Amicar Syrup

Pronunciation: a-mee-noe-ka-PROE-ik
Generic Name: Aminocaproic Acid
Brand Name: Amicar

Amicar Syrup is used for:

Preventing and treating severe bleeding in patients with medical conditions that cause blood clots to dissolve faster than normal and lead to severe bleeding, including hemophilia; aplastic anemia; lung, prostate, stomach and cervical cancer; cirrhosis; and certain complications of surgery.

Amicar Syrup is an antifibrinolytic. It works by blocking the breakdown of blood clots.

Do NOT use Amicar Syrup if:

• you are allergic to any ingredient in Amicar Syrup


• you are experiencing blood clots

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

Before using Amicar Syrup:

Some medical conditions may interact with Amicar Syrup. 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


• if you have upper urinary tract bleeding, kidney problems, liver problems, certain blood disorders (eg, hemophilia, uremia), blood clotting problems (active intravascular clotting), undiagnosed bleeding disorder, heart problems, or a history of seizures

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

• Factor IX complex concentrates or anti-inhibitor coagulant concentrates because the risk of blood clots may be increased

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

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

• Amicar Syrup may be taken with or without food.


• Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure your dose.


• Do not miss any doses.


• If you miss a dose of Amicar Syrup, contact your doctor immediately.

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

Important safety information:

• Amicar Syrup may cause dizziness or changes in vision. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to Amicar Syrup. Using Amicar Syrup alone, with certain other medicines, or with alcohol may lessen your ability to drive or perform other potentially dangerous tasks.


• LAB TESTS, including creatine phosphokinase levels, may be performed to monitor your progress or to check for side effects. Be sure to keep all doctor and lab appointments.


• Amicar Syrup is not recommended for use in CHILDREN. Safety and effectiveness have not been confirmed.


• PREGNANCY and BREAST-FEEDING: If you plan on becoming pregnant, discuss with your doctor the benefits and risks of using Amicar Syrup during pregnancy. It is unknown if Amicar Syrup is excreted in breast milk. If you are or will be breast feeding while you are using Amicar Syrup, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Amicar Syrup:

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

Confusion; decreased vision; diarrhea; dizziness; fatigue or tiredness; general body discomfort; headache; lightheadedness; muscle aches or swelling; nausea; pain; ringing in the ears; stomach pain; stuffy nose; swelling; vomiting; watery eyes.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); delirium; fainting; fever; hallucinations; muscle pain or weakness; seizures; slow heartbeat; sore throat; stroke; sudden change in the amount of urine you are producing; swelling of ankles, feet, or hands; unusual bleeding or bruising.

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: Amicar side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include fainting; seizures; severe or unusual weakness; sudden change in amount of urine you produce.

Proper storage of Amicar Syrup:

Store Amicar Syrup at room temperature, between 59 and 86 degrees F (15 and 30 degrees C), in a tightly closed container. Store away from heat, moisture, and light. Do not freeze. Do not store in the bathroom. Keep Amicar Syrup out of the reach of children and away from pets.

General information:

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


• Amicar Syrup 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 Amicar Syrup. 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 Amicar resources

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

Compare Amicar with other medications

• Fibrinolytic Bleeding

isoniazid Oral, Intramuscular

eye-soe-NYE-a-zid

Intramuscular route(Solution)

Severe and sometimes fatal hepatitis has been reported with isoniazid therapy and may occur even after many months of treatment. The risk for hepatitis increases with advancing age and alcohol use. Patients given isoniazid should be carefully monitored and interviewed at monthly intervals. For persons 35 and older, in addition to monthly symptom reviews, hepatic enzymes (specifically, AST and ALT (formerly SGOT and SGPT, respectively) should be measured prior to starting isoniazid therapy and periodically throughout treatment. An increased risk of fatal hepatitis associated with isoniazid has been reported in women, particularly black and Hispanic women. The risk may also be increased during the post partum period. More careful monitoring should be considered in these groups, possibly including more frequent laboratory monitoring .

Oral route(Tablet;Syrup)

Severe and sometimes fatal hepatitis has been reported with isoniazid therapy and may occur even after many months of treatment. The risk for hepatitis increases with advancing age and alcohol use. Patients given isoniazid should be carefully monitored and interviewed at monthly intervals. For persons 35 and older, in addition to monthly symptom reviews, hepatic enzymes (specifically, AST and ALT (formerly SGOT and SGPT, respectively) should be measured prior to starting isoniazid therapy and periodically throughout treatment. An increased risk of fatal hepatitis associated with isoniazid has been reported in women, particularly black and Hispanic women. The risk may also be increased during the post partum period. More careful monitoring should be considered in these groups, possibly including more frequent laboratory monitoring .

Commonly used brand name(s)

In the U.S.

• Nydrazid

In Canada

• Pms-Isoniazid

Available Dosage Forms:

• Syrup


• Tablet


• Solution

Therapeutic Class: Antitubercular

Chemical Class: Isonicotinic Acid

Uses For isoniazid

Isoniazid is used to treat tuberculosis (TB) or prevent its return (reactivation). It may be given alone, or in combination with other medicines, to treat TB or to prevent its return (reactivation). isoniazid may also be used for other problems as determined by your doctor.

isoniazid may cause some serious side effects, including damage to the liver. Liver damage is more likely to occur in patients over 50 years of age. You and your doctor should talk about the good isoniazid will do, as well as the risks of taking it.

If you are being treated for active tuberculosis (TB): To help clear up your TB infection completely, you must keep taking isoniazid for the full time of treatment, even if you begin to feel better. This is very important. It is also important that you do not miss any doses.

Isoniazid is available only with your doctor's prescription.

Before Using isoniazid

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 isoniazid, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to isoniazid 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

Isoniazid can cause serious side effects in any patient. Therefore, it is especially important that you discuss with the child's doctor the good that isoniazid may do as well as the risks of using it.

Geriatric

Hepatitis may be especially likely to occur in patients over 50 years of age, who are usually more sensitive than younger adults to the effects of isoniazid.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during 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 isoniazid, 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 isoniazid 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.

• Itraconazole


• Levodopa


• Rifampin

Using isoniazid 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.

• Acetaminophen


• Aminosalicylic Acid


• Carbamazepine


• Diazepam


• Disulfiram


• Enflurane


• Ethionamide


• Fosphenytoin


• Ketoconazole


• Meperidine


• Phenytoin


• Warfarin

Interactions with Food/Tobacco/Alcohol

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

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

• Ethanol

Using isoniazid with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use isoniazid, or give you special instructions about the use of food, alcohol, or tobacco.

• food


• Tyramine Containing Food

Other Medical Problems

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

• Alcohol abuse (or history of) or


• Liver disease—There may be an increased chance of hepatitis with daily drinking of alcohol or in patients with liver disease

• Kidney disease (severe)—There may be an increased chance of side effects in patients with severe kidney disease

• Seizure disorders such as epilepsy—There may be an increased chance of seizures (convulsions) in some patients

Proper Use of isoniazid

Make certain your health care professional knows if you are on a low-sodium, low-sugar, or any other special diet. Most medicines contain more than just the active ingredient, and many liquid medicines contain alcohol.

If you are taking isoniazid by mouth and it upsets your stomach, take it with food. Antacids may also help. However, do not take aluminum-containing antacids within 1 hour of taking isoniazid. They may keep isoniazid from working properly.

For patients taking the oral liquid form of isoniazid:

• Use a specially marked measuring spoon or other device to measure each dose accurately. The average household teaspoon may not hold the right amount of liquid.

To help clear up your tuberculosis (TB) completely, it is very important that you keep taking isoniazid for the full time of treatment, even if you begin to feel better after a few weeks. You may have to take it every day for as long as 6 months to 2 years. It is important that you do not miss any doses.

Your doctor may also want you to take pyridoxine (e.g., Hexa-Betalin, vitamin B 6) every day to help prevent or lessen some of the side effects of isoniazid. This is not usually needed in children, who receive enough pyridoxine in their diet. If it is needed, it is very important to take pyridoxine every day along with isoniazid. Do not miss any doses.

Dosing

The dose of isoniazid 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 isoniazid. 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 oral dosage forms (tablets, syrup):
  
  • For preventing the return (reactivation) of tuberculosis:
    
    • Adults and teenagers—300 milligrams (mg) once a day.
    
    
    • Children—Dose is based on body weight. The usual dose is 10 mg per kilogram (kg) (4.5 mg per pound) of body weight, up to 300 mg, once a day.
    
    
  
  
  • For treatment of tuberculosis:
    
    • Adults and teenagers—300 mg once a day; or 15 mg per kg (6.8 mg per pound) of body weight, up to 900 mg, two times a week or three times a week, depending on the schedule your doctor chooses for you.
    
