metformin and pioglitazone

met-FOR-min hye-droe-KLOR-ide, pye-oh-GLI-ta-zone hye-droe-KLOR-ide

Oral route(Tablet)

May cause or worsen congestive heart failure, is not recommended in patients with symptomatic heart failure, and is contraindicated in patients with established NYHA Class III or IV heart failure. Monitor patients for signs and symptoms of heart failure after initiation or dose increases and if heart failure occurs, consider dose reduction or discontinuing metformin/pioglitazone (immediate and extended-release formulations) and manage according to current standards of care .Lactic acidosis is a rare, but serious complication that can occur due to metformin accumulation during treatment with metformin/pioglitazone (immediate and extended-release). Risk factors for lactic acidosis include sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure. Nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress may occur. Laboratory symptoms include low pH, increased anion gap and elevated blood lactate. If lactic acidosis is suspected, metformin hydrochloride/pioglitazone hydrochloride (immediate or extended-release formulations) should be discontinued and the patient hospitalized immediately .

Commonly used brand name(s)

In the U.S.

• Actoplus Met


• Actoplus Met XR

Available Dosage Forms:

• Tablet


• Tablet, Extended Release

Therapeutic Class: Hypoglycemic

Chemical Class: Metformin

Uses For metformin and pioglitazone

Pioglitazone and metformin combination is used to treat a type of diabetes mellitus called type 2 diabetes. It is used together with a proper diet and exercise to help control blood sugar levels.

Pioglitazone helps your body use insulin better. Metformin reduces the absorption of sugar from the stomach, reduces the release of stored sugar from the liver, and helps your body use sugar better.

metformin and pioglitazone is available only with your doctor's prescription.

Before Using metformin and pioglitazone

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 metformin and pioglitazone, the following should be considered:

Allergies

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

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of pioglitazone and metformin combination in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of pioglitazone and metformin combination in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require caution and an adjustment in the dose for patients receiving pioglitazone and metformin combination.

Pregnancy

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

Breast Feeding

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

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking metformin and pioglitazone, 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 metformin and pioglitazone with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Acetrizoic Acid


• Diatrizoate


• Ethiodized Oil


• Iobenzamic Acid


• Iobitridol


• Iocarmic Acid


• Iocetamic Acid


• Iodamide


• Iodipamide


• Iodixanol


• Iodohippuric Acid


• Iodopyracet


• Iodoxamic Acid


• Ioglicic Acid


• Ioglycamic Acid


• Iohexol


• Iomeprol


• Iopamidol


• Iopanoic Acid


• Iopentol


• Iophendylate


• Iopromide


• Iopronic Acid


• Ioseric Acid


• Iosimide


• Iotasul


• Iothalamate


• Iotrolan


• Iotroxic Acid


• Ioversol


• Ioxaglate


• Ioxitalamic Acid


• Ipodate


• Metrizamide


• Metrizoic Acid


• Tyropanoate Sodium

Using metformin and pioglitazone 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.

• Acetazolamide


• Alatrofloxacin


• Balofloxacin


• Cimetidine


• Ciprofloxacin


• Clinafloxacin


• Dichlorphenamide


• Dofetilide


• Enoxacin


• Fleroxacin


• Flumequine


• Gatifloxacin


• Gemifloxacin


• Grepafloxacin


• Levofloxacin


• Lomefloxacin


• Moxifloxacin


• Norfloxacin


• Ofloxacin


• Pefloxacin


• Prulifloxacin


• Rufloxacin


• Sparfloxacin


• Temafloxacin


• Tolvaptan


• Topiramate


• Tosufloxacin


• Trovafloxacin Mesylate


• Zonisamide

Using metformin and pioglitazone 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.

• Acebutolol


• Alprenolol


• Atenolol


• Atorvastatin


• Betaxolol


• Bevantolol


• Bisoprolol


• Bitter Melon


• Bucindolol


• Carteolol


• Carvedilol


• Celiprolol


• Cephalexin


• Clorgyline


• Desogestrel


• Dienogest


• Dilevalol


• Drospirenone


• Enalaprilat


• Enalapril Maleate


• Esmolol


• Estradiol Cypionate


• Estradiol Valerate


• Ethinyl Estradiol


• Ethynodiol Diacetate


• Etonogestrel


• Fenugreek


• Gemfibrozil


• Glucomannan


• Guar Gum


• Iproniazid


• Isocarboxazid


• Ketoconazole


• Labetalol


• Levobunolol


• Levonorgestrel


• Medroxyprogesterone Acetate


• Mepindolol


• Mestranol


• Metipranolol


• Metoprolol


• Moclobemide


• Nadolol


• Nebivolol


• Nialamide


• Norelgestromin


• Norethindrone


• Norgestimate


• Norgestrel


• Oxprenolol


• Pargyline


• Penbutolol


• Phenelzine


• Pindolol


• Procarbazine


• Propranolol


• Psyllium


• Rifampin


• Selegiline


• Sotalol


• Talinolol


• Tertatolol


• Timolol


• Toloxatone


• Topiramate


• Tranylcypromine


• Trospium

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.

Other Medical Problems

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

• Adrenal gland problem (underactive) or


• Congestive heart failure, acute or unstable or


• Dehydration, severe or


• Kidney problems or


• Liver disease or


• Pituitary gland problem (underactive) or


• Poorly nourished condition or


• Sepsis (severe infection) or


• Weakened physical condition—Use with caution. May cause side effects to become worse.

• Anemia (low red blood cells) or


• Diabetic macular edema (swelling of the back of the eye) or


• Edema (fluid retention or swelling) or


• Heart disease or


• Liver disease or


• Vitamin B12 deficiency—Use with caution. May make these conditions worse.

• Bladder cancer, active or


• Diabetic ketoacidosis (ketones in the blood) or


• Heart failure, severe or


• Kidney disease, severe or


• Liver disease, active or


• Metabolic acidosis (acid in the blood) or


• Type I diabetes—Should not be used in patients with these conditions.

• Fever or


• Infection or


• Surgery or


• Trauma—Use with caution. These conditions may cause problems with blood sugar control.

• Fragile bones (especially in women)—Use with caution. metformin and pioglitazone may increase the risk for fractures.

Proper Use of metformin and pioglitazone

Take metformin and pioglitazone only as directed by your doctor. Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered.

Carefully follow the special diet your doctor gave you. This is the most important part of controlling your diabetes and will help the medicine work properly. Also, exercise regularly and test for sugar in your blood or urine as directed.

metformin and pioglitazone should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

metformin and pioglitazone should be taken with meals to help reduce the unwanted stomach effects that may occur during the first few weeks.

Swallow the extended-release tablet whole. Do not crush, break, or chew it.

Part of the extended-release tablet may pass into your stool (bowel movement). This is normal and nothing to worry about.

Dosing

The dose of metformin and pioglitazone 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 metformin and pioglitazone. 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 (extended-release tablets, tablets):
  
  • For type 2 diabetes:
    
    • Adults—At first, pioglitazone 15 to 30 milligrams (mg) plus metformin 500 to 1000 mg per day once or twice daily. Your doctor may adjust your dose as needed. However, the dose is usually not more than pioglitazone 45 mg plus metformin 2550 mg per day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

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

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

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

Precautions While Using metformin and pioglitazone

It is very important that your doctor check your progress at regular visits to make sure that metformin and pioglitazone is working properly. Blood and urine tests may be needed to check for unwanted effects.

