Lovenox

Generic Name: enoxaparin (Subcutaneous route, Injection route)

ee-nox-a-PAR-in

Injection route(Solution)

Epidural or spinal hematomas, which may result in long-term or permanent paralysis, may occur in patients who are anticoagulated with low molecular weight heparins or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. Factors that can increase the risk of developing these hematomas include: use of indwelling epidural catheters, concomitant use of drugs affecting hemostasis such as NSAIDs, platelet inhibitors, or other anticoagulants, or history of traumatic or repeated epidural or spinal puncture, spinal deformity, or spinal surgery. Monitor patients frequently for neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider risks/benefits before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis .

Commonly used brand name(s)

In the U.S.

• Lovenox

Available Dosage Forms:

• Solution


• Injectable

Therapeutic Class: Anticoagulant

Pharmacologic Class: Low Molecular Weight Heparin

Uses For Lovenox

Enoxaparin is used to prevent deep venous thrombosis, a condition in which harmful blood clots form in the blood vessels of the legs. These blood clots can travel to the lungs and can become lodged in the blood vessels of the lungs, causing a condition called pulmonary embolism. This medicine is used for several days after hip or knee replacement surgery, and in some cases following abdominal surgery, while you are unable to walk. It is during this time that blood clots are most likely to form. Enoxaparin is also used if you are unable to get out of bed because of a serious illness. In addition, enoxaparin is used to prevent blood clots from forming in the arteries of the heart during certain types of chest pain and heart attacks.

Enoxaparin is used together with warfarin to treat acute deep vein thrombosis with or without pulmonary embolism. It is also used to treat certain types of acute heart attacks.

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

Before Using Lovenox

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

Allergies

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

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of enoxaparin 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 enoxaparin in the elderly. However, elderly patients are more likely to have bleeding problems and age-related kidney disease, which may require an adjustment in the dose for patients receiving enoxaparin, especially those who weigh less than 45 kilograms (99 lb).

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

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

Interactions with Medicines

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

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

• Abciximab


• Aceclofenac


• Acemetacin


• Acenocoumarol


• Alclofenac


• Alteplase, Recombinant


• Anistreplase


• Antithrombin, Recombinant


• Apazone


• Argatroban


• Benoxaprofen


• Bivalirudin


• Bromfenac


• Bufexamac


• Carprofen


• Citalopram


• Clometacin


• Clonixin


• Clopidogrel


• Dabigatran Etexilate


• Dalteparin


• Danaparoid


• Dexketoprofen


• Diclofenac


• Diflunisal


• Dipyridamole


• Dipyrone


• Drotrecogin Alfa


• Droxicam


• Eptifibatide


• Escitalopram


• Etodolac


• Etofenamate


• Felbinac


• Fenbufen


• Fenoprofen


• Fentiazac


• Floctafenine


• Flufenamic Acid


• Fluoxetine


• Flurbiprofen


• Fluvoxamine


• Fondaparinux


• Heparin


• Ibuprofen


• Indomethacin


• Indoprofen


• Isoxicam


• Ketoprofen


• Ketorolac


• Lepirudin


• Lornoxicam


• Meclofenamate


• Mefenamic Acid


• Meloxicam


• Nabumetone


• Naproxen


• Niflumic Acid


• Nimesulide


• Oxaprozin


• Oxyphenbutazone


• Paroxetine


• Phenindione


• Phenprocoumon


• Phenylbutazone


• Pirazolac


• Piroxicam


• Pirprofen


• Propyphenazone


• Proquazone


• Reteplase, Recombinant


• Rivaroxaban


• Sertraline


• Streptokinase


• Sulindac


• Suprofen


• Tenecteplase


• Tenidap


• Tenoxicam


• Tiaprofenic Acid


• Ticlopidine


• Tinzaparin


• Tirofiban


• Tolmetin


• Urokinase


• Warfarin


• Zomepirac

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

• Aspirin


• Benorilate


• Choline Magnesium Trisalicylate


• Mesalamine


• Olsalazine


• Salicylamide


• Salicylic Acid


• Salsalate


• Sodium Salicylate


• Sodium Thiosalicylate


• Trolamine Salicylate

Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

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

• Blood disease or bleeding problems or


• Blood vessel problems or


• Catheter insertion in the spine or


• Diabetic retinopathy (eye problem) or


• Heart infection or


• Heart valves, prosthetic or


• Hypertension (high blood pressure), uncontrolled or


• Septic shock or


• Stomach or intestinal ulcer or bleeding, active or


• Stroke, recent or history of or


• Surgery (e.g., eye, brain, or spine), recent or history of or


• Thrombocytopenia, heparin-induced, or history of or


• Threatened miscarriage


• Weight of less than 99 pounds in women or 126 pounds in men—Use with caution. The risk of bleeding may be increased.