    
    • Children—Dose is based on body weight. The usual dose is 10 to 20 mg per kg (4.5 to 9.1 mg per pound) of body weight, up to 300 mg, once a day; or 20 to 40 mg per kg (9.1 to 18.2 mg per pound) of body weight, up to 900 mg, two times a week or three times a week, depending on the schedule your doctor chooses for you.
    
    
  
  


• For injection dosage form:
  
  • For preventing the return (reactivation) of tuberculosis:
    
    • Adults and teenagers—300 mg once a day.
    
    
    • Children—Dose is based on body weight. The usual dose is 10 mg per kg (4.5 mg per pound) of body weight, up to 300 mg, once a day.
    
    
  
  
  • For treatment of tuberculosis:
    
    • Adults and teenagers—300 mg once a day; or 15 mg per kg (6.8 mg per pound) of body weight, up to 900 mg, two times a week or three times a week, depending on the schedule your doctor chooses for you.
    
    
    • Children—Dose is based on body weight. The usual dose is 10 to 20 mg per kg (4.5 to 9.1 mg per pound) of body weight, up to 300 mg, once a day; or 20 to 40 mg per kg (9.1 to 18.2 mg per pound) of body weight, up to 900 mg, two times a week or three times a week, depending on the schedule your doctor chooses for you.
    
    
  
  

Missed Dose

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

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using isoniazid

It is very important that your doctor check your progress at regular visits. Also, check with your doctor immediately if blurred vision or loss of vision, with or without eye pain, occurs during treatment. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

If your symptoms do not improve within 2 to 3 weeks, or if they become worse, check with your doctor.

Certain foods such as cheese (Swiss or Cheshire) or fish (tuna, skipjack, or Sardinella) may rarely cause reactions in some patients taking isoniazid. Check with your doctor if redness or itching of the skin, hot feeling, fast or pounding heartbeat, sweating, chills or clammy feeling, headache, or lightheadedness occurs while you are taking isoniazid.

Liver problems may be more likely to occur if you drink alcoholic beverages regularly while you are taking isoniazid. Also, the regular use of alcohol may keep isoniazid from working properly. Therefore, you should strictly limit the amount of alcoholic beverages you drink while you are taking isoniazid.

If isoniazid causes you to feel very tired or very weak; or causes clumsiness; unsteadiness; a loss of appetite; nausea; numbness, tingling, burning, or pain in the hands and feet; or vomiting, check with your doctor immediately. These may be early warning signs of more serious liver or nerve problems that could develop later.

• For diabetic patients:


• isoniazid may cause false test results with some urine sugar tests. Check with your doctor before changing your diet or the dosage of your diabetes medicine.

isoniazid 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

• Clumsiness or unsteadiness


• dark urine


• loss of appetite


• nausea or vomiting


• numbness, tingling, burning, or pain in hands and feet


• unusual tiredness or weakness


• yellow eyes or skin

Rare

• Blurred vision or loss of vision, with or without eye pain


• convulsions (seizures)


• fever and sore throat


• joint pain


• mental depression


• mood or other mental changes


• skin rash


• unusual bleeding or bruising

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

• Diarrhea


• stomach pain

For injection form

• Irritation at the place of injection

Dark urine and yellowing of the eyes or skin (signs of liver problems) are more likely to occur in patients over 50 years of age.

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: isoniazid Oral, Intramuscular side effects (in more detail)

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

More isoniazid Oral, Intramuscular resources

• Isoniazid Oral, Intramuscular Side Effects (in more detail)
• Isoniazid Oral, Intramuscular Use in Pregnancy & Breastfeeding
• Drug Images
• Isoniazid Oral, Intramuscular Drug Interactions
• Isoniazid Oral, Intramuscular Support Group
• 2 Reviews for Isoniazid Oral, Intramuscular - Add your own review/rating

Compare isoniazid Oral, Intramuscular with other medications

• Mycobacterium kansasii
• Tuberculosis, Active
• Tuberculosis, Latent
• Tuberculosis, Prophylaxis

Actoplus Met XR

pioglitazone hydrochloride and metformin hydrochloride

Dosage Form: tablet, film coated, extended release
ACTOPLUS MET®

(pioglitazone hydrochloride and metformin hydrochloride) tablets

ACTOPLUS MET® XR

(pioglitazone hydrochloride and metformin hydrochloride extended-release) tablets

WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS

Congestive Heart Failure

• Thiazolidinediones, including pioglitazone, which is a component of ACTOPLUS MET and Actoplus Met XR, cause or exacerbate congestive heart failure in some patients (see WARNINGS, Pioglitazone). After initiation of ACTOPLUS MET or Actoplus Met XR, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to the current standards of care. Furthermore, discontinuation or dose reduction of ACTOPLUS MET or Actoplus Met XR must be considered.


• ACTOPLUS MET and Actoplus Met XR are not recommended in patients with symptomatic heart failure. Initiation of ACTOPLUS MET or Actoplus Met XR in patients with established NYHA Class III or IV heart failure is contraindicated (see CONTRAINDICATIONS and WARNINGS, Pioglitazone).

Lactic Acidosis

• Lactic acidosis is a rare, but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure.


• The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.


• Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate.


• If acidosis is suspected, ACTOPLUS MET or Actoplus Met XR should be discontinued and the patient hospitalized immediately (see WARNINGS, Metformin Hydrochloride).

Actoplus Met XR Description

ACTOPLUS MET® tablets are formulated with pioglitazone hydrochloride and immediate-release metformin hydrochloride. ACTOPLUS MET® XR tablets are formulated with pioglitazone hydrochloride and extended-release metformin hydrochloride. Both ACTOPLUS MET® and ACTOPLUS MET® XR contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: pioglitazone and metformin. ACTOPLUS MET® is available in 15 mg pioglitazone/500 mg metformin hydrochloride and 15 mg pioglitazone/850 mg metformin hydrochloride tablets. ACTOPLUS MET® XR is available in 15 mg pioglitazone/1000 mg extended-release metformin hydrochloride and 30 mg pioglitazone/1000 mg extended-release metformin hydrochloride tablets.

Pioglitazone is an oral antihyperglycemic agent that acts primarily by decreasing insulin resistance. Pioglitazone is used in the management of type 2 diabetes. Pharmacological studies indicate that pioglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone improves glycemic control while reducing circulating insulin levels.

Pioglitazone (±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, biguanides, or the α-glucosidase inhibitors. The molecule contains one asymmetric center, and the synthetic compound is a racemate. The two enantiomers of pioglitazone interconvert in vivo. The structural formula is as shown:

pioglitazone hydrochloride

Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of C19H20N2O3S•HCl and a molecular weight of 392.90. It is soluble in N,N-dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin hydrochloride is a white crystalline powder with a molecular formula of C4H11N5•HCl and a molecular weight of 165.62. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown:

metformin hydrochloride

ACTOPLUS MET is available as a tablet for oral administration containing pioglitazone hydrochloride and metformin hydrochloride equivalent to 15 mg pioglitazone and 500 mg metformin hydrochloride (ACTOPLUS MET 15 mg/500 mg) or 850 mg metformin hydrochloride (ACTOPLUS MET 15 mg/850 mg). ACTOPLUS MET is formulated with the following excipients: povidone, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, hypromellose 2910, polyethylene glycol 8000, titanium dioxide, and talc.

Actoplus Met XR is available as a tablet for once-a-day oral administration containing pioglitazone hydrochloride and metformin hydrochloride equivalent to 15 mg pioglitazone and 1000 mg metformin hydrochloride (Actoplus Met XR 15 mg/1000 mg) or 30 mg pioglitazone and 1000 mg metformin hydrochloride (Actoplus Met XR 30 mg/1000 mg). Actoplus Met XR is formulated with the following excipients: candelilla wax, cellulose acetate, povidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, hypromellose, polyethylene glycols (PEG 400, PEG 8000), sodium lauryl sulfate, titanium dioxide, and triacetin. Tablets are imprinted with ink containing shellac, iron oxide red (15 mg/1000 mg strength only), FD&C Blue No. 2 Lake (30 mg/1000 mg strength only), propylene glycol, and ammonium hydroxide.