Check with your doctor right away if you start having chest pain; shortness of breath; excessive swelling of the hands, wrist, ankles, or feet; or if you are rapidly gaining weight. These may be symptoms of a serious heart problem.

Let your doctor or dentist know you are taking metformin and pioglitazone. Your doctor may advise you to stop taking metformin and pioglitazone before you have major surgery or diagnostic tests, especially tests that use a contrast dye.

Under certain conditions, too much metformin can cause a serious condition called lactic acidosis. The symptoms of lactic acidosis are severe and appear quickly. Lactic acidosis usually occurs when other serious health problems are present, such as a heart attack or kidney failure. The symptoms of lactic acidosis include: abdominal or stomach discomfort; decreased appetite; diarrhea; fast or shallow breathing; a general feeling of discomfort; muscle pain or cramping; and unusual sleepiness, tiredness, or weakness. If you have more than one of these symptoms together, you should get immediate emergency medical help.

Tell your doctor right away if you have any of these symptoms: loss of appetite, nausea, vomiting, stomach pain, unusual tiredness or weakness, weight loss, or yellow eyes or skin. These may be symptoms of a serious liver problem.

Check with your doctor right away if blurred vision, decreased vision, or any other change in vision occurs while you are taking metformin and pioglitazone. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

Certain women may be at an increased risk for pregnancy while taking metformin and pioglitazone. If you had problems ovulating and had irregular periods in the past, metformin and pioglitazone may cause you to ovulate. This could increase your chance of becoming pregnant. If you are a woman of childbearing potential, you should discuss birth control options with your doctor.

metformin and pioglitazone may increase the risk for bone fractures in women. Ask your doctor about ways to keep your bones strong to help prevent fractures.

metformin and pioglitazone may increase your risk for bladder cancer if you take it for more than 12 months. Tell your doctor right away if you have blood in the urine; a frequent, strong, or increased urge to urinate; painful urination; or pain in the back, lower abdomen, or stomach.

It is very important to carefully follow any instructions from your doctor about:

• Alcohol—Drinking alcohol may cause severe low blood sugar. Discuss this with your doctor.


• Other medicines—Do not take other medicines unless they have been discussed with your doctor. This especially includes nonprescription medicines such as aspirin, and medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems.


• Counseling—Other family members need to learn how to prevent side effects or help with side effects if they occur. Also, patients with diabetes may need special counseling about diabetes medicine dosing changes that might occur with lifestyle changes, such as changes in exercise or diet. Counseling on contraception and pregnancy may be needed because of the problems that can occur during pregnancy in patients with diabetes.


• Travel—Keep a recent prescription and your medical history with you. Be prepared for an emergency as you would normally. Make allowances for changing time zones and keep your meal times as close as possible to your usual meal times.


• In case of emergency—There may be a time when you need emergency help for a problem caused by your diabetes. You need to be prepared for these emergencies. It is a good idea to wear a medical identification (ID) bracelet or neck chain at all times. Also, carry an ID card in your wallet or purse that says you have diabetes and that lists all of your medicines.


• Symptoms of fluid retention—Know what to do if you start to retain fluid. Fluid retention may worsen or lead to heart problems.

metformin and pioglitazone can cause hypoglycemia (low blood sugar). Low blood sugar can also occur if you delay or miss a meal or snack, exercise more than usual, drink alcohol, or cannot eat because of nausea or vomiting. The symptoms of low blood sugar must be treated before they lead to unconsciousness (passing out). Different people feel different symptoms of low blood sugar. It is important that you learn which symptoms of low blood sugar you usually have so that you can treat it quickly.

• Symptoms of low blood sugar include anxiety; behavior change similar to being drunk; blurred vision; cold sweats; confusion; cool, pale skin; difficulty with thinking; drowsiness; excessive hunger; fast heartbeat; headache that continues; nausea; nervousness; nightmares; restless sleep; shakiness; slurred speech; or unusual tiredness or weakness.


• If the symptoms of low blood sugar occur, eat glucose tablets or gel, corn syrup, honey, or sugar cubes; or drink fruit juice, non-diet soft drinks, or sugar dissolved in water to relieve the symptoms. Also, check your blood for low blood sugar. Glucagon is used in emergency situations when severe symptoms such as seizures (convulsions) or unconsciousness occur. Have a glucagon kit available, along with a syringe and needle, and know how to use it. Members of your family also should know how to use it.

Hyperglycemia (high blood sugar) may occur if you do not take enough or skip a dose of your medicine, overeat or do not follow your meal plan, have a fever or infection, or do not exercise as much as usual.

• Symptoms of high blood sugar include blurred vision; drowsiness; dry mouth; flushed, dry skin; fruit-like breath odor; increased urination (frequency and amount); ketones in the urine; loss of appetite; stomachache, nausea, or vomiting; tiredness; trouble with breathing (rapid and deep); unconsciousness; or unusual thirst.


• If the symptoms of high blood sugar occur, check your blood sugar level and call your doctor for instructions.

metformin and pioglitazone 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

• Bladder pain


• bloody or cloudy urine


• difficult, burning, or painful urination


• frequent urge to urinate


• lower back or side pain


• swelling of the face, fingers, feet, or lower legs


• weight gain

Less common

• Pain or swelling in the arms or legs without any injury


• pale skin


• troubled breathing with exertion


• unusual bleeding or bruising


• unusual tiredness or weakness

Rare

• Abdominal or stomach discomfort


• anxiety


• blurred vision


• chills


• cold sweats


• coma


• confusion


• cool, pale skin


• decreased appetite


• depression


• diarrhea


• dizziness


• fast heartbeat


• fast, shallow breathing


• general feeling of discomfort


• headache


• increased hunger


• muscle pain or cramping


• nausea


• nervousness


• nightmares


• seizures


• shakiness


• shortness of breath


• sleepiness


• slurred speech

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

• Body aches or pain


• cough


• difficulty with breathing


• ear congestion


• fever, sneezing, or sore throat


• loss of voice


• runny nose


• stuffy nose

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: metformin and pioglitazone side effects (in more detail)

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

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

More metformin and pioglitazone resources

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

Compare metformin and pioglitazone with other medications

• Diabetes, Type 2

testolactone

tes-toe-LAK-tone

Commonly used brand name(s)

In the U.S.

• Teslac

Available Dosage Forms:

• Tablet

Therapeutic Class: Antineoplastic Agent

Pharmacologic Class: Androgen

Uses For testolactone

Testolactone belongs to the general group of medicines called antineoplastics. It is used to treat some cases of breast cancer in females.

Testolactone is available only with your doctor's prescription.

Before Using testolactone

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 testolactone, the following should be considered:

Allergies

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

Geriatric

Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of testolactone in the elderly with use in other age groups.

Pregnancy

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

Breast Feeding

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

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

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

• Heart or kidney disease

Proper Use of testolactone

Use testolactone only as directed by your doctor. Do not use more or less of it, and do not use it more often than your doctor ordered. The exact amount of medicine you need has been carefully worked out. Taking too much may increase the chance of side effects, while taking too little may not improve your condition.