• Major bleeding, active or


• Thrombocytopenia (low platelet count in the blood)—Should not use in patients with these conditions.

• Kidney disease—Use with caution. The effects may be increased because of slower removal from the body.

Proper Use of Lovenox

A nurse or other trained health professional will usually give you this medicine in the hospital. This medicine is given as a shot under your skin.

If you are using enoxaparin at home, your doctor will teach you how to inject yourself with the medicine. Be sure to follow the directions carefully. Check with your doctor if you have any problems using the medicine.

You will be shown the body areas where this shot can be given. Use a different body area each time you give yourself a shot. Keep track of where you give each shot to make sure you rotate body areas. This will help prevent skin problems from the injections.

If the medicine in the prefilled syringe has changed color, or if you see particles in it, do not use it.

Dosing

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

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

• For injection dosage form:
  
  • For prevention of blood clots after unstable angina (chest pain) or non–Q-wave myocardial infarction (a type of heart attack):
    
    • Adults—Dose is based on body weight and must be determined by your doctor. The dose is usually 1 milligram (mg) per kilogram (kg) of body weight injected under the skin every twelve hours for 2 to 8 days. Aspirin 100 to 325 mg orally once a day may also be given. However, the dose is 1 mg per kg once a day if you have a poorly performing kidney.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For prevention of deep venous thrombosis (abdominal surgery):
    
    • Adults—40 milligrams (mg) injected under the skin once a day for 7 to 10 days. The first dose should be given 2 hours before the surgery. However, the dose is 30 mg once a day if you have a poorly performing kidney.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For prevention of deep venous thrombosis (hip or knee replacement surgery):
    
    • Adults—30 milligrams (mg) injected under the skin every twelve hours for 7 to 10 days. Alternatively, for hip replacement surgery, the dose may be 40 mg injected under the skin once a day for three weeks. The dose is 30 mg once a day if you have a poorly performing kidney.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For prevention of deep venous thrombosis (in patients with a serious illness who cannot get out of bed):
    
    • Adults—40 milligrams (mg) injected under the skin once a day for 6 to 11 days. The dose is 30 mg once a day if you have a poorly performing kidney.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For treatment of acute deep vein thrombosis with or without pulmonary embolism:
    
    • Adults—Dose is based on body weight and must be determined by your doctor. However, the dose is usually 1 milligram (mg) per kilogram (kg) of body weight every 12 hours injected under the skin for 7 days. The dose is 1 mg per kg once a day if you have a poorly performing kidney.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For treatment of certain type of acute heart attack
    
    • Adults—Dose is based on body weight and must be determined by your doctor. However, the dose is usually 30 milligrams (mg) injected into your vein and 1 milligram (mg) per kilogram (kg) of body weight injected under the skin followed by 1 mg per kg every 12 hours injected under the skin for 8 days. Aspirin 75 to 325 mg orally once a day may also be given.
    
    
    • Older adults—Dose is based on body weight and must be determined by your doctor. However, the starting dose is 0.75 milligram (mg) per kilogram (kg) of body weight injected under the skin every 12 hours for 8 days. Aspirin 75 to 325 mg orally once a day may also be given.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

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

Storage

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

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

If you were given a bottle of medicine to use with your syringes, you must use the medicine within 28 days after the first shot. Throw away the unused medicine in the bottle after 28 days.

Throw away used needles in a hard, closed container that the needles cannot poke through. Keep this container away from children and pets.

Precautions While Using Lovenox

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood tests will be needed to check for unwanted effects. Be sure to keep all appointments.

You may bleed or bruise more easily while you are using this medicine. Stay away from rough sports or other situations where you could be bruised, cut , or injured. Be careful when using sharp objects, including razors and fingernail clippers. Avoid nose picking and forceful nose blowing.