Actoplus Met XR: SYSTEM COMPONENTS AND PERFORMANCE

Actoplus Met XR consists of an extended-release metformin core coated tablet with an immediate-release pioglitazone layer. The metformin core tablet is an extended-release formulation using the patented single composition osmotic technology (SCOT™) for once-daily (q.d.) oral administration. The tablet is similar in appearance to other film-coated oral administered tablets but it consists of an osmotically active core formulation that is surrounded by a semipermeable membrane and coated with a pioglitazone drug layer. Two laser drilled exit ports exist in the membrane, one on either side of the tablet. The core formulation is composed primarily of drug with small concentrations of excipients. The semipermeable membrane is permeable to water but not to higher molecular weight components of biological fluids. Upon ingestion, the pioglitazone layer is dissolved, water is then taken up through the membrane, which in turn dissolves the metformin and excipients in the core formulation. The dissolved metformin and excipients exit through the laser drilled ports in the membrane. The rate of drug delivery is constant and dependent upon the maintenance of a constant osmotic gradient across the membrane. This situation exists so long as there is undissolved metformin present in the core tablet. Following the dissolution of the core materials, the rate of drug delivery slowly decreases until the osmotic gradient across the membrane falls to zero at which time delivery ceases. The membrane coating remains intact during the transit of the dosage form through the gastrointestinal tract and is excreted in the feces.

Actoplus Met XR - Clinical Pharmacology

Mechanism of Action

ACTOPLUS MET and Actoplus Met XR

ACTOPLUS MET and Actoplus Met XR combine two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: pioglitazone, a member of the thiazolidinedione class, and metformin hydrochloride, a member of the biguanide class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.

Pioglitazone

Pioglitazone depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

Metformin hydrochloride

Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS, General: Metformin hydrochloride) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacokinetics and Drug Metabolism

Absorption and Bioavailability

ACTOPLUS MET

In bioequivalence studies of ACTOPLUS MET 15 mg/500 mg and 15 mg/850 mg, the area under the curve (AUC) and maximum concentration (Cmax) of both the pioglitazone and the immediate-release metformin component following a single dose of the combination tablet were bioequivalent to pioglitazone (ACTOS®) 15 mg concomitantly administered with immediate-release metformin (Glucophage®) 500 mg or 850 mg tablets, respectively, under fasted conditions in healthy subjects (Table 1).

Table 1. Mean (SD) Pharmacokinetic Parameters for ACTOPLUS MET®

Regimen	N	AUC(0-inf) (ng∙h/mL)	N	Cmax (ng/mL)	N	Tmax (h)	N	T1/2 (h)
pioglitazone
15 mg/500 mg ACTOPLUS MET®	51	5984 (1599)	63	585 (198)	63	1.8 (0.9)	51	8.7 (3.9)
15 mg pioglitazone and 500 mg immediate-release metformin	54	5810 (1472)	63	608 (204)	63	1.7 (0.9)	54	7.9 (3.1)
15 mg/850 mg ACTOPLUS MET®	52	5671 (1585)	60	569 (222)	60	1.9 (0.8)	52	7.2 (1.8)
15 mg pioglitazone and 850 mg immediate-release metformin	55	5957 (1680)	61	603 (239)	61	2.0 (1.5)	55	7.2 (1.8)
metformin
15 mg/500 mg ACTOPLUS MET®	59	7783 (2266)	63	1203 (325)	63	2.3 (0.9)	59	8.6 (14.3)
15 mg pioglitazone and 500 mg immediate-release metformin	59	7599 (2385)	63	1215 (329)	63	2.5 (0.9)	59	6.7 (5.9)
15 mg/850 mg ACTOPLUS MET®	47	11927 (3311)	60	1827 (536)	60	2.4 (0.9)	47	17.6 (20.1)
15 mg pioglitazone and 850 mg immediate-release metformin	52	11569 (3494)	61	1797 (525)	61	2.3 (0.8)	52	17.0 (18.1)

Administration of ACTOPLUS MET 15 mg/850 mg with food resulted in no change in overall exposure of pioglitazone. With metformin there was no change in AUC; however, mean peak serum concentration of metformin was decreased by 28% when administered with food. A delayed time to peak serum concentration was observed for both components (1.9 hours for pioglitazone and 0.8 hours for metformin) under fed conditions. These changes are not likely to be clinically significant.

Actoplus Met XR

In bioequivalence studies of Actoplus Met XR 15 mg/1000 mg and 30 mg/1000 mg, the area under the curve (AUC) and maximum concentration (Cmax) of both the pioglitazone and the extended-release metformin components following a single dose of the combination tablet were bioequivalent to pioglitazone (ACTOS®)15 mg and 30 mg concomitantly administered with extended-release metformin hydrochloride (FORTAMET®) 1000 mg tablets under fed conditions in healthy subjects (Table 2).

Table 2. Mean (SD) Pharmacokinetic Parameters for ACTOPLUS MET® XR

Regimen	N	AUC(0-inf) (ng∙h/mL)	N	Cmax (ng/mL)	N	Tmax (h)	N	T1/2 (h)
pioglitazone
15 mg/1000 mg ACTOPLUS MET® XR	59	5113 (1598)	60	487 (126)	60	3.0 (1.0)	60	5.8 (1.4)
15 mg pioglitazone and 1000 mg extended-release metformin	59	5979 (1726)	60	560 (130)	60	3.1 (1.1)	60	6.3 (2.0)
30 mg/1000 mg ACTOPLUS MET® XR	55	8242 (2587)	57	777 (250)	57	3.5 (1.4)	55	6.7 (3.8)
30 mg pioglitazone and 1000 mg extended-release metformin	55	9177 (2200)	57	866 (243)	57	3.1 (1.3)	55	7.6 (3.3)
metformin
15 mg/1000 mg ACTOPLUS MET® XR	50	14454 (3579)	60	1551 (404)	60	7.2 (1.9)	50	11.7 (7.0)
15 mg pioglitazone and 1000 mg extended-release metformin	50	14787 (3313)	60	1590 (361)	60	6.9 (1.8)	50	11.0 (5.0)
30 mg/1000 mg ACTOPLUS MET® XR	54	12705 (3577)	58	1322 (335)	58	8.0 (2.0)	54	11.1 (5.0)
30 mg pioglitazone and 1000 mg extended-release metformin	54	12796 (3882)	58	1332 (414)	58	7.4 (2.0)	54	11.4 (5.5)

Administration of ACTOPLUS MET® XR 30 mg/1000 mg with food resulted in no change in total (AUC) exposure of pioglitazone; however, a decrease in Cmax by approximately 18% was observed. With the extended-release metformin component there was an increase in Cmax by approximately 98% and AUC exposure by approximately 85% when administered with food. These levels are comparable to exposures obtained with extended release metformin when administered with food. Time to peak serum concentration was prolonged by approximately 3 and 2 hours for pioglitazone and extended-release metformin respectively, under fed conditions.

Pioglitazone

Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption.

Metformin hydrochloride

The absolute bioavailability of a 500 mg immediate-release metformin tablet given under fasting conditions is approximately 50% - 60%. Studies using single oral doses of immediate-release metformin tablets of 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of immediate-release metformin, as shown by approximately a 40% lower mean peak plasma concentration, a 25% lower AUC in plasma concentration versus time curve, and a 35 minute prolongation of time to peak plasma concentration following administration of a single 850 mg tablet of immediate-release metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

The appearance of metformin in plasma from an extended-release metformin tablet is slower and more prolonged compared to immediate-release metformin (see FORTAMET prescribing information). In a multiple-dose crossover study, 23 patients with type 2 diabetes mellitus were administered either extended-release metformin hydrochloride 2000 mg once a day (after dinner) or immediate-release (IR) metformin hydrochloride 1000 mg twice a day (after breakfast and after dinner). After 4 weeks of treatment, steady-state pharmacokinetic parameters, area under the concentration-time curve (AUC), time to peak plasma concentration (Tmax), and maximum concentration (Cmax) were evaluated. Results are presented in Table 3.

Table 3. Extended-Release Metformin vs. Immediate-Release Metformin Steady-State Pharmacokinetic Parameters at 4 Weeks

Pharmacokinetic Parameters (mean ± SD)	Extended-Release Metformin 2000 mg (administered daily with dinner)	Immediate-Release Metformin 2000 mg (administered as 1000 mg twice daily)
AUC0-24 hrs (ng ∙ hr/mL)	26,811 ± 7055	27,371 ± 5,781
Tmax (hr)	6 (3-10)	3 (1-8)
Cmax (ng/mL)	2849 ± 797	1820 ± 370

In four single-dose studies and one multiple-dose study, the bioavailability of extended-release metformin 2000 mg given once daily, in the evening, under fed conditions [as measured by the area under the plasma concentration versus time curve (AUC)] was similar to the same total daily dose administered as immediate-release metformin 1000 mg given twice daily. The geometric mean ratios (extended-release metformin/immediate-release metformin) of AUC0-24hr, AUC0-72hr, and AUC0-inf. for these five studies ranged from 0.96 to 1.08.