Testolactone sometimes causes nausea and vomiting. However, it may have to be taken for several weeks or months to be effective. Even if you begin to feel ill, do not stop using testolactone without first checking with your doctor. Ask your health care professional for ways to lessen these effects.

If you vomit shortly after taking a dose of testolactone, check with your doctor. You will be told whether to take the dose again or to wait until the next scheduled dose.

Dosing

The dose of testolactone 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 testolactone. 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.

Missed Dose

If you miss a dose of testolactone, 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 testolactone

It is very important that your doctor check your progress at regular visits to make sure that testolactone is working properly and to check for unwanted effects.

testolactone 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 as soon as possible if any of the following side effects occur:

Less common

• Numbness or tingling of fingers, toes, or face

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:

Less common

• Diarrhea


• loss of appetite


• nausea or vomiting


• pain or swelling in feet or lower legs


• swelling or redness of tongue

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: testolactone side effects (in more detail)

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

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

More testolactone resources

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

• testolactone Concise Consumer Information (Cerner Multum)


• Testolactone MedFacts Consumer Leaflet (Wolters Kluwer)


• Teslac Prescribing Information (FDA)

Compare testolactone with other medications

• Breast Cancer, Palliative

Innozide

INNOZIDE 20/12.5 mg Tablets

(enalapril maleate/hydrochlorothiazide)

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may want to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What 'Innozide' is and what it is used for


• 2. Before you take 'Innozide'


• 3. How to take 'Innozide'


• 4. Possible side effects


• 5. How to store 'Innozide'


• 6. Further information

What 'Innozide' is and what it is used for

Innozide contains enalapril maleate and hydrocholorothaizide:

• enalapril belongs to a group of medicines known as ACE inhibitors, which work by widening your blood vessels


• hydrochlorothiazide belongs to a group of medicines known as water tablets (diuretics), which increase the volume of urine you produce.

The effect of these medicines is to lower your blood pressure. 'Innozide' is used to treat high blood pressure (hypertension). Taking both medicines that 'Innozide' contains can increase their effect compared to taking just one.

Before you take 'Innozide'

Do not take 'Innozide' if:

• you have ever had an allergic reaction to 'Innozide', a similar medicine or to any of the ingredients (listed in Section 6). The signs may have been itching, nettle rash, wheezing or swelling of your hands, throat, mouth or eyelids



• you are allergic to a type of medicine called ‘sulphonamides'



• you are in the last 6 months of pregnancy, see section headed 'Pregnancy'.



• you are breast feeding



• you are not passing urine



• you have a condition know as renal artery stenosis (narrowing of the arteries that supply the blood to your kidneys).

Do not take 'Innozide' if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before taking 'Innozide'.

Take special care with 'Innozide'

Check with your doctor or pharmacist before taking your medicine if:

• you have kidney problems, have had a recent kidney transplantation, are a dialysis patient, or are taking water tablets (diuretics)



• you are on a salt restricted diet, or have suffered from excessive vomiting or diarrhoea recently



• you have a heart condition called ‘aortic stenosis', ‘hypertrophic cardiomyopathy' or ‘outflow obstruction'



• you have collagen vascular disease, are taking immunosuppressant therapy (used for the treatment of autoimmune disorders such as rheumatoid arthritis or following transplant surgery)



• you are taking allopurinol, (used for the treatment of gout), or procainamide, (used to treat abnormal heart rhythms). If you develop an infection (symptoms may be high temperature or fever), you should let your doctor know immediately. Your doctor may take a blood sample from time to time to check your white blood cell count



• you have a history of ‘angioedema' while taking other medicines. The signs may have been itching, nettle rash, wheezing or swelling of your hands, throat, mouth or eyelids



• you have diabetes and are taking antidiabetic medicines, including insulin to control your diabetes (you should monitor your blood for low blood glucose levels, especially during the first month of treatment)



• you are taking potassium supplements or potassium containing salt substitutes



• you are taking lithium, used for the treatment of some psychiatric illnesses



• you have been told by your doctor that you have an intolerance to some sugars.



• you think you are pregnant (or might become) pregnant. 'Innozide' is not recommended in early pregnancy and may cause serious harm to your baby after 3 months of pregnancy, see section headed Pregnancy.

If you are about to have any of the following procedures, you should tell your doctor who is treating you that you are taking 'Innozide':

• any surgery or receive anaesthetics (even at the dentist)



• a treatment called LDL apheresis, to remove cholesterol from your blood using a machine



• desensitisation treatment, to reduce the effect of an allergy to bee or wasp stings.

Routine tests

When you first start to take 'Innozide', your doctor will monitor your blood pressure frequently to ensure you have been given the correct dose. In addition, for some patients the doctor may want to do some tests to measure your potassium, sodium, magnesium, creatinine and liver enzyme levels.

Tell you doctor if you have or will take an anti-doping test since this medication can produce a positive result.

Children

Innozide is not recommended for use in children.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription as some drugs may affect each other's action. This includes herbal medicines. Also some other medicines can affect the way 'Innozide' work:

• potassium sparing water tablets (diuretics) such as spironolactone, eplerenone, triamterene or amiloride, potassium supplements, or potassium-containing salt substitutes. 'Innozide' may increase the levels of potassium in your blood leading to high potassium levels. This causes few signs and is usually seen by a test



• water tablets (diuretics) such as thiazides, furosemide, bumetanide



• other medicines that lower blood pressure, such as nitroglycerine, nitrates, and vasodilators



• lithium, used for the treatment of some psychiatric illnesses. 'Innozide' should not be taken with this drug



• barbiturates (sedatives used for sleeplessness or epilepsy)



• tricyclic antidepressants such as amitriptyline, used for depression, antipsychotics such as phenothiazines, used for severe anxiety



• pain killers such as morphine or anaesthetics, because your blood pressure may become too low



• cholestyramine or colestipol (used to help control cholesterol levels)



• medicines used for, stiffness and inflammation associated with painful conditions, particularly those affecting your muscles, bones and joints:
  
  
  • including gold therapy which can lead to flushing of your face, feeling sick (nausea), vomiting and low blood pressure, when taken with 'Innozide', and
  
  
  
  • non-steroidal anti-inflammatory drugs (NSAIDs), for example diflunisal or diclofenac. They may prevent your blood pressure from being well controlled and may increase the level of potassium in your blood
  
  
  



• medicines such as ephedrine, used in some cough and cold remedies, or noradrenaline and adrenaline used for low blood pressure, shock, cardiac failure, asthma or allergies. If used with 'Innozide' these drugs may keep your blood pressure high




• ACTH (to test whether your adrenal glands are working properly)



• Corticosteroids (used to treat certain conditions such as rheumatism, arthritis, allergic conditions, asthma or certain blood disorders)



• Allopurinol (used to treat gout)



• Ciclosporins (immunosuppressive agents used for autoimmune disorders)



• Medicines for the treatment of cancer



• Antacids (used for indigestion relief)



• Procainamide, amiodarone or sotalol (used to treat abnormal heart rhythms)



• Digitalis (used to treat heart rhythm problems)



• Carbenoxalone (used to treat stomach ulcers)



• Excessive use of laxatives



• antidiabetic medicines such as insulin. 'Innozide' may cause your blood sugar levels to drop even further if you take it with antidiabetics.

