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Thursday, 22 September 2016

Lotyn

Lotyn may be available in the countries listed below.

Ingredient matches for Lotyn

Lovastatin

Lovastatin is reported as an ingredient of Lotyn in the following countries:

Indonesia

International Drug Name Search

Concerta

Generic Name: methylphenidate (Oral route)

meth-il-FEN-i-date

Oral route(Tablet;Tablet, Extended Release;Tablet, Chewable;Solution)

Use cautiously in emotionally unstable patients, such as those with a history of drug dependence or alcoholism, due to abuse potential. Chronic abuse can lead to marked tolerance and psychic dependence with varying degrees of abnormal behavior including psychotic episodes. Careful supervision during drug withdrawal, since severe depression as well as the effects of chronic overactivity can be unmasked .

Commonly used brand name(s)

In the U.S.

Concerta

Metadate CD

Metadate ER

Methylin

Methylin ER

Ritalin

Ritalin LA

Ritalin-SR

Available Dosage Forms:

Tablet, Extended Release

Capsule, Extended Release

Tablet, Chewable

Solution

Tablet

Therapeutic Class: CNS Stimulant

Chemical Class: Amphetamine Related

Uses For Concerta

Methylphenidate belongs to the group of medicines called central nervous system (CNS) stimulants. It is used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy. Narcolepsy is an uncontrollable desire for sleep or a sudden attack of deep sleep.

Methylphenidate works in the treatment of ADHD by increasing attention and decreasing restlessness in children and adults who are overactive, cannot concentrate for very long, or are easily distracted and impulsive. This medicine is used as part of a total treatment program that also includes social, educational, and psychological treatment.

This medicine is available only with a doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although not specifically included in product labeling, methylphenidate may be used in certain patients with the following condition:

Depressive disorder secondary to physical illness in patients who cannot take antidepressant medicines.

Before Using Concerta

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 this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine 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 in children. Safety and efficacy have not been established in children younger than 6 years of age.

Geriatric

Appropriate studies on the relationship of age to the effects of Concerta® extended release tablets have not been performed in the geriatric population. However, no geriatric-specific problems have been documented to date.

No information is available on the relationship of age to the effects of Ritalin® and Ritalin LA® in geriatric patients.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

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 this medicine, 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 this medicine 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

Selegiline

Toloxatone

Tranylcypromine

Using this medicine 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. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Proper Use of methylphenidate

This section provides information on the proper use of a number of products that contain methylphenidate. It may not be specific to Concerta. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. If too much is taken, it may become habit-forming. If you or your child think this medicine is not working properly after you have taken it for several weeks, check with your doctor first and do not increase the dose.

This medicine should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions. Ask your pharmacist for the Medication Guide if you do not have one.

To help prevent trouble with sleeping, take the last dose of the short-acting tablets before 6 p.m., unless your doctor gives you or your child a different time.

If you or your child are taking the long-acting forms of this medicine:

The Concerta® extended release tablets, Ritalin LA® capsules, and Ritalin SR® tablets are to be swallowed whole with water or other liquids. Do not break, open, crush, or chew them before swallowing.

If you or your child are unable to swallow the Ritalin LA® extended-release capsule whole, carefully open the capsule and sprinkle the small beads over a spoonful of applesauce. The mixture of drug and applesauce should be taken right away without chewing. The drug and applesauce mixture can not be stored for future use.

If you are taking the Concerta® extended-release tablets, you may sometimes notice what looks like a tablet in your stool. This is the empty tablet shell that is left after the medicine has been absorbed into your body.

You may take Concerta® extended release tablets with or without food.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For attention deficit hyperactivity disorder (ADHD):
- For short-acting oral dosage form (tablets):
  - Adults—5 to 20 milligrams (mg) two or three times a day, taken 30 to 45 minutes before meals.
  - Teenagers and children 6 years of age and older—At first, 5 mg two times a day, taken before breakfast and lunch. If needed, your doctor may increase the dose once a week by 5 to 10 mg a day until symptoms improve or a maximum dose of 60 mg is reached.
  - Children up to 6 years of age—Use and dose must be determined by the doctor.
- For long-acting oral dosage form (extended-release tablets):
  - For patients who have not been treated with Concerta®:
    - Adults—At first, 18 to 36 milligrams (mg) once a day in the morning. Your doctor may increase your dose as needed. However, the dose is usually not more than 72 mg a day.
    - Teenagers and children 6 years of age and older—At first, 18 mg once a day in the morning. Your doctor may increase your dose as needed. However, the dose is usually not more than 72 mg a day.
    - Children up to 6 years of age—Use and dose must be determined by your doctor.
  - For patients already using Concerta®:
    - Adults, teenagers, and children 6 years of age and older—At first, 18 to 72 milligrams (mg) once a day in the morning, depending on your previous dose of methylphenidate. Your doctor may increase your dose as needed. However, the dose is usually not more than 72 mg a day.
    - Children up to 6 years of age—Use and dose must be determined by your doctor.
- For long-acting oral dosage form (sustained-release tablets):
  - Adults, teenagers, and children 6 years of age and older—The dose must be determined by the doctor.
  - Children up to 6 years of age—Use and dose must be determined by the doctor.
- For the long-acting oral dosage form (extended-release capsules):
  - Adults, teenagers, and children 6 years of age and older—10 to 20 milligrams (mg) once a day, taken in the morning before breakfast. If needed, your doctor may increase the dose once a week by 10 mg a day as needed up to 60 mg a day.
  - Children up to 6 years of age—Use and dose must be determined by the doctor.

For narcolepsy:
- For short-acting oral dosage form (tablets):
  - Adults—5 to 20 milligrams (mg) two or three times a day, taken 30 to 45 minutes before meals.
  - Teenagers and children 6 years of age and older—At first, 5 mg two times a day, taken before breakfast and lunch. If needed, your doctor may increase the dose once a week by 5 to 10 mg a day until symptoms improve or a maximum dose of 60 mg is reached.
  - Children up to 6 years of age—Use and dose must be determined by your doctor.
- For long-acting oral dosage form (sustained-release tablets):
  - Adults and teenagers and children 6 years of age and older—The dose must be determined by the doctor.
  - Children up to 6 years of age—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using Concerta

Your doctor should check you or your child's progress at regular visits to make sure this medicine is working properly and to decide if you or your child should continue to take it. Blood tests may be needed to check for unwanted effects.

You or your child will also need to have your blood pressure measured before starting this medicine and while you or your child are using it. If you notice any change to you or your child's recommended blood pressure, call your doctor right away. If you have questions about this, talk to your doctor.

You or your child should not use this medicine if you have used a drug for depression called an MAO inhibitor (MAOI), such as Eldepryl®, Marplan®, Nardil®, or Parnate®, in the past 14 days.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines, herbal or vitamin supplements, and medicine for appetite control, asthma, colds, cough, hayfever, or sinus problems.

Methylphenidate may cause dizziness, drowsiness, or changes in vision. Do not drive a car, ride a bicycle, operate machinery, or do other things that might be dangerous until you know how this medicine affects you.

Methylphenidate may cause serious heart or blood vessel problems. This may be more likely in patients who have a family history of heart disease. Check with your doctor right away if you or your child have chest pain, shortness of breath, or fainting while using this medicine.

Tell your doctor right away if you or your family notices any unusual changes in behavior, such as an increase in aggression, hostility, agitation, irritability, or suicidal thinking or behaviors. Also tell your doctor if you or your child have hallucinations or any unusual thoughts, especially if they are new or getting worse quickly.

This medicine may cause slow growth. If your child is using this medicine, the doctor will need to keep track of your child's height and weight to make sure that your child is growing properly.

Concerta Side Effects

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:

More common

Fast heartbeat

Less common

Chest pain

fever

joint pain

skin rash or hives

Rare

Black, tarry stools

blood in the urine or stools

blurred vision or other changes in vision

convulsions

crusting, dryness, or flaking of the skin

muscle cramps

pinpoint red spots on the skin

scaling, severe redness, soreness, or swelling of the skin

uncontrolled vocal outbursts or tics (uncontrolled and repeated body movements)

unusual bleeding or bruising

Incidence not known

Confusion

cracks in the skin

delusions (false beliefs)

depersonalization (feeling like surroundings are not real)

depression (severe)

hallucinations (seeing, hearing, or feeling things that are not there)

hives or welts

loss of heat from the body

mood changes

numbness of the hands

painful or difficult urination

pale skin

red, irritated eyes

red, swollen, or scaly skin

severe or sudden headache

shortness of breath

sore throat

sores, ulcers, or white spots on the lips or in the mouth

sudden loss of coordination

sudden slurring of speech

swollen glands

troubled breathing with exertion

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:

Symptoms of overdose

Agitation

confusion (severe)

convulsions

dryness of the mouth or mucous membranes

false sense of well-being

fast, pounding, or irregular heartbeat

fever

flushing

hallucinations (seeing, hearing, or feeling things that are not there)

headache (severe)

increased sweating

large pupils

muscle twitching

overactive reflexes

sweating

trembling or shaking

vomiting

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:

More common

Loss of appetite

nervousness

sleeplessness

stuffy nose

trouble with sleeping

unable to sleep

unusually warm skin

Less common

Anger

dizziness

drowsiness

fear

headache

irritability

muscle aches

nausea

nervousness

runny nose

scalp hair loss

stomach pain

talking, feeling, and acting with excitement

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.