Make sure any doctor or dentist who treats you knows that you are using this medicine. You may need to stop using this medicine several days before having surgery or medical tests.

Enoxaparin may cause bleeding problems. This risk is higher if you have a catheter in your back for pain medicine or anesthesia (sometimes called an "epidural"), or if you have kidney problems. The risk of bleeding increases if your kidney problems get worse. Check with your doctor right away if you have any unusual bleeding or bruising; black, tarry stools; bleeding gums; blood in the urine or stools; tingling, numbness, or weakness of the lower legs; or pinpoint red spots on your skin.

This medicine may increase your chance of bleeding or bruising. Check with your doctor right away if you notice any unusual bleeding or bruising; black, tarry stools; blood in the urine or stools; or pinpoint red spots on your skin. Avoid picking your nose. If you need to blow your nose, blow it gently.

Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.

Make sure your doctor knows if you have received enoxaparin or heparin before and had a reaction called thrombocytopenia (low platelet count in the blood), or if new blood clots formed while you were receiving the medicine.

Tell your doctor if you have recently given birth, fallen or suffered a blow to the body or head, or had medical or dental surgery. These events may increase the risk of serious bleeding while you are taking enoxaparin.

Lovenox® multiple-dose vials contain benzyl alcohol as a preservative. Tell your doctor right away if you are pregnant or have had an allergic reaction to benzyl alcohol.

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

Lovenox 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

• Bleeding gums


• coughing up blood


• difficulty with breathing or swallowing


• dizziness


• headache


• increased menstrual flow or vaginal bleeding


• nosebleeds


• paralysis


• prolonged bleeding from cuts


• red or black, tarry stools


• red or dark brown urine


• shortness of breath

Less common

• Bruising


• chest discomfort


• collection of blood under the skin


• confusion


• continuing bleeding or oozing from the nose and/or mouth, or surgical wound


• convulsions (seizures)


• fever


• irritability


• lightheadedness


• lower back pain


• pain or burning while urinating


• swelling of the hands or feet


• tightness in the chest


• uncontrolled bleeding at the site of injection


• vomiting of blood or material that looks like coffee grounds


• wheezing

Rare

• Back pain


• burning, pricking, tickling, or tingling sensation


• chest pain


• chills


• cough


• decreased urine output


• dilated neck veins


• dizziness or lightheadedness when getting up suddenly from a lying or sitting position


• extreme fatigue


• fainting


• fast or irregular heartbeat


• general feeling of discomfort or illness


• irregular breathing


• leg weakness


• problems with bowel or bladder function


• skin rash or hives


• sneezing


• sore throat


• sudden fainting


• swelling of the face, fingers, feet, genitals, mouth, or tongue


• thickening of the bronchial secretions


• troubled breathing


• weight gain

Incidence not known

• Abdominal or stomach pain


• deep, dark purple bruise


• hives or welts


• irregular heartbeat


• itching, pain, redness, or swelling


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


• nausea or vomiting


• nervousness


• numbness or tingling in the hands, feet, or lips


• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue


• redness of the skin


• skin rash


• unusual tiredness or weakness


• weakness or heaviness of the legs

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


• irritation, pain, or redness at the place of injection

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: Lovenox side effects (in more detail)

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More Lovenox resources

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

• Lovenox Prescribing Information (FDA)


• Lovenox Monograph (AHFS DI)


• Lovenox MedFacts Consumer Leaflet (Wolters Kluwer)


• Lovenox Consumer Overview

Compare Lovenox with other medications

• Acute Coronary Syndrome
• Angina
• Deep Vein Thrombosis
• Deep Vein Thrombosis Prophylaxis after Abdominal Surgery
• Deep Vein Thrombosis Prophylaxis after Hip Replacement Surgery
• Deep Vein Thrombosis Prophylaxis after Knee Replacement Surgery
• Deep Vein Thrombosis, Prophylaxis
• Heart Attack

aspirin powder

Dosage Form: powder
aspirin powder

INDICATIONS

INDICATIONS: For use as an aid in reducing fever and for mild analgesia.

DIRECTIONS

DIRECTIONS: Administer orally.

Cattle, Horses: 5 - 60 gm

Calves, Foals:  0.5 - 6.0 gm

Sheep, Swine:  1 - 3 gm

Poultry:  0.15% Level in Ration

CONTENTS

CONTENTS: Each Pound Contains: Acetylsalicylic Acid (Aspirin) ... 1 lb.

STORE IN A COOL DRY PLACE NOT ABOVE 30Oc (86OF)


TAKE TIME OBSERVE LABEL DIRECTIONS

ASPIRIN  aspirin  powder

Product Information Product Type OTC ANIMAL DRUG NDC Product Code (Source) 58005-080 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ASPIRIN (ASPIRIN) ASPIRIN 454 g  in 454 g

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 58005-080-51 454 g In 1 BAG None 2 58005-080-75 11300 g In 1 PAIL None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
unapproved drug other		10/05/2001

Labeler - Sparhawk Laboratories, Inc. (958829558)

Revised: 02/2010Sparhawk Laboratories, Inc.

More aspirin powder resources

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

Compare aspirin powder with other medications

• Angina
• Angina Pectoris Prophylaxis
• Ankylosing Spondylitis
• Antiphospholipid Syndrome
• Aseptic Necrosis
• Back Pain
• Fever
• Heart Attack
• Ischemic Stroke
• Ischemic Stroke, Prophylaxis
• Juvenile Rheumatoid Arthritis
• Kawasaki Disease
• Myocardial Infarction, Prophylaxis
• Niacin Flush
• Osteoarthritis
• Pain
• Prevention of Thromboembolism in Atrial Fibrillation
• Prosthetic Heart Valves
• Prosthetic Heart Valves, Mechanical Valves
• Revascularization Procedures, Prophylaxis
• Rheumatic Fever
• Rheumatoid Arthritis
• Sciatica
• Systemic Lupus Erythematosus
• Thromboembolic Stroke Prophylaxis
• Transient Ischemic Attack

Angettes 75

The wording of leaflets is regularly updated. This electronic text is the most up-to-date version and may differ from the leaflet in your pack. If you have any questions about the information provided, please ask your doctor or pharmacist.

ANGETTES 75

(Aspirin 75 mg)

Please read this leaflet before you take your medicine. It gives a summary of information about your medicine. If you want to know more, or are not sure about anything, ask your doctor or pharmacist.

REMEMBER:

This medicine is for you. Never give this medicine to anyone else. It may harm them even if they have the same symptoms as you.

What Is In Angettes 75?

The active ingredient in Angettes 75mg is aspirin 75mg. The tablets are packaged in blister packs of 28 tablets.

The other ingredients are: lactose, maize starch, sodium saccharin,

Who Supplies Angettes 75?

Product Licence Holder:

Bristol-Myers Pharmaceuticals

Uxbridge

Middlesex

UB8 1DH

Tel:0800 7311736

Manufacturer:

Bristol-Myers Squibb SARL

La Goualle

BP No. 6

19250-Meymac

France

What Is This Medicine For?

Low doses of aspirin have been shown to help prevent the red blood cells sticking together too much. Angettes 75 is therefore useful for patients suffering from angina and after a heart attack or stroke and following by-pass surgery. You should, however, speak to your doctor before using aspirin for the first time in these circumstances. Aspirin also helps to relieve pain and to reduce fever and inflammation.

Before Taking Your Medicine:

Should you be taking this medicine?

Angettes 75 are NOT intended for children under 16 years of age. There is a possible association between aspirin and Reye's syndrome when given to children. Reye's syndrome is a very rare disease, which can be fatal. For this reason aspirin should not be given to children aged under 16 years, unless on the advice of a doctor.

Do NOT take these tablets if you answer YES to any of the following questions. Go back to your doctor for advice as soon as possible.

• 1. Have you had an allergic reaction to similar tablets or any of the ingredients in Angettes 75?


• 2. Do you have, or have you ever had, a stomach ulcer?


• 3. Are you a haemophiliac or do you suffer from any disease which affects the clotting of your blood?.


• 4. Do you suffer from asthma?

What if I am pregnant, think I might be pregnant or planning to become pregnant?

Aspirin is not associated with any problems during pregnancy except during labour and delivery. However as with all medicines it is advisable to check with your doctor or pharmacist whether Angettes 75 is suitable for you

Can you take other medicines?

Do not take other medicines while you are taking Angettes 75, unless you have told your doctor or pharmacist and asked their advice. If you are taking allopurinol (treatment for gout), probenecid (treatment for gout and used with antibiotics for certain infections), or an anticoagulant (eg. warfarin, heparin), remind your doctor before taking Angettes 75.

Is it all right to drink alcohol?

You should check with your doctor whether drinking is advisable for you.

Who should you tell that you are taking Angettes 75?

Doctor - before having surgery or emergency treatment, or if he prescribes any new treatment.

Dentist - before having dental surgery.

Pharmacist - before buying any medicines.

Taking Your Medicine:

How should you take Angettes 75?

The usual daily dose is 1-2 tablets once a day. Sometimes a higher dose may be required, especially for a short time, and up to 4 tablets a day may be taken if your doctor advises it.

Can you take the tablets before or after meals?

It does not matter.

How long should you take them for?

Continue with Angettes 75 until your doctor tells you otherwise.

What if you take too many tablets or a child swallows some?

Go to your nearest hospital Casualty Department or tell your doctor immediately. If you are going to the hospital, take the empty container and any remaining tablets with you.

What if you miss or forget to take a dose?

If you miss a dose do not worry. Just carry on taking your normal dose when the next one is due. DO NOT take a double dose to make up for the one you missed.

Undesirable Effects

Are there any unwanted effects of Angettes 75?

All medicines may cause some unwanted or 'side-effects' in a few patients. Aspirin may trigger asthma attacks and wheezing or difficulty in breathing in asthma sufferers or other hypersensitivity reactions in susceptible individuals. If you notice any blood or discoloration in your stools, TELL YOUR DOCTOR IMMEDIATELY.

Looking After Your Medicine

You will see an "EXPIRY DATE" on the outer packaging of Angettes 75. Do not use the tablets after this date.

Keep all your medicines where children cannot reach them, preferably in a locked cupboard or medicine cabinet. Do not store Angettes 75 above 30°C. They should not get too hot or damp; so do not leave your tablets near a radiator, on a window sill or in the bathroom.

If your doctor decides to stop the tablets, ask your pharmacist to tell you what to do with any you have left.

DATE OF LAST REVISION: June 2005

Janumet

Generic Name: sitagliptin and metformin hydrochloride

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

WARNING: 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, Janumet1 should be discontinued and the patient hospitalized immediately. [See Warnings and Precautions (5.1).]

Indications and Usage for Janumet

Janumet is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin is appropriate. [See Clinical Studies (14).]

Important Limitations of Use

Janumet should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

Janumet has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Janumet. [See Warnings and Precautions (5.2).]

Janumet Dosage and Administration

Recommended Dosing

The dosage of Janumet should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.

Janumet should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side effects due to metformin.

The starting dose of Janumet should be based on the patient’s current regimen. Janumet should be given twice daily with meals. The following doses are available:

50 mg sitagliptin/500 mg metformin hydrochloride

50 mg sitagliptin/1000 mg metformin hydrochloride.

The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin.

The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of Janumet is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.

Patients treated with an insulin secretagogue or insulin

Co-administration of Janumet with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.9)].

No studies have been performed specifically examining the safety and efficacy of Janumet in patients previously treated with other oral antihyperglycemic agents and switched to Janumet. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Dosage Forms and Strengths

• 50 mg/500 mg tablets are light pink, capsule-shaped, film-coated tablets with “575” debossed on one side.


• 50 mg/1000 mg tablets are red, capsule-shaped, film-coated tablets with “577” debossed on one side.

Contraindications

Janumet (sitagliptin/metformin HCl) is contraindicated in patients with:

• Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions (5.1)].


• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.


• History of a serious hypersensitivity reaction to Janumet or sitagliptin (one of the components of Janumet), such as anaphylaxis or angioedema. [See Warnings and Precautions (5.14); Adverse Reactions (6.2).]

Janumet should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function [see Warnings and Precautions (5.11)].

Warnings and Precautions

Lactic Acidosis

Metformin hydrochloride

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Janumet; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 μg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking metformin, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure [see Warnings and Precautions (5.4, 5.6, 5.7, 5.11)].

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur [see Warnings and Precautions (5.12)]. Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling [see Warnings and Precautions (5.8, 5.13)].

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery [see Contraindications (4); Warnings and Precautions (5.6, 5.7, 5.10, 5.11, 5.12)].

Pancreatitis

There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking Janumet. After initiation of Janumet, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, Janumet should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Janumet.

Impaired Hepatic Function

Since impaired hepatic function has been associated with some cases of lactic acidosis, Janumet should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Assessment of Renal Function

Metformin and sitagliptin are known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Janumet. In the elderly, Janumet should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging can be associated with reduced renal function. [See Warnings and Precautions (5.1); Use in Specific Populations (8.5).]

 There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. Before initiation of therapy with Janumet and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and Janumet discontinued if evidence of renal impairment is present.

Vitamin B12 Levels

In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Janumet and any apparent abnormalities should be appropriately investigated and managed. [See Adverse Reactions (6.1).]

Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two- to three-year intervals may be useful.

Alcohol Intake

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Janumet.

Surgical Procedures

Use of Janumet should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes

A patient with type 2 diabetes previously well controlled on Janumet who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Janumet must be stopped immediately and other appropriate corrective measures initiated.

Use with Medications Known to Cause Hypoglycemia

Sitagliptin

When sitagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin [see Adverse Reactions (6)]. Therefore, patients also receiving an insulin secretagogue (e.g., sulfonylurea) or insulin may require a lower dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see Dosage and Administration (2.1)].

Metformin hydrochloride

Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs.

Concomitant Medications Affecting Renal Function or Metformin Disposition

Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion [see Drug Interactions (7.1)], should be used with caution.

Radiologic Studies with Intravascular Iodinated Contrast Materials

Intravascular contrast studies with iodinated materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin [see Contraindications (4)]. Therefore, in patients in whom any such study is planned, Janumet should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

Hypoxic States

Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on Janumet therapy, the drug should be promptly discontinued.

Loss of Control of Blood Glucose

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Janumet and temporarily administer insulin. Janumet may be reinstituted after the acute episode is resolved.

Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of Janumet. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue Janumet, assess for other potential causes for the event, and institute alternative treatment for diabetes. [See Adverse Reactions (6.2).]

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Janumet or any other anti-diabetic drug.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Sitagliptin and Metformin Co-administration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise

Table 1 summarizes the most common (≥5% of patients) adverse reactions reported (regardless of investigator assessment of causality) in a 24-week placebo-controlled factorial study in which sitagliptin and metformin were co-administered to patients with type 2 diabetes inadequately controlled on diet and exercise.

 

Table 1: Sitagliptin and Metformin Co-administered to Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise: Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo)*

	Number of Patients (%)
	Placebo	Sitagliptin 100 mg QD	Metformin 500 mg/ Metformin 1000 mg bid†	Sitagliptin 50 mg bid + Metformin 500 mg/ Metformin 1000 mg bid†
	N = 176	N = 179	N = 364†	N = 372†
* Intent-to-treat population. † Data pooled for the patients given the lower and higher doses of metformin.
Diarrhea	7 (4.0)	5 (2.8)	28 (7.7)	28 (7.5)
Upper Respiratory Tract Infection	9 (5.1)	8 (4.5)	19 (5.2)	23 (6.2)
Headache	5 (2.8)	2 (1.1)	14 (3.8)	22 (5.9)

Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone

In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin regimen, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo. Discontinuation of therapy due to clinical adverse reactions was similar to the placebo treatment group (sitagliptin and metformin, 1.9%; placebo and metformin, 2.5%).

Gastrointestinal Adverse Reactions

The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin were similar to those reported for patients treated with metformin alone. See Table 2.

Table 2: Pre-selected Gastrointestinal Adverse Reactions (Regardless of Investigator Assessment of Causality) Reported in Patients with Type 2 Diabetes Receiving Sitagliptin and Metformin

	Number of Patients (%)
	Study of Sitagliptin and Metformin in Patients Inadequately Controlled on Diet and Exercise				Study of Sitagliptin Add-on in Patients Inadequately Controlled on Metformin Alone
	Placebo	Sitagliptin 100 mg QD	Metformin 500 mg/ Metformin 1000 mg bid*	Sitagliptin 50 mg bid + Metformin 500 mg/ Metformin 1000 mg bid*	Placebo and Metformin ≥1500 mg daily	Sitagliptin 100 mg QD and Metformin ≥1500 mg daily
	N = 176	N = 179	N = 364	N = 372	N = 237	N = 464
* Data pooled for the patients given the lower and higher doses of metformin. † Abdominal discomfort was included in the analysis of abdominal pain in the study of initial therapy.
Diarrhea	7 (4.0)	5 (2.8)	28 (7.7)	28 (7.5)	6 (2.5)	11 (2.4)
Nausea	2 (1.1)	2 (1.1)	20 (5.5)	18 (4.8)	2 (0.8)	6 (1.3)
Vomiting	1 (0.6)	0 (0.0)	2 (0.5)	8 (2.2)	2 (0.8)	5 (1.1)
Abdominal Pain†	4 (2.3)	6 (3.4)	14 (3.8)	11 (3.0)	9 (3.8)	10 (2.2)

Sitagliptin in Combination with Metformin and Glimepiride

In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin and glimepiride (sitagliptin, N=116; placebo, N=113), the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: hypoglycemia (Table 3) and headache (6.9%, 2.7%).

Sitagliptin in Combination with Metformin and Rosiglitazone

In a placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin and rosiglitazone (sitagliptin, N=181; placebo, N=97), the adverse reactions reported regardless of investigator assessment of causality through Week 18 in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54, the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).

Sitagliptin in Combination with Metformin and Insulin

In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin and insulin (sitagliptin, N=229; placebo, N=233), the only adverse reaction reported regardless of investigator assessment of causality in ≥5% of patients treated with sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 3).

Hypoglycemia

In all (N=5) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required although most (77%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When the combination of sitagliptin and metformin was co-administered with a sulfonylurea or with insulin, the percentage of patients reporting at least one adverse reaction of hypoglycemia was higher than that observed with placebo and metformin co-administered with a sulfonylurea or with insulin (Table 3).

Table 3: Incidence and Rate of Hypoglycemia* (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Clinical Studies of Sitagliptin in Combination with Metformin Co-administered with Glimepiride or Insulin

* Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required: Intent-to-treat population. † Based on total number of events (i.e., a single patient may have had multiple events). ‡ Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure.
Add-On to Glimepiride +     Metformin (24 weeks)	Sitagliptin 100 mg + Metformin + Glimepiride	Placebo + Metformin + Glimepiride
	N = 116	N = 113
Overall (%)	19 (16.4)	1 (0.9)
Rate (episodes/patient-year)†	0.82	0.02
Severe (%)‡	0 (0.0)	0 (0.0)
Add-On to Insulin     + Metformin (24 weeks)	Sitagliptin 100 mg + Metformin + Insulin	Placebo + Metformin + Insulin
	N = 229	N = 233
Overall (%)	35 (15.3)	19 (8.2)
Rate (episodes/patient-year)†	0.98	0.61
Severe (%)‡	1 (0.4)	1 (0.4)

The overall incidence of reported adverse reactions of hypoglycemia in patients with type 2 diabetes inadequately controlled on diet and exercise was 0.6% in patients given placebo, 0.6% in patients given sitagliptin alone, 0.8% in patients given metformin alone, and 1.6% in patients given sitagliptin in combination with metformin. In patients with type 2 diabetes inadequately controlled on metformin alone, the overall incidence of adverse reactions of hypoglycemia was 1.3% in patients given add-on sitagliptin and 2.1% in patients given add-on placebo.

In the study of sitagliptin and add-on combination therapy with metformin and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on sitagliptin and 0.0% in patients given add-on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in patients given add-on sitagliptin and 1.0% in patients given add-on placebo.

With the combination of sitagliptin and metformin, no clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed.

In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo) control (N=4817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4708 patient-years for sitagliptin and 4 patients with an event in 3942 patient-years for control) [See Warnings and Precautions (5.2).]

The most common adverse experience in sitagliptin monotherapy reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo was nasopharyngitis.

The most common (>5%) established adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.

Laboratory Tests

Sitagliptin

The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and metformin (7.6%) compared to patients treated with placebo and metformin (8.7%). In most but not all studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to a small increase in neutrophils. This change in laboratory parameters is not considered to be clinically relevant.

Metformin hydrochloride

In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation. [See Warnings and Precautions (5.5).]

Postmarketing Experience

Additional adverse reactions have been identified during postapproval use of Janumet or sitagliptin, one of the components of Janumet. These reactions have been reported when Janumet or sitagliptin have been used alone and/or in combination with other antihyperglycemic agents. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome [see Warnings and Precautions (5.14)]; upper respiratory tract infection; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage (1); Warnings and Precautions (5.2)]; worsening renal function, including acute renal failure (sometimes requiring dialysis) [see Warnings and Precautions (5.4)]; constipation; vomiting; headache.