If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking 'Innozide'.

Taking 'Innozide' with food and drink

'Innozide' can be taken with or without food. However, if you drink alcohol while taking 'Innozide', it may cause your blood pressure to drop too much and you may experience dizziness, light-headedness or faintness. You should keep your alcohol intake to a minimum.

Pregnancy and breast-feeding

You must tell your doctor if you think that you are (or might become) pregnant. Usually, your doctor will advise you to take another medicine instead of 'Innozide', as 'Innozide' is not recommended in early pregnancy, and may cause serious harm to your baby if it is used after 3 months of pregnancy.

Appropriate antihypertensive drug must usually replace 'Innozide' before starting a pregnancy. The product should not be used during the 2^nd and 3^rd trimester of pregnancy.

Your doctor will normally advise you to stop taking 'Innozide' as soon as you know you are pregnant. If you become pregnant during therapy with 'Innozide', please inform and see your physician without delay.

Tell your doctor if you are breast feeding. Small amounts of enalapril are found in breast milk. While taking 'Innozide', breast feeding is not recommended.

Driving and using machines

Certain side effects, such as dizziness and weariness, have been reported with 'Innozide' which may affect some patients' ability to drive or operate machinery.

Important information about some of the ingredients of 'Innozide'

'Innozide' contains lactose, which is a type of sugar. It is important to tell your doctor if you suffer from lactose intolerance.

How to take 'Innozide'

Taking this medicine

• You should take this medicine by mouth.


• Always take 'Innozide' exactly as your doctor told you.


• The number of tablets you take each day will depend upon your condition.

You should check with your doctor or pharmacist if you are not sure.

REMEMBER, this medicine is for you. Do not share it with anyone else. It may not suit them.

The usual dose for many people is:

• One tablet each day.


• Your doctor may increase the dose to two tablets each day.


• Do not take more or less than your doctor has prescribed.

If you take more 'Innozide' than you should

Contact your doctor immediately if you think you have taken more of your tablets than you should. The most common signs and symptoms of an overdose are a fall in blood pressure and stupor (a state of almost complete lack of consciousness). Other symptoms may include dizziness or light-headedness due to a fall in blood pressure, forceful and rapid heartbeat, rapid pulse, anxiety, cough, kidney failure, and rapid breathing.

If you forget to take 'Innozide'

• If you forget to take a tablet, skip the missed dose.


• Take the next dose as usual.


• Do not take a double dose to make up for a forgotten dose.

If you stop taking 'Innozide'

Do not stop taking your medicine, unless your doctor has told you to. If you do your blood pressure may increase. If your blood pressure becomes too high it may affect your heart and kidneys.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Innozide Side Effects

Like all medicines 'Innozide' can cause side effects, although not everybody gets them. The following side effects may happen with this medicine:

It is vital to stop taking 'Innozide' and seek medical attention immediately if you begin to have the following symptom:

• allergic reaction- you may get an itch, short of breath or wheezy and develop swelling of your hands, mouth, throat, face or eyes.

Stop taking 'Innozide' immediately and see your doctor if you have any of the following side effects

• severe dizziness, light-headedness, especially at the start of treatment or when your dose is increased or when you stand up.

Other possible side effects

Very common (affects more than 1 in 10 people)

• blurred vision, cough, feeling sick (nausea), weakness

Common (affects less than 1 in 10 people)

• headache, depression, low blood pressure, fainting


• chest pain, heart rhythm changes, angina, fast heart beat, shortness of breath


• diarrhoea, pain around your stomach area (abdomen), changes in taste, fluid retention (oedema), feeling tired


• rash, hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported.


• increased blood potassium level, increases in serum creatinine (both are usually detected by a test); increased levels of cholesterol, increased levels of triglycerides, increased levels of uric acid in the blood.

Uncommon (affects less than 1 in100 people)

• anaemia, anxiety, a sense of heightened awareness or a shaky feeling (caused by low blood sugar), confusion, feeling sleepy, difficulty sleeping, feeling nervous, tingling or numbness, feeling like you are spinning (vertigo)



• low blood pressure (which may make you feel dizzy when you stand up), uneven heart beats, heart attack or stroke (in high risk patients)



• runny nose, sore throat and hoarseness, difficulty breathing or asthma



• a blockage in your intestine (ileus), pancreatitis, being sick, indigestion, constipation, not feeling like eating properly (anorexia), stomach irritation, dry mouth, flatulence, gout



• burning, aching pain with an empty feeling and hunger, particularly when the stomach is empty (caused by a peptic ulcer), excessive sweating, itching, hives (urticaria), hair loss, protein in your urine (usually detected by a test)



• impotence, decreased libido, muscle cramps, flushing, ringing in your ears, feeling lethargic, high temperature



• increases in blood urea and decreases in blood sodium levels (usually detected by a test).

Rare (affects less than 1 in 1,000 people)

• strange dreams, sleeping problems


• decreases in your white blood cells, red blood cells, platelets, bone marrow depression (all are usually detected by tests)


• swollen glands, autoimmune diseases, low blood flow to your fingers and toes causing redness and pain (Raynaud's), fluid on your lungs, runny or sore nose


• eosinophilic pneumonia (signs may be cough, high temperature and difficulty breathing)


• pain, swelling or ulcers in your mouth, infection or pain and swelling of your tongue, kidney problems such as lower back pain and reduction in the volume of urine you pass


• liver failure or hepatitis, this may cause yellowing of your skin (jaundice)


• excessive redness of your skin, blisters, skin peeling off in sheets


• development of breasts in men


• increased liver enzymes or blood ‘bilirubin' (usually detected by a blood test), decrease in blood glucose

Very rare (affects less than 1 in 10,000 people)

• intestinal ‘angioedema'. Signs may include stomach pain, feeling sick and vomiting, elevated calcium level in blood

Others (it is unknown how many people may be affected)

A complex side effect has also been reported which may include some or all of the following signs:

• fever, inflammation of your blood vessels, pain and inflammation of muscles or joints


• blood disorders affecting the components of your blood (usually detected by a blood test)


• rash, hypersensitivity to sunlight and other effects on your skin.

If any of these side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store 'Innozide'

Keep your tablets out of the reach and sight of children.

Do not store above 25°C. Store in the original container.

Do not put them into another container as they might get mixed up.

Do not take them past the expiry date which is clearly marked on the pack.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What 'Innozide' contains:

The active ingredients in 'Innozide' Tablets are enalapril maleate and hydrochlorothiazide .Each tablet contains 20 mg enalapril maleate and 12.5 mg hydrochlorothiazide.

The other ingredients in 'Innozide' are Sodium hydrogen carbonate E500, lactose, maize starch, yellow ferric oxide E172, pregelatinised starch, magnesium stearate E572.

What Innozide looks like and the contents of the pack

'Innozide' is available as round, fluted, yellow tablets with ‘MSD 718' on one side and scored on the other.

'Innozide' Tablets are available in blister packs containing 28 tablets.