In a single-dose, four-period replicate crossover design study, comparing two 500 mg extended-release metformin tablets to one 1000 mg extended-release metformin tablet administered in the evening with food to 29 healthy male subjects, two 500 mg extended-release metformin tablets were found to be equivalent to one 1000 mg extended-release metformin tablet.

In a study carried out with extended-release metformin, there was a dose-associated increase in metformin exposure over 24 hours following oral administration of 1000, 1500, 2000, and 2500 mg.

In three studies with extended-release metformin using different treatment regimens (2000 mg after dinner, 1000 mg after breakfast and after dinner, and 2500 mg after dinner), the pharmacokinetics of metformin as measured by AUC appeared linear following multiple-dose administration.

The extent of absorption (as measured by AUC) of extended-release metformin increased by approximately 60% when given with food. When extended-release metformin was administered with food, Cmax was increased by approximately 30% and Tmax was more prolonged compared with the fasting state (6.1 versus 4.0 hours).

Distribution

Pioglitazone

The mean apparent volume of distribution (V/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (> 99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound (> 98%) to serum albumin.

Metformin hydrochloride

Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of immediate-release metformin, steady-state plasma concentrations of metformin are reached within 24 - 48 hours and are generally <1 µg/mL. During controlled clinical trials of immediate-release metformin, maximum metformin plasma levels did not exceed 5 µg/mL, even at maximum doses.

Metabolism, Elimination and Excretion

Pioglitazone

Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) are pharmacologically active in animal models of type 2 diabetes. In addition to pioglitazone, M-III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC.

In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see PRECAUTIONS, Drug Interactions, Pioglitazone). Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.

Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.

The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr.

Metformin hydrochloride

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Metabolism studies with extended-release metformin tablets have not been conducted.

In healthy nondiabetic adults (N=18) receiving extended-release metformin 2500 mg daily, the percent of the metformin dose excreted in urine over 24 hours was 40.9% and the renal clearance was 542 ± 310 mL/min. After repeated administration of extended-release metformin, there is little or no accumulation of metformin in plasma, with most of the drug being eliminated via renal excretion over a 24-hour dosing interval.

Special Populations

Renal Insufficiency

Pioglitazone

The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance < 30 mL/min) renal impairment when compared to normal subjects.

Metformin hydrochloride

In patients with decreased renal function (based on creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see CONTRAINDICATIONS and WARNINGS, Metformin hydrochloride, also see GLUCOPHAGE® prescribing information, CLINICAL PHARMACOLOGY, Pharmacokinetics). Since metformin is contraindicated in patients with renal impairment, ACTOPLUS MET and Actoplus Met XR are also contraindicated in these patients.

Hepatic Insufficiency

Pioglitazone

Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values.

Therapy with ACTOPLUS MET or Actoplus Met XR should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal (see PRECAUTIONS, General: Pioglitazone).

Metformin hydrochloride

No pharmacokinetic studies of metformin have been conducted in subjects with hepatic insufficiency.

Elderly

Pioglitazone

In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant.

Metformin hydrochloride

Limited data from controlled pharmacokinetic studies of immediate-release metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see GLUCOPHAGE® prescribing information, CLINICAL PHARMACOLOGY, Special Populations, Geriatrics).

ACTOPLUS MET or Actoplus Met XR treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see WARNINGS, Metformin hydrochloride and DOSAGE AND ADMINISTRATION; also see GLUCOPHAGE® prescribing information).

Pediatrics

Pioglitazone

Pharmacokinetic data in the pediatric population are not available. Use in pediatric patients is not recommended for the treatment of diabetes due to lack of long-term safety data. Risks including fractures and other adverse effects associated with pioglitazone, one of the components of ACTOPLUS MET and Actoplus Met XR, have not been determined in this population (see WARNINGS and PRECAUTIONS).

Metformin hydrochloride

After administration of a single oral immediate-release metformin 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), and all with normal renal function.

Pharmacokinetic data for extended-release metformin tablets in the pediatric population are not available.

Gender

Pioglitazone

As monotherapy and in combination with sulfonylurea, metformin, or insulin, pioglitazone improved glycemic control in both males and females. The mean Cmax and AUC values were increased 20% to 60% in females. In controlled clinical trials, decreases from baseline in HbA1c were generally greater for females than for males (average mean difference in HbA1c 0.5%). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.

Metformin hydrochloride

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of immediate-release metformin was comparable in males and females.

Five studies indicated that with extended-release metformin treatment, the pharmacokinetic results for males and females were comparable.

Ethnicity

Pioglitazone

Pharmacokinetic data among various ethnic groups are not available.

Metformin hydrochloride

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of immediate-release metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Drug-Drug Interactions

Co-administration of a single dose of immediate-release metformin (1000 mg) and pioglitazone after 7 days of pioglitazone (45 mg) did not alter the pharmacokinetics of the single dose of metformin. Specific pharmacokinetic drug interaction studies with ACTOPLUS MET or Actoplus Met XR have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.

Pioglitazone

The following drugs were studied in healthy volunteers with co-administration of pioglitazone 45 mg once daily. Results are listed below:

Oral Contraceptives

Co-administration of pioglitazone (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC (0-24h) and Cmax respectively. There were no significant changes in norethindrone AUC (0-24h) and Cmax. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown.

Midazolam

Administration of pioglitazone for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC.

Nifedipine ER

Co-administration of pioglitazone for 7 days with 30 mg nifedipine ER administered orally once daily for 4 days to male and female volunteers resulted in a ratio of least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73 - 0.95) for Cmax and 0.88 (0.80 - 0.96) for AUC. In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown.

Ketoconazole

Co-administration of pioglitazone for 7 days with ketoconazole 200 mg administered twice daily resulted in a ratio of least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06 - 1.23) for Cmax, 1.34 (1.26 - 1.41) for AUC and 1.87 (1.71 - 2.04) for Cmin.

Atorvastatin Calcium

Co-administration of pioglitazone for 7 days with atorvastatin calcium (LIPITOR®) 80 mg once daily resulted in a ratio of least square mean (90% CI) values for unchanged pioglitazone of 0.69 (0.57 - 0.85) for Cmax, 0.76 (0.65 - 0.88) for AUC and 0.96 (0.87 - 1.05) for Cmin. For unchanged atorvastatin the ratio of least square mean (90% CI) values were 0.77 (0.66 - 0.90) for Cmax, 0.86 (0.78 - 0.94) for AUC and 0.92 (0.82 - 1.02) for Cmin.

Cytochrome P450

See PRECAUTIONS, Drug Interactions, Pioglitazone

Gemfibrozil

Concomitant administration of gemfibrozil (oral 600 mg twice daily), an inhibitor of CYP2C8, with pioglitazone (oral 30 mg) in 10 healthy volunteers pre-treated for 2 days prior with gemfibrozil (oral 600 mg twice daily) resulted in pioglitazone exposure (AUC0-24) being 226% of the pioglitazone exposure in the absence of gemfibrozil (see PRECAUTIONS, Drug Interactions, Pioglitazone).1

Rifampin

Concomitant administration of rifampin (oral 600 mg once daily), an inducer of CYP2C8 with pioglitazone (oral 30 mg) in 10 healthy volunteers pre-treated for 5 days prior with rifampin (oral 600 mg once daily) resulted in a decrease in the AUC of pioglitazone by 54% (see PRECAUTIONS, Drug Interactions, Pioglitazone).2

In other drug-drug interaction studies, pioglitazone had no significant effect on the pharmacokinetics of fexofenadine, glipizide, digoxin, warfarin, ranitidine HCl or theophylline.

Metformin hydrochloride

See PRECAUTIONS, Drug Interactions, Metformin hydrochloride

Pharmacodynamics and Clinical Effects

Pioglitazone

Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin levels, and lower HbA1c values. Based on results from an open-label extension study, the glucose-lowering effects of pioglitazone appear to persist for at least one year. In controlled clinical studies, pioglitazone in combination with metformin had an additive effect on glycemic control.

Patients with lipid abnormalities were included in placebo-controlled monotherapy clinical studies with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL cholesterol and total cholesterol compared to the placebo group. A similar pattern of results was seen in 16-week and 24-week combination therapy studies of pioglitazone with metformin.

Clinical Studies

There have been no clinical efficacy studies conducted with ACTOPLUS MET or Actoplus Met XR. However, the efficacy and safety of the separate components have been previously established and the co-administration of the separate components has been evaluated for efficacy and safety in two clinical studies. These clinical studies established an added benefit of pioglitazone in patients with inadequately controlled type 2 diabetes while on metformin therapy. Bioequivalence of ACTOPLUS MET with co-administered pioglitazone and immediate-release metformin tablets and Actoplus Met XR with co-administered pioglitazone and extended-release metformin tablets was demonstrated for both tablet strengths of ACTOPLUS MET and Actoplus Met XR, respectively (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism).

