Pulmicort Flexhaler

Generic Name: budesonide (Inhalation route)

bue-DES-oh-nide

Commonly used brand name(s)

In the U.S.

• Pulmicort


• Pulmicort Flexhaler


• Pulmicort Respules


• Pulmicort Turbuhaler

In Canada

• Pulmicort Nebuamp


• Rhinocort Turbuhaler

Available Dosage Forms:

• Suspension


• Powder


• Solution


• Aerosol Powder


• Aerosol Liquid

Therapeutic Class: Anti-Inflammatory

Pharmacologic Class: Adrenal Glucocorticoid

Uses For Pulmicort Flexhaler

Budesonide is used to help prevent the symptoms of asthma. When used regularly every day, inhaled budesonide decreases the number and severity of asthma attacks. However, it will not relieve an asthma attack that has already started.

Budesonide is a corticosteroid or steroid (cortisone-like medicine). It works by preventing inflammation (swelling) in the lungs, which makes the asthma attack less severe. Inhaled budesonide may be used with other asthma medicines such as bronchodilators, which are also used to open up narrowed breathing passages in the lungs.

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

Before Using Pulmicort Flexhaler

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 Pulmicort Respules® in children 12 months to 8 years of age. However, safety and efficacy have not been established in children younger than 12 months of age.

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of Pulmicort Flexhaler™ in children 6 years of age and older. However, safety and efficacy have not been established in children younger than 6 years of age.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of inhaled budesonide in the elderly. However, elderly patients are more likely to have age-related liver, kidney, or heart problems, which may require an adjustment in the dose for patients receiving inhaled budesonide.

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 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.

• Boceprevir


• Bupropion


• Telaprevir

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.

• Erythromycin


• Itraconazole


• Ketoconazole

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.

Other Medical Problems

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

• Asthma attack, acute—Should not be used in patients with this condition.

• Bone problems (e.g., osteoporosis) or


• Cataracts or


• Glaucoma—Use with caution. May make these conditions worse.

• Chickenpox, including recent exposure or


• Measles or


• Herpes simplex virus infection of the eye or


• Infections (virus, bacteria, or fungus) or


• Tuberculosis, active or history of—This medicine can reduce the body's ability to fight off these infections.

• Milk protein allergy, severe—Use with caution. The Pulmicort Flexhaler™ contains lactose (milk sugar with milk protein), which may cause side effects for patients with this condition.

Proper Use of budesonide

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

Inhaled budesonide is used to prevent asthma attacks. It is not used to stop an attack that has already started. For relief of an asthma attack that has already started, you or your child should use another medicine. If you do not have another medicine to use for an acute asthma attack or if you have any questions about this, check with your doctor.

Use this medicine only as directed. Do not use more of it and do not use it more often than your doctor ordered. Also, do not stop taking this medicine without telling your doctor. To do so may increase the chance of side effects.

In order for this medicine to help prevent asthma attacks, it must be used every day in regularly spaced doses, as ordered by your doctor. This medicine usually begins to work in about 24 to 48 hours, but up to 2 to 6 weeks may pass before you feel the full effects.

Do not change your dose or stop using this medicine without first checking with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping it completely. Some conditions may become worse when the medicine is stopped suddenly, which can be dangerous.

When using the Pulmicort Flexhaler™:

• This medicine comes as a powder that you breathe into the lungs with a special inhaler that is placed in the mouth. It is used by adults, teenagers, and children who are 6 years of age and older.


• The medicine comes with patient instructions. Read the instructions carefully before using this medicine. If you or your child do not understand the instructions or are not sure how to use the inhaler, check with your doctor.


• When you use the inhaler for the first time, it may not deliver the right amount of medicine with the first puff. Before using this medicine, test or prime it.


• Hold the inhaler so that the white cover points up, then twist the cover and lift it off. Hold the inhaler upright (mouthpiece up) using the brown grip, then twist the middle of the inhaler fully in one direction as far as it will go, and then back again in the other direction. You will hear a click. Repeat this process one more time.


• You do not have to prime it again after this, even if you have not used it for a long time.


• After the inhaler is primed, twist the cover and lift it off.


• To load a dose, hold the inhaler in the upright position, then twist the grip fully in one direction as far as it will go, and then fully back again in the other direction. You will hear a click.


• Turn your head away from the inhaler and breathe out. Do not shake the inhaler.


• Place the mouthpiece between your lips and breathe in deeply and forcefully. You may not taste or feel the medicine.


• Do not chew or bite on the mouthpiece.


• Remove the inhaler from your mouth and breathe out. Do not blow or breathe into the inhaler.


• Repeat these steps if more than one dose is needed.


• When you are finished, place the cover back on the inhaler and twist shut. Rinse your mouth with water and spit out the water. Do not swallow the water. This helps prevent hoarseness, throat irritation, and infections in the mouth.


• Do not use the inhaler if it has been damaged or if the mouthpiece has become detached.


• Do not use a spacer with the Pulmicort Flexhaler™.


• Keep the inhaler clean and dry at all times. Follow the patient directions for cleaning and storing the inhaler.


• The inhaler has a dose indicator that keeps track of how many times you can use the inhaler before you need to open a new one. Check the dose indicator just below the mouthpiece. The dose indicator usually starts with either the number 60 or 120 when full.


• Discard the whole device when all doses have been used. The inhaler is empty when the number zero appears in the middle of the dose indicator window. You will be given a new inhaler each time you refill your prescription.

When using the Pulmicort Respules® liquid:

• This medicine comes as a liquid that you breathe into the lungs with a special breathing machine called a jet nebulizer. The nebulizer has a face mask or mouthpiece. It is used by children who are 12 months to 8 years of age.


• Your doctor will tell you which type of nebulizer to use with this medicine and will show you how to use the nebulizer. The medicine and nebulizer come with patient instructions. Read the instructions carefully before using the medicine or the machine. If you or your child do not understand the instructions or are not sure how to use the nebulizer, check with your doctor.


• Use this medicine at the same time each day, unless your child's doctor tells you otherwise.


• Do not mix this liquid with other medicines.


• Open the sealed aluminum foil envelope containing the medicine. Remove one container from the strip of five plastic containers with sealed caps. Write the current date on the back of the envelope when you open the foil pouch.


• Each container has one dose of medicine.


• Place the unused containers back in the foil pouch. This will protect the medicine from light.


• Shake the container in a circular motion before using it.


• Hold the container upright and open it by twisting off the cap.


• Slowly squeeze out all of the contents of the container into the nebulizer cup. Throw the empty container away.


• If your child is using a face mask, make sure that the mask fits tightly on the face to avoid getting the medicine in the eyes.


• Turn on the compressor to begin nebulizing the medication. The nebulizer turns the medicine into a fine mist that the child breathes into the lungs using the mouthpiece or mask.


• After the dose is completed, wash your child's face to prevent skin irritation.


• Rinsing your child's mouth with water after each dose may help prevent hoarseness, throat irritation, and infections in the mouth. Do not allow your child to swallow the water after rinsing.

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 preventing an asthma attack:
  
  • For inhalation dosage form (powder inhaler):
    
    • Adults and children 6 years of age and older—At first, one or two puffs two times a day. Your doctor may increase your dose as needed.
    
    
    • Children younger than 6 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  • For inhalation dosage form (suspension in a nebulizer):
    
    • Children 12 months to 8 years of age—0.5 to 1 milligram (mg) in a nebulizer once a day, or divided and given twice a day. Each container of liquid has one dose and a new container is used for each dose.
    
    
    • Infants younger than 12 months 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

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.

Store the Pulmicort Flexhaler™ in a dry place at room temperature with the cover tightly in place.

Store the unused Pulmicort Respules® in an upright position at room temperature. Keep the medicine containers in the foil pouch until you are ready to use them. Do not freeze the containers. Once you have opened a foil pouch, the containers will only be good for 2 weeks. Throw away any unused containers if it has been longer than 2 weeks since you opened the pouch.

Precautions While Using Pulmicort Flexhaler

It is very important that your doctor check you or your child's progress at regular visits. This will allow your doctor to see if the medicine is working properly and to check for any unwanted effects caused by this medicine.

You or your child should not use this medicine if your asthma attack has already started. Your doctor will prescribe another medicine (e.g., a short-acting inhaler) for you to use in case of an acute asthma attack. Call your doctor if you have any questions about this.