Marketing Authorisation Holder and Manufacturer

The marketing Authorisation Holder is

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

UK

The product is manufactured by

Merck Manufacturing Division

Merck Sharp & Dohme Limited

Shotton Lane

Cramlington

Northumberland

NE23 3JU

UK

This leaflet was last approved in May 2008

This leaflet gives you some of the most important patient information about 'Innozide'. If you have any questions after you have read it, ask your doctor or pharmacist, who will give you further information.

denotes registered trademark of

Merck & Co., Inc.

Whitehouse Station

NJ

USA

© Merck Sharp & Dohme Limited 2008. All rights reserved.

(logo) MSD

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

UK

PIL.CRN.07.UK.2768

MetroLotion

Generic Name: metronidazole topical (MET roe NYE da zole)

Brand Names: MetroCream, MetroGel, MetroLotion, Noritate

What is MetroLotion (metronidazole topical)?

Metronidazole is an antibiotic that fights bacteria in the body.

Metronidazole topical (for the skin) is used to treat skin lesions caused by rosacea.

Metronidazole topical may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about MetroLotion (metronidazole topical)?

Do not use metronidazole topical if you have ever had an allergic reaction to it.

Before using metronidazole topical, tell your doctor if you are allergic to any drugs, or if you have a blood cell disorder such as anemia or decreased white blood cells.

Tell your doctor about all other medications you use, especially a blood thinner such as warfarin (Coumadin).

Metronidazole topical is for use only on the skin. Avoid getting this medication in your eyes. If this does happen, rinse thoroughly with cool water. Do not use topical metronidazole in the vagina. Call your doctor if you have severe stinging or burning when you apply metronidazole topical. Use this medication for the entire length of time prescribed by your doctor. Your symptoms may get better before any infection is completely treated. Do not use metronidazole topical to treat any other skin infection your doctor has not prescribed it for.

What should I discuss with my doctor before using MetroLotion (metronidazole topical)?

Do not use metronidazole topical if you have ever had an allergic reaction to it.

Before using metronidazole topical, tell your doctor if you are allergic to any drugs, or if you have a blood cell disorder such as anemia or decreased white blood cells.

If you have any of these conditions, you may need a dose adjustment or special tests to safely use metronidazole topical.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Metronidazole passes into breast milk and could harm a nursing infant. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I use MetroLotion (metronidazole topical)?

Use this medication exactly as it was prescribed for you. Do not use the medication in larger amounts, or use it for longer than recommended by your doctor.

Wash and gently dry your skin before applying metronidazole topical

Apply the medication in a thin layer and rub in completely. You may apply cosmetics after using metronidazole topical.

Use this medication for the entire length of time prescribed by your doctor. Your symptoms may get better before any infection is completely treated. Do not use metronidazole topical to treat any other skin infection your doctor has not prescribed it for. Store metronidazole topical at room temperature away from moisture or heat.

What happens if I miss a dose?

Use the medication as soon as you remember. If it is almost time for the next dose, skip the missed dose and use the medicine at the next regularly scheduled time. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

An overdose of metronidazole applied to the skin is not expected to produce life-threatening symptoms.

What should I avoid while using MetroLotion (metronidazole topical)?

Metronidazole topical is for use only on the skin. Avoid getting this medication in your eyes. If this does happen, rinse thoroughly with cool water. Do not use topical metronidazole in the vagina.

MetroLotion (metronidazole topical) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Call your doctor if you have severe stinging or burning when you apply metronidazole topical.

Less serious side effects may include:

• 
  

  mild burning or stinging when the medication is applied;

  
  


• 
  

  numbness or tingly feeling in your hands or feet;

  
  


• 
  

  cough, stuffy nose, sore throat, cold symptoms;

  
  


• 
  

  vaginal itching or discharge;

  
  


• 
  

  headache;

  
  


• 
  

  dry, scaly, or itchy skin;

  
  


• 
  

  nausea; or

  
  


• 
  

  metallic taste in your mouth.

  
  

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect MetroLotion (metronidazole topical)?

Tell your doctor about all other medications you use, especially a blood thinner such as warfarin (Coumadin).

It is not likely that other drugs you take orally or inject will have an effect on topically applied metronidazole. But many drugs can interact with each other. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

More MetroLotion resources

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

• MetroLotion Cream MedFacts Consumer Leaflet (Wolters Kluwer)


• MetroCream Prescribing Information (FDA)


• MetroGel Prescribing Information (FDA)


• Metrocream


• Metrogel-Vaginal Advanced Consumer (Micromedex) - Includes Dosage Information


• Metrolotion


• Metrolotion Topical Advanced Consumer (Micromedex) - Includes Dosage Information


• Noritate Prescribing Information (FDA)


• Rozex Emulsion MedFacts Consumer Leaflet (Wolters Kluwer)


• Vandazole Prescribing Information (FDA)


• Vitazol Prescribing Information (FDA)

Compare MetroLotion with other medications

• Perioral Dermatitis
• Rosacea

Where can I get more information?

• Your pharmacist can provide more information about metronidazole topical.

See also: MetroLotion side effects (in more detail)

Pradaxa 75 mg hard capsules

1. Name Of The Medicinal Product

2. Qualitative And Quantitative Composition

Each hard capsule contains 75 mg of dabigatran etexilate (as mesilate).

Excipients: Each hard capsule contains 2 micrograms sunset yellow (E110).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Hard capsule

Imprinted capsules with light blue, opaque cap and cream-coloured, opaque body of size 2 filled with yellowish pellets. The cap is imprinted with the Boehringer Ingelheim company symbol, the body with “R75”.

4. Clinical Particulars

4.1 Therapeutic Indications

Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery.

4.2 Posology And Method Of Administration

Posology

Prevention of Venous Thromboembolism (VTE)

Patients following elective knee replacement surgery

The recommended dose of Pradaxa is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be initiated orally within 1–4 hours of completed surgery with a single capsule and continuing with 2 capsules once daily thereafter for a total of 10 days.

Patients following elective hip replacement surgery

The recommended dose of Pradaxa is 220 mg once daily taken as 2 capsules of 110 mg. Treatment should be initiated orally within 1–4 hours of completed surgery with a single capsule and continuing with 2 capsules once daily thereafter for a total of 28-35 days.

For both surgeries, if haemostasis is not secured, initiation of treatment should be delayed. If treatment is not started on the day of surgery then treatment should be initiated with 2 capsules once daily.

Renal impairment

Treatment with Pradaxa in patients with severe renal impairment (creatinine clearance (CrCL) < 30 ml/min) is contraindicated (see section 4.3).

In patients with moderate renal impairment (CrCL 30-50 ml/min), there is limited clinical experience. These patients should be treated with caution. The recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (see sections 4.4 and 5.1).

Concomitant use of Pradaxa with strong P-glycoprotein (P-gp) inhibitors, i.e. amiodarone, quinidine or verapamil

Dosing should be reduced to 150 mg taken once daily as 2 capsules of 75 mg Pradaxa in patients who receive concomitantly dabigatran etexilate and amiodarone, quinidine or verapamil (see sections 4.4 and 4.5). In this situation Pradaxa and these medicinal products should be taken at the same time.