Clinical Trials of Pioglitazone Add-on Therapy in Patients Not Adequately Controlled on Metformin

Two treatment-randomized, controlled clinical studies in patients with type 2 diabetes were conducted to evaluate the safety and efficacy of pioglitazone plus metformin. Both studies included patients receiving metformin, either alone or in combination with another antihyperglycemic agent, who had inadequate glycemic control. All other antihyperglycemic agents were discontinued prior to starting study treatment. In the first study, 328 patients received either 30 mg of pioglitazone or placebo once daily for 16 weeks in addition to their established metformin regimen. In the second study, 827 patients received either 30 mg or 45 mg of pioglitazone once daily for 24 weeks in addition to their established metformin regimen.

In the first study, the addition of pioglitazone 30 mg once daily to metformin treatment significantly reduced the mean HbA1c by 0.8% and the mean fasting plasma glucose (FPG) by 38 mg/dL at Week 16 compared to that observed with metformin alone. In this 16 week study, patients randomized to either pioglitazone or placebo treatment received a median metformin daily dose of 1500 mg with doses ranging from 500 mg to 3400 mg. In the second study, the mean reductions from Baseline at Week 24 in HbA1c were 0.8% and 1.0% for the 30 mg and 45 mg doses, respectively. Mean reductions from Baseline in FPG were 38 mg/dL and 51 mg/dL, respectively. In this 24 week study, patients randomized to either pioglitazone 30 mg or pioglitazone 45 mg treatment received a median metformin daily dose of 1700 mg with doses ranging from 500 mg to 3000 mg. Based on these reductions in HbA1c and FPG (Table 4), the addition of pioglitazone to metformin resulted in significant improvements in glycemic control irrespective of the metformin dose.

Table 4. Glycemic Parameters in 16-Week and 24-Week Pioglitazone + Metformin Hydrochloride Combination Studies

Parameter	Placebo + Metformin	Pioglitazone 30 mg + metformin
* significant change from Baseline p ≤ 0.050. † significant difference from placebo plus metformin, p ≤ 0.050. ‡ patients who achieved HbA1c ≤ 6.1% or ≥ 0.6% decrease from Baseline. § patients who achieved a decrease in FPG by ≥ 30 mg/dL. ¶ significant difference from 30 mg pioglitazone, p ≤ 0.050.
16-Week Study
HbA1c (%)	N=153	N=161
Baseline mean	9.8	9.9
Mean change from Baseline at 16 Weeks	0.2	-0.6* , †
Difference in change from placebo + metformin		-0.8
Responder rate (%) ‡	22	54
Fasting Plasma Glucose (FPG) (mg/dL)	N=157	N=165
Baselin

Adrenaclick Auto-Injector

Pronunciation: EP-i-NEF-rin
Generic Name: Epinephrine
Brand Name: Adrenaclick or Twinject

Adrenaclick Auto-Injector is used for:

Treating severe allergic reactions (eg, difficulty breathing; rash; hives; itching; tightness in the chest; swelling of the mouth, lips, or tongue) caused by insect stings or bites, foods, drugs, or other causes. It may also be used for other conditions as determined by your doctor.

Adrenaclick Auto-Injector is a sympathomimetic. It works on different receptors in the body to relax the smooth muscle of the lungs, which improves breathing.

Do NOT use Adrenaclick Auto-Injector if:

• you are allergic to any ingredient in Adrenaclick Auto-Injector, unless your doctor tells you otherwise

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

Before using Adrenaclick Auto-Injector:

Some medical conditions may interact with Adrenaclick Auto-Injector. 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 (eg, sulfites)


• if you have glaucoma, heart disease, chest pain, high blood pressure, blood vessel problems, diabetes, Parkinson disease, thyroid problems, mood or mental disorders, depression, asthma, or an irregular heartbeat

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

• Alpha-blockers (eg, prazosin), beta-blockers (eg, propanolol), droxidopa, ergot alkaloids (eg, ergotamine), or phenothiazines (eg, chlorpromazine) because the risk of high or low blood pressure and fast or slow heartbeat may be increased


• Bromocriptine, furazolidone, linezolid, or tricyclic antidepressants (eg, amitriptyline) because the risk of side effects, such as headache, high temperature, and high blood pressure, may be increased


• Antihistamines (eg, diphenhydramine), catechol-O-methyltransferase (COMT) inhibitors (eg, entacapone), digoxin, diuretics (eg, furosemide, hydrochlorothiazide), levothyroxine, monoamine oxidase inhibitors (MAOIs) (eg, phenelzine), or medicines for irregular heartbeat (eg, quinidine) because they may increase the risk of Adrenaclick Auto-Injector's side effects


• Guanethidine because its effectiveness may be decreased by Adrenaclick Auto-Injector

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

Use Adrenaclick Auto-Injector as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• An extra patient leaflet is available with Adrenaclick Auto-Injector. Talk to your pharmacist if you have questions about this information.


• Adrenaclick Auto-Injector may be given as an injection at your doctor's office, hospital, or clinic. If you will be using Adrenaclick Auto-Injector at home, a health care provider will teach you how to use it. Be sure you understand how to use Adrenaclick Auto-Injector. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.


• Check Adrenaclick Auto-Injector regularly. Replace the injector unit if it contains particles, is discolored (pink or brown), or is cracked or damaged in any way.


• Inject Adrenaclick Auto-Injector only into the outer thigh. Do not inject into the buttocks or into a vein.


• Immediately after use, go to the nearest hospital emergency room. You may need further medical attention. Tell the doctor or health care provider that you have received an injection of epinephrine. Show the thigh where the injection was given to the doctor. Give your used auto-injector to the doctor for inspection and proper disposal.


• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.


• Adrenaclick Auto-Injector is usually given as a one-time dose in an emergency situation. If you are unable to use Adrenaclick Auto-Injector, seek medical attention immediately.


• If you miss a dose of Adrenaclick Auto-Injector, contact your doctor right away.

Ask your health care provider any questions you may have about how to use Adrenaclick Auto-Injector.

Important safety information:

• Never put your thumb, fingers, or hand over the tip of the auto-injector. Do NOT remove the cap until ready to use.


• Only inject Adrenaclick Auto-Injector into the outer thigh. Never inject Adrenaclick Auto-Injector into hands, fingers, feet, or toes. Doing so may cause a loss of blood flow and result in tissue damage to these areas. If you accidentally inject Adrenaclick Auto-Injector into any of these areas, seek immediate emergency medical attention.


• It may be helpful to train others how to give Adrenaclick Auto-Injector in case you are unable to give it to yourself during a reaction.


• Diabetes patients - Adrenaclick Auto-Injector may raise your blood sugar. High blood sugar may make you feel confused, drowsy, or thirsty. It can also make you flush, breathe faster, or have a fruit-like breath odor. If these symptoms occur, tell your doctor right away.


• Patients with Parkinson disease may notice a temporary worsening of symptoms (eg, uncontrolled muscle movements). If these symptoms persist, contact your doctor.


• Use Adrenaclick Auto-Injector with caution in the ELDERLY; they may be more sensitive to its effects.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Adrenaclick Auto-Injector while you are pregnant. It is not known if Adrenaclick Auto-Injector is found in breast milk. If you are or will be breast-feeding while you use Adrenaclick Auto-Injector, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Adrenaclick Auto-Injector:

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

Anxiety; difficulty sleeping; dizziness; fearfulness; headache; nausea; nervousness; paleness; sweating; tremors; vomiting; weakness.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; fast or irregular heartbeat; wheezing.

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: Adrenaclick side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include chest pain; extreme paleness or coldness of the skin; fast or irregular heartbeat; one-sided weakness; severe headache or dizziness; trouble breathing.

Proper storage of Adrenaclick Auto-Injector:

Store Adrenaclick Auto-Injector at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store in the carrying case provided. Do not refrigerate or freeze. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Adrenaclick Auto-Injector out of the reach of children and away from pets.

General information:

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


• Adrenaclick Auto-Injector 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 Adrenaclick Auto-Injector. 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 Adrenaclick resources

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

Compare Adrenaclick with other medications

• Adams-Stokes Syndrome
• Allergic Reactions
• Asthma, acute
• Asystole
• AV Heart Block
• COPD, Acute
• Electromechanical Dissociation
• Shock

Adrenaclick

epinephrine

Dosage Form: injection, auto-injector
Adrenaclick™

(epinephrine injection, USP) auto-injector

Available as      0.15 mg     0.3 mg

each unit delivers 0.15 mg or 0.3 mg of epinephrine

PRESCRIBING INFORMATION

Adrenaclick Description

Adrenaclick™ auto-injector contains 1.1 mL epinephrine injection, USP (1 mg/mL), from which one dose of either 0.15 mg (0.15 mL) or 0.3 mg (0.3 mL) each is available for use by injection. The dose is administered by autoinjection after the patient prepares and fires Adrenaclick™ as directed. The remaining volume is not available for use and should be discarded. See PATIENT DIRECTIONS FOR USE on the accompanying Patient Information Leaflet.

This single, available dose of epinephrine injection, USP contains either 0.15 mg or 0.3 mg l-epinephrine, sodium chloride, chlorobutanol and sodium bisulfite, all sealed under nitrogen.

Epinephrine is a sympathomimetic catecholamine. Its naturally occurring l-isomer, which is twenty times as active as the d-isomer, is obtained in pure form by separation from the synthetically produced racemate.

Chemically, epinephrine is 1-(3,4-dihydroxyphenyl)-2-(methylamino)ethanol with the following structure:

Epinephrine deteriorates rapidly on exposure to air or light, turning pink from oxidation to adrenochrome and brown from the formation of melanin. Epinephrine solutions that show evidence of discoloration should be discarded.

Adrenaclick contains no latex.

Adrenaclick - Clinical Pharmacology

Epinephrine is the drug of choice for the emergency treatment of severe allergic reactions (Type I) to allergens, such as those present in certain insect venoms, foods, or drugs. It can also be used in the treatment of anaphylaxis of unknown cause (idiopathic anaphylaxis) or exercise-induced anaphylaxis. Epinephrine, when given intramuscularly or subcutaneously, has a rapid onset and short duration of action. Epinephrine acts on both alpha and beta adrenergic receptors. Through its action on alpha adrenergic receptors, epinephrine lessens the vasodilation and increased vascular permeability that occurs during an anaphylactic reaction and can lead to loss of intravascular fluid volume and hypotension. Through its action on beta adrenergic receptors, epinephrine causes bronchial smooth muscle relaxation that helps alleviate bronchospasm, wheezing, and dyspnea that may occur during anaphylaxis. Epinephrine also helps alleviate pruritus, urticaria, and angioedema, and may be effective in relieving gastrointestinal and genitourinary symptoms of anaphylaxis because of its relaxer effects on the smooth muscle of the stomach, intestine, uterus and urinary bladder.

Indications and Usage for Adrenaclick

Adrenaclick (epinephrine injection, USP) is indicated in the emergency treatment of severe allergic reactions (Type I) including anaphylaxis to stinging insects (e.g. order Hymenoptera, which includes bees, wasps, hornets, yellow jackets and fire ants), and biting insects (e.g. triatoma, mosquitos), allergen immunotherapy, foods, drugs, diagnostic testing substances (e.g. radiocontrast media), and other allergens, as well as anaphylaxis to unknown substances (idiopathic anaphylaxis) or exercise-induced anaphylaxis. Adrenaclick is intended for immediate administration in patients with a history of anaphylactic reactions. Selection of the appropriate dosage strength is determined according to patient body weight (See DOSAGE AND ADMINISTRATION section).

Such reactions may occur within minutes after exposure and consist of flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, wheezing, dyspnea due to laryngeal spasm, pruritus, rashes, urticaria, or angioedema. Adrenaclick is designed as emergency supportive therapy only and is not a replacement or substitute for immediate medical care.

Contraindications

There are no absolute contraindications to the use of epinephrine in a life-threatening allergic reaction.

Warnings

Adrenaclick should only be injected into the anterolateral aspect of the thigh. Accidental injection into the hands or feet may result in loss of blood flow to the affected area and should be avoided. DO NOT INJECT INTO BUTTOCK. If there is an accidental injection into these areas, advise the patient to inform the healthcare provider of the accidental injection when he/she goes to the nearest emergency room for further treatment of anaphylaxis.

Avoid possible inadvertent intravascular administration. Large doses or accidental intravenous injection of epinephrine may result in cerebral hemorrhage due to a sharp rise in blood pressure. DO NOT INJECT INTRAVENOUSLY. Rapidly acting vasodilators can counteract the marked pressor effects of epinephrine if there is such inadvertent administration.

Epinephrine is the preferred treatment for serious allergic reactions or other emergency situations even though this product contains sodium bisulfite, a sulfite that may, in other products, cause allergic-type reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations, even if the patient is sulfite-sensitive.

Epinephrine should be administered with caution to patients with cardiac arrhythmias, coronary artery or organic heart disease, or hypertension. In patients with coronary insufficiency or ischemic heart disease, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias. It should be recognized that the presence of these conditions is not a contraindication to epinephrine administration in an acute, life-threatening situation.

Epinephrine is light sensitive and should be stored in the carrying-case provided. Store at room temperature (20°-25°C/68°-77°F) with excursions permitted to 15°-30°C (59°-86°F). Do not refrigerate; protect from freezing. Patients should periodically check the solution in Adrenaclick for any discoloration and/or precipitates. If the solution is discolored or contains a precipitate, the patient should replace their Adrenaclick.

Precautions

(1) General

Adrenaclick is not intended as a substitute for immediate medical care. In conjunction with the administration of epinephrine, the patient should seek appropriate medical care. More than two sequential doses of epinephrine should only be administered under direct medical supervision.

Epinephrine is essential for the treatment of anaphylaxis. Patients with a history of severe allergic reactions should be instructed about the circumstances under which epinephrine should be used (See INDICATIONS AND USAGE Section). It should be determined that the patient is at risk of future anaphylaxis, since there are some concerns in specific patients with epinephrine administration. (a) Epinephrine should be used with caution in patients with cardiac arrhythmias, coronary artery or organic heart disease, hypertension, or in patients who are on medications that may sensitize the heart to arrhythmias, e.g., digitalis, diuretics, or anti-arrhythmics. In such patients, epinephrine may precipitate or aggravate angina pectoris as well as produce ventricular arrhythmias. (b) The effects of epinephrine may be potentiated by tricyclic antidepressants and monoamine oxidase inhibitors. (c) Some patients may be at greater risk of developing adverse reactions after epinephrine administration. These include patients with hyperthyroidism, cardiovascular disease, hypertension, diabetes, and elderly individuals, and pregnant women. It must be noted that, despite these concerns, epinephrine is essential for the treatment of anaphylaxis. Therefore, patients with these conditions, or any other person who might be in a position to administer epinephrine to a patient with these conditions experiencing anaphylaxis, should be instructed about the circumstances under which epinephrine should be used.

(2) Information for Patients

Complete patient information, including dosage, directions for proper administration, and precautions, can be found inside each Adrenaclick package within the Patient Information Leaflet.

Epinephrine may produce symptoms and signs that include an increase in pulse rate, the sensation of a more forceful heartbeat, palpitations, a throbbing headache, pallor, feelings of overstimulation, anxiety, weakness, shakiness, dizziness, or nausea. These signs and symptoms usually subside rapidly, especially with rest, quiet, and recumbency. Patients with hypertension or hyperthyroidism may develop more severe or persistent effects, and patients with coronary artery disease could experience angina. Patients with diabetes may develop increased blood glucose levels following epinephrine administration. Patients with Parkinson's disease may notice a temporary worsening of symptoms.

(3) Drug Interactions

Patients who receive epinephrine while concomitantly taking cardiac glycosides or diuretics should be observed carefully for the development of cardiac arrhythmias.

The effects of epinephrine may be potentiated by tricyclic antidepressants, monoamine oxidase inhibitors, sodium levothyroxine, and certain antihistamines, notably chlorpheniramine, tripelennamine, and diphenhydramine.

The cardiostimulating and bronchodilating effects of epinephrine are antagonized by beta-adrenergic blocking drugs, such as propranolol. The vasoconstricting and hypertensive efffects are antagonized by alpha-adrenergic blocking drugs, such as phentolamine. Ergot alkaloids and phenothiazines may also reverse the pressor effects of epinephrine.

(4) Carcinogenesis, Mutagenesis, Impairment of Fertility

There are no data from either animal or human studies regarding the carcinogenicity or mutagenicity of epinephrine, and no studies have been conducted to determine its potential for the impairment of fertility. This should not prevent the use of epinephrine under the conditions noted under INDICATIONS AND USAGE section.

