convulsions
• difficulty with breathing
• high fever
• increased sweating
• loss of bladder control
• severe muscle stiffness
• tiredness
• uncontrolled vocal outbursts or tics (uncontrolled repeated body movements)
• unusually pale skin

• Blistering, burning, crusting, dryness, or flaking of the skin
• chest pain
• difficulty with swallowing
• hives, itching, scaling, severe redness, soreness, or swelling of the skin
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• painful or difficult urination
• pale skin
• paleness or cold feeling in the fingertips and toes
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• swollen glands
• tingling or pain in the fingers or toes when exposed to cold
• troubled breathing with exertion

Some side effects 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:

• Abdominal or stomach pain
• decreased weight
• difficulty with moving
• drowsiness
• headache
• loss of appetite
• muscle pain or stiffness
• redness of the skin
• trouble sleeping
• vomiting
• welts

• Decreased appetite
• stuffy or runny nose
• weight loss

• Bigger, dilated, or enlarged pupils (black part of the eye)
• bleeding, bruising, burning, itching, redness, skin rash, swelling, or soreness at the application site
• blurred or loss of vision
• disturbed color perception
• double vision
• hair loss
• halos around lights
• increased sensitivity of the eyes to light
• night blindness
• overbright appearance of lights
• thinning of the hair
• tunnel vision

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

This medication is used to treat attention deficit hyperactivity disorder - ADHD. It works by changing the amounts of certain natural substances in the brain. Methylphenidate belongs to a class of drugs known as stimulants. It can help increase your ability to pay attention, stay focused on an activity, and control behavior problems. It may also help you to organize your tasks and improve listening skills.

How to use Methylphenidate Patch, Transdermal 24 Hours

Read the Medication Guide provided by your pharmacist before you start using methylphenidate and each time you get a refill. Read and follow all directions in the Patient Information Leaflet. Learn how to properly use, store, and discard the patches. If you have any questions, ask your doctor or pharmacist.

Apply this medication to the skin as directed by your doctor, usually once daily in the morning, 2 hours before you need the effects of this drug. Then remove the patch as directed by your doctor, usually 9 hours later. Applying this medication late in the day may cause trouble sleeping (insomnia). If you apply this patch in the early morning and still have trouble sleeping, your doctor may direct you to remove the patch within less than 9 hours. Carefully follow your doctor's instructions.

This medication should be applied to a clean, dry area of skin on the hip. Before applying the patch, gently wash, rinse, and dry the application area. Do not apply to cut or irritated skin. Remove the patch from the pouch and apply right away as directed. Do not cut the patch. When using a new patch the next day, apply to an area of skin on the other hip to avoid irritation. Do not apply a heating pad or other heat to the patch area since this may increase the risk of side effects. Bathing, swimming, or showering may affect how well the patch stays on the skin. If the patch does not stick properly or falls off, replace with a new patch at another site. Remove the new patch at your usual time, usually 9 hours after applying the first patch.

After removing the patch, fold it in half with the sticky sides together and throw it away as directed. Do not touch the sticky side with your fingers. Wash your hands after applying or removing the patch.

Use this medication regularly to get the most benefit from it. To help you remember, use it at the same time each day.

The dosage is based on your medical condition and response to treatment. Your doctor may direct you to gradually increase or decrease your dose. Also, if you have used it for a long time, do not suddenly stop using this drug without consulting your doctor.

This medication may cause withdrawal reactions, especially if it has been used regularly for a long time or in high doses. In such cases, withdrawal symptoms (such as depression, suicidal thoughts, or other mental/mood changes) may occur if you suddenly stop using this medication. To prevent withdrawal reactions, your doctor may reduce your dose gradually. Consult your doctor or pharmacist for more details, and report any withdrawal reactions right away.

When used for a long time, this medication may not work as well. Talk with your doctor if this medication stops working well.

Though it helps many people, this medication may sometimes cause addiction. This risk may be higher if you have a substance use disorder (such as overuse of or addiction to drugs/alcohol). Use this medication exactly as prescribed to lower the risk of addiction. Ask your doctor or pharmacist for more details.

Tell your doctor if your condition does not improve or if it worsens.

Nervousness, trouble sleeping, loss of appetite, weight loss, dizziness, nausea, vomiting, or headache may occur. Mild irritation or redness at the application site may also occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

This medication may raise your blood pressure. Check your blood pressure regularly and tell your doctor if the results are high.

Tell your doctor right away if you have any serious side effects, including: signs of blood flow problems in the fingers or toes (such as coldness, numbness, pain, or skin color changes), unusual wounds on the fingers or toes, fast/pounding/irregular heartbeat, mental/mood/behavior changes (such as agitation, aggression, mood swings, abnormal thoughts, thoughts of suicide), uncontrolled muscle movements (such as twitching, shaking), sudden outbursts of words/sounds that are hard to control, vision changes (such as blurred vision), slow healing sores/ulcers on the tips of fingers/toes.

Get medical help right away if you have any very serious side effects, including: fainting, seizure, symptoms of a heart attack (such as chest/jaw/left arm pain, shortness of breath, unusual sweating), symptoms of a stroke (such as weakness on one side of the body, slurred speech, sudden vision changes, confusion).

Rarely, males (including young boys and teens) may have a painful or prolonged erection lasting 4 or more hours while using this medication. Caregivers/parents should also be watchful for this serious side effect in boys. If a painful or prolonged erection occurs, stop using this drug and get medical help right away, or permanent problems could occur. Ask your doctor or pharmacist for more details.

This patch may cause the skin under it to lighten (whiten) in color. This may sometimes occur even on skin that was never covered by this patch. The lightened skin color may be permanent, so tell your doctor right away if you notice any skin color changes.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

This medication patch may be harmful if chewed or swallowed. If someone has overdosed, remove the patch if possible. For serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: vomiting, agitation, confusion, sweating, flushing, muscle twitching, hallucinations, seizures, loss of consciousness.

Notes

Do not share this medication with others. It is against the law.

Laboratory and/or medical tests (such as blood pressure, complete blood count, height/weight monitoring in children) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

If switching from another form of methylphenidate to this patch, carefully follow your doctor's instructions.

Missed Dose

If you miss a dose, use it as soon as you remember. If it is near bedtime or near the time of the next dose, skip themissed dose and resume your usual dosing schedule. Do not double the dose to catch up.

Storage

This medication comes in a sealed tray or outer pouch. After opening the sealed tray/outer pouch, use/discard patches within 2 months.

Store the individual protective pouches at room temperature away from light and moisture. Do not refrigerate or freeze. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed (see also How to Use section). Read the Medication Guide for details. In the US, the FDA recommends flushing this medication down the toilet. You may also throw the patches away in a container with a lid. Consult your pharmacist or local waste disposal company.Information last revised June 2017. Copyright(c) 2017 First Databank, Inc.