In patients with moderate renal impairment and concomitantly treated with dabigatran etexilate and verapamil, a dose reduction of Pradaxa to 75 mg daily should be considered (see sections 4.4 and 4.5).

Elderly

In elderly patients (> 75 years) there is limited clinical experience. These patients should be treated with caution. The recommended dose is 150 mg taken once daily as 2 capsules of 75 mg (see sections 4.4 and 5.1).

Hepatic impairment

Patients with elevated liver enzymes > 2 upper limit of normal (ULN) were excluded in clinical trials investigating the VTE prevention following elective hip or knee replacement surgery. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population (see sections 4.4 and 5.2).

Weight

There is very limited clinical experience in patients with a body weight < 50 kg or > 110 kg at the recommended posology. Given the available clinical and kinetic data no adjustment is necessary (see section 5.2), but close clinical surveillance is recommended (see section 4.4).

Gender

Given the available clinical and kinetic data, no dose adjustment is necessary (see section 5.2).

Switching

Pradaxa treatment to parenteral anticoagulant

It is recommended to wait 24 hours after the last dose before switching from Pradaxa to a parenteral anticoagulant (see section 4.5).

Parenteral anticoagulants to Pradaxa

Dabigatran etexilate should be given 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment (e.g. intravenous Unfractionated Heparin (UFH)) (see section 4.5).

Paediatric population

There is no relevant use of Pradaxa in the paediatric population in the indication: primary prevention of venous thromboembolic events in patients who have undergone elective total hip replacement surgery or total knee replacement surgery.

Pradaxa is not recommended for use in patients below 18 years due to lack of data on safety and efficacy.

Missed dose

It is recommended to continue with the remaining daily doses of dabigatran etexilate at the same time of the next day.

No double dose should be taken to make up for missed individual doses.

Method of administration

Pradaxa should be swallowed as a whole with water, with or without food.

Patients should be instructed not to open the capsule as this may increase the risk of bleeding (see sections 5.2 and 6.6).

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients

• Patients with severe renal impairment (CrCL < 30 ml/min)

• Active clinically significant bleeding

• Organic lesion at risk of bleeding

• Spontaneous or pharmacological impairment of haemostasis

• Hepatic impairment or liver disease expected to have any impact on survival

• Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole and tacrolimus (see section 4.5)

4.4 Special Warnings And Precautions For Use

Hepatic impairment

Patients with elevated liver enzymes > 2 ULN were excluded in controlled clinical trials investigating the VTE prevention following elective hip or knee replacement surgery. No treatment experience is available for this subpopulation of patients, and therefore the use of Pradaxa is not recommended in this population.

Haemorrhagic risk

As with all anticoagulants, dabigatran etexilate should be used with caution in conditions with an increased risk of bleeding. Bleeding can occur at any site during therapy with dabigatran. An unexplained fall in haemoglobin and/or haematocrit or blood pressure should lead to a search for a bleeding site.

Factors, such as decreased renal function (30-50 ml/min CrCL), age

Use of acetylsalicylic acid (ASA), clopidogrel or non steroidal antiinflammatory drug (NSAID), as well as the presence of esophagitis, gastritis or gastroesophageal reflux requiring proton pump inhibitors (PPI) or histamine 2 (H₂)-blocker treatment increase the risk of GI bleeding. The administration of a PPI can be considered to prevent GI bleeding.

Close clinical surveillance (looking for signs of bleeding or anaemia) is recommended throughout the treatment period, especially if risk factors are combined (see section 5.1).

Table 1 summarises factors which may increase the haemorrhagic risk.

Pharmacodynamic and kinetic factors	Age
Factors increasing dabigatran plasma levels	Major: • Moderate renal impairment (30-50 ml/min CrCL) • P-gp inhibitor co-medication Minor: Low body weight (< 50 kg)
Pharmacodynamic interactions	• ASA • NSAID • Clopidogrel
Diseases / procedures with special haemorrhagic risks	• Congenital or acquired coagulation disorders • Thrombocytopenia or functional platelet defects • Active ulcerative GI disease • Recent GI bleeding • Recent biopsy or major trauma • Recent ICH • Brain, spinal or ophthalmic surgery • Bacterial endocarditis

The measurement of dabigatran related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors.

The activated partial thromboplastin time (aPTT) test is widely available and provides an approximate indication of the anticoagulation intensity achieved with dabigatran. In patients who are bleeding or at risk of bleeding, the aPTT test may be useful to assist in determining an excess of anticoagulant activity. However, the aPTT test has limited sensitivity and is not suitable for precise quantification of anticoagulant effect, especially at high plasma concentrations of dabigatran. High aPTT values should be interpreted with caution.

If required, more sensitive quantitative tests such as calibrated diluted Thrombin Time (dTT) should be performed (see section 5.1).

Patients who develop acute renal failure must discontinue Pradaxa (see section 4.3).

Limited data is available in patients < 50 kg (see section 5.2).

When severe bleedings occur treatment must be discontinued and the source of bleeding investigated (see section 4.9).

Agents that may enhance the risk of haemorrhage should not be administered concomitantly or should be administered with caution with Pradaxa (see section 4.5).

Interaction with P- gp inducers

Concomitant administration of P-gp inducers (such as rifampicin, St. John`s wort (Hypericum perforatum), carbamazepine, or phenytoin) is expected to result in decreased dabigatran plasma concentrations, and should be avoided (see sections 4.5 and 5.2).

Surgery and interventions

Patients on dabigatran etexilate who undergo surgery or invasive procedures are at increased risk for bleeding. Therefore surgical interventions may require the temporary discontinuation of dabigatran etexilate.

Caution should be exercised when treatment is temporarily discontinued for interventions and anticoagulant monitoring is warranted. Clearance of dabigatran in patients with renal insufficiency may take longer (see section 5.2). This should be considered in advance of any procedures. In such cases a coagulation test (see sections 4.4 and 5.1) may help to determine whether haemostasis is still impaired.

Preoperative phase

Table 2 summarizes discontinuation rules before invasive or surgical procedures.

Renal function (CrCL in ml/min)	Estimated half-life (hours)	Stop dabigatran before elective surgery
High risk of bleeding or major surgery	Standard risk
	~ 13	2 days before	24 hours before
	~ 15	2-3 days before	1-2 days before
	~ 18	4 days before	2-3 days before (> 48 hours)

If an acute intervention is required, dabigatran etexilate should be temporarily discontinued. A surgery / intervention should be delayed if possible until at least 12 hours after the last dose. If surgery cannot be delayed the risk of bleeding may be increased. This risk of bleeding should be weighed against the urgency of intervention.

Spinal anaesthesia/epidural anaesthesia/lumbar puncture

Procedures such as spinal anaesthesia may require complete haemostatic function.

The risk of spinal or epidural haematoma may be increased in cases of traumatic or repeated puncture and by the prolonged use of epidural catheters. After removal of a catheter, an interval of at least 2 hours should elapse before the administration of the first dose of dabigatran etexilate. These patients require frequent observation for neurological signs and symptoms of spinal or epidural haematoma.