Drug Interactions

Cationic Drugs

Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Janumet and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Digoxin

There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the co-administration of 100 mg sitagliptin for 10 days. These increases are not considered likely to be clinically meaningful. Digoxin, as a cationic drug, has the potential to compete with metformin for common renal tubular transport systems, thus affecting the serum concentrations of either digoxin, metformin or both. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or Janumet is recommended.

Glyburide

In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects make the clinical significance of this interaction uncertain.

Furosemide

A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.

Nifedipine

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

The Use of Metformin with Other Drugs

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Janumet the patient should be closely observed to maintain adequate glycemic control.

In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B:

Janumet

There are no adequate and well-controlled studies in pregnant women with Janumet or its individual components; therefore, the safety of Janumet in pregnant women is not known. Janumet should be used during pregnancy only if clearly needed.

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to Janumet while pregnant. Health care providers are encouraged to report any prenatal exposure to Janumet by calling the Pregnancy Registry at 1-800-986-8999.

No animal studies have been conducted with the combined products in Janumet to evaluate effects on reproduction. The following data are based on findings in studies performed with sitagliptin or metformin individually.

Sitagliptin

Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies with sitagliptin in pregnant women.

Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30 and 20 times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.

Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.

Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.

Metformin hydrochloride

Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Nursing Mothers

No studies in lactating animals have been conducted with the combined components of Janumet. In studies performed with the individual components, both sitagliptin and metformin are secreted in the milk of lactating rats. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Janumet is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Janumet in pediatric patients under 18 years have not been established.

Geriatric U

Zinc Plus Lozenges

Pronunciation: zink/VYE-ta-min
Generic Name: Zinc/Vitamin B12/Vitamin C
Brand Name: Zinc Plus Lozenges

Zinc Plus Lozenges is used for:

Treating or preventing low levels of vitamin B, C, and zinc. It may also be used for other conditions as determined by your doctor.

Zinc Plus Lozenges is a vitamin and mineral combination. It works by providing vitamins and minerals to the body to help meet nutritional needs.

The FDA has not approved Zinc Plus Lozenges to treat these conditions.

Do NOT use Zinc Plus Lozenges if:

• you are allergic to any ingredient in Zinc Plus Lozenges

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

Before using Zinc Plus Lozenges:

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

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


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


• if you have allergies to medicines, foods, or other substances

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

Ask your health care provider if Zinc Plus Lozenges 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 Zinc Plus Lozenges:

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

• Take Zinc Plus Lozenges by mouth with food.


• Do not swallow, crush, or chew lozenges. Place the lozenge in mouth and allow it to slowly dissolve. Do not eat, drink, or smoke while the lozenge is dissolving.


• Do not eat or drink fruit juices ½ an hour before or after dissolving the lozenge because it may decrease the effectiveness of Zinc Plus Lozenges.


• Do not take tetracyclines (eg, doxycycline) within 2 hours before or after you take Zinc Plus Lozenges.


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

Ask your health care provider any questions you may have about how to use Zinc Plus Lozenges.

Important safety information:

• Do not take large doses of vitamins (megadoses or megavitamin therapy) while you use Zinc Plus Lozenges unless your doctor tells you to.


• Zinc Plus Lozenges has zinc in it. Before you start any new medicine, check the label to see if it has zinc in it too. If it does or if you are not sure, check with your doctor or pharmacist.


• Zinc Plus Lozenges should be used with extreme caution in CHILDREN; they may be more likely to chew or choke on the lozenges.


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

Possible side effects of Zinc Plus Lozenges:

All medicines may cause side effects, but many people have no, or minor, side effects. No COMMON side effects have been reported with Zinc Plus Lozenges. 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).

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: Zinc Plus side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Zinc Plus Lozenges:

Store Zinc Plus Lozenges at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Zinc Plus Lozenges out of the reach of children and away from pets.

General information:

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


• Zinc Plus Lozenges 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 Zinc Plus Lozenges. 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 Zinc Plus resources

• Zinc Plus Side Effects (in more detail)
• Zinc Plus Use in Pregnancy & Breastfeeding
• Zinc Plus Drug Interactions
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