Avandamet

Name: Avandamet

Inform MD

Before receiving Avandamet, tell your doctor about all your medical conditions, including if you:

  • have heart problems or heart failure
  • have kidney problems
  • have type 1 (“juvenile”) diabetes or had diabetic ketoacidosis. These conditions should be treated with insulin.
  • are going to have dye injected into a vein for an X-ray, CAT scan, heart study, or other type of scanning
  • drink a lot of alcohol (all the time or short binge drinking).
  • develop a serious condition such as a heart attack, severe infection, or a stroke.
  • are 80 years old or older. People who are over 80 years old should not take metformin/rosiglitazone unless their kidney function is checked and it is normal.
  • have a type of diabetic eye disease called macular edema (swelling of the back of the eye).
  • have liver problems. Your doctor should do blood tests to check your liver before you start taking metformin/rosiglitazone and during treatment as needed.
  • had liver problems while taking Rezulin (troglitazone), another medicine for diabetes.

Tell your doctor if you are pregnant or breastfeeding.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins or herbal supplements. 

What is metformin and rosiglitazone?

Metformin and rosiglitazone is a combination of two oral diabetes medicines. Metformin and rosiglitazone is used together with diet and exercise to improve blood sugar control in adults with type 2 diabetes mellitus. This medicine is not for treating type 1 diabetes.

Metformin and rosiglitazone is not recommended for use with insulin. Taking this medicine while you are using insulin may increase your risk of serious heart problems.

Metformin and rosiglitazone may also be used for purposes not listed in this medication guide.

Commonly used brand name(s)

In the U.S.

  • Avandamet

Available Dosage Forms:

  • Tablet

Therapeutic Class: Hypoglycemic

Chemical Class: Metformin

Before Using Avandamet

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 rosiglitazone 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 rosiglitazone 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 rosiglitazone 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 this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

  • 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
  • Ioxaglate
  • Ioxitalamic Acid
  • Ipodate
  • Metrizamide
  • Metrizoic Acid
  • Tyropanoate Sodium

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.

  • Abiraterone
  • Aspirin
  • Balofloxacin
  • Besifloxacin
  • Bupropion
  • Ceritinib
  • Ciprofloxacin
  • Dasabuvir
  • Dofetilide
  • Dolutegravir
  • Enoxacin
  • Entacapone
  • Fleroxacin
  • Flumequine
  • Gatifloxacin
  • Gemifloxacin
  • Insulin
  • Insulin Aspart, Recombinant
  • Insulin Bovine
  • Insulin Degludec
  • Insulin Detemir
  • Insulin Glargine, Recombinant
  • Insulin Glulisine
  • Insulin Lispro, Recombinant
  • Ioversol
  • Lanreotide
  • Levofloxacin
  • Lomefloxacin
  • Moxifloxacin
  • Nadifloxacin
  • Norfloxacin
  • Octreotide
  • Ofloxacin
  • Ombitasvir
  • Paritaprevir
  • Pasireotide
  • Pazufloxacin
  • Pefloxacin
  • Pioglitazone
  • Pixantrone
  • Prulifloxacin
  • Ritonavir
  • Rufloxacin
  • Sparfloxacin
  • Thioctic Acid
  • Tosufloxacin
  • Vandetanib

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.

  • Acebutolol
  • Atenolol
  • Betaxolol
  • Bisoprolol
  • Bitter Melon
  • Carteolol
  • Carvedilol
  • Celiprolol
  • Esmolol
  • Fenofibrate
  • Fenofibric Acid
  • Fenugreek
  • Furazolidone
  • Gemfibrozil
  • Glucomannan
  • Guar Gum
  • Iproniazid
  • Isocarboxazid
  • Labetalol
  • Levobunolol
  • Linezolid
  • Methylene Blue
  • Metipranolol
  • Metoprolol
  • Moclobemide
  • Nadolol
  • Nebivolol
  • Nialamide
  • Opicapone
  • Oxprenolol
  • Patiromer
  • Penbutolol
  • Phenelzine
  • Pindolol
  • Practolol
  • Procarbazine
  • Propranolol
  • Psyllium
  • Ranolazine
  • Rasagiline
  • Rifampin
  • Safinamide
  • Selegiline
  • Sotalol
  • Timolol
  • Tranylcypromine
  • Trimethoprim
  • Verapamil

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 this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Adrenal gland problem (underactive) or
  • Alcohol abuse, history of or
  • Dehydration, severe 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 body swelling) or
  • Heart attack, history of or
  • Heart disease, history of or
  • Vitamin B12 deficiency—Use with caution. May make these conditions worse.
  • Angina, severe and acute or
  • Diabetic ketoacidosis (high ketones in the blood) or
  • Heart attack, acute or
  • Heart failure, severe or with symptoms or
  • Kidney disease, severe or
  • Liver disease or
  • Metabolic acidosis (acid in the blood) or
  • Type 1 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. This medicine may increase the risk for fractures.