Post-surgical patients with an increased risk for bleeding

Patients at risk for bleeding or patients at risk of overexposure, notably patients with moderate renal impairment (CrCL 30-50 ml/min), should be treated with caution (see sections 4.4 and 5.1). Resume treatment after complete haemostasis is achieved.

Patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events

There are limited efficacy and safety data for dabigatran available in these patients and therefore they should be treated with caution.

Hip fracture surgery

There is no data on the use of Pradaxa in patients undergoing hip fracture surgery. Therefore treatment is not recommended.

Colorants

Pradaxa hard capsules contain the colorant sunset yellow (E110), which may cause allergic reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Anticoagulants and antiplatelet aggregation agents

The following treatments have not been studied and may increase the risk of bleeding when used concomitantly with Pradaxa: UFH, low molecular weight heparins (LMWH), and heparin derivatives (fondaparinux, desirudin), thrombolytic agents, GPIIb/IIIa receptor antagonists, ticlopidine, prasugrel, dextran, sulfinpyrazone, rivaroxaban, and vitamin K antagonists (see section 4.4).

UFH can be administered at doses necessary to maintain a patent central venous or arterial catheter (see sections 4.2 and 4.4).

Clopidogrel: In a phase I study in young healthy male volunteers, the concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. In addition, dabigatran AUC_max,ss and the coagulation measures for dabigatran effect or the inhibition of platelet aggregation as measure of clopidogrel effect remained essentially unchanged comparing combined treatment and the respective mono-treatments. With a loading dose of 300 mg or 600 mg clopidogrel, dabigatran AUC_max,ss were increased by about 30-40 % (see section 4.4).

ASA: The effect of concomitant administration of dabigatran etexilate and ASA on the risk of bleeds was studied in patients with atrial fibrillation in a phase II study in which a randomized ASA co-administration was applied. Based on logistic regression analysis, co-administration of ASA and 150 mg dabigatran etexilate twice daily may increase the risk for any bleeding from 12 % to 18 % and 24 % with 81 mg and 325 mg ASA, respectively (see section 4.4).

NSAIDs: NSAIDs given for short-term perioperative analgesia have been shown not to be associated with increased bleeding risk when given in conjunction with dabigatran etexilate. With chronic use NSAIDs increased the risk of bleeding by approximately 50 % on both dabigatran and warfarin. Therefore, due to the risk of haemorrhage, notably with NSAIDs with elimination half-lives > 12 hours, close observation for signs of bleeding is recommended (see section 4.4).

LMWH: The concomitant use of LMWHs, such as enoxaparin and dabigatran etexilate has not been specifically investigated. After switching from 3-day treatment of once daily 40 mg enoxaparin s.c., 24 hours after the last dose of enoxaparin the exposure to dabigatran was slightly lower than that after administration of dabigatran etexilate (single dose of 220 mg) alone. A higher anti-FXa/FIIa activity was observed after dabigatran etexilate administration with enoxaparin pre-treatment compared to that after treatment with dabigatran etexilate alone. This is considered to be due to the carry-over effect of enoxaparin treatment, and regarded as not clinically relevant. Other dabigatran related anti-coagulation tests were not changed significantly by the pre-treatment of enoxaparin.

Interactions linked to dabigatran etexilate and dabigatran metabolic profile

Dabigatran etexilate and dabigatran are not metabolised by the cytochrome P450 system and have no in vitro effects on human cytochrome P450 enzymes. Therefore, related medicinal product interactions are not expected with dabigatran.

Transporter interactions

P-gp inhibitors

Dabigatran etexilate is a substrate for the efflux transporter P-gp. Concomitant administration of strong P-gp inhibitors (such as amiodarone, verapamil, quinidine, ketoconazole and clarithromycin) is expected to result in increased dabigatran plasma concentrations.

If not otherwise specifically described, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with strong P-gp inhibitors. A coagulation test helps to identify patients with an increased bleeding risk due to increased dabigatran exposure (see sections 4.2, 4.4 and 5.1).

Systemic ketoconazole, cyclosporine, itraconazole and tacrolimus are contraindicated (see section 4.3). Caution should be exercised with other strong P-gp inhibitors (e.g. amiodarone, quinidine or verapamil) (see sections 4.2 and 4.4).

Ketoconazole: Ketoconazole increased total dabigatran AUC_0- and C_max values by 138 % and 135 %, respectively, after a single dose of 400 mg , and 153 % and 149 %, respectively, after multiple dosing of 400 mg ketoconazole once daily. The time to peak, terminal half-life and mean residence time were not affected by ketoconazole (see section 4.4). Concomitant treatment with systemic ketoconazole is contraindicated (see section 4.3).

Amiodarone: When Pradaxa was co-administered with a single oral dose of 600 mg amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran AUC and C_max were increased by about 60 % and 50 %, respectively. The mechanism of the interaction has not been completely clarified. In view of the long half-life of amiodarone the potential for drug interaction may exist for weeks after discontinuation of amiodarone (see sections 4.2 and 4.4).

Patients treated for prevention of VTEs after hip or knee replacement surgery, dosing should be reduced to 150 mg taken once daily as 2 capsules of 75 mg Pradaxa if they receive concomitantly dabigatran etexilate and amiodarone (see section 4.2). Close clinical surveillance is recommended when dabigatran etexilate is combined with amiodarone and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

Quinidine: Quinidine was given as 200 mg dose every 2nd hour up to a total dose of 1000 mg. Dabigatran etexilate was given twice daily over 3 consecutive days, on the 3^rd day either with or without quinidine. Dabigatran AUC_max,ss were increased on average by 53 % and 56 %, respectively with concomitant quinidine (see sections 4.2 and 4.4).

Patients treated for prevention of VTEs after hip or knee replacement surgery, dosing should be reduced to 150 mg taken once daily as 2 capsules of 75 mg Pradaxa if they receive concomitantly dabigatran etexilate and quinidine (see section 4.2). Close clinical surveillance is recommended when dabigatran etexilate is combined with quinidine and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

Verapamil: When dabigatran etexilate (150 mg) was co-administered with oral verapamil, the C_max and AUC of dabigatran were increased but magnitude of this change differs depending on timing of administration and formulation of verapamil (see sections 4.2 and 4.4).

The greatest elevation of dabigatran exposure was observed with the first dose of an immediate release formulation of verapamil administered one hour prior to dabigatran etexilate intake (increase of C_max by about 180 % and AUC by about 150 %). The effect was progressively decreased with administration of an extended release formulation (increased of C_max by about 90 % and AUC by about 70 %) or administration of multiple doses of verapamil (increased of C_max by about 60 % and AUC by about 50 %).

Therefore, close clinical surveillance (looking for signs of bleeding or anaemia) is required when dabigatran is co-administered with verapamil. In patients with normal renal function after the hip or knee replacement surgery, receiving dabigatran etexilate and verapamil concomitantly, the dose of Pradaxa should be reduced to 150 mg taken once daily as 2 capsules of 75 mg . In patients with moderate renal impairment and concomitantly treated with dabigatran etexilate and verapamil, a dose reduction of Pradaxa to 75 mg daily should be considered (see sections 4.2 and 4.4). Close clinical surveillance is recommended when dabigatran etexilate is combined with verapamil and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

There was no meaningful interaction observed when verapamil was given 2 hours after dabigatran etexilate (increased of C_max by about 10 % and AUC by about 20 %). This is explained by completed dabigatran absorption after 2 hours (see section 4.4).