If your or your child's symptoms do not improve within one to two weeks, or if they become worse, check with your doctor.

This medicine may weaken your immune system. Avoid being around people who are sick or who have infections such as chickenpox or measles. Tell your doctor right away if you think you or your child have been exposed to chickenpox or measles.

If you or your child develop a skin rash, hives, or any type of allergic reaction (including anaphylaxis) to this medicine, stop using the medicine and check with your doctor as soon as possible.

This medicine may also increase your risk of having infections or sores in your mouth or throat. Check with your doctor right away if you or your child have any signs of a throat infection.

This medicine may decrease bone mineral density when used for a long time. A low bone mineral density can cause weak bones or osteoporosis. If you have any questions about this, talk to your doctor.

This medicine may cause children to grow more slowly than normal. This would cause a child to not gain weight or get taller. Talk with your child's doctor if you think this is a problem or if you have any concerns.

This medicine may increase your risk of having an adrenal gland that is less active than normal. The adrenal gland makes steroids for your body. This is more likely for people who use steroids for a long time or use high doses. Check with your doctor right away if you or your child have more than one of the following symptoms: darkening of the skin, diarrhea, dizziness, fainting, loss of appetite, depression, nausea, skin rash, unusual tiredness or weakness, or vomiting. Rarely, menstrual cycle changes, acne, pimples, or weight gain (fat deposits) around the face, neck, and trunk may occur while using this medicine.

Check with your doctor immediately if blurred vision, difficulty in reading, or any other change in vision occurs during or after treatment. Your doctor may want you or your child to have your eyes checked by an ophthalmologist (eye doctor).

Make sure any doctor or dentist knows that you or your child are using this medicine. You might need to stop using this medicine several days before having surgery.

Your doctor may want you or your child to carry a medical identification card that says this medicine is being used. You or your child may need additional medicine during an emergency, a severe asthma attack, an illness, or unusual stress.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Pulmicort Flexhaler 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

• Body aches or pain


• chills


• congestion


• cough


• diarrhea


• dryness or soreness of the throat


• fever


• general feeling of discomfort or illness


• headache


• hoarseness


• joint pain


• loss of appetite


• muscle aches and pains


• nausea


• pain or tenderness around the eyes and cheekbones


• shivering


• shortness of breath or troubled breathing


• sneezing


• sore throat


• stuffy or runny nose


• sweating


• tender, swollen glands in the neck


• tightness of the chest or wheezing


• trouble with sleeping


• trouble with swallowing


• unusual tiredness or weakness


• voice changes


• vomiting

Less common

• Bruising


• darkening of the skin


• depression


• dizziness


• earache


• excessive muscle tone


• fainting


• fractures


• large, flat, blue, or purplish patches in the skin


• lower back or side pain


• muscle stiffness


• muscle tension or tightness


• painful or difficult urination


• redness or swelling in the ear


• skin rash


• sore mouth or tongue


• white patches in the mouth or on the tongue

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

• Back pain

Less common

• Acid or sour stomach


• belching


• change in taste or bad, unusual, or unpleasant (after) taste


• difficulty with breathing


• difficulty with moving


• dry mouth


• ear congestion


• headache, severe and throbbing


• heartburn


• indigestion


• muscle cramping


• neck pain


• sleeplessness


• stomach discomfort, upset, or pain


• swollen joints


• unable to sleep


• unexplained runny nose or sneezing


• weakness

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: Pulmicort Flexhaler 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.

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More Pulmicort Flexhaler resources

• Pulmicort Flexhaler Side Effects (in more detail)
• Pulmicort Flexhaler Use in Pregnancy & Breastfeeding
• Pulmicort Flexhaler Drug Interactions
• Pulmicort Flexhaler Support Group
• 2 Reviews for Pulmicort Flexhaler - Add your own review/rating

• Pulmicort Flexhaler Concise Consumer Information (Cerner Multum)


• Pulmicort Flexhaler Prescribing Information (FDA)


• Pulmicort Flexhaler Powder MedFacts Consumer Leaflet (Wolters Kluwer)


• Budesonide Professional Patient Advice (Wolters Kluwer)


• budesonide Concise Consumer Information (Cerner Multum)


• Budesonide Monograph (AHFS DI)


• Entocort EC Prescribing Information (FDA)


• Entocort EC Sustained-Release Capsules MedFacts Consumer Leaflet (Wolters Kluwer)


• Pulmicort Respules Suspension MedFacts Consumer Leaflet (Wolters Kluwer)


• Pulmicort Turbuhaler Powder MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Pulmicort Flexhaler with other medications

• Asthma, Maintenance

Lactaid

Pronunciation: LAK-tase
Generic Name: Lactase
Brand Name: Examples include Lactaid and SureLac

Lactaid is used for:

Helping you consume dairy foods without gas, cramps, bloating, or diarrhea.

Lactaid is an enzyme. It works by helping the digestion of milk sugar.

Do NOT use Lactaid if:

• you are allergic to any ingredient in Lactaid

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

Before using Lactaid:

Some medical conditions may interact with Lactaid. 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

Some MEDICINES MAY INTERACT with Lactaid. However, no specific interactions with Lactaid are known at this time.

This may not be a complete list of all interactions that may occur. Ask your health care provider if Lactaid 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 Lactaid:

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

• Swallow Lactaid with the first bite or drink of dairy product.


• If you continue to consume foods containing dairy after 20 to 45 minutes, take another tablet.


• If you miss a dose of Lactaid, take it as soon as possible.

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

Important safety information:

• Lactaid is not recommended for use in CHILDREN younger than 4 years of age. Safety and effectiveness in this age group have not been confirmed.


• PREGNANCY and BREAST-FEEDING: It is unknown if Lactaid may cause harm to the fetus. If you become pregnant while taking Lactaid, discuss with your doctor the benefits and risks of using Lactaid during pregnancy. It is unknown if Lactaid is excreted in breast milk. If you are or will be breast-feeding while you are taking Lactaid, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Lactaid:

All medicines may cause side effects, but many people have no, or minor, side effects. When used in small doses, no COMMON side effects have been reported with Lactaid. Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

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: Lactaid 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.

Proper storage of Lactaid:

Store Lactaid at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Keep Lactaid out of the reach of children and away from pets.

General information:

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


• Lactaid 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 Lactaid. 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

Copyright © 2012 Wolters Kluwer Health, Inc.

More Lactaid resources

• Lactaid Side Effects (in more detail)
• Lactaid Use in Pregnancy & Breastfeeding
• Lactaid Support Group
• 0 Reviews for Lactaid - Add your own review/rating

Compare Lactaid with other medications

• Lactose Intolerance

Humulin R U-500

Dosage Form: injection, solution
INFORMATION FOR THE PHYSICIAN

HUMULIN® R

REGULAR

U-500 (CONCENTRATED)

INSULIN HUMAN INJECTION, USP

(rDNA ORIGIN)

DESCRIPTION

Humulin R® U-500 is a polypeptide hormone structurally identical to human insulin synthesized through rDNA technology in a special non-disease-producing laboratory strain of Escherichia coli bacteria. Humulin R U-500 has the empirical formula C257H383N65O77S6 and a molecular weight of 5808.

Humulin R U-500 is a sterile, clear, aqueous and colorless solution that contains human insulin (rDNA origin) 500 units/mL, glycerin 16 mg/mL, metacresol 2.5 mg/mL and zinc oxide to supplement the endogenous zinc to obtain a total zinc content of 0.017 mg/100 units, and water for injection. The pH is 7.0 to 7.8. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH.

Humulin R U-500 is for subcutaneous injection only. It should not be used intravenously or intramuscularly. Humulin R U-500 contains 500 units of insulin in each milliliter (5-times more concentrated than Humulin R U-100 [see DOSAGE AND ADMINISTRATION]). It also contains 16 mg glycerin, 2.5 mg metacresol as a preservative, and zinc-oxide calculated to supplement endogenous zinc to obtain a total zinc content of 0.017 mg/100 units and water for injection. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH.

Adequate insulin dosage permits patients with diabetes to effectively utilize carbohydrates, proteins and fats. Regardless of dose strength, insulin enables carbohydrate metabolism to occur and thus to prevent the production of ketone bodies by the liver. Some patients might develop severe insulin resistance such that daily doses of several hundred units of insulin or more are required.

CLINICAL PHARMACOLOGY

Regulation of glucose metabolism is the primary activity of insulin. Insulin lowers blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis, proteolysis, and gluconeogenesis, and enhance protein synthesis and conversion of excess glucose into fat.

Administered insulin, including Humulin R U-500, substitutes for inadequate endogenous insulin secretion and partially corrects the disordered metabolism and inappropriate hyperglycemia of diabetes mellitus, which are caused by either a deficiency or a reduction in the biologic effectiveness of insulin. When administered in appropriate doses at prescribed intervals to patients with diabetes mellitus, Humulin R U-500 restores their ability to metabolize carbohydrates, proteins and fats.

As with all insulin preparations, the duration of action of Humulin R U-500 is dependent on dose, site of injection, blood supply, temperature, and physical activity.

Humulin R U-500 is unmodified by any agent that might prolong its action. Clinical experience has shown that it frequently has time action characteristics reflecting both prandial and basal activity. It takes effect within 30 minutes, has a peak similar to that observed with U-100 regular human insulin and has a relatively long duration of activity following a single dose (up to 24 hours) as compared with U-100 regular insulins. This effect has been credited to the high concentration of the preparation. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual.

Indications and Usage for Humulin R U-500

Humulin R U-500 is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 1 and type 2 diabetes mellitus.

Humulin R U-500 is useful for the treatment of insulin-resistant patients with diabetes requiring daily doses of more than 200 units, since a large dose may be administered subcutaneously in a reasonable volume.

Contraindications

Humulin R U-500 is contraindicated during episodes of hypoglycemia and in patients hypersensitive to Humulin R U-500 or any of its excipients.

Warnings

Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (e.g., regular, NPH, analog, etc.), species, or method of administration may result in the need for a change in dosage.

Humulin R U-500 contains 500 units of insulin in each milliliter (5-times more concentrated than Humulin R U-100). For Humulin R U-500, extreme caution must be observed in the measurement of dosage because inadvertent overdose may result in serious adverse reaction or life-threatening hypoglycemia.

Precautions

Dosing Confusion/Dosing Errors

Medication errors associated with Humulin R U-500 have occurred and resulted in patients experiencing hyperglycemia, hypoglycemia or death. The majority of errors occurred due to errors in dispensing, prescribing or administration. Attention to the following details may prevent:

• Dispensing errors

The Humulin R U-500 vial, which contains 20 mL, versus the Humulin R U-100 vial, which contains 10 mL – is marked with a band of diagonal brown stripes to distinguish it from the U-100 vial, which has no stripes. “U-500” is also highlighted in red on the label.

• Prescribing errors (see DOSAGE AND ADMINISTRATION)

The prescribed dose of Humulin R U-500 should always be expressed in actual units of Humulin R U-500 along with corresponding markings on the syringe the patient is using (i.e., a U-100 insulin syringe or tuberculin syringe [see DOSAGE AND ADMINISTRATION]).

• Administration errors (see DOSAGE AND ADMINISTRATION)

A majority of these errors occurred due to dosing confusion when the Humulin R U-500 dose was prescribed in units or volume corresponding to a U-100 syringe or tuberculin syringe markings, respectively, or the prescribed dose was administered without recognizing that the markings on the syringe used do not directly correspond to U-500 dose. Instructions for use should always be read and followed before use.

Instruct the patient to inform hospital or emergency department staff of the dose of Humulin R U-500 prescribed, in the event of a future hospitalization or visit to the Emergency Department.

A conversion chart is provided and should always be used when administering Humulin R U-500 doses with U-100 insulin syringes or tuberculin syringes.

Hypoglycemia

Hypoglycemia is the most common adverse reaction of all insulin therapies, including Humulin R U-500. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with Humulin R U-500.

As with all insulin preparations, the time course of Humulin R U-500 action may vary in different individuals or at different times in the same individual and is dependent on dose, site of injection, blood supply, temperature, and physical activity.

Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stresses. Concomitant oral antidiabetic treatment may need to be adjusted.

Any patient who requires Humulin R U-500 for control of diabetes should be under close observation until appropriate dosage is established. The response will vary among patients. Most patients will require 2 or 3 injections per day.

Insulin resistance, in some patients is transitory; after several weeks or months during which high dosage is required, responsiveness to the pharmacologic effect of insulin may be regained and dosage can be reduced.

The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also alter the risk of hypoglycemia (see PRECAUTIONS, Drug Interactions).

As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This may prevent a risk in situations where these abilities are especially important, such as driving or operating other machinery.

Severe hypoglycemia may develop 18 to 24 hours after the original injection of Humulin R U-500.

Hyperglycemia, Diabetic Ketoacidosis, and Hyperosmolar Non-Ketotic Syndrome

Hyperglycemia, diabetic ketoacidosis, or hyperosmolar coma may develop if the patient takes less Humulin R U-500 than needed to control blood glucose levels. This could be due to increases in insulin demand during illness or infection, neglect of diet, omission or improper administration of prescribed insulin doses or use of drugs that affect glucose metabolism or insulin sensitivity. Early signs of diabetic ketoacidosis include glycosuria and ketonuria. Polydipsia, polyuria, loss of appetite, fatigue, dry skin, abdominal pain, nausea and vomiting and compensatory tachypnea come on gradually, usually over a period of some hours or days, in conjunction with hyperglycemia and ketonemia. Severe sustained hyperglycemia may result in hyperosmolar coma or death.

Hypokalemia

Insulin stimulates potassium movement into the cells, possibly leading to hypokalemia, that left untreated may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).

Hypersensitivity and Allergic Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Humulin R U-500 (see ADVERSE REACTIONS).

Localized reactions and generalized myalgias have been reported with the use of metacresol as an injectable excipient.

Renal or Hepatic Impairment

Frequent glucose monitoring and insulin dose reduction may be required in patients with renal or hepatic impairment.

Drug Interactions

Some medications may alter insulin requirements and the risk for hypoglycemia and hyperglycemia (see ADVERSE REACTIONS, Drug Interactions).

Use in Pregnancy

Pregnancy Category B — All pregnancies have background risk of birth defects, miscarriage, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and is decreased with good glucose control. It is important for patients to maintain good control of diabetes before conception and during pregnancy. Special attention should be paid to diet, exercise and insulin regimens. Insulin requirements may decrease during the first trimester, usually increase during the second and third trimesters and rapidly decline after delivery. Careful glucose monitoring is essential in these patients. Female patients should be advised to tell their physician if they intend to become, or if they become pregnant.

Studies show that endogenous insulin only crosses the placenta in minimal amounts. While there are no adequate and well-controlled studies in pregnant women, an extensive body of published literature demonstrates the maternal and fetal benefits of insulin treatment in patients with diabetes during pregnancy. Humulin R U-500 is a recombinant human insulin that is identical to the endogenous hormone; therefore, reproduction and fertility studies were not performed in animals.

Labor and Delivery

Careful glucose monitoring and management of patients with diabetes during labor and delivery are required.

Nursing Mothers

Endogenous insulin is present in human milk. Insulin orally ingested is degraded in the gastrointestinal tract. In lactating infants, no adverse reactions have been associated with maternal use of insulin. In a study of eight preterm infants between 26 to 30 weeks gestation, enteral administration of Humulin R did not result in hypoglycemia. Good glucose control supports lactation in patients with diabetes. Patients with diabetes who are lactating may require adjustments in insulin dose and/or diet.

Pediatric Use

There are no well-controlled studies of use of Humulin R U-500 in children.

Adverse Reactions

Hypoglycemia

Hypoglycemia is one of the most frequent adverse events experienced by insulin users.

Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:

sweating	drowsiness
dizziness	sleep disturbances
palpitation	anxiety
tremor	blurred vision
hunger	slurred speech
restlessness	depressed mood
tingling in the hands, feet, lips, or tongue	irritability
lightheadedness	abnormal behavior
inability to concentrate	unsteady movement
headache	personality changes

Signs of severe hypoglycemia can include:

disorientation	seizures
unconsciousness	coma
death

Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, autonomic diabetic neuropathy, use of medications such as beta-adrenergic blockers, changing insulin preparations, or intensified control (3 or more insulin injections per day) of diabetes.