Proper Use of Avandamet

Use this medicine 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.

This medicine should come with a Medication Guide. It is very important that you read and understand this information. Ask your doctor if you have any questions.

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

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.

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 oral dosage form (tablets):
    • For type 2 diabetes:
      • For patients inadequately controlled on diet and exercise:
        • Adults—At first, rosiglitazone 2 milligrams (mg) plus metformin 500 mg once or two times a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than rosiglitazone 8 mg plus metformin 2000 mg per day, divided into two doses.
        • Children—Use and dose must be determined by your doctor.
      • For patients on metformin therapy:
        • Adults—rosiglitazone 4 milligrams (mg) per day plus the dose of metformin already being taken, divided into two doses. Your doctor may adjust your dose as needed.
        • Children—Use and dose must be determined by your doctor.
      • For patients on rosiglitazone therapy:
        • Adults—metformin 1000 milligrams (mg) per day plus the dose of rosiglitazone already being taken, divided into two doses. Your doctor may adjust your dose as needed.
        • Children—Use and dose must be determined by your doctor.
      • For patients previously treated with rosiglitazone and metformin:
        • Adults—The dose is the same as the dose you are already taking. Your doctor may adjust your dose as needed.
        • 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.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
  • Bone pain.
  • Change in eyesight.
  • Feeling very tired or weak.
  • Trouble swallowing.
  • A fast heartbeat.
  • It is common to have stomach problems like upset stomach, throwing up, or loose stools (diarrhea) when you start taking Avandamet. If you have stomach problems later during care, call your doctor right away. This may be a sign of an acid health problem in the blood (lactic acidosis).
  • Low blood sugar can happen. The chance of low blood sugar may be raised when this medicine is used with other drugs for high blood sugar (diabetes). Signs may be dizziness, headache, feeling sleepy, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating. Call your doctor right away if you have any of these signs. Follow what you have been told to do if you get low blood sugar. This may include taking glucose tablets, liquid glucose, or some fruit juices.
  • This medicine may raise the chance of heart attack. Call your doctor right away if you have chest pain or pressure; pain in the arms, back, neck, jaw, or stomach; shortness of breath; cold sweats; very bad dizziness or passing out; or very upset stomach or throwing up.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Avandamet Dosage and Administration

The dosage of antidiabetic therapy with Avandamet should be individualized on the basis of effectiveness and tolerability. The risk-benefit of initiating monotherapy versus dual therapy with Avandamet should be considered.

Starting Dose

Avandamet is generally given in divided doses with meals.

All patients should start the rosiglitazone component of Avandamet at the lowest recommended dose. Further increases in the dose of rosiglitazone should be accompanied by careful monitoring for adverse events related to fluid retention [see Boxed Warning, Warnings and Precautions (5.2)].

Patients Inadequately Controlled on Diet and Exercise: If therapy with a combination tablet containing rosiglitazone and metformin is considered appropriate for a patient with type 2 diabetes mellitus inadequately controlled on diet and exercise alone, the recommended starting dose of Avandamet is 2 mg/500 mg administered once or twice daily. For patients with HbA1c >11% or fasting plasma glucose (FPG) >270 mg/dL, a starting dose of 2 mg/500 mg twice daily may be considered. The dose of Avandamet may be increased in increments of 2 mg/500 mg per day given in divided doses if patients are not adequately controlled after 4 weeks. The maximum dose of Avandamet is 8 mg/2,000 mg per day.

Patients Inadequately Controlled on Rosiglitazone or Metformin Monotherapy: If therapy with a combination tablet containing rosiglitazone and metformin is considered appropriate for a patient with type 2 diabetes mellitus inadequately controlled on rosiglitazone or metformin monotherapy, then the selection of the dose of Avandamet should be based on the patient’s current doses of rosiglitazone and/or metformin.