See also: Concerta side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Concerta resources

Concerta Side Effects (in more detail)
Concerta Use in Pregnancy & Breastfeeding
Drug Images
Concerta Drug Interactions
Concerta Support Group
106 Reviews for Concerta - Add your own review/rating

Concerta Consumer Overview

Concerta Prescribing Information (FDA)

Concerta Extended-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Daytrana Prescribing Information (FDA)

Daytrana System MedFacts Consumer Leaflet (Wolters Kluwer)

Daytrana Consumer Overview

Metadate CD Prescribing Information (FDA)

Metadate CD Controlled-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)

Metadate ER Prescribing Information (FDA)

Methylin Prescribing Information (FDA)

Methylin MedFacts Consumer Leaflet (Wolters Kluwer)

Methylin ER Controlled-Release Tablets MedFacts Consumer Leaflet (Wolters Kluwer)

Methylphenidate Hydrochloride Monograph (AHFS DI)

Ritalin Consumer Overview

Ritalin Prescribing Information (FDA)

Ritalin LA Prescribing Information (FDA)

Ritalin LA Extended-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Concerta with other medications

ADHD
Narcolepsy

Wednesday, 21 September 2016

Carvedilol

Pronunciation: kar-VE-dil-ol
Generic Name: Carvedilol
Brand Name: Coreg

Carvedilol is used for:

Treating high blood pressure or certain types of heart failure. It may also be used after a heart attack to improve survival in certain patients. It may be used along with other medicines. It may also be used for other conditions as determined by your doctor.

Carvedilol is an alpha- and beta-blocker. It works by relaxing the blood vessels, slowing down the heart, and decreasing the amount of blood it pumps out. This decreases blood pressure, helps the heart pump more efficiently, and reduces the workload on the heart.

Do NOT use Carvedilol if:

you are allergic to any ingredient in Carvedilol

you have certain types of irregular heartbeat (eg, moderate to severe heart block, sick sinus syndrome), very severe heart failure (eg, requires treatment in a hospital), or shock caused by severe heart problems

you have a very slow heartbeat and you do not have a permanent pacemaker

you have asthma or other severe breathing problems

you have severe liver problems

you are taking mibefradil

Contact your doctor or health care provider right away if any of these apply to you.

Before using Carvedilol:

Some medical conditions may interact with Carvedilol. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

if you are pregnant, planning to become pregnant, or are breast-feeding

if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement

if you have allergies to medicines, foods, or other substances or are taking medicine for allergies

if you have a history of other heart problems (eg, heart failure, slow or irregular heartbeat, angina) or low blood pressure

if you have a history of liver or kidney problems, blood vessel disease, blood flow problems (eg, in the legs or feet), lung or breathing problems (eg, chronic bronchitis emphysema, chronic obstructive pulmonary disease), diabetes, low blood sugar, thyroid problems, or glaucoma

if you have an adrenal gland tumor (pheochromocytoma)

if you will be having surgery

Some MEDICINES MAY INTERACT with Carvedilol. Tell your health care provider if you are taking any other medicines, especially any of the following:

Mibefradil because the risk of serious heart side effects may be increased

Many prescription and nonprescription medicines (eg, used for infections, inflammation, aches and pains, high blood pressure, heart problems, irregular heartbeat, cancer, diabetes, depression, mental or mood problems, multiple sclerosis [MS], prostate problems, immune system suppression, allergic reactions, asthma, high cholesterol, seizures, thyroid problems), multivitamin products, and herbal or dietary supplements (eg, herbal teas, coenzyme Q10, garlic, ginseng, ginkgo, St. John's wort) may interact with Carvedilol, increasing the risk of side effects

This may not be a complete list of all interactions that may occur. Ask your health care provider if Carvedilol may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Carvedilol:

Use Carvedilol as directed by your doctor. Check the label on the medicine for exact dosing instructions.

An extra patient leaflet is available with Carvedilol. Talk to your pharmacist if you have questions about this information.

Take Carvedilol by mouth with food.

Take Carvedilol on a regular schedule to get the most benefit from it. Taking Carvedilol at the same time each day will help you remember to take it.

Continue to take Carvedilol even if you feel well. Do not miss any doses.

Do not suddenly stop taking Carvedilol. You may have an increased risk of side effects. If you need to stop Carvedilol or add a new medicine, your doctor will gradually lower your dose.

If you miss a dose of Carvedilol, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Carvedilol.

Important safety information:

Carvedilol may cause dizziness, fainting, or blurred vision. These effects may be worse if you take it with alcohol or certain medicines. Use Carvedilol with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.

Carvedilol may cause dizziness, light-headedness, or fainting. These effects may occur within the first hour after you take your dose. They may be more likely when you start taking Carvedilol or if your dose is increased. Alcohol, hot weather, exercise, or fever may increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Sit or lie down at the first sign of any of these effects. Tell your doctor if these effects occur.

Do NOT take more than the recommended dose without checking with your doctor.

Do not suddenly stop taking Carvedilol. Sharp chest pain, irregular heartbeat, and sometimes heart attack may occur if you suddenly stop Carvedilol. The risk may be greater if you have certain types of heart disease. Your doctor should slowly lower your dose over several weeks if you need to stop taking it. This should be done even if you only take Carvedilol for high blood pressure. Heart disease is common and you may not know you have it. Limit physical activity while you are lowering your dose. If new or worsened chest pain or other heart problems occur, contact your doctor right away. You may need to start taking Carvedilol again.

Patients who take medicine for high blood pressure often feel tired or run down for a few weeks after starting treatment. Be sure to take your medicine even if you may not feel "normal." Tell your doctor if you develop any new symptoms.

Tell your doctor or dentist that you take Carvedilol before you receive any medical or dental care, emergency care, or surgery.

If you have a history of any severe allergic reaction, talk with your doctor. You may be at risk for an even more severe allergic reaction if you come into contact with the substance that caused your allergy. Some medicines used to treat severe allergies may also not work as well while you are using Carvedilol.

Diabetes patients - Carvedilol may affect your blood sugar. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.

Diabetes patients - Carvedilol may hide signs of low blood sugar, such as a rapid heartbeat. Be sure to watch for other signs of low blood sugar. Low blood sugar may make you anxious, sweaty, weak, dizzy, drowsy, or faint. It may also make your vision change; give you a headache, chills, or tremors; or make you more hungry. Check blood sugar levels closely. Ask your doctor before you change the dose of your diabetes medicine.

Lab tests, including blood pressure and heart function, may be performed while you use Carvedilol. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.

Use Carvedilol with caution in the ELDERLY; they may be more sensitive to its effects, especially dizziness.

Carvedilol should be used with extreme caution in CHILDREN younger than 18 years old; safety and effectiveness in these children have not been confirmed.

PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Carvedilol while you are pregnant. It is not known if Carvedilol is found in breast milk. Do not breast-feed while taking Carvedilol.

Possible side effects of Carvedilol:

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Diarrhea; dizziness; dry eyes; fatigue; light-headedness; weakness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); change in the amount of urine produced; chest pain; cold or numb legs or feet; fainting; irregular or unusually slow heartbeat; persistent or severe vision changes; red, swollen, blistered, or peeling skin; severe dizziness; shortness of breath; sudden, unusual weight gain; swelling of the hands, ankles, or feet; unusual bruising or bleeding; unusual leg pain; very cold or blue fingers or toes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Carvedilol side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include chest pain; fainting; seizures; severe dizziness; slow heartbeat; slow, shallow, or difficult breathing.

Proper storage of Carvedilol:

Store Carvedilol below 86 degrees F (30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Carvedilol out of the reach of children and away from pets.

General information:

If you have any questions about Carvedilol, please talk with your doctor, pharmacist, or other health care provider.

Carvedilol is to be used only by the patient for whom it is prescribed. Do not share it with other people.

If your symptoms do not improve or if they become worse, check with your doctor.

Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Carvedilol. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

More Carvedilol resources

Carvedilol Side Effects (in more detail)
Carvedilol Dosage
Carvedilol Use in Pregnancy & Breastfeeding
Drug Images
Carvedilol Drug Interactions
Carvedilol Support Group
36 Reviews for Carvedilol - Add your own review/rating

Carvedilol Prescribing Information (FDA)

Carvedilol Monograph (AHFS DI)

Carvedilol Professional Patient Advice (Wolters Kluwer)

carvedilol Advanced Consumer (Micromedex) - Includes Dosage Information

Coreg Consumer Overview

Coreg Prescribing Information (FDA)

Coreg CR Prescribing Information (FDA)

Compare Carvedilol with other medications

Angina
Atrial Fibrillation
Heart Failure
High Blood Pressure
Left Ventricular Dysfunction

Vitamin B12

Class: Vitamin B Complex
VA Class: VT100
Chemical Name: 5,6-dimethyl-benzimidazolyl cyanocobamide,
CAS Number: 68-19-9
Brands: Nascobal

Introduction

A cobalt-containing, B complex vitamin.^a Cyanocobalamin and hydroxocobalamin are synthetic forms of vitamin B₁₂.^a

Hydroxocobalamin: Antidote for cyanide poisoning.¹⁰⁴

Uses for Vitamin B12

Vitamin B₁₂ Deficiency

Treatment of pernicious anemia and other vitamin B₁₂ deficiency states.^a ¹⁰² ¹⁰⁵

Parenteral cyanocobalamin or hydroxocobalamin: Treatment of vitamin B₁₂ deficiency due to inadequate intrinsic factor (IF) secretion; impaired intestinal absorption; or dietary deficiency associated with a vegetarian diet.^a ¹⁰² ¹⁰⁵

Cyanocobalamin is considered the parenteral vitamin B₁₂ preparation of choice; hydroxocobalamin may be preferred for initial treatment.^a

Cyanocobalamin nasal spray: Used to maintain hematologic status in adults with pernicious anemia with no nervous system involvement who have responded to parenteral vitamin B ₁₂ therapy.¹⁰³ Also used as a supplement for vitamin B₁₂ deficiency due to dietary deficiency, impaired absorption, inadequate secretion of IF, or certain other conditions.¹⁰³

Dietary Requirements

Adequate intake needed to prevent vitamin B₁₂ deficiency and neurologic complications associated with vitamin B₁₂ deficiency.¹⁰¹

Adequate intake of vitamin B₁₂ usually can be accomplished through consumption of foodstuffs; however, about 10–30% of geriatric individuals are unable to absorb naturally occurring vitamin B₁₂ and should consume vitamin B₁₂-fortified food or supplements.¹⁰¹ Inadequate intake can occur in vegetarians and their breast-fed infants.^a Mixed foods whose main ingredient is meat, fish, or poultry; milk; and fortified ready-to-eat cereals are the main sources of vitamin B₁₂ in the diet of US adults and children.¹⁰¹

Recommended Dietary Allowance (RDA) in adults based on amount needed to maintain hematologic status and normal serum vitamin B₁₂ concentrations.¹⁰¹

Adequate intake (AI) established for infants ≤6 months of age based on observed mean vitamin B₁₂ intake of infants fed principally human milk; AI for infants 7–12 months of age based on AI for younger infants and data in adults.¹⁰¹

RDA for children 1–18 years of age based on data in adults.¹⁰¹

Metabolic Disorders

Parenteral cyanocobalamin: Management of hereditary deficiency of transcobalamin II.^a

Schilling Test

Parenteral cyanocobalamin and hydroxocobalamin: Used in conjunction with cyanocobalamin Co 57 in Schilling test to study vitamin B₁₂ absorption. ^a

Cyanide Poisoning

Hydroxocobalamin (Cyanokit): Treatment of known or suspected cyanide poisoning.¹⁰⁴ ¹⁰⁷ ¹⁰⁸ ¹⁰⁹ Used in conjunction with airway and cardiovascular support and management of seizure activity.¹⁰⁴

Vitamin B12 Dosage and Administration

Administration

Cyanocobalamin is administered orally, intranasally, or by IM or deep sub-Q injection.^a ¹⁰² ¹⁰³

Hydroxocobalamin is administered by IM injection or IV infusion.¹⁰⁴ ¹⁰⁵

Oral Administration

Oral therapy is inferior to parenteral therapy. ^a May be used for treatment of dietary vitamin B₁₂ deficiency in patients with normal GI absorption.^a

Parenteral Administration

Cyanocobalamin: Administer by IM or deep sub-Q injection.¹⁰² If administered sub-Q, avoid injection into the dermis or upper subcutaneous tissue.^a Avoid administering IV; vitamin is rapidly excreted in urine when administered IV.¹⁰²

Hydroxocobalamin: Administer by IM injection (vitamin deficiency)¹⁰⁵ or by IV infusion (cyanide poisoning).¹⁰⁴ Avoid administering IV for vitamin deficiency.¹⁰⁵

For drug compatibility information, see Compatibility under Stability.

IV Administration for Cyanide Poisoning

Hydroxocobalamin: (Cyanokit); Administer by IV infusion.¹⁰⁴

May require a dedicated IV line.¹⁰⁴ Administration through the same IV line as blood products not recommended.¹⁰⁴

Reconstitution

Reconstitute vial containing 2.5 g of hydroxocobalamin with 100 mL of 0.9% sodium chloride injection; invert or rock vial for at least 30 seconds.¹⁰⁴ Do not shake vial.¹⁰⁴ Lactated Ringer's injection or 5% dextrose injection can be used if 0.9% sodium chloride injection is not available.¹⁰⁴ Reconstituted solution contains 25 mg/mL.¹⁰⁴

Rate of Administration

Initial 5-g dose: 15 minutes.¹⁰⁴

Second 5-g dose: 15 minutes (for patients in extremis) to 2 hours; rate depends on patient condition.¹⁰⁴

Intranasal Administration

Administer intranasally using a metered-dose pump.¹⁰³ Administer 1 hour before or 1 hour after ingestion of hot foods or liquids.¹⁰³

Prior to intranasal administration, clear nasal passages.¹¹⁰ Insert the nasal adapter 1 cm into one nostril, point the tip of the adapter toward the back of the nose, hold the other nostril closed, and tilt head slightly forward, pump the drug into nostril, sniff gently during and immediately after dosing, return head to upright position, remove pump unit from nose.¹¹⁰ ^a

Efficacy has not been established in patients with nasal congestion, allergic rhinitis, or upper respiratory tract infection; defer use until these symptoms have subsided.¹⁰³

Prime the pump before each use.¹⁰³

Dosage

Vitamin B ₁₂ deficiency: Duration of therapy depends on cause; long-term therapy not needed when other therapeutic measures correct the underlying cause of the deficiency.^a

Cyanocobalamin metered-dose pump delivers 500 mcg of the drug (0.1 mL) per actuation.¹⁰³

Pediatric Patients

Vitamin B ₁₂ Deficiency

IM

Hydroxocobalamin: Initially, single doses of 100 mcg to total dose of 1–5 mg given over ≥2 weeks.¹⁰⁵

Hydroxocobalamin: Maintenance, 30–50 mcg every 4 weeks.¹⁰⁵

Dietary and Replacement Requirements

Oral

Infants born to vegan mothers: Supplement with AI from birth because these infants' vitamin B₁₂ stores are low and their mother’s milk may supply very small amounts of the vitamin.¹⁰¹

Infants ≤6 months of age: Recommended AI is 0.4 mcg (0.06 mcg/kg) daily.¹⁰¹

Infants 7–12 months of age: Recommended AI is 0.5 mcg (0.06 mcg/kg) daily.¹⁰¹

Children 1–3 years of age: RDA is 0.9 mcg daily.¹⁰¹

Children 4–8 years of age: RDA is 1.2 mcg daily.¹⁰¹

Children 9–13 years of age: RDA is 1.8 mcg daily.¹⁰¹

Children 14-18 years of age: RDA is 2.4 mcg daily.¹⁰¹

The RDAs will not meet the needs of individuals with malabsorption syndrome.¹⁰¹

Cyanide Poisoning†

IV

Hydroxocobalamin: 70 mg/kg has been used.¹⁰⁴ ¹⁰⁷

Adults

Vitamin B ₁₂ Deficiency

IM or Sub-Q

Cyanocobalamin: Initially, 100 mcg daily for 6–7 days.¹⁰² If clinical manifestations improve and reticulocyte response observed, administer 100 mcg every other day for 7 doses and then 100 mcg every 3–4 days for 2–3 weeks.¹⁰²

Cyanocobalamin: Maintenance, 100 mcg every month.¹⁰²

IM

Hydroxocobalamin: Initially, 30 mcg daily for 5–10 days.¹⁰⁵

Hydroxocobalamin: Maintenance, 100–200 mcg every month.¹⁰⁵

Intranasal

Maintenance, 500 mcg (one actuation) once weekly.¹⁰³ Increase dose in patients who experience a decline in serum vitamin B₁₂ concentrations after 1 month of therapy.¹⁰³

Dietary and Replacement Requirements

Oral

Men and women ≥19 years of age: RDA is 2.4 mcg daily.¹⁰¹

Adults ≥51 years of age should obtain most of their vitamin B₁₂ from fortified food or a vitamin B₁₂ supplement.¹⁰¹

The RDAs will not meet the needs of individuals with malabsorption syndrome.¹⁰¹

Cyanide Poisoning

IV

Hydroxocobalamin: Initially, 5 g (two 2.5-g vials).¹⁰⁴ A second 5-g dose may be administered, based on the severity of the poisoning and clinical response.¹⁰⁴

Schilling Test

IM or Sub-Q

Cyanocobalamin: Flushing dose is 1000 mcg.¹⁰²

IM

Hydroxocobalamin: Flushing dose is 1000 mcg. ¹⁰⁵

Special Populations

Pregnant Women

RDA for pregnant women is 2.6 mcg daily.¹⁰¹

Lactating Women

RDA for lactating women is 2.8 mcg daily.¹⁰¹

Requirements increased in lactating women to ensure adequate concentration of the vitamin in milk.¹⁰¹

Cautions for Vitamin B12

Contraindications

Known hypersensitivity to vitamin B₁₂, cobalt, or any ingredient in the formulation.¹⁰² ¹⁰³ ¹⁰⁵

No contraindications when used for treatment of cyanide poisoning.¹⁰⁴

Warnings/Precautions

Warnings

Hypokalemia

Fatal hypokalemia reported in intensively treated patients with megaloblastic anemia.^a ¹⁰² ¹⁰³ ¹⁰⁵ Monitor serum potassium concentrations during early vitamin B₁₂ therapy and administer potassium if necessary.¹⁰⁵ ^a

Polycythemia Vera

Vitamin B₁₂ deficiency may suppress signs of polycythemia vera; treatment may unmask this condition.^a

Ocular Effects

Avoid use in patients with early Leber’s disease (hereditary optic nerve atrophy); rapid and severe optic nerve atrophy reported.¹⁰² ¹⁰³

Sensitivity Reactions

Anaphylaxis reported with parenteral preparations.¹⁰² ¹⁰³

Hydroxocobalamin (Cyanokit): Rash, mainly acneiform, reported in 20 or 44% of individuals receiving a 5- or 10-g dose, respectively.¹⁰⁴

Skin Test

Administer an intradermal test dose prior to administration of vitamin B₁₂ for vitamin deficiency in patients who may be sensitive to cobalamins.^a

General Precautions

Laboratory Monitoring

Obtain hematocrit, reticulocyte count, vitamin B₁₂, folate, and iron levels prior to treatment for vitamin B₁₂ deficiency.¹⁰² ¹⁰³ Monitor hematologic parameters as necessary during therapy.¹⁰² ¹⁰³

Aluminum

Some cyanocobalamin injection preparations contain aluminum, which may be toxic.¹⁰² Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired.¹⁰² Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.¹⁰²

Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum >4–5 mcg/kg daily accumulate aluminum at levels associated with CNS and bone toxicity.¹⁰² Tissue loading may occur at even lower rates of administration.¹⁰²

Benzyl Alcohol in Neonates

Cyanocobalamin injection may contain benzyl alcohol as a preservative; benzyl alcohol has been associated with toxicity in neonates.¹⁰² ¹¹¹ ¹¹² ¹¹³ ¹¹⁴ ¹¹⁵ ¹¹⁶ (See Pediatric Precautions.)

Blood Pressure

Transient elevations in BP reported in individuals receiving IV hydroxocobalamin.¹⁰⁴

Undiagnosed Anemia

Use extreme caution if folic acid is administered to patients with undiagnosed anemia; may obscure the diagnosis of pernicious anemia by alleviating hematologic manifestations of the disease while allowing neurologic complications to progress.^a

Renal Effects

Oxalate crystals observed in the urine of healthy individuals and cyanide poisoning victims following administration of hydroxocobalamin.¹⁰⁴

Specific Populations

Pregnancy

Category C.¹⁰² ¹⁰³ ¹⁰⁴ ¹⁰⁵

Lactation

Distributed into human milk.¹⁰² ¹⁰³

Hydroxocobalamin (Cyanokit): Caution advised; no data available to determine when breast-feeding may be restarted following administration of IV hydroxocobalamin.¹⁰⁴

Pediatric Use

Hydroxocobalamin (Cyanokit): Safety and efficacy not established.¹⁰⁴

Cyanocobalamin: Benzyl alcohol has been associated with toxicity (“gasping syndrome”) in neonates; each mL of cyanocobalamin injection (e.g., preparation manufacturered by Abraxis) contains 15 mg of benzyl alcohol.¹⁰² ¹¹¹ ¹¹² ¹¹³ ¹¹⁴ ¹¹⁵ ¹¹⁶

Geriatric Use

Hydroxocobalamin (Cyanokit): No substantial differences in safety and efficacy relative to younger adults.¹⁰⁴ Dosage adjustment not needed.¹⁰⁴

Hepatic Impairment

Hydroxocobalamin (Cyanokit): Safety and efficacy not studied in patients with hepatic impairment.¹⁰⁴

Renal Impairment

Hydroxocobalamin (Cyanokit): Safety and efficacy not studied in patients with renal impairment.¹⁰⁴ Hydroxocobalamin and cyanocobalamin excreted unchanged in urine.¹⁰⁴

Common Adverse Effects

Usually nontoxic even in large doses; mild transient diarrhea, peripheral vascular thrombosis, itching, transitory exanthema, urticaria, body swelling reported in patients receiving parenteral preparations.^a

Interactions for Vitamin B12

Colchicine, aminosalicylic acid and its salts, and excessive alcohol intake lasting >2 weeks may reduce absorption of vitamin B₁₂ from the GI tract.¹⁰² ¹⁰³

Specific Drugs and Laboratory Tests

Drug	Interaction	Comments
Ascorbic acid	May destroy substantial amounts of dietary vitamin B₁₂^a	Consider this if large doses of ascorbic acid are ingested within 1 hour of administration of oral vitamin B₁₂^a
Chloramphenicol	May antagonize the hematopoietic response to vitamin B₁₂ in vitamin-deficient patients^a	Monitor; consider alternate anti-infectives ^a
Cyanide antidotes	Safety of concomitant use of hydroxocobalamin with other cyanide antidotes not established¹⁰⁴	Caution¹⁰⁴ (See Parenteral under Stability and IV Administration under Dosage and Administration)
Laboratory parameters determined by colorimetric methods	Hydroxocobalamin (Cyanokit): Deep red color in blood and/or urine may interfere with certain laboratory tests (e.g., clinical chemistry, hematology, coagulation, urine parameters)¹⁰⁴	Consult the product labeling for specific information
Methotrexate	Invalidates diagnostic microbiologic blood assays for vitamin B₁₂¹⁰² ¹⁰³
Prednisone	Increased absorption of vitamin B₁₂ and secretion of IF reported in a few patients with pernicious anemia^a	Does not occur in patients with partial or total gastrectomy; clinical importance unknown^a
Pyrimethamine	Invalidates diagnostic microbiologic blood assays for vitamin B₁₂¹⁰² ¹⁰³
Test for intrinsic factor (IF) antibodies	Prior administration of cyanocobalamin may result in false-positive test results^a

Vitamin B12 Pharmacokinetics

Absorption

Bioavailability

Irregularly absorbed from the distal small intestine following oral administration. ^a Requires gastric IF for active absorption from the GI tract.^a

Following parenteral (IM or sub-Q) administration, hydroxocobalamin is absorbed more slowly than cyanocobalamin.^a

Following administration of cyanocobalamin nasal spray, bioavailability is about 6.1% compared with IM administration.¹⁰³

Distribution

Extent

Distributed into liver, bone marrow, and other tissues.¹⁰³ ^a

Crosses the placenta and is distributed into milk.^a

Elimination

Elimination Route

50–98% may be excreted in urine.¹⁰²

Stability

Storage

Oral

Tablets

Cool dry place. ¹⁰⁶

Parenteral

Solution for Injection

20–25°C; protect from light.¹⁰²

Powder for Injection

25°C (may be exposed to 15–30°C).¹⁰⁴ May be stored for short periods at temperatures that occur with usual transport (15 days 5–40°C), transport in the desert (4 days 5–60°C), and freeze/defrost cycles (15 days in a range from -20 to 40°C).¹⁰⁴

Store reconstituted solution at ≤40°C; discard 6 hours after reconstitution.¹⁰⁴

Nasal Spray

Upright at 15–30°C; protect from light. ¹⁰³ Keep covered in carton until needed.¹⁰³ Protect from freezing.¹⁰³

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Hydroxocobalamin (Cyanokit): Incompatible with ascorbic acid, diazepam, dobutamine, dopamine, fentanyl, nitroglycerin, pentobarbital, propofol, sodium nitrite, sodium thiosulfate, thiopental.¹⁰⁴

Cyanocobalamin injection: Reported to be incompatible with chlorpromazine hydrochloride, phytonadione, prochlorperazine edisylate, warfarin sodium, ascorbic acid, dextrose, heavy metals, oxidizing or reducing agents, and alkaline or strongly acidic solutions.^a

Cyanocobalamin: Solution Compatibility^HID

Compatible
Dextran 6% in dextrose 5%
Dextran 6% in sodium chloride 0.9%
Dextrose-Ringer's injection combinations
Dextrose-Ringer’s injection, lactated, combinations
Dextrose-saline combinations
Dextrose 2½, 5, or 10% in water
Fructose 10% in sodium chloride 0.9%
Fructose 10% in water
Invert sugar 5 and 10% in sodium chloride 0.9%
Invert sugar 5 and 10% in water
Ionosol products
Ringer's injection
Ringer's injection, lactated
Sodium chloride 0.45 or 0.9%
Sodium lactate (1/6) M

Cyanocobalamin: Drug Compatibility

Admixture CompatibilityHID
Compatible
Ascorbic acid injection
Chloramphenicol sodium phosphate
Metaraminol bitartrate
Vitamin B complex with C

Y-Site CompatibilityHID
Compatible
Heparin sodium
Hydrocortisone sodium succinate
Potassium chloride
Vitamin B complex with C

ActionsActions

An exogenous source of vitamin B₁₂ is required for nucleoprotein and myelin synthesis, cell reproduction, normal growth, and the maintenance of normal erythropoiesis.^a

In cyanide poisoning, hydroxocobalamin binds to the cyanide ion to form cyanocobalamin which is excreted in the urine.¹⁰⁴

Advice to Patients

Advise patients with pernicious anemia that they must receive maintenance dosages of cyanocobalamin or hydroxocobalamin for the remainder of their lives to prevent irreversible neurologic damage.^a

Advise patient of necessity of follow-up tests to confirm adequacy of therapy.¹⁰³

Advise individuals who follow a vegetarian diet that contains no animal products to take oral vitamin B₁₂ regularly.¹⁰² ¹⁰³

Importance of informing patients using intranasal cyanocobalamin to administer the dose at least 1 hour before or after ingestion of hot foods or liquids.¹⁰³

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹⁰² ¹⁰³

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹⁰² ¹⁰³ Importance of vitamin B₁₂ supplements in pregnant and lactating women who follow a vegetarian diet.¹⁰² ¹⁰³ Advise women given hydroxocobalamin for cyanide poisoning to discuss timing of resumption of breast-feeding with their clinician.¹⁰⁴

Advise patients given hydroxocobalamin for cyanide poisoning that skin redness may last up to 2 weeks and urine coloration may last up to 5 weeks.¹⁰⁴ Importance of avoiding direct sun exposure while skin is discolored.¹⁰⁴

Importance of informing patients of other important precautionary information.^a (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Cyanocobalamin
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	25 mcg*
		50 mcg*
		100 mcg*
		250 mcg*
		500 mcg*
		1000 mcg*
Parenteral	Injection	100 mcg/mL*
		1000 mcg/mL*
Nasal	Spray	500 mcg/metered spray	Nascobal (with benzalkonium chloride)	QOL Medical

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Hydroxocobalamin
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection	1000 mcg/mL*
	For Injection	2.5 g	Cyanokit	Dey

Vitamin B₁₂ is also commercially available in combination with other vitamins and minerals.^a

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 05/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Cyanocobalamin 1000MCG/ML Solution (AMERICAN REGENT): 10/$13.99 or 20/$18.98

Cyanocobalamin 1000MCG/ML Solution (AMERICAN REGENT): 25/$35.99 or 75/$89.97

Cyanocobalamin 1000MCG/ML Solution (AMERICAN REGENT): 30/$19.99 or 90/$45.98

Nascobal 500MCG/0.1ML Solution (PAR): 2/$295.98 or 6/$875.99

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. National Research Council Food and Nutrition Board Subcommittee on the Tenth Edition of the RDAs. Recommended dietary allowances. 10th ed. Washington, DC: National Academy Press; 1989:158-65.

101. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes of the Food and Nutrition Board, Institute of Medicine, National Academy of Sciences. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B₆, folate, vitamin B₁₂, pantothenic acid, biotin, and choline. Washington, DC: National Academy Press; 1998. (Prepublication copy uncorrected proofs.)

102. Abraxis Pharmaceuticals. Cyanocobalamin injection prescribing information. Schaumburg, IL; 2005 Jun.

103. QOL Medical Company. Nascobal (cyanocobalamin nasal spray) prescribing information. Kirkland, WA; 2006 Aug.

104. Dey. Cyanokit (hydroxocobalamin for injection) prescribing information. Napa, CA; 2006 Dec. (

105. Watson Laboratories. Hydroxocobalamin injection prescribing information. Corona, CA; 2006 Feb.

106. Nature's bounty vitamin B₁₂ 1000 mcg tablets package information. From (). Accessed 31 May 2007.

107. Geller RJ, Barthold C, Saiers JA, Hall AH. Pediatric cyanide poisoning: causes, manifestations, management, and unmet needs. Pediatrics. 2006; 118:2146-58. [PubMed 17079589]

108. Borron SW, Baud FJ, Mégarbane B, Bismuth C. Hydroxocobalamin for severe acute cyanide poisoning by ingestion or inhalation. Am J Emerg Med. 2007; 25:551-8. [PubMed 17543660]

109. Borron SW, Baud FJ, Barriot P et al. Prospective study of hydroxocobalamin for acute cyanide poisoning in smoke inhalation. Ann Emerg Med. 2007; 49:794-801. [PubMed 17481777]

110. QOL Medical Company. Nascobal (cyanocobalamin nasal spray) patient information. Kirkland, WA; 2006.

111. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics. 1983; 72:356-8. [IDIS 175725] [PubMed 6889041]

112. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull. 1982; 12:10-11. [PubMed 7188569]

113. Anon. Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly Rep. 1982; 31:290-91. [IDIS 150868] [PubMed 6810084]

114. Gershanik J. Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982; 307:1384-8. [IDIS 160823] [PubMed 7133084]

115. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol. 1984; 1:288-92. [PubMed 6440575]

116. Anderson CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol. 1984; 148:344-6. [IDIS 181207] [PubMed 6695984]

a. AHFS drug information 2007. McEvoy GK, ed. Vitamin B₁₂. Bethesda, MD: American Society of Health-System Pharmacists, 2007; 3628-31.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:444-7.

Tuesday, 20 September 2016

Sensipin

Sensipin may be available in the countries listed below.

Ingredient matches for Sensipin

Clozapine

Clozapine is reported as an ingredient of Sensipin in the following countries:

Bangladesh

International Drug Name Search

A.N.B. Vitamin B1

A.N.B. Vitamin B1 may be available in the countries listed below.

Ingredient matches for A.N.B. Vitamin B1

Thiamine

Thiamine hydrochloride (a derivative of Thiamine) is reported as an ingredient of A.N.B. Vitamin B1 in the following countries:

Myanmar

International Drug Name Search

Monday, 19 September 2016

Carticel

Dosage Form: implant
FULL PRESCRIBING INFORMATION

Indications and Usage for Carticel

Carticel is indicated for the repair of symptomatic cartilage defects of the femoral condyle (medial, lateral or trochlea), caused by acute or repetitive trauma, in patients who have had an inadequate response to a prior arthroscopic or other surgical repair procedure (e.g., debridement, microfracture, drilling/abrasion arthroplasty, or osteochondral allograft/autograft).

Carticel should be used only in conjunction with debridement, placement of a periosteal flap and rehabilitation. The independent contributions of the autologous cultured chondrocytes and other components of the therapy to outcome are unknown.

Carticel is not indicated for the treatment of cartilage damage associated with generalized osteoarthritis.

Carticel is not recommended for patients with total meniscectomy unless surgically reconstructed prior to or concurrent with Carticel implantation.

Carticel Dosage and Administration

For Autologous Implantation Only

Dosage

Patients in the Swedish series [see Clinical Studies (14)] received a wide range of cell doses per cm2 of defect. Available data on 70 of 78 patients with femoral condyle defects showed a median dose of 1.6 million cells/cm2 of defect. The middle 80% of these patients received from 0.64 million to 3.3 million cells/cm2.

Each Carticel finished product vial contains approximately 12 million cells. Genzyme provides a single vial for each defect measuring ≤ 7 cm2. Two vials of Carticel are provided for defects 7 to 14 cm2, and three vials are provided for defects > 14 cm2. This is based on Genzyme’s greater than 10 years of experience with Carticel.

Handling Precautions and Preparation

2.2.1 Handling Precautions

The Carticel product is intended solely for autologous use. Prior to Carticel implantation, match the patient name and ID number on the certificate of analysis to the patient’s chart and the patient ID on the shipping box, transport cylinder and vial.

Healthcare providers should employ universal precautions in handling the biopsy samples and the Carticel product [see Risk of Transmissible Infectious Diseases (5.2)].

Refer to the Indications and Usage (1) and Warnings and Precautions (5) Sections for additional considerations regarding the use of Carticel.

2.2.2 Preparation

NOTE:

The exterior of the Carticel vial containing the cultured cells is NOT sterile. Follow strict sterile technique protocols.

When treating a defect that requires multiple vials of cells, resuspend, aspirate and inject one vial at a time.

Remove red plastic lid from vial. Wipe the vial surface and lid with alcohol.

Inspect vial contents for particulates, discoloration or turbidity. The cellular product appears as a yellowish clump in the bottom of the vial. Do not administer if contents appear turbid prior to cell suspension.

While holding vial in a vertical position, insert the needle of the intraspinal catheter into the vial. The needle must be positioned just above the fluid level. Slowly remove the inner needle from the catheter, leaving flexible tip behind. Attach a tuberculin syringe to catheter.

Lower the catheter tip into the media and position just above the cell pellet. Aspirate all the medium from the vial leaving only the cell pellet behind. Slowly expel medium back into the vial. This action will break the cell pellet and resuspend the cells in the medium.

Lower the catheter tip to the base of the vial and aspirate all contents into syringe, leaving the vial empty. Slowly inject the contents into the vial again. This will assure complete suspension of the cells. Repeat these steps as needed to ensure all cells are resuspended. Cell resuspension is complete when cell particles are no longer apparent, and the medium is a consistent, “cloudy” mixture. Aspirate all contents of vial into syringe. Always hold syringe vertical to keep an air pocket at the proximal end of syringe.

Administration

Implantation of the Carticel product should be restricted to physicians who have completed Genzyme Biosurgery’s Surgeon Training Program.

Implantation of the Carticel product is performed during arthrotomy and requires both preparation of the defect bed and a periosteal flap to secure the implant. Complete hemostasis must be achieved prior to periosteal fixation and cell implantation. See the Carticel Surgical Manual, Genzyme document #65021 for instructions on the performance of these procedures.

2.3.1 Implantation

Insert the catheter tip through the superior opening of the periosteal chamber at the site of the defect. Advance catheter to most inferior aspect of the defect.

Slowly inject a cell dose while moving the catheter tip from side to side and withdrawing the catheter proximally. This will ensure an even distribution of the cells throughout the defect.

Complete the implantation by closing the superior opening of the periosteum as instructed. See Carticel Surgical Manual, Genzyme document #65021.

Dosage Forms and Strengths

One vial of Carticel (autologous cultured chondrocytes) contains approximately 12 million cells.

Contraindications

Carticel should not be used in patients with a known history of hypersensitivity to gentamicin, other aminoglycosides or materials of bovine origin.

Gentamicin is added to both the cartilage biopsy transport media and in the culture media used during the processing of Carticel. Residual quantities of gentamicin up to 5 µg/mL are present in the Carticel product.

Fetal bovine serum is a component in the culture medium used to propagate the autologous chondrocytes. Trace quantities of bovine-derived proteins may be present in the Carticel product.

Warnings and Precautions

Subsequent Surgical Procedures

Review of the data from the Study of the Treatment of Articular Repair (STAR) and the Registry Based Study (RBS) [see Clinical Trials Experience (6.1)] as well as the Carticel worldwide experience (adverse reactions solicited through the Cartilage Repair Registry (CRR) and spontaneous reports) as of November 21, 1997 showed that the occurrence of a subsequent surgical procedure, primarily arthroscopic, following Carticel implantation is common. In the STAR study, 49% of patients underwent a subsequent surgical procedure, irrespective of relationship to Carticel (6.2). Symptoms leading to arthroscopic intervention included catching, locking, clicking or pain. Patients who develop clinical signs of tissue hypertrophy, including catching or clicking, should be evaluated and arthroscopy may be indicated for treatment or further assessment.

Risk of Transmissible Infectious Diseases

The Carticel product is intended solely for autologous use. Patients undergoing the surgical procedures associated with Carticel are not routinely tested for transmissible infectious diseases. Therefore, the cartilage biopsy and the Carticel product may carry the risk of transmitting infectious diseases to the health care provider handling these tissues. Accordingly, healthcare providers should employ universal precautions in handling the biopsy samples and the Carticel product.

Pre-surgical Assessment of Comorbidities

The following conditions should be assessed and treated prior to or concurrent with implantation with Carticel:

Unstable meniscus tears should be repaired or resected.

If the patient has had a total meniscectomy, absent meniscus should be reconstructed.

Instability of the knee may adversely affect the success of the procedure and should be corrected. The anterior and posterior cruciate ligaments should be free of laxity as well as stable and intact. It is recommended that cruciate deficiencies be corrected.

Abnormal weight-distribution within the joint may adversely affect the success of the procedure and should be corrected. The tibial/femoral joint should be properly aligned. When treating trochlear defects, abnormal patellar mechanics should be assessed and corrected.

Product Safety and Sterility

The safety of the Carticel product is unknown in patients with malignancy in the area of cartilage biopsy or implant. The potential exists for in vitro expansion and subsequent implantation of malignant or dysplastic cells present in biopsy tissue. In addition, implantation of normal autologous chondrocytes could theoretically stimulate growth of malignant cells in the area of the implant, although there have been no reported incidents in humans or animals.

The Carticel product is shipped following a preliminary sterility test with a 48-hour incubation to determine absence of microbial growth. Final (14 day incubation) sterility test results are not available at the time of implantation.

Adverse Reactions

Information on the safety of implanted autologous chondrocytes is derived from the Study of the Treatment of Articular Repair (STAR) [see Clinical Studies (14)], the Cartilage Repair Registry, the Swedish Series, and post-marketing adverse event reporting.

The most common serious adverse events (> 5% of patients) derived from the STAR study include arthrofibrosis/joint adhesion, graft overgrowth, chondromalacia or chondrosis, cartilage injury, graft complication, meniscal lesion and graft delamination. Only serious adverse events were collected in this study.

Clinical Trials Experience

The adverse reaction rates as well as the rate and type of subsequent surgical procedures from Carticel studies of different designs cannot be directly compared amongst each other. Adverse reaction data from these studies do, however, provide a basis for identifying adverse reactions that may be related to product use and for estimating their frequency.

Study of the Treatment of Articular Repair (STAR)

In the STAR study [see Study of the Treatment of Articular Repair (STAR) (14.2.2)], patients who had experienced an inadequate response to a prior cartilage repair procedure underwent Carticel implantation to the index lesion. A total of 154 patients were implanted with Carticel; 28 patients discontinued the study early. The numbers of patients completing the 24 and 48 month follow-up visits are 136 and 115, respectively. Mean patient age was 35 years at consent. The majority of patients were Caucasian (135; 88%) and male (106; 69%).

Seventy-six (76) (49% of 154) patients underwent 113 subsequent surgical procedures (SSPs) on the treated knee, irrespective of relationship to Carticel, during the 4 year follow up. Of the 76 patients, 52 patients had 1 SSP, 15 patients had 2 SSPs, and 9 patients had 3 or more SSPs. Sixty-one (61) (80%) of the 76 patients who had an SSP underwent a procedure within the first 24 months after implantation. The majority of patients, 83% (63 of the 76), underwent an arthroscopy or manipulation under anesthesia only. Table 1 shows the interventions during SSPs in > 2% of patients.

Table 1: Interventions during Subsequent Surgical Procedures, Regardless of Relationship, in > 2% of Patients
Intervention	% of 154 Patients
* Includes debridement of index lesion and other defects † Includes debridement of other joint structures in addition to cartilage (e.g., patellar fat pad)
Debridement of Cartilage Lesion*	31% (47/154)
Lysis of Adhesions	14% (21/154)
Synovectomy / Synovial Plica Excision	12% (19/154)
Other Debridement†	10% (16/154)
Chondroplasty	6% (10/154)
Meniscectomy	6% (10/154)
Loose Body Removal	5% (7/154)
Microfracture – Index lesion	5% (7/154)
Scar Tissue Removal	5% (7/154)
Release of Patellar Retinaculum	4% (6/154)
Hardware Removal	4% (6/154)
Microfracture – New lesion	4% (6/154)
Osteotomy	3% (5/154)

Lysis of adhesions was the most frequent surgical intervention performed in the first 6 months. After 6 months, cartilage debridement was the most frequently performed intervention. In the STAR study, 61% (46/76) of patients who required an SSP after Carticel did not meet failure criteria by either modified Cincinnati score or surgical criteria (e.g., graft delamination or surgical procedure violating the subchondral bone.)

The most clinically significant interventions or findings involving the Carticel graft or periosteal patch are as follows: 3 Carticel grafts were completely removed and 1 was partially removed due to delamination. Partial delamination or fraying of the graft or periosteal patch was reported in 10 additional patients. Four (4) of these patients underwent reattachment/repair of the periosteal patch. Finally, a partially intact graft was found in 1 patient who was re-implanted. Detailed lists of interventions and findings that may have been associated with the graft or periosteal patch are presented in Tables 1 and 2, respectively.

Table 2 shows the serious adverse events (SAEs) that occurred in ≥ 5% of patients, regardless of relationship to study treatment.

Table 2: Most Frequent Serious Adverse Events (in ≥ 5% of Patients), Regardless of Relationship, in the STAR Study
Serious Adverse Events	% of 154 Patients
* Encompasses cartilage injuries throughout the joint e.g., onset of new defects and tibial plateau fibrillation † Includes periosteal patch complications, graft fraying or fibrillation
Arthrofibrosis/Joint Adhesions	16% (25/154)
Graft Overgrowth	15% (23/154)
Chondromalacia or Chondrosis	12% (18/154)
Cartilage Injury*	11% (17/154)
Graft Complication†	10% (15/154)
Meniscal Lesion	8% (12/154)
Graft Delamination	6% (9/154)
Osteoarthritis	5% (7/154)

Registry Based Study (RBS)

Data from a cohort of 97 Carticel treated patients, who were retrospectively evaluated in the Registry Based Study [see Registry-Based Study (RBS) (14.2.1)], showed that 39% (38/97) of patients had a SSP within 3 years of which 63% (24/38) were assessed as related to Carticel. Shaving or trimming (debridement) of overgrown tissue (hypertrophic) commonly relieved patients’ symptoms. In the RBS, 67% (16/24) of patients who required arthroscopy after Carticel had a good clinical benefit in terms of improved function and relief of symptoms. Table 3 shows the findings at surgery for the 38 patients who underwent a surgical procedure after Carticel.

Table 3: Most Frequent Findings (in ≥ 5% of Patients) at Subsequent Surgical Procedures in the Registry Based Study
Symptoms or Surgical Findings (MedDRA preferred term)	% of 97 Patients
Graft overgrowth	10% (10/97)
Partial graft delamination	8% (8/97)
Chondromalacia	8% (8/97)
Arthrofibrosis/Joint adhesions	8% (8/97)
Arthralgia	7% (7/97)
Synovitis	6% (6/97)
Meniscal lesion	5% (5/97)
Loose Body	5% (5/97)

Swedish Series

Of 153 patients treated with autologous cultured chondrocyte implantation in the Swedish Series [see Clinical Studies (14)], 22% (34/153) of patients experienced the adverse reactions presented in Table 4 below.

Table 4: Initial ACI Experience Swedish Series Serious Adverse Reactions (Occurring at a frequency of 1% or more)
Serious Adverse Reactions	% of 153 Patients
Tissue hypertrophy	See below
Intra-articular adhesions	8%
Superficial wound infection	3%
Hypertrophic synovitis	3%
Post-operative hematoma	2%
Adhesions of the bursa suprapatellaris	2%
Hypertrophic synovium	1%

About 1% of patients developed severe adhesions resulting in “frozen knee” and requiring lysis. Adverse reactions noted at a level of less than 1% included keloid-like scar, pannus formation, significant swelling of the joint, pain with post-operative fever, and hematoma following arthroscopy.

In this series, arthroscopy was scheduled to be undertaken at 18 months of follow up, regardless of patient symptoms. Of the patients who had arthroscopy, 43% (37/86) had hypertrophic tissue. Forty of the 85 patients had femoral condyle defects. Of these, 25% (10/40) of patients had some hypertrophic tissue noted at follow-up arthroscopy. Some patients had clinical symptoms that included painful crepitations or catching, and these symptoms generally resolved after arthroscopic resection of the hypertrophic tissue. Ten percent (10%) of patients with hypertrophy required additional treatment after hypertrophic tissue recurred following initial resection. Not all patients with tissue hypertrophy noted at arthroscopy were symptomatic.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Carticel. Most of these reactions are reported voluntarily, and it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Furthermore, the reported frequency of spontaneous reports underestimates the true frequency of adverse reactions. As of July 31, 2006, approximately 12,500 patients have been implanted with Carticel and 559 patients have reported serious adverse reactions after treatment. The most frequently identified operative findings in these patients, in descending order of frequency, were graft overgrowth, graft delamination (partial or complete), arthrofibrosis, joint adhesions, meniscus lesion or tear, graft complications, chondromalacia, loose body in knee joint, and joint malalignment.

USE IN SPECIFIC POPULATIONS

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Carticel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Carticel Description

Autologous cultured chondrocytes, the Carticel product, are derived from in vitro expansion of chondrocytes harvested from the patient’s normal, femoral articular cartilage. Biopsies from a lesser-weight bearing area are the source of chondrocytes, which are isolated, expanded through cell culture, and implanted into articular cartilage defects beneath an autologous periosteal flap. Prior to final packaging, cell viability is assessed to be at least 80%.

Each single use container of autologous cultured chondrocytes has approximately 12 million cells aseptically processed and suspended in 0.4 mL of sterile, buffered Dulbecco’s Modified Eagles Medium (DMEM). Both the biopsy transport media and the cell culture media contain gentamicin. Residual quantities of gentamicin up to 5 µg/mL may be present in the Carticel product.

Carticel - Clinical Pharmacology

Hyaline cartilage forms the articular surface of the femoral condyle. Studies have shown that implantation of autologous chondrocytes into the articular defect can result in the development of hyaline-like cartilage [see Clinical Studies (14)].1,2,3,4,5 Normal hyaline cartilage consists of chondrocytes (≤ 5% total volume) and extracellular matrix (≥ 95% total volume). The matrix contains a variety of macromolecules, including type II collagen and proteoglycan. The structure of the matrix allows the hyaline cartilage to absorb shock and withstand shearing and compression forces. Normal hyaline cartilage also has an extremely low coefficient of friction at the articular surface. Damage to articular cartilage from acute or repetitive trauma often results in pain and disability. However, because hyaline cartilage is avascular, spontaneous healing of large defects is not believed to occur in humans.

A variety of surgical procedures have been used in attempts to promote repair of articular cartilage, and a few studies have evaluated the histology resulting from these interventions. Generally, procedures such as marrow stimulation techniques (MST) have been shown to produce fibrocartilage or hybrid mixtures of fibrocartilage and hyaline cartilage. Published data show that autologous chondrocyte implantation (ACI) is more likely than MST to result in hyaline-like cartilage at the repair site.1,2,4,5 However, because of differences in study design, lesion size and concomitant patient conditions, these data are not sufficient to draw conclusions concerning the long-term correlation of histology and clinical outcomes.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or mutagenicity data are available for Carticel in animals or in humans. No studies on the effects of Carticel on fertility have been conducted.

Animal Pharmacology and/or Toxicology

Pre-approval Studies

Bioactivity of autologous chondrocytes implanted under a periosteal patch was reported in the BLA for three rabbit studies6,7,8 of up to 52 weeks duration post-implant and one dog study9 of up to 18 months duration post-implant.

Rabbit Studies

Histologic evaluations were performed at 8, 12 and 52 weeks. Improved healing of experimental defects implanted with autologous chondrocytes was observed compared to periosteal flap alone at 8, 12 and 52 weeks.

Dog Study

Histologic evaluations were performed at 6 and 12 weeks and 12 and 18 months. Autologous chondrocytes showed improved healing compared to both empty defects and to defects covered with periosteum alone at 6 and 12 weeks. However, by the 12 and 18 month evaluations, the repair tissue had deteriorated so that no advantage of ACI over periosteum alone controls was demonstrated.

Beyond histologic variability of the defect site, no adverse tissue reaction was identified in any animals in these studies.

Post-approval Studies

Five additional large animal, post-approval studies were performed.

Goat Studies

Three of four goat studies were 16 weeks in duration. In the fourth study, the goats were sacrificed immediately after periosteal membrane placement. Despite difficulty in postoperative management of goats and resulting subchondral plate collapse in some animals in the 16-week studies, results from all four studies suggested that chondrocytes may contribute to histological repair of focal cartilage lesions. In the only bilateral joint study, serious subchondral collapse and uniformly poor repair resulted in inconclusive data. No safety issues were identified in any of these studies.

Horse Study

The 8-week study included two experimental arms in order to model repair of cartilage lesions with or without subchondral penetration. Both models exhibited destruction/dislodgement of the periosteal flap; however, results suggested that chondrocytes may contribute to histologic repair in cartilage defects with subchondral penetration.

While the defects in all animal models exhibited highly variable repair tissue quality (resulting in only moderate histologic scores) the best repairs with implanted chondrocytes produced hyaline-like cartilage characterized by matrix predominating in type II collagen and saffranin-O or toluidine blue staining proteoglycan. Chondrocyte labeling in one of the rabbit studies8 and in an independent study in goats by Dell’Accio et al10 demonstrated that the hyaline-like matrix in these defects was the product of the implanted autologous chondrocytes.

Clinical Studies

Pre-approval Studies

Clinical information regarding the use of autologous cultured chondrocytes was obtained from 2 open-label, observational studies consisting of a series of patients treated in Sweden and the Cartilage Repair Registry. Patients in the Swedish series received an autologous cultured chondrocyte product similar to Carticel.

14.1.1 Swedish Series

The series consists of 153 patients who received autologous chondrocyte implantation for various defects of the knee. Patients presented with cartilage defects of the femoral condyle, patella, tibia, a combination of these, or osteochondritis dissecans, with or without comorbidity such as anterior cruciate ligament insufficiency requiring reconstruction.

Following autologous chondrocyte implantation, patients were followed for various durations. Clinical follow-up ranged from 1 week to 94 months; 86 patients had at least 18 months of follow-up. Most patients had arthroscopic evaluation; a subset had biopsy and histological evaluations. All patients were retrospectively classified as having one of three clinical outcomes: resumed all activities, some improvement, or no improvement. Clinical outcomes were also reported for patient subgroups including: 1) 40 patients with femoral condyle lesions, 2) 12 patients with osteochondritis dissecans lesions and 3) 22 patients who failed a prior debridement.

1) Clinical Outcome - Patients with Femoral Condyle Lesions

A total of 78 of 153 patients had femoral condyle lesions with or without co-morbidity. Patients had one or more defects ranging in size from < 1-20 cm2. Of the patients with femoral condyle lesions, 40 were evaluable after at least 18 months (median = 25; range = 18 to 94 months). Clinical outcomes for the 40 patients are summarized in Table 5.

Table 5: Patient Response to Treatment
Defect	Resumed All Activities	Some Improvement	No Improvement	Total Patients
Femoral Condyle	7 (29%)	8 (33%)	9 (38%)	24
Femoral Condyle plus other Non-Cartilage Repair	4 (25%)	9 (56%)	3 (19%)	16
Total	11 (28%)	17 (42%)	12 (30%)	40

2) Clinical Outcome – Patients With Osteochondritis Dissecans Lesions

Of the 12 patients who received autologous cultured chondrocytes for treatment of an osteochondritis lesion, 6 of the 12 had “resumed all activities”, 4 had “some improvement” and 2 had “no improvement” after the 18-month (median = 25; range = 18-94 months) follow-up period.

3) Clinical Outcome – Failed Earlier Procedures

Debridement of the cartilage defect is often performed along with administration of autologous cultured chondrocytes. To help differentiate the effects of the autologous cultured chondrocyte implantation procedure from those of debridement alone, an analysis was performed on 22 patients who had failed prior debridement and had a follow-up period after autologous cultured chondrocyte implantation which was at least as long as the time period to failure of their initial debridement. At the end of follow-up, 5 of the 22 patients had a functional outcome rating of “resumed all activities”, 8 of the 22 patients had a rating of “some improvement” and 9 of the 22 patients had a rating of “no improvement”. Thus, 13 of the 22 patients (59%) who had failed an earlier debridement had outcomes that were more favorable and durable following autologous cultured chondrocyte implantation than their previous debridement without cells.

Histological Outcome

Twenty-two (22) patients in the Swedish series had histological evaluation of biopsies from the implant site one or more years after their autologous chondrocyte implantation. Fifteen (15) of those patients had defects of the femoral condyle and 7 had defects of the patella. Six (6) of the 15 femoral condyle biopsies showed hyaline-like cartilage, 5 had a mixture of hyaline and fibrocartilage, and 4 had only fibrocartilage. Of the 6 biopsies with hyaline-like cartilage, 2 had minimal to no surface irregularities and 4 had some surface irregularities (e.g., fissures, fibrillations, etc.).