Clarithromycin: When clarithromycin (500 mg twice daily) was administered together with dabigatran etexilate in healthy volunteers, increase of AUC by about 19 % and C_max by about 15 % was observed without any clinical safety concern. However, in patients receiving dabigatran, a clinically relevant interaction cannot be excluded when combined with clarithromycin. Therefore, a close monitoring should be exercised when dabigatran etexilate is combined with clarithromycin and particularly in the occurrence of bleeding, notably in patients having a mild to moderate renal impairment.

The following potent P-gp inhibitors have not been clinically studied but from in vitro results a similar effect as with ketoconazole may be expected:

Itraconazole, tacrolimus and cyclosporine, which are contra-indicated (see section 4.3).

Neither clinical nor in vitro test results are available for posaconazole which is not recommended for concomitant treatment with Pradaxa. Inadequate clinical data are available regarding the co-administration of Pradaxa and dronedarone, and their co-administration is not recommended (see section 4.4).

P-gp inducers

Concomitant administration of a P-gp inducer (such as rifampicin, St. John´s wort (Hypericum perforatum), carbamazepine, or phenytoin) is expected to result in decreased dabigatran concentrations and should be avoided (see sections 4.4 and 5.2).

Rifampicin: Pre-dosing of the probe inducer rifampicin at a dose of 600 mg once daily for 7 days decreased total dabigatran peak and total exposure by 65.5 and 67 %, respectively. The inducing effect was diminished resulting in dabigatran exposure close to the reference by day 7 after cessation of rifampicin treatment. No further increase in bioavailability was observed after another 7 days.

Other drugs affecting P-gp

Protease inhibitors including ritonavir and its combinations with other protease inhibitors affect P-gp (either as inhibitor or as inducer). They have not been studied and are therefore not recommended for concomitant treatment with Pradaxa.

P-gp substrate

Digoxin: In a study performed with 24 healthy subjects, when Pradaxa was co-administered with digoxin, no changes on digoxin and no clinical relevant changes on dabigatran exposure have been observed.

Gastric pH

Pantoprazole: When Pradaxa was co-administered with pantoprazole, a decrease in the dabigatran area under the plasma concentration-time curve of approximately 30 % was observed. Pantoprazole and other proton-pump inhibitors (PPI) were co-administered with Pradaxa in clinical trials, and concomitant PPI treatment did not appear to reduce the efficacy of Pradaxa.

Ranitidine: Ranitidine administration together with Pradaxa had no clinically relevant effect on the extent of absorption of dabigatran.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of Pradaxa in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Women of child-bearing potential should avoid pregnancy during treatment with dabigatran etexilate. Pradaxa should not be used during pregnancy unless clearly necessary.

Breast-feeding

There are no clinical data of the effect of dabigatran on infants during breast feeding.

Breast-feeding should be discontinued during treatment with Pradaxa.

Fertility

No data human available.

In animal studies an effect on female fertility was observed in the form of a decrease in implantations and an increase in pre-implantation loss at 70 mg/kg (representing a 5-fold higher plasma exposure level compared to patients). No other effects on female fertility were observed. There was no influence on male fertility. At doses that were toxic to the mothers (representing a 5- to 10-fold higher plasma exposure level to patients), a decrease in foetal body weight and embryofoetal viability along with an increase in foetal variations were observed in rats and rabbits. In the pre- and post-natal study, an increase in foetal mortality was observed at doses that were toxic to the dams (a dose corresponding to a plasma exposure level 4-fold higher than observed in patients).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

A total of 10.084 patients were treated in 4 actively controlled VTE prevention trials with at least one dose of the medicinal product. Of these 5419 were treated with 150 mg or 220 mg daily of Pradaxa, while 389 received doses less than 150 mg daily and 1168 received doses in excess of 220 mg daily.

The most commonly reported adverse reactions are bleedings occurring in total in approximately 14 % of patients; the frequency of major bleeds (including wound site bleedings) is less than 2 %.

Although rare in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.

Adverse reactions

Table 3 shows the adverse reactions ranked under headings of SOC and frequency using the following convention: very common (

SOC / Preferred Term.	Dabigatran etexilate 150 mg	Dabigatran etexilate 220 mg
Number of patients treated	2737	2682
Blood and lymphatic system disorders
Anaemia	Common	Common
Thrombocytopenia	Uncommon	Uncommon
Haemoglobin decreased	Common	Common
Haematocrit decreased	Uncommon	Uncommon
Immune system disorder
Drug hypersensitivity	Uncommon	Uncommon
Pruritus	Uncommon	Uncommon
Rash	Uncommon	Uncommon
Urticaria	Rare	Rare
Bronchospasm	Not known	Not known
Nervous system disorders
Intracranial haemorrhage	Uncommon	Uncommon
Vascular disorders
Haematoma	Uncommon	Uncommon
Haemorrhage	Uncommon	Uncommon
Wound haemorrhage	Uncommon	Uncommon
Respiratory, thoracic and mediastinal disorders
Epistaxis	Common	Common
Gastrointestinal disorders
Gastrointestinal haemorrhage	Common	Common
Rectal haemorrhage	Uncommon	Uncommon
Haemorrhoidal haemorrhage	Uncommon	Uncommon
Abdominal pain	Common	Common
Diarrhoea	Common	Common
Dyspepsia	Common	Common
Nausea	Common	Common
Gastrointestinal ulcer	Uncommon	Uncommon
Gastroesophagitis	Uncommon	Uncommon
Gastroesophageal reflux disease	Uncommon	Uncommon
Vomiting	Uncommon	Uncommon
Dysphagia	Uncommon	Uncommon
Hepatobiliary disorders
Alanine aminotransferase increased	Uncommon	Uncommon
Aspartate aminotransferase increased	Uncommon	Uncommon
Hepatic function abnormal/ Liver function Test abnormal	Uncommon	Uncommon
Hepatic enzyme increased	Uncommon	Uncommon
Hyperbilirubinaemia	Uncommon	Uncommon
Skin and subcutaneous tissue disorder
Skin haemorrhage	Uncommon	Uncommon
Musculoskeletal and connective tissue and bone disorders
Haemarthrosis	Uncommon	Uncommon
Renal and urinary disorders
Haematuria	Uncommon	Uncommon
General disorders and administration site conditions
Injection site haemorrhage	Rare	Rare
Catheter site haemorrhage	Rare	Rare
Bloody discharge	Uncommon	Uncommon
Injury, poisoning and procedural complications
Incision site haemorrhage	Rare	Rare
Traumatic haemorrhage	Uncommon	Uncommon
Post procedural haematoma	Uncommon	Uncommon
Post procedural haemorrhage	Uncommon	Uncommon
Anaemia postoperative	Uncommon	Uncommon
Post procedural discharge	Uncommon	Uncommon
Wound secretion	Uncommon	Uncommon
Surgical and medical procedures
Wound drainage	Uncommon	Uncommon
Post procedural drainage	Rare	Rare

Bleeding

The table 4 shows the number (%) of patients