(5) Pregnancy

Pregnancy Category C

Epinephrine has been shown to have developmental effects in rabbits at a subcutaneous dose of 1.2 mg/kg (approximately 30 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis), in mice at a subcutaneous dose of 1 mg/kg (approximately 7 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis), and in hamsters at a subcutaneous dose of 0.5 mg/kg (approximately 5 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). These effects were not seen in mice at a subcutaneous dose of 0.5 mg/kg (approximately 3 times the maximum recommended daily subcutaneous or intramuscular dose on a mg/m2 basis). Although there are no adequate and well-controlled studies in pregnant women, epinephrine crosses the placenta and could lead to fetal anoxia, spontaneous abortion or both. Therefore, epinephrine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Adverse Reactions

Adverse reactions to epinephrine include transient, moderate anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; nausea and vomiting; headache, and/or respiratory difficulties. These symptoms occur in some persons receiving therapeutic doses of epinephrine, but are more likely to occur in patients with hypertension or hyperthyroidism. Large doses of epinephrine can cause acute hypertension. Arrhythmias, including fatal ventricular fibrillation, have been reported, particularly in patients with underlying cardiac disease or those receiving certain drugs [see (3) Drug Interactions]. Rapid rises in blood pressure have produced cerebral hemorrhage, particularly in elderly patients with cardiovascular disease. Angina may occur in patients with coronary artery disease. The potential for epinephrine to produce these types of adverse reactions does not contraindicate its use in an acute, life-threatening allergic reaction.

Overdosage

Epinephrine is rapidly inactivated in the body, and treatment following overdose with epinephrine is primarily supportive. If necessary, pressor effects may be counteracted by rapidly acting vasodilators or alpha-adrenergic blocking drugs. If prolonged hypotension follows such measures, it may be necessary to administer another pressor drug.

Overdosage of epinephrine may produce extremely elevated arterial pressure, which may result in cerebrovascular hemorrhage, particularly in elderly patients.

If an epinephrine overdose induces pulmonary edema that interferes with respiration, treatment consists of a rapidly acting alpha-adrenergic blocking drug and/or respiratory support.

Epinephrine overdosage can also cause transient bradycardia followed by tachycardia, and these may be accompanied by potentially fatal cardiac arrhythmias. Premature ventricular contractions may appear within one minute after injection and may be followed by multifocal ventricular tachycardia (prefibrillation rhythm). Subsidence of the ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular block. Treatment of arrhythmias consists of administration of a beta-adrenergic blocking drug such as propranolol.

Overdosage sometimes results in extreme pallor and coldness of the skin, metabolic acidosis, and kidney failure. Suitable corrective measures must be taken in such situations.

Adrenaclick Dosage and Administration

The physician who prescribes Adrenaclick™ should review this Prescribing Information insert in detail with the patient. This review should include the proper use of Adrenaclick to ensure that subcutaneous or intramuscular injections are given into the anterolateral aspect of the thigh, through clothing if necessary. The accompanying Patient Information Leaflet and Wrap Label should also be reviewed with the patient.

Adrenaclick is capable of delivering one dose of either 0.15 mg or 0.3 mg (0.15 mL or 0.3 mL of epinephrine). This dose is available for auto-injection by the patient.

Selection of the appropriate Adrenaclick dosage strength is determined according to patient body weight.

Adrenaclick 0.15 mg	For use by patients who weigh 15 - 30 kilograms (approximately 33 - 66 pounds)
Adrenaclick 0.3 mg	For use by patients who weigh 30 kilograms (approximately 66 pounds) or greater

The usual dose of epinephrine for allergic emergencies in patients who weigh 30 kilograms or greater is 0.3 mg (0.3 mL of epinephrine).

Since the doses of epinephrine delivered from Adrenaclick are fixed, the physician should consider other forms of injectable epinephrine if doses lower than those available from Adrenaclick are felt to be necessary. The prescribing physician should carefully assess each patient to determine the most appropriate dose of epinephrine, recognizing the life-threatening nature of the reactions for which this drug is being prescribed.

Patients should be instructed to periodically visually inspect the epinephrine solution for particulate matter and discoloration. If the solution contains particulate matter or develops a pinkish color or becomes darker than slightly yellow, the patient should immediately contact their physician for a replacement, since these changes indicate that the effectiveness of the drug product may be decreased.

How is Adrenaclick Supplied

Adrenaclick is a patient (or caregiver) actuated product that contains 1.1 mL of epinephrine injection, USP (1 mg/mL), of which one dose can be delivered by auto-injection. THE REMAINING VOLUME THAT IS LEFT AFTER THIS FIXED DOSE CANNOT BE FURTHER ADMINISTERED AND SHOULD BE DISCARDED WITH THE DEVICE AS OUTLINED IN THE PATIENT INFORMATION LEAFLET.

Adrenaclick 0.15 mg is available in a single unit carton, NDC 59630-803-01, containing one Adrenaclick 0.15 mg auto-injector and in a Two-Pack, NDC 59630-803-02, containing two Adrenaclick 0.15 mg auto-injectors.

Adrenaclick 0.3 mg is available in a single unit carton, NDC 59630-804-01, containing one Adrenaclick 0.3 mg auto-injector and in a Two-Pack, NDC 59630-804-02, containing two Adrenaclick 0.3 mg auto-injectors.

PROTECT FROM LIGHT. STORE AT ROOM TEMPERATURE, 20°-25°C (68°-77°F) WITH EXCURSIONS PERMITTED TO 15°-30°C (59°-86°F). PROTECT FROM FREEZING. DO NOT REFRIGERATE.

Rx only.

Manufactured for and Distributed by:

Sciele Pharma, Inc.,

A SHIONOGI COMPANY

Atlanta, GA 30328

©2009 Sciele Pharma, Inc., Atlanta, GA. All rights reserved. This product may be covered by some or all of the following patents, patent applications and foreign equivalents thereof: U.S. Patent No. 5,665,071 and other pending U.S. Patent applications.

Printed in USA

Revised October, 2009

For inquiries call 1-888-894-6528

Adrenaclick™

(epinephrine injection, USP) auto-injector

Available as 0.15 mg 0.3 mg

Patient Information

The patient, and caregiver, if possible, should read this information carefully before using Adrenaclick™ (a-dren-a-click). You must know how to use Adrenaclick before you have an emergency. This information contains additional details beyond the quick-reference instructions on the Adrenaclick label. This information does not replace talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about Adrenaclick?

Use Adrenaclick and go to your doctor or emergency room right away for more medical treatment.

• Epinephrine, the active ingredient in Adrenaclick helps treat life-threatening allergic reactions.


• Make sure to tell your doctor about all your medical conditions and allergies.


• Always get medical treatment right away after using Adrenaclick.

Since you cannot predict when a life-threatening allergic reaction will occur, carry Adrenaclick with you at all times.

Look at the medicine in your Adrenaclick regularly. If it looks cloudy (has particles in it), is discolored, or if the expiration date has passed, the Adrenaclick should be replaced.

After administration, liquid will remain in the auto-injector that can't be used and should be discarded with the auto-injector as outlined in this Patient Information Leaflet.

What is Adrenaclick?

Adrenaclick is an emergency injection ("shot") of epinephrine. It is a medicine used for life-threatening allergic reactions such as severe swelling, breathing problems, or loss of blood pressure. Allergic reactions can be caused by stinging and biting insects (bugs), allergy injections, food, medicines, exercise, or unknown causes.

Life-threatening allergic reactions may show up as closing of your breathing airways, wheezing, sneezing, hoarseness, hives, itching, swelling, skin redness, fast heartbeat, weak pulse, feeling very anxious, confusion, stomach pain, losing control of urine or bowel movements (incontinence), faintness, or "passing out" (unconsciousness).

• Adrenaclick 0.15mg is for patients who weigh 33-66 pounds (15-30 kg).


• Adrenaclick 0.3mg is for patients who weigh 66 pounds (30 kg) or greater.


• Use of Adrenaclick must be followed by emergency medical care.


• Each Adrenaclick unit contains a single dose of epinephrine.

Who should not use Adrenaclick?

There are no absolute contraindications to the use of Adrenaclick in a life-threatening allergic reaction. People with certain medical conditions have a higher chance of getting serious side effects from Adrenaclick.

Tell your doctor about all your medical conditions, but especially if you:

• have heart disease or high blood pressure


• have diabetes


• have thyroid conditions


• have asthma


• have depression or other mental disease


• have Parkinson's disease


• are pregnant


• are allergic to any of the ingredients in Adrenaclick

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Some medicines may cause serious side effects if taken while you use Adrenaclick. Some medicines may affect how Adrenaclick works, or Adrenaclick may affect how your other medicines work. Diabetic patients may need to adjust the dose of their diabetes medicines or insulin after using Adrenaclick.