To switch to Avandamet for patients currently treated with metformin, the usual starting dose of Avandamet is 4 mg rosiglitazone (total daily dose) plus the dose of metformin already being taken (see Table 1).

To switch to Avandamet for patients currently treated with rosiglitazone, the usual starting dose of Avandamet is 1,000 mg metformin (total daily dose) plus the dose of rosiglitazone already being taken (see Table 1).

When switching from combination therapy of rosiglitazone plus metformin as separate tablets, the usual starting dose of Avandamet is the dose of rosiglitazone and metformin already being taken.

Table 1. Avandamet Starting Dose for Patients Treated With Metformin and/or Rosiglitazone

PRIOR THERAPY

Usual Avandamet Starting Dose

Total Daily Dose

Tablet Strength

Number of Tablets

Metformina

1,000 mg/day

2 mg/500 mg

1 tablet twice a day

2,000 mg/day

2 mg/1,000 mg

1 tablet twice a day

Rosiglitazone

4 mg/day

2 mg/500 mg

1 tablet twice a day

8 mg/day

4 mg/500 mg

1 tablet twice a day

a   For patients on doses of metformin between 1,000 and 2,000 mg/day, initiation of Avandamet requires individualization of therapy.

Dose Titration

Avandamet is generally given in divided doses with meals, with gradual dose escalation. This reduces gastrointestinal side effects (largely due to metformin) and permits determination of the minimum effective dose for the individual patient.

Sufficient time should be given to assess adequacy of therapeutic response. FPG should be used initially to determine the therapeutic response to Avandamet. If additional glycemic control is needed, the daily dose of Avandamet may be increased by increments of 4 mg rosiglitazone and/or 500 mg metformin.

After an increase in metformin dosage, dose titration is recommended if patients are not adequately controlled after 1 to 2 weeks. After an increase in rosiglitazone dosage, dose titration is recommended if patients are not adequately controlled after 8 to 12 weeks.

Maximum Dose

The maximum recommended total daily dose of Avandamet is 8 mg rosiglitazone (taken as 4 mg twice daily) and 2,000 mg metformin (taken as 1,000 mg twice daily).

Specific Patient Populations

Renal Impairment: Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of Avandamet. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly [see Warnings and Precautions (5.1)].

Hepatic Impairment: Liver enzymes should be measured prior to initiating treatment with Avandamet. Therapy with Avandamet should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT >2.5X upper limit of normal at start of therapy). After initiation of Avandamet, liver enzymes should be monitored periodically per the clinical judgment of the healthcare professional [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)].

Geriatric: The initial and maintenance dosing of Avandamet should be conservative in patients with advanced age, due to the potential for decreased renal function in this population.

Pediatric: Safety and effectiveness of Avandamet in pediatric patients have not been established. Avandamet and rosiglitazone are not recommended for use in pediatric patients.

Pregnancy: Avandamet is not recommended for use in pregnancy.

Adverse Reactions

The following adverse reactions are discussed in more detail elsewhere in the labeling:

• Lactic Acidosis [see Warnings and Precautions (5.1)] • Cardiac Failure [see Warnings and Precautions (5.2)] • Major Adverse Cardiovascular Events [see Warnings and Precautions (5.3)] • Edema [see Warnings and Precautions (5.4)] • Weight Gain [see Warnings and Precautions (5.5)] • Hepatic Effects [see Warnings and Precautions (5.6)] • Macular Edema [see Warnings and Precautions (5.7)] • Fractures [see Warnings and Precautions (5.8)] • Hematologic Effects [see Warnings and Precautions (5.9)] • Vitamin B12 Levels [see Warnings and Precautions (5.10)] • Ovulation [see Warnings and Precautions (5.12)]

Clinical Trial 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Patients With Inadequate Glycemic Control on Diet and Exercise: Table 4 summarizes the incidence and types of adverse reactions without regard to causality reported in a controlled, 32‑week, double-blind clinical trial of Avandamet in patients with inadequate glycemic control on diet and exercise (N = 468).