Without recognition of early warning symptoms, the patient may not be able to take steps to avoid more serious hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should monitor their blood glucose more frequently, especially prior to activities such as driving. Mild to moderate hypoglycemia may be treated by eating foods or taking drinks that contain sugar. Patients should always carry a quick source of sugar, such as hard candy, non-diet carbohydrate-containing drinks or glucose tablets.

Hypoglycemia when using Humulin R U-500 can be prolonged and severe.

Hypokalemia

See Precautions

Lipodystrophy

Administration of insulin subcutaneously can result in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue).

Allergy

Local Allergy — Patients occasionally experience erythema, local edema, and pruritus at the site of injection. This condition usually is self-limiting. In some instances, this condition may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique.

Systemic Allergy — Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalized allergy (anaphylaxis) may be life threatening.

Weight gain

Weight gain can occur with some insulin therapies and has been attributed to the anabolic effects of insulin and the decrease in glycosuria.

Peripheral Edema

Insulin may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

Drug Interactions

The concurrent use of oral antihyperglycemic diabetes agents with Humulin R U-500 is not recommended since there are limited data to support such use.

A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring.

Drugs that may increase the blood-glucose-lowering effect of Humulin R U-500 and susceptibility to hypoglycemia:

• Oral antihyperglycemic diabetes agents, salicylates, sulfa antibiotics, certain antidepressants (monoamine oxidase inhibitors, selective serotonin reuptake inhibitors [SSRIs]), pramlintide, disopyramide, fibrates, fluoxetine, propoxyphene, pentoxifylline, ACE inhibitors, angiotensin II receptor blocking agents, beta-adrenergic blockers, inhibitors of pancreatic function (e.g., octreotide), and alcohol.

Drugs that may reduce the blood-glucose-lowering effect:

• Corticosteroids, isoniazid, certain lipid-lowering drugs (e.g., niacin), estrogens, oral contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents, somatropin, atypical antipsychotics, glucagon, protease inhibitors and thyroid replacement therapy.

Drugs that may increase or decrease blood-glucose-lowering effect:

• Beta-adrenergic blockers, clonidine, lithium salts, and alcohol.


• Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.

Drugs that may mask the signs of hypoglycemia:

• Beta-adrenergic blockers, clonidine, guanethidine, and reserpine.

OVERDOSAGE

Excess insulin may cause hypoglycemia and hypokalemia. Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

Humulin R U-500 Dosage and Administration

Humulin R U-500 is usually given two or three times daily before meals. The dosage and time of Humulin R U-500 should be individualized and determined, based on the physician's advice, in accordance with the needs of the patient. The injection of Humulin R U-500 should be followed by a meal within approximately 30 minutes of administration.

The average range of total daily insulin requirement for maintenance therapy in insulin-treated patients without severe insulin resistance lies between 0.5 and 1.0 unit/kg/day. However, in pre-pubertal children it usually varies from 0.7 to 1.0 unit/kg/day, but can be much lower during the period of partial remission. In situations of insulin resistance, e.g., during puberty or due to obesity, the daily insulin requirement may be substantially higher. Initial dosages for type 2 diabetes patients are often lower, e.g., 0.2 to 0.4 units/kg/day.

Humulin R U-500 is useful for the treatment of insulin resistant patients with diabetes requiring daily doses of more than 200 units, since a large dose may be administered subcutaneously in a reasonable volume.

Humulin R U-500 may be administered by subcutaneous injection in the abdominal wall, the thigh, the gluteal region or in the upper arm. Subcutaneous injection into the abdominal wall ensures a faster absorption than from other injection sites. Injection into a lifted skin fold minimizes the risk of intramuscular injection. Injection sites should be rotated within the same region. As with all insulin, the duration of action will vary according to the dose, injection site, blood flow, temperature, and level of physical activity.

Humulin R U-500 should only be administered subcutaneously. Do not administer Humulin R U-500 intravenously or intramuscularly.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Never use Humulin R U-500 if it has become viscous (thickened) or cloudy; use it only if it is clear and colorless. Humulin R U-500 should not be used after the printed expiration date.

Do not mix Humulin R U-500 with other insulins, as there are no data to support such use.

When administering Humulin R U-500

If U-100 insulin syringes are used, since their markings are in units and are designed and intended for use with the less concentrated U-100 insulin products, it is extremely important to explain the amount of Humulin R U-500 insulin to be administered in both actual dose and with specification of “unit markings” on the U-100 syringe.

If tuberculin syringes are used, since their markings are in volume (mL), the actual amount of Humulin R U-500 should be explained in both actual dose and with specification of volume (mL). Table 1 contains conversion information using both U-100 insulin and tuberculin syringes to help avoid dose confusion.

Table 1: Conversion Information for Humulin R U-500 Insulin Dose When Using a U-100 Insulin Syringe or a Tuberculin Syringe

Humulin R U-500 dose (units)	U-100 insulin syringe (unit markings)	Tuberculin syringe (volume in mL)
25	5	0.05
50	10	0.1
75	15	0.15
100	20	0.2
125	25	0.25
150	30	0.3
175	35	0.35
200	40	0.4
225	45	0.45
250	50	0.5
275	55	0.55
300	60	0.6
325	65	0.65
350	70	0.7
375	75	0.75
400	80	0.8
425	85	0.85
450	90	0.9
475	95	0.95
500	100	1.0
Dose (actual Humulin R U-500 units)	Divide dose (actual Humulin R U-500 units) by 5	Divide dose (actual Humulin R U-500 units) by 500

For doses other than those listed above refer to the following formulas:

U-100 insulin syringe

Divide prescribed Dose (actual units) by 5 = Unit markings in a U-100 insulin syringe.

Tuberculin syringe

Divide prescribed Dose (actual units) by 500 = Volume (mL) in a tuberculin syringe

Storage

Not in-use (unopened): Humulin R U-500 vials not in-use should be stored in a refrigerator, (2° to 8°C [36° to 46°F]), but not in the freezer.

In-use (opened): The Humulin R U-500 vial currently in-use can be kept unrefrigerated as long as it is kept as cool as possible (below 30°C [86°F]) away from heat and light. In-use vials must be used within 31 days or be discarded, even if they still contain Humulin R U-500.

Do not use Humulin R U-500 after the expiration date stamped on the label or if it has been frozen.

How is Humulin R U-500 Supplied

 Vials, 500 units/mL, 20 mL (HI-500) (1s),      NDC 0002-8501-01

Literature revised March 21, 2011

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA

Copyright © 1996, 2011, Eli Lilly and Company. All rights reserved.

PA 3054 AMP

PATIENT INFORMATION

Humulin®(HU-mu-lin) R

Regular

U-500 (Concentrated)

insulin human injection, USP (rDNA origin)

Read the Patient Information that comes with Humulin® R U-500 before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your diabetes or treatment.

What is the most important information I should know about Humulin R U-500?

Humulin R U-500 (500 units/mL) contains 5 times as much insulin in 1 mL as standard U-100 (100 units/mL) insulin. This means that it is more concentrated than standard U-100 insulin.

Know your insulin. Make sure you know the strength, dose and type of insulin that is prescribed for you. Do not change the strength, dose or type of insulin you use unless told to do so by your healthcare provider.

It is important that you take the right dose of Humulin R U-500. Taking too much Humulin R U-500 can cause life-threatening low blood sugar (hypoglycemia) or death. Taking too little Humulin R U-500 can cause high blood sugar (hyperglycemia).

There are no special syringes to measure Humulin R U-500. It is important that you use only the syringes that your healthcare provider tells you to use. Your healthcare provider should tell you how much Humulin R U-500 to take and when to take it. Your healthcare provider should show you how to draw up Humulin R U-500. The amount of Humulin R U-500 will be less than the amount of standard U-100 insulin which would be drawn up into the syringe. See the section, “How should I take Humulin R U-500?”

What is Humulin R U-500?

Humulin R U-500 is a prescription medicine used to treat high blood sugar in people with diabetes mellitus. Humulin R U-500 is a man-made insulin that is similar to the insulin produced by the human pancreas. Humulin R U-500 is used along with diet and exercise to lower blood sugar in people with:

• type 1 diabetes.


• type 2 diabetes whose blood sugars are not controlled well with diabetes medicine taken by mouth.

Humulin R U-500 is useful for the treatment of insulin-resistant patients with diabetes who need more than 200 units of insulin a day.

It is not known if Humulin R U-500 is safe and effective in children.

Who should not take Humulin R U-500?

Do not take Humulin R U-500 if:

• your blood sugar is too low (hypoglycemia). See the section, “What are the possible side effects of Humulin R U-500?” for more information on low blood sugar.


• you are allergic to any of the ingredients in Humulin R U-500. See the end of this leaflet for a complete list of ingredients in Humulin R U-500.

What should I tell my healthcare provider before taking Humulin R U-500?

Before you take Humulin R U-500, tell your healthcare provider if you:

• have liver or kidney problems or any other medical conditions. Certain medical conditions can affect your insulin needs and your dose of Humulin R U-500.


• are pregnant, plan to become pregnant, or are breast-feeding. It is not known if Humulin R U-500 will harm your unborn baby or breast-feeding child. You and your healthcare provider should talk about the best way to manage your diabetes while you are pregnant or breast-feeding. It is especially important to keep good control of your blood sugar during pregnancy.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Many medicines can affect your blood sugar levels and your insulin needs. Your Humulin R U-500 dose may need to change if you take other medicines. Especially tell your healthcare provider if you take other medicines to treat your diabetes.

Know the medicines you take. Keep a list of your medicines with you and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take Humulin R U-500?

• Take Humulin R U-500 exactly as prescribed.


• Do not make any changes to your strength, dose or type of insulin unless you are told to do so by your healthcare provider.


• Check the label carefully to make sure you have the right type and strength of insulin prescribed for you.


• Your healthcare provider should show you how to prepare and inject Humulin R U-500 before you start taking it.


• Humulin R U-500 should look clear and colorless. Do not use Humulin R U-500 if it does not look clear, colorless or has particles in it. Talk with your pharmacist or healthcare provider if you have any questions.


• Follow your healthcare provider's instructions about how often you should check your blood sugar level for hypoglycemia (too low blood sugar) and hyperglycemia (too high blood sugar).


• Humulin R U-500 starts working about 30 minutes after injection. The effects of Humulin R U-500 may last up to 24 hours.


• You should eat a meal within 30 minutes of injecting Humulin R U-500.


• Choose an injection area (upper arm, abdomen, buttocks, or thigh). Change injection sites within the area you choose for each dose. Do not inject into the exact same spot for each injection. Never inject Humulin R U-500 into a vein or muscle.


• Inject Humulin R U-500 under your skin (subcutaneous), as shown to you by your healthcare provider.


• Your healthcare provider should regularly check your diabetes with blood tests, including your blood sugar levels and hemoglobin A1C.


• If you take too much Humulin R U-500, your blood sugar may fall too low (hypoglycemia). You can treat mild low blood sugar (hypoglycemia) by drinking or eating something sugary right away. Always carry a quick source of sugar, such as hard candy, fruit juice or glucose tablets.


• Your healthcare provider may prescribe a glucagon emergency kit so that others can give you an injection if your blood sugar becomes too low (hypoglycemic) and you are unable to take sugar by mouth.

There are no special syringes to measure Humulin R U-500. It is important that you use only the syringes that your healthcare provider tells you to use to give your injections of Humulin R U-500. You should use either a U-100 insulin syringe or tuberculin syringe as instructed by your healthcare provider.

• If you are using U-100 insulin syringes, your healthcare provider should explain how to use this syringe to give the prescribed dose with the unit markings on the syringe.


• If you are using tuberculin syringes, your healthcare provider should explain how to use this syringe to give the prescribed dose with volume markings on the syringe.

If you do not use the right syringe type, you may take the wrong dose of Humulin R U-500. This can cause you to have too low blood sugar (hypoglycemia) or too high blood sugar (hyperglycemia).

Make sure you know:

• your prescribed dose of Humulin R U-500.


• which syringe to use and how to draw up your prescribed dose.

If you do not understand your dose, talk with your healthcare provider about how much insulin to take.

If you are hospitalized or go to an emergency room, make sure to tell the hospital staff the actual dose of Humulin R U-500 that your healthcare provider has prescribed for you.

Your healthcare provider may change your dose of Humulin R U-500 because of:

• illness


• change in diet


• stress


• change in physical activity or exercise


• other medicines you take


• travel

Check your blood sugar and stay on the diet and exercise plan as prescribed by your healthcare provider.

• Do not share needles or syringes with others.


• Place used needles and syringes in a closable, puncture-resistant container. You may use a sharps container (such as a red biohazard container) or a hard plastic container (such as a detergent bottle) or a metal container (such as an empty coffee can). Ask your healthcare provider for instructions on the right way to throw away the container. There may be state and local laws about how you should throw away used needles and syringes.


• Do not throw the container in household trash and do not recycle.

What should I avoid while taking Humulin R U-500?

• Alcohol. Drinking alcohol may affect your blood sugar when you take Humulin R U-500.


• Driving and operating machinery. You may have trouble paying attention or reacting if you have low blood sugar (hypoglycemia). Be careful when you drive a car or operate machinery. Ask your healthcare provider if it is all right for you to drive if you have:
  
  • Low blood sugar (hypoglycemia)
  
  
  • Decreased or no warning signs of low blood sugar
  
  

What are the possible side effects of Humulin R U-500?

Humulin R U-500 can cause serious side effects, including:

• See the section “What is the most important information I should know about Humulin R U-500?”


• Low blood sugar (hypoglycemia).

Symptoms of low blood sugar may happen suddenly with Humulin R U-500. Symptoms of mild or moderate low blood sugar may include:

sweating	drowsiness
dizziness	trouble sleeping
fast heart beat	feeling anxious
tremor	blurred vision
hunger	slurred speech
restlessness	depressed mood
tingling in the hands, feet, lips or tongue	feeling irritable
lightheadedness	abnormal behavior
trouble concentrating	walking unsteady
headache	personality changes

Humulin R U-500 can cause low blood sugar (hypoglycemia) that is severe and that can last a long time.

• Severe low blood sugar can cause you to become confused, pass out (become unconscious), have seizures or coma, and could cause death.

Talk to your healthcare provider about how to tell if you have low blood sugar and what to do if this happens while taking Humulin R U-500. Know your symptoms of low blood sugar. Follow your healthcare provider's instructions for treating your low blood sugar.

Tell your healthcare provider if low blood sugar is a problem for you. Your healthcare provider may need to change the amount of Humulin R U-500 that you take, change your meal plans or your exercise program to help you avoid low blood sugar.

• Serious allergic reactions. Get medical help right away if you have any of these symptoms of a severe allergic reaction:
  
  • rash all over your body
  
  
  • shortness of breath
  
  
  • trouble breathing (wheezing)
  
  
  • fast heart beat
  
  
  • sweating
  
  
  • feel faint
  
  
  • Low potassium (hypokalemia) in your blood. Your healthcare provider may do blood tests to check you for low potassium.
  
  

Common side effects of Humulin R U-500 include:

• Skin thickening or pits at the injection site (lipodystrophy). Change (rotate) where you inject your insulin to help prevent these skin changes from happening. Do not inject insulin into this type of skin. Do not inject into the exact same spot for each injection.


• Injection site reactions (local allergic reaction). Symptoms may include: redness, swelling and itching at the injection site. Tell your healthcare provider if you have skin reactions that do not go away.


• Weight gain


• Swelling due to fluid retention

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effect of Humulin R U-500. For more information, ask your healthcare provider or pharmacist.

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

How should I store Humulin R U-500?

Unopened vials of Humulin R U-500:

• Keep unopened vials of Humulin R U-500 in a refrigerator at 36°F to 46°F (2°C to 8°C).


• Do not freeze. Do not use Humulin R U-500 if it has been frozen.


• Do not use Humulin R U-500 after the expiration date stamped on the label.

Opened (in-use) vial of Humulin R U-500:

• Keep opened vial of Humulin R U-500 in the refrigerator or at room temperature below 86°F (30°C).


• Keep Humulin R U-500 away from heat and direct sunlight.


• The opened vial must be used within 31 days of opening. Throw away any opened vial after 31 days of use, even if there is insulin left in the vial.


• Do not use Humulin R U-500 after the expiration date stamped on the label.

Keep Humulin R U-500 and all medicines out of the reach of children.

General Information about Humulin R U-500

Medicines are sometimes prescribed for purposes other than those listed in patient information leaflets. Do not use Humulin R U-500 for a condition for which it was not prescribed. Do not give Humulin R U-500 to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about Humulin R U-500. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Humulin R U-500 that is written for healthcare professionals.

For more information about Humulin R U-500 call 1-800-545-5979 or go to www.lilly.com.

What are the ingredients in Humulin R U-500?

Active ingredient: human insulin rDNA origin

Inactive ingredients: glycerin, metacresol, zinc oxide, water for injection, sodium hydroxide or hydrochloric acid.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Patient Information revised May 20, 2011

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA

PA 8901 AMP

PACKAGE CARTON – Humulin R U-500 Vial 20 mL 1ct

Rx only

NDC 0002-8501-01

20 mL

HI-500

U-500

(Concentrated)

Humulin® R

REGULAR

insulin human injection, USP (rDNA origin)

500 units per mL

IMPORTANT:

SEE INSTRUCTIONS FOR USE.

www.lilly.com

Lilly

HUMULIN  R U-500 insulin human  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0002-8501 Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Insulin human (Insulin human) Insulin human 500 [iU]  in 1 mL

Inactive Ingredients Ingredient Name Strength Glycerin 16 mg  in 1 mL Metacresol 2.5 mg  in 1 mL Zinc 0.085 mg  in 1 mL Water   Hydrochloric acid   Sodium hydroxide

Product Characteristics Color

Epilim 100mg Crushable Tablets

1. Name Of The Medicinal Product

Epilim 100mg Crushable Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 100mg of Sodium Valproate.

3. Pharmaceutical Form

Tablet.

4. Clinical Particulars

4.1 Therapeutic Indications

In the treatment of generalized, partial or other epilepsy.

4.2 Posology And Method Of Administration

Epilim 100mg Crushable Tablets are for oral administration.

Daily dosage requirements vary according to age and body weight.

Epilim tablets may be given twice daily. Uncoated tablets may be crushed if necessary.

In patients where adequate control has been achieved Epilim Chrono formulations are interchangeable with other conventional or prolonged release formulations on an equivalent daily dosage basis.

Dosage

Usual requirements are as follows:

Adults

Dosage should start at 600mg daily increasing by 200mg at three-day intervals until control is achieved. This is generally within the dosage range 1000mg to 2000mg per day, ie 20-30mg/kg/day body weight. Where adequate control is not achieved within this range the dose may be further increased to 2500mg per day.

Children over 20kg

Initial dosage should be 400mg/day (irrespective of weight) with spaced increases until control is achieved; this is usually within the range 20-30mg/kg body weight per day. Where adequate control is not achieved within this range the dose may be increased to 35mg/kg body weight per day.

Children under 20kg

20mg/kg of body weight per day; in severe cases this may be increased but only in patients in whom plasma valproic acid levels can be monitored. Above 40mg/kg/day, clinical chemistry and haematological parameters should be monitored.

Use in the elderly

Although the pharmacokinetics of Epilim are modified in the elderly, they have limited clinical significance and dosage should be determined by seizure control. The volume of distribution is increased in the elderly and because of decreased binding to serum albumin, the proportion of free drug is increased. This will affect the clinical interpretation of plasma valproic acid levels.

In patients with renal insufficiency

It may be necessary to decrease the dosage. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading (see section 5.2 Pharmacokinetic Properties.)

In patients with hepatic insufficiency

Salicylates should not be used concomitantly with Epilim since they employ the same metabolic pathway (see also sections 4.4 Special Warnings and Precautions for Use and 4.8 Undesirable Effects).

Liver dysfunction, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid (see sections 4.3 Contraindications and 4.4 Special Warnings and Precautions for Use).

Salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye's syndrome). In addition in conjunction with Epilim, concomitant use in children under 3 years can increase the risk of liver toxicity (see section 4.4.1 Special warnings).

Combined Therapy

When starting Epilim in patients already on other anticonvulsants, these should be tapered slowly: initiation of Epilim therapy should then be gradual, with target dose being reached after about 2 weeks. In certain cases it may be necessary to raise the dose by 5 to 10mg/kg/day when used in combination with anticonvulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbital and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain seizure control on a reduced dose of Epilim. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.

NB: In children requiring doses higher than 40mg/kg/day clinical chemistry and haematological parameters should be monitored.

Optimum dosage is mainly determined by seizure control and routine measurement of plasma levels is unnecessary. However, a method for measurement of plasma levels is available and may be helpful where there is poor control or side effects are suspected (see section 5.2 Pharmacokinetic Properties).

4.3 Contraindications

- Active liver disease

- Personal or family history of severe hepatic dysfunction, especially drug related

- Hypersensitivity to sodium valproate

- Porphyria

4.4 Special Warnings And Precautions For Use

Although there is no specific evidence of sudden recurrence of underlying symptoms following withdrawal of valproate, discontinuation should normally only be done under the supervision of a specialist in a gradual manner. This is due to the possibility of sudden alterations in plasma concentrations giving rise to a recurrence of symptoms. NICE has advised that generic switching of valproate preparations is not normally recommended due to the clinical implications of possible variations in plasma concentrations.

4.4.1 Special warnings

Liver dysfunction:

Conditions of occurrence:

Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been very rarely reported. Experience in epilepsy has indicated that patients most at risk, especially in cases of multiple anticonvulsant therapy, are infants and in particular young children under the age of 3 years and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic or degenerative disease associated with mental retardation.

After the age of 3 years, the incidence of occurrence is significantly reduced and progressively decreases with age.

The concomitant use of salicylates should be avoided in children under 3 years due to the risk of liver toxicity. Additionally, salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye's syndrome).

Monotherapy is recommended in children under the age of 3 years when prescribing Epilim, but the potential benefit of Epilim should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy

In most cases, such liver damage occurred during the first 6 months of therapy, the period of maximum risk being 2-12 weeks.

Suggestive signs:

Clinical symptoms are essential for early diagnosis. In particular the following conditions, which may precede jaundice, should be taken into consideration, especially in patients at risk (see above: 'Conditions of occurrence'):

- non specific symptoms, usually of sudden onset, such as asthenia, malaise, anorexia, lethargy, oedema and drowsiness, which are sometimes associated with repeated vomiting and abdominal pain.

- in patients with epilepsy, recurrence of seizures.

These are an indication for immediate withdrawal of the drug.

Patients (or their family for children) should be instructed to report immediately any such signs to a physician should they occur. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately.

Detection:

Liver function should be measured before therapy and then periodically monitored during the first 6 months of therapy, especially in those who seem most at risk, and those with a prior history of liver disease.

Amongst usual investigations, tests which reflect protein synthesis, particularly prothrombin rate, are most relevant.

Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of Epilim therapy.

As a matter of precaution and in case they are taken concomitantly salicylates should also be discontinued since they employ the same metabolic pathway.

As with most antiepileptic drugs, increased liver enzymes are common, particularly at the beginning of therapy; they are also transient.

More extensive biological investigations (including prothrombin rate) are recommended in these patients; a reduction in dosage may be considered when appropriate and tests should be repeated as necessary.

Pancreatitis: Pancreatitis, which may be severe and result in fatalities, has been very rarely reported. Patients experiencing nausea, vomiting or acute abdominal pain should have a prompt medical evaluation (including measurement of serum amylase).Young children are at particular risk; this risk decreases with increasing age. Severe seizures and severe neurological impairment with combination anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, Epilim should be discontinued.

Women of childbearing potential (see section 4.6): This medicine should not be used in women of child-bearing potential unless clearly necessary (i.e. in situations where other treatments are ineffective or not tolerated). This assessment is to be made before Epilim is prescribed for the first time, or when a women of child bearing potential treated with Epilim plans a pregnancy. Women of child-bearing potential must use effective contraception during treatment.

Suicidal ideation and behaviour:

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for sodium valproate.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

Carbapenem agents:

The concomitant use of valproate and carbapenem agents is not recommended.

4.4.2 Precautions

Haematological: Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding (see section 4.8 Undesirable Effects).

Renal insufficiency:

In patients with renal insufficiency, it may be necessary to decrease dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring (see sections 4.2 Posology and Method of Administration and 5.2. Pharmacokinetic Properties).

Systemic lupus erythematosus: Although immune disorders have only rarely been noted during the use of Epilim, the potential benefit of Epilim should be weighed against its potential risk in patients with systemic lupus erythematosus (see also section 4.8 Undesirable Effects).

Hyperammonaemia: When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia with Epilim.

Weight gain: Epilim very commonly causes weight gain, which may be marked and progressive. Patients should be warned of the risk of weight gain at the initiation of therapy and appropriate strategies should be adopted to minimise it (see section 4.8 Undesirable Effects).

Pregnancy: Women of childbearing potential should not be started on Epilim without specialist neurological advice. Adequate counselling should be made available to all pregnant women with epilepsy of childbearing potential regarding the risks associated with pregnancy - because of the potential teratogenic risk to the foetus (see also section 4.6 Pregnancy and Lactation).

Diabetic patients: Epilim is eliminated mainly through the kidneys, partly in the form of ketone bodies; this may give false positives in the urine testing of possible diabetics.

Alcohol: Alcohol intake is not recommended during treatment with valproate

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

4.5.1 Effects of Epilim on other drugs

- Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines

Epilim may potentiate the effect of other psychotropics such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, clinical monitoring is advised and the dosage of the other psychotropics should be adjusted when appropriate.

In particular, a clinical study has suggested that adding olanzapine to valproate or lithium therapy may significantly increase the risk of certain adverse events associated with olanzapine e.g. neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder and somnolence.

- Lithium

Epilim has no effect on serum lithium levels

- Phenobarbital

Epilim increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.

- Primidone

Epilim increases primidone plasma levels with exacerbation of its adverse effects (such as sedation); these signs cease with long term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.

- Phenytoin

Epilim decreases phenytoin total plasma concentration. Moreover Epilim increases phenytoin free form with possible overdosage symptoms (valproic acid displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore clinical monitoring is recommended; when phenytoin plasma levels are determined, the free form should be evaluated.

- Carbamazepine

Clinical toxicity has been reported when Epilim was administered with carbamazepine as Epilim may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.

- Lamotrigine

Epilim reduces the metabolism of lamotrigine and increases the lamotrigine mean half life by nearly two fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore clinical monitoring is recommended and dosages should be adjusted (lamotrigine dosage decreased) when appropriate.

- Felbamate

Valproic acid may decrease the felbamate mean clearance by up to 16%.

- Zidovudine

Epilim may raise zidovudine plasma concentration leading to increased zidovudine toxicity.

- Vitamin K-dependent anticoagulants

The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from plasma protein binding sites by valproic acid. The prothrombin time should be closely monitored.

- Temozolomide

Co-administration of temozolomide and Epilim may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.

4.5.2 Effects of other drugs on Epilim

Antiepileptics with enzyme inducing effect (including phenytoin, phenobarbital, carbamazepine) decrease valproic acid plasma concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy.

On the other hand, combination of felbamate and Epilim decreases valproic acid clearance by 22% to 50% and consequently increase the valproic acid plasma concentrations. Epilim dosage should be monitored.

Mefloquine and chloroquine increase valproic acid metabolism and may lower the seizure threshold; therefore epileptic seizures may occur in cases of combined therapy. Accordingly, the dosage of Epilim may need adjustment.

In case of concomitant use of Epilim and highly protein bound agents (e.g. aspirin), free valproic acid plasma levels may be increased.

Valproic acid plasma levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.

Carbapenem antibiotics such as imipenem, panipenem and meropenem: Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem agents resulting in a 60%-100% decrease in valproic acid levels within two days, sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid should be avoided (section 4.4). If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood levels should be performed.

Colestyramine may decrease the absorption of Epilim.

Rifampicin may decrease the valproic acid blood levels resulting in a lack of therapeutic effect. Therefore, valproate dosage adjustment may be necessary when it is co-administered with rifampicin.

4.5.3 Other Interactions

Caution is advised when using Epilim in combination with newer anti-epileptics whose pharmacodynamics may not be well established.

Concomitant administration of valproate and topiramate has been associated with encephalopathy and/or hyperammonaemia. In patients taking these two drugs, careful monitoring of signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.

Epilim usually has no enzyme-inducing effect; as a consequence, Epilim does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception, including the oral contraceptive pill.

4.6 Pregnancy And Lactation

Women of childbearing potential should not be started on Epilim without specialist neurological advice.

Adequate counselling should be made available to all women with epilepsy of childbearing potential regarding the risks associated with pregnancy because of the potential teratogenic risk to the foetus (See also section 4.6.1).Women who are taking Epilim and who may become pregnant should receive specialist neurological advice and the benefits of its use should be weighed against the risks.

Epilim is the antiepileptic of choice in patients with certain types of epilepsy such as generalised epilepsy ± myoclonus/photosensitivity. For partial epilepsy, Epilim should be used only in patients resistant to other treatment.

If pregnancy is planned, consideration should be given to cessation of Epilim treatment, if appropriate.

When Epilim treatment is deemed necessary, precautions to minimize the potential teratogenic risk should be followed. (See also section 4.6.1 paragraph entitled “In view of the above”)

4.6.1 Pregnancy

- Risk associated with epilepsy and antiepileptics

In offspring born to mothers with epilepsy receiving any anti-epileptic treatment, the overall rate of malformations has been demonstrated to be higher than the rate (approximately 3 %) reported in the general population. An increased number of children with malformations have been reported in cases of multiple drug therapy. Malformations most frequently encountered are cleft lip and cardio-vascular malformations.

No sudden discontinuation in the anti-epileptic therapy should be undertaken as this may lead to breakthrough seizures which could have serious consequences for both the mother and the foetus.

Antiepileptic drugs should be withdrawn under specialist supervision.

- Risk associated with seizures

During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia carry a particular risk of death for mother and the unborn child.

- Risk associated with valproate

In animals: teratogenic effects have been demonstrated in the mouse, rat and rabbit.

There is animal experimental evidence that high plasma peak levels and the size of an individual dose are associated with neural tube defects.

In humans: Available data suggest an increased incidence of minor or major malformations including neural tube defects, cranio-facial defects, malformations of the limbs, cardiovascular malformations, hypospadias and multiple anomalies involving various body systems in offspring born to mothers with epilepsy treated with valproate. The data suggest that the use of valproate is associated with a greater risk of certain types of these malformations (in particular neural tube defects) than some other anti-epileptic drugs.

Data have suggested an association between in-utero exposure to valproate and the risk of developmental delay (frequently associated with dysmorphic features), particularly of verbal IQ. However, the interpretation of the observed findings in offspring born to mothers with epilepsy treated with sodium valproate remains uncertain, in the view of possible confounding factors such as low maternal IQ, genetic, social, environmental factors and poor maternal seizure control during pregnancy.

Both valproate monotherapy and valproate as part of polytherapy are associated with abnormal pregnancy outcome. Available data suggest that antiepileptic polytherapy including valproate is associated with a higher risk of abnormal pregnancy outcome than valproate monotherapy.

Autism spectrum disorders have also been reported in children exposed to valproate in utero.

- In view of the above data

The following recommendations should be taken into consideration: This medicine should not be used during pregnancy and in women of child-bearing potential unless clearly necessary (i.e. in situations where other treatments are ineffective or not tolerated). This assessment is to be made before Epilim is prescribed for the first time, or when a women of child bearing potential treated with Epilim plans a pregnancy. Women of child-bearing potential must use effective contraception during treatment. Women of child-bearing potential should be informed of the risks and benefits of the use of Epilim during pregnancy.

If a women plans a pregnancy or becomes pregnant, Epilim therapy should be reassessed whatever the indication:

• In epilepsy, valproate therapy should not be discontinued without reassessment of the benefit/risk. If further to a careful evaluation of the risks and benefits, Epilim treatment is to be continued during pregnancy, it is recommended to use Epilim in divided doses over the day at the lowest effective dose. The use of a prolonged release formulation may be preferable to any other treatment form.

• In addition, if appropriate, folate supplementation should be started before pregnancy at relevant dosage (5mg daily) as it may minimise the risk of neural tube defects.

• Specialised prenatal monitoring should be instituted in order to detect the possible occurrence of neural tube defects or other malformations.

The available evidence suggests that anticonvulsant monotherapy is preferred. Dosage should be reviewed before conception and the lowest effective dose used, in divided doses, as abnormal pregnancy outcome tends to be associated with higher total daily dosage and with the size of an individual dose. The incidence of neural tube defects rises with increasing dosage, particularly above 1000mg daily. The administration in several divided doses over the day and the use of a prolonged release formulation is preferable in order to avoid high peak plasma levels.