How should I use Adrenaclick?

• Do NOT remove the gray caps until you are ready to use.


• Never put thumb, fingers, or hand over the red tip. The needle comes out of the red tip. Accidental injection into hand or feet may result in the loss of blood flow to these areas. If this happens, go immediately to the nearest emergency room.


• Hold Adrenaclick in the thigh while slowly counting to 10 to make sure all medicine is delivered.


• Inject Adrenaclick only into the middle of the outer side of your thigh (upper leg).


• Additional video instructions on the use of Adrenaclick are available at www.Adrenaclick.com.

What should I avoid while using Adrenaclick?

• Avoid injecting Adrenaclick into your buttock or any other part of your body, other than the middle of the outer side of your thigh (upper leg).


• Avoid injecting Adrenaclick into a vein.

What are the possible side effects of Adrenaclick?

Too much epinephrine (Adrenaclick) can cause dangerously high blood pressure, stroke, or death.

If you take certain medicines, you may develop serious life-threatening side effects from the epinephrine in Adrenaclick. Be sure to tell your doctor about all the medicines you take, especially medicines for asthma.

Patients with certain medical conditions, or who take certain medicines, may get more side effects from Adrenaclick, or the side effects may last longer. This includes patients who take certain types of medicines for asthma, allergies, depression, hyperthyroidism, high blood pressure, and heart disease. Patients with heart disease may feel chest pain (angina). Patients with mental disease or Parkinson's disease may have worsening symptoms of their illness. Adrenaclick (epinephrine) can cause the following reactions. Some reactions can be serious. They usually go away with rest.

Common side effects of Adrenaclick include:

• faster, irregular (wrong) or 'pounding' heartbeat


• throbbing headache


• paleness


• feelings of over excitement, anxiety, or fear


• weakness or shakiness


• dizziness


• nausea and vomiting


• sweating

These are not all the possible side effects of Adrenaclick. For more information, ask your doctor or pharmacist.

How should I store Adrenaclick?

The medicine in Adrenaclick can be damaged by light. Therefore, keep it in the protective carrying case provided. Keep it at room temperature and protect it from freezing. Do not refrigerate.

Keep Adrenaclick with you at all times.

Check your Adrenaclick regularly to be sure:

• it has not expired


• the medicine in Adrenaclick is not cloudy, discolored, or has particles in it.

Replace the Adrenaclick if needed.

General information about the safe and effective use of Adrenaclick.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Adrenaclick for a condition for which it was not prescribed. Do not give Adrenaclick to other people, even if they have the same symptons you have. It may harm them.

This leaflet summarizes the most important information about Adrenaclick. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Adrenaclick that is written for health professionals.

© 2009 Sciele Pharma, Inc., Atlanta, GA. All rights reserved.

This product may be covered by some or all of the following patents, patent applications and foreign equivalents thereof: US Patent No. 5,665,071 and other pending US Patent applications.

Rx only

Manufactured for and Distributed by:

Sciele Pharma, Inc.,

Atlanta, GA 30328 USA

Printed in U.S.A.

51007-03

PATIENT PACKAGE INSERT

Adrenaclick™

(epinephrine injection, USP) auto-injector

Available as 0.15 mg    0.3 mg

Patient Directions for Use

Before Use Make Sure Medicine Is Ready When You Need It

Look at the medicine in the Adrenaclick regularly. If it looks cloudy, is discolored, has particles in it, or if the expiration date has passed, the Adrenaclick should be replaced.

Do NOT remove GRAY caps until you are ready to use the Adrenaclick.

The following instructions should be followed for both Adrenaclick 0.15mg and Adrenaclick 0.3mg. Additional video instructions on the use of Adrenaclick are available at www.Adrenaclick.com.

STEP A

• Pull off GRAY end cap with the [1]; you will now see a RED tip. Never put thumb, finger, or hand over the RED tip.


• Pull off GRAY end cap with [2].

STEP B

• Put the RED tip against the middle of the outer side of your thigh (upper leg) as shown. It can go through clothes.
  
  
  


• Press down hard until the needle enters your thigh (upper leg) through your skin. Hold it in place while slowly counting to 10.


• Remove the Adrenaclick from your thigh.


• Check the RED tip. If the needle is exposed you received the dose. If needle is not visible, repeat Step B.

Get emergency medical help right away.

Call 911

AFTER USE/DISPOSAL

• The remaining liquid that is left after this fixed dose cannot be further administered and should be discarded.
  
  
  


• Put the auto-injector, needle first, into the carrying case.


• Put the light gray case top over the non-needle end of the Adrenaclick unit and close the case.


• Give your used Adrenaclick to a healthcare worker for proper disposal. Do NOT throw away in a regular trash can.

PRINCIPAL DISPLAY PANEL - 0.15 mg Carton

Rx Only

Contains TWO Adrenaclick™ 0.15 mg Auto-Injectors

Two-Pack

NDC 59630-803-02

Adrenaclick™

(epinephrine injection, USP) auto-injector

0.15 mg

For Subcutaneous or

Intramuscular Use Only

For Allergic Emergencies (Anaphylaxis)

Manufactured for and Distributed by:

Sciele Pharma, Inc.

Atlanta, GA 30328 USA

Patient Reminder Program, See Details Inside

PRINCIPAL DISPLAY PANEL - 0.3 mg Carton

Rx Only

Contains TWO Adrenaclick™ 0.3 mg Auto-Injectors

Two-Pack

NDC 59630-804-02

Adrenaclick™

(epinephrine injection, USP) auto-injector

0.3 mg

For Subcutaneous or

Intramuscular Use Only

For Allergic Emergencies (Anaphylaxis)

Manufactured for and Distributed by:

Sciele Pharma, Inc.

Atlanta, GA 30328 USA

Patient Reminder Program, See Details Inside

Adrenaclick  epinephrine  injection

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 59630-803 Route of Administration INTRAMUSCULAR, SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Epinephrine (Epinephrine) Epinephrine 1 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength sodium chloride   chlorobutanol   sodium bisulfite

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 59630-803-01 1 CASE In 1 CARTON contains a CASE 1 1 CARTRIDGE In 1 CASE This package is contained within the CARTON (59630-803-01) and contains a CARTRIDGE 1 0.15 mL In 1 CARTRIDGE This package is contained within a CASE and a CARTON (59630-803-01) 2 59630-803-02 2 CASE In 1 CARTON contains a CASE 2 1 CARTRIDGE In 1 CASE This package is contained within the CARTON (59630-803-02) and contains a CARTRIDGE 2 0.15 mL In 1 CARTRIDGE This package is contained within a CASE and a CARTON (59630-803-02)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA020800	12/15/2009

Adrenaclick  epinephrine  injection

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 59630-804 Route of Administration INTRAMUSCULAR, SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Epinephrine (Epinephrine) Epinephrine 1 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength sodium chloride   chlorobutanol   sodium bisulfite

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 59630-804-01 1 CASE In 1 CARTON contains a CASE 1 1 CARTRIDGE In 1 CASE This package is contained within the CARTON (59630-804-01) and contains a CARTRIDGE 1 0.3 mL In 1 CARTRIDGE This package is contained within a CASE and a CARTON (59630-804-01) 2 59630-804-02 2 CASE In 1 CARTON contains a CASE 2 1 CARTRIDGE In 1 CASE This package is contained within the CARTON (59630-804-02) and contains a CARTRIDGE 2 0.3 mL In 1 CARTRIDGE This package is contained within a CASE and a CARTON (59630-804-02)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA020800	12/15/2009

Labeler - Sciele Pharma, Inc. (802728477)

Establishment
Name	Address	ID/FEI	Operations
Phillips Plastics		037807828	Manufacture

Revised: 12/2009Sciele Pharma, Inc.

More Adrenaclick resources

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

• Adrenaclick Auto-Injector MedFacts Consumer Leaflet (Wolters Kluwer)


• Adrenaclick Concise Consumer Information (Cerner Multum)


• Adrenaclick Advanced Consumer (Micromedex) - Includes Dosage Information


• Asthmahaler Aerosol MedFacts Consumer Leaflet (Wolters Kluwer)


• Epinephrine Professional Patient Advice (Wolters Kluwer)


• Epinephrine Monograph (AHFS DI)


• Epinephrine (Mydriatic) eent Monograph (AHFS DI)

Compare Adrenaclick with other medications

• Adams-Stokes Syndrome
• Allergic Reactions
• Asthma, acute
• Asystole
• AV Heart Block
• COPD, Acute
• Electromechanical Dissociation
• Shock