Arthroscopic Outcome

As an objective outcome evaluation, 86 of the 153 patients had a follow-up arthroscopy for investigational purposes at 18 months or more post-implantation. In some cases, the quality of repair observed at arthroscopy was considered to be supportive of the clinical or functional outcomes. A substantial number of patients were noted at arthroscopy to have tissue hypertrophy [see Adverse Reactions (6)].

14.1.2 Cartilage Repair Registry

The Cartilage Repair Registry (CRR) was established upon the introduction of Carticel into orthopedic practice in March of 1995. The CRR was designed to prospectively collect the clinical outcomes of Carticel and other cartilage repair treatments for chondral lesions in the knee. Clinical data were collected at baseline arthroscopy, implantation, intervals of 6 and 12 months, and annually thereafter; adverse reaction data were collected on an ongoing basis through CRR adverse reaction collection and spontaneous reporting. Inclusion in the CRR was based on a qualifying event that was defined as a knee arthroscopy in which a chondral lesion was identified and a cartilage biopsy was harvested. Participation in the CRR was voluntary, and not all patients biopsied or implanted were included. As of November 21, 1997, 891 patients had been implanted worldwide, and 644 of these patients were included in the CRR. Functional outcomes were based on responses to a modified version of the Cincinnati Knee Rating System.

Data from a subset of 191 US patients in the CRR as of December 31, 1996 who had undergone repair of lesions on the femoral condyle (medial, lateral or trochlea) were assessed to support licensure. Patients were between the ages of 15-57, 66% (126/191) were male, and 34% (64/191) were female and one patient’s gender was not reported. Of these 191 patients, 38 had at least 12 months of follow-up. At study baseline, these 38 patients’ mean rating of overall condition was 3.2, which is defined as fair to poor: limitations that affect activities of daily living-no sports possible. At 12 month follow-up, these patients reported an overall condition score of 6.4 defined as good: some limitation with sports but can participate if patient compensates. Although these patients were rated according to outcome measurements different from those used in the Swedish series, the results were consistent with the Swedish experience.

Post-approval Studies

Two post-approval studies were conducted and completed as a condition of approval for Carticel: the Registry Based Study (RBS) and the Study of the Treatment of Articular Repair (STAR).

14.2.1 Registry-Based Study (RBS)

The RBS was a retrospective analysis of data collected for a cohort of 97 U.S. patients treated between March of 1995 and March of 1997. Of the 97 patients enrolled, 95% completed 1-year follow-up, 80% completed 2-year follow-up and 74% completed 3-year follow-up. Of these 97 patients, 44 were part of the subset of 191 US patients in the CRR described above. A limitation of this study is the lack of a control group. Patients included in this study had a prior non-Carticel cartilage repair procedure (e.g., debridement or marrow stimulation procedure) performed at the time of the index arthroscopy, subsequently failed this procedure and went on to receive Carticel. In the 5 years prior to the index arthroscopy for the study, this patient population had received prior knee surgeries to include: 47% (46/97) of patients had at least one debridement/lavage of a cartilage defect, 25% (24/97) of patients had a bone marrow stimulation procedure, 31% (30/97) had at least one diagnostic arthroscopy, 30% (29/97) had at least one meniscus repair/meniscectomy and 10% (10/97) of patients had a ligament repair/reconstruction performed on the treated knee.

Using a modified Cincinnati Knee Rating System at study baseline, this patient population had a mean overall condition score of 3.1 defined as fair to poor: limitations that affect activities of daily living-no sports possible. Patients included were between the ages of 16-56, 69% (67/97) were male and 31% (30/97) were female. For the type of defect, 62% (60/97) of the defects were acute while 37% (36/97) were chronic. Of the treated defects, 75% (73/97) were treated on the medial femoral condyle (MFC), 26% (25/97) on the lateral femoral condyle (LFC) and 19% (18/97) on the trochlea. Adverse reactions collected during this study are provided in Adverse Reactions (6).

14.2.2 Study of the Treatment of Articular Repair (STAR)

The STAR study was an open-label within patient comparison of a prior non-Carticel (index) procedure to implantation of Carticel for articular cartilage defects of the distal femur. All patients had experienced an inadequate response to a prior non-Carticel surgical treatment, defined as both: a) patient and surgeon agreement that the patient’s symptoms/function required surgical re-treatment of the defect and b) the patient’s rating of the overall condition of the knee was a score ≤ 5 using the Modified Cincinnati Knee Rating System. In this patient population, the median time to meet the failure criteria was 3.4 months for the prior non-Carticel procedure and 90% of patients failed within 10.3 months. Patients who met these criteria were treated with Carticel and assessed every 6 months for up to 4 years.

Treatment failure for Carticel was defined as any of the following: a) the patient underwent surgical retreatment that violated the subchondral bone or reimplantation with Carticel for the same index defect, b) complete delamination or removal of the graft, or c) the patient’s rating of the overall condition of the knee using the Modified Cincinnati Knee Rating System failed to improve from the baseline knee score over 3 consecutive 6-month intervals.

A total of 154 patients were treated with Carticel. At the index surgery required for study entry, patients had one or more of the following interventions: 120 patients (78%) had debridement, 44 patients (29%) had microfracture, 18 (12%) had subchondral drilling, 10 (6%) had abrasion arthroplasty, and 7 (5%) had an osteochondral autograft. The mean lesion size was 4.6 (± 3.2, SD) cm2. Fifty patients (32%) had multiple lesions in the reference knee and 29 patients had Carticel implanted in more than one lesion. Lesions that were implanted were located on the medial femoral condyle in 109 patients, lateral femoral condyle in 32 patients and trochlea in 46 patients. Forty patients (26%) had lesions which involved osteochondritis dissecans (OCD).

Of the 154 patients treated with Carticel, 28 patients discontinued the study early. The numbers of patients completing the 24 and 48 month follow-up visits are 136 and 115, respectively. The majority of Carticel patients (N= 117) did not meet failure criteria during the study. By the end of the study, a total of 37 patients met the treatment failure criteria. Results for the 40 patients with OCD lesions were comparable to the total study population as 34 (85%) did not meet the failure criteria for the study and 6 (15%) failed treatment with Carticel. Table 6 illustrates, during each year of follow-up, the number of patients who failed Carticel by the surgical criteria along with the number of patients who failed by the Overall Modified Cincinnati scale criteria.

Table 6: Category and Timing of Treatment Failure for Patients who Met Treatment Failure Criteria (N=37)
	1 Year	2 Years	3 Years	4 Years	Total
Patients Who Failed During the Interval	14	11	11	1	37
Surgery criteria	0	5	5	1	11
Overall Modified Cincinnati Scale criteria	14	6	6	0	26

The Overall Modified Cincinnati mean baseline score for the patient population as a whole was 3.26, poor: significant limitations that affect activities of daily living, to fair: moderate limitations that affect activities of daily living, no sports possible. At 48 months, the mean score was 6.39, good: some limitations with sports but can participate/compensate. The improvement was statistically significant. Table 7 shows the improvement in the Overall Modified Cincinnati score over time.

Table 7: Mean Overall Modified Cincinnati Score at Baseline and Follow-up Visits
* Scores are for patients who returned for follow-up. Patients who failed by score criteria are included and patients who failed by surgical criteria are excluded from the scores for timepoints after the failure criteria were met.
Visit	Baseline N=154	Month 12 N=146	Month 24 N=131	Month 36 N=104	Month 48 N=101
Overall Modified Cincinnati Score* Mean (SD)	3.26 (1.02)	5.58 (1.99)	5.92 (2.08)	5.87 (2.19)	6.39 (2.31)

In addition to the change over time in activity level as measured with the Overall Modified Cincinnati Scale, there were similar and consistent changes in knee symptoms and function as measured with the Knee Injury and Osteoarthritis Outcome Score (KOOS), a measure of knee-specific symptoms and function consisting of the following five subscales: pain, symptoms, sports and recreation, knee-related quality of life, and activities of daily living. At 12 months post-Carticel implant, the mean improvement from baseline for the patient population as a whole in each subscale was as follows: pain 19 (N = 146), symptoms 15 (N = 147), sports and recreation 17 (N = 129), knee-related quality of life 18 (N = 147), and activities of daily living 18 (N = 145). At 48 months post-Carticel implant, the mean improvement from baseline was as follows: pain 24 (N = 100), symptoms 19 (N = 101), sports and recreation 31 (N = 86), knee-related quality of life 32 (N = 101), and activities of daily living 23 (N = 99).

Adverse reactions collected during this study are provided in Adverse Reactions (6).

REFERENCES

Knutsen G, Engebretsen L, Ludvigsen T, et al. Autologous chondrocyte implantation compared with microfracture in the knee. J Bone Joint Surg, 2004; 86A:455-464.

Bentley G, Biant LC, Carrington RWJ, et al. A prospective, randomized comparison of autologous chondrocyte implantation versus mosaicplasty for osteochondral defects in the knee. J Bone Joint Surg Br. 2003;85-B:223-230.

Brittberg M, Lindahl A, Nilsson A, et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994;331:889-895.

Peterson L, Minas T, Brittberg M, et al. Two- to 9-year outcome after autologous chondrocyte transplantation of

Thursday, 22 September 2016

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Wednesday, 21 September 2016

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