Pregnancies should be carefully screened by ultrasound, and other techniques if appropriate (see Section 4.4 Special Warnings and Precautions for use).

- Risk in the neonate

Very rare cases of haemorrhagic syndrome have been reported in neonates whose mothers have taken Epilim during pregnancy. This haemorrhagic syndrome is related to hypofibrinogenemia; afibrinogenemia has also been reported and may be fatal. These are possibly associated with a decrease of coagulation factors. However, this syndrome has to be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and other anti-epileptic enzyme inducing drugs.

Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.

Cases of hypoglycaemia have been reported in neonates, whose mothers have taken valproate during the third trimester of the pregnancy.

4.6.2 Lactation

Excretion of Epilim in breast milk is low, with a concentration between 1 % to 10 % of total maternal serum levels. Although there appears to be no contra-indication to breastfeeding, physicians are advised that in any individual case, consideration should be given to the safety profile of Epilim, specifically haematological disorders (see section 4.8 Undesirable Effects).

4.7 Effects On Ability To Drive And Use Machines

Use of Epilim may provide seizure control such that the patient may be eligible to hold a driving licence.

Patients should be warned of the risk of transient drowsiness, especially in cases of anticonvulsant polytherapy or association with benzodiazepines (see section 4.5 Interactions with Other Medicaments and Other Forms of Interaction).

4.8 Undesirable Effects

Congenital and familial/genetic disorders: (see section 4.6 Pregnancy and Lactation)

Hepato-biliary disorders: rare cases of liver injury (see section 4.4.1 Warnings) Severe liver damage, including hepatic failure sometimes resulting in death, has been reported (see also sections 4.2, 4.3 and 4.4.1). Increased liver enzymes are common, particularly early in treatment, and may be transient (see section 4.4.1).

Gastrointestinal disorders (nausea, gastralgia, diarrhoea) frequently occur at the start of treatment, but they usually disappear after a few days without discontinuing treatment. These problems can usually be overcome by taking Epilim with or after food or by using Enteric Coated Epilim.

Very rare cases of pancreatitis, sometimes lethal, have been reported (see section 4.4 Special Warnings and Special Precautions for Use).

Nervous system disorders:

Sedation has been reported occasionally, usually when in combination with other anticonvulsants. In monotherapy it occurred early in treatment on rare occasions and is usually transient. Rare cases of lethargy occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Encephalopathy and coma have very rarely been observed. These cases have often been associated with too high a starting dose or too rapid a dose escalation or concomitant use of other anticonvulsants, notably phenobarbital or topiramate. They have usually been reversible on withdrawal of treatment or reduction of dosage.

Very rare cases of extrapyramidal symptoms which may not be reversible including reversible parkinsonism, or reversible dementia associated with reversible cerebral atrophy have been reported. Dose-related ataxia and fine postural tremor have occasionally been reported.

An increase in alertness may occur; this is generally beneficial but occasionally aggression, hyperactivity and behavioural deterioration have been reported.

Psychiatric disorder: Confusion has been reported

Metabolic disorders:

Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur frequently, are usually transient and should not cause treatment discontinuation. However, they may present clinically as vomiting, ataxia, and increasing clouding of consciousness. Should these symptoms occur Epilim should be discontinued. Very rare cases of hyponatraemia have been reported.

Syndrome of inappropriate secretion of ADH (SIADH)

Hyperammonaemia associated with neurological symptoms has also been reported (see section 4.4.2 Precautions). In such cases further investigations should be considered.

Blood and lymphatic system disorders:

Frequent occurrence of thrombocytopenia, rare cases of anaemia, leucopenia or pancytopenia. The blood picture returned to normal when the drug was discontinued.

Bone marrow failure, including pure red cell aplasia.

Agranulocytosis.

Isolated finding of a reduction in blood fibrinogen and/or an increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (Epilim has an inhibitory effect on the second phase of platelet aggregation). Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations (see also section 4.6 Pregnancy and Lactation).

Skin and subcutaneous tissue disorders:

Rash rarely occurs with valproate. In very rare cases toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme have been reported.

Transient hair loss, which may sometimes be dose-related, has often been reported. Regrowth normally begins within six months, although the hair may become more curly than previously. Hirsutism and acne have been very rarely reported.

Reproductive system and breast disorders:

Amenorrhoea and dysmenorrhea have been reported. Very rarely gynaecomastia has occurred. Male infertility.

Vascular disorders:

The occurrence of vasculitis has occasionally been reported.

Ear disorders:

Hearing loss, either reversible or irreversible has been reported rarely; however a cause and effect relationship has not been established.

Renal and urinary disorders:

There have been isolated reports of a reversible Fanconi's syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria), but the mode of action is as yet unclear.

Very rare cases of enuresis have been reported.

Immune system disorders:

Angioedema, Drug Rash with Eosinophilia, Systemic Symptoms (DRESS) syndrome and allergic reactions (ranging from rash to hypersensitivity reactions) have been reported.

General disorders:

Very rare cases of non-severe peripheral oedema have been reported.

Increase in weight may also occur. Weight gain being a risk factor for polycystic ovary syndrome, it should be carefully monitored (see section 4.4 Special Warnings and Special Precautions for Use).

4.9 Overdose

Cases of accidental and deliberate Epilim overdosage have been reported. At plasma concentrations of up to 5 to 6 times the maximum therapeutic levels, there are unlikely to be any symptoms other than nausea, vomiting and dizziness.

Signs of massive overdose, i.e. plasma concentration 10 to 20 times maximum therapeutic levels, usually include CNS depression or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory function, metabolic acidosis. A favourable outcome is usual, however some deaths have occurred following massive overdose.

Symptoms may however be variable and seizures have been reported in the presence of very high plasma levels (see also section 5.2 Pharmacokinetic Properties).

Cases of intracranial hypertension related to cerebral oedema have been reported.

Hospital management of overdose should be symptomatic, including cardio-respiratory monitoring. Gastric lavage may be useful up to 10 to 12 hours following ingestion.

Haemodialysis and haemoperfusion have been used successfully.

Naloxone has been successfully used in a few isolated cases, sometimes in association with activated charcoal given orally. In case of massive overdose, haemodialysis and haemoperfusion have been used successfully.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Sodium valproate is an anticonvulsant.

The most likely mode of action for Epilim is potentiation of the inhibitory action of gamma amino-butyric acid (GABA) through an action on the further synthesis or further metabolism of GABA.

In certain in-vitro studies it was reported that Epilim could stimulate HIV replication but studies on peripheral blood mononuclear cells from HIV-infected subjects show that Epilim does not have a mitogen-like effect on inducing HIV replication. Indeed the effect of Epilim on HIV replication ex-vivo is highly variable, modest in quantity, appears to be unrelated to the dose and has not been documented in man.

5.2 Pharmacokinetic Properties

The half-life of Epilim is usually reported to be within the range 8-20 hours. It is usually shorter in children.

In patients with severe renal insufficiency it may be necessary to alter dosage in accordance with free plasma valproic acid levels.

The reported effective therapeutic range for plasma valproic acid levels is 40-100mg/litre (278-694 micromol/litre). This reported range may depend on time of sampling and presence of co-medication. The percentage of free (unbound) drug is usually between 6% and 15% of the total plasma levels. An increased incidence of adverse effects may occur with plasma levels above the effective therapeutic range.

The pharmacological (or therapeutic) effects of Epilim may not be clearly correlated with the total or free (unbound) plasma valproic acid levels.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maize Starch, Kaolin light (natural), Silica colloidal hydrated, Magnesium stearate and Purified water*. (* not detected in final formulation).

6.2 Incompatibilities

None.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Epilim is hygroscopic. The tablets should not be removed from their foil until immediately before they are taken. Where possible, blister strips should not be cut.Store in a dry place below 30°C.

6.5 Nature And Contents Of Container

Epilim 100mg Crushable Tablets are supplied in blister packs further packed into a cardboard carton. Pack sizes of 100 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey GU1 4YS

UK

8. Marketing Authorisation Number(S)

PL 04425/0317

9. Date Of First Authorisation/Renewal Of The Authorisation

18 August 1993

10. Date Of Revision Of The Text

13 July 2011

LEGAL STATUS

POM