Table 4. Adverse Events (≥5% for Avandamet) Reported by Patients With Inadequate Glycemic Control on Diet and Exercise in a 32-Week, Double-blind Clinical Trial of Avandamet

Preferred Term

Avandamet

Metformin

Rosiglitazone

N = 155

N = 154

N = 159

%

%

%

Nausea/vomiting

16

13

8

Diarrhea

14

21

7

Headache

11

12

10

Dyspepsia

10

8

9

Upper respiratory tract infection

9

7

8

Dizziness

8

3

5

Edema

6

3

7

Nasopharyngitis

6

5

4

Abdominal pain

5

6

7

Arthralgia

5

3

7

Loose stools

5

6

1

Constipation

5

4

6

Mild (no intervention required) to moderate (minor intervention required) symptomatic hypoglycemia was reported by 12% (18/155) of patients treated with Avandamet, 14/154 (9%) with metformin, and 8% (13/159) with rosiglitazone. Approximately half of these episodes were accompanied by a simultaneous capillary glucose measurement, and the rate of confirmed hypoglycemia (blood glucose ≤50 mg/dL) was low in this clinical trial: 0.6% (1/155) for Avandamet, 1.3% (2/154) for metformin, and 0% with rosiglitazone. No hypoglycemic episode led to withdrawal in patients treated with Avandamet, and no patients required medical intervention due to hypoglycemia.

The incidence of edema was 6% on Avandamet compared with 7% on rosiglitazone and 3% on metformin.

The incidence of anemia was 4% in patients treated with Avandamet compared with either rosiglitazone (2%) or metformin (0%).

Patients Inadequately Controlled on Rosiglitazone Monotherapy: The incidence and types of adverse events reported in controlled, 26-week clinical trials of rosiglitazone administered in combination with metformin 2,500 mg/day in comparison with adverse reactions reported in association with rosiglitazone and metformin monotherapies are shown in Table 5. Overall, the types of adverse reactions without regard to causality reported when rosiglitazone was used in combination with metformin were similar to those reported during monotherapy with rosiglitazone.

Table 5. Adverse Events (≥5% for Rosiglitazone Plus Metformin) Reported by Patients in 26-Week, Double-blind Clinical Trials of Rosiglitazone Added to Metformin Therapy

Preferred Term

Rosiglitazone + Metformin

Rosiglitazone

Placebo

Metformin

N = 338

N = 2,526

N = 601

N = 225

%

%

%

%

Upper respiratory tract infection

16.0

9.9

8.7

8.9

Diarrhea

12.7

2.3

3.3

15.6

Injury

8.0

7.6

4.3

7.6

Anemia

7.1

1.9

0.7

2.2

Headache

6.5

5.9

5.0

8.9

Sinusitis

6.2

3.2

4.5

5.3

Fatigue

5.9

3.6

5.0

4.0

Back pain

5.0

4.0

3.8

4.0

Viral infection

5.0

3.2

4.0

3.6

Arthralgia

5.0

3.0

4.0

2.2

Reports of hypoglycemia in patients treated with rosiglitazone added to maximum metformin therapy in double-blind trials were more frequent (3.0%) than in patients treated with rosiglitazone (0.6%) or metformin monotherapies (1.3%) or placebo (0.2%). Overall, anemia and edema were generally mild to moderate in severity and usually did not require discontinuation of treatment with rosiglitazone.

Edema was reported in 4.8% of patients receiving rosiglitazone compared with 1.3% on placebo, and 2.2% on metformin monotherapy and 4.4% on rosiglitazone in combination with maximum doses of metformin.

Reports of anemia (7.1%) were greater in patients treated with rosiglitazone added to metformin compared with monotherapy with rosiglitazone. Lower pre-treatment hemoglobin/hematocrit levels in patients enrolled in the metformin and rosiglitazone combination therapy clinical trials may have contributed to the higher reporting rate of anemia in these trials [see Adverse Reactions (6.2)].

Combination With Insulin: The incidence of hypoglycemia (confirmed by fingerstick blood glucose concentration ≤50 mg/dL) was 14% for patients on Avandamet plus insulin compared with 10% for patients on insulin monotherapy.

The incidence of edema was 7% when insulin was added to Avandamet compared with 3% with insulin monotherapy. This trial excluded patients with pre-existing heart failure or new or worsening edema on Avandamet. However, in 26-week, double-blind, fixed-dose trials of rosiglitazone added to insulin, edema was reported with higher frequency (rosiglitazone in combination with insulin, 14.7%; insulin, 5.4%) [see Warnings and Precautions (5.2)].

In trials in which rosiglitazone was added to insulin, rosiglitazone increased the risk of congestive heart failure [see Warnings and Precautions (5.2)].

In a trial in which insulin was added to Avandamet, no myocardial ischemia was observed in the insulin group (N = 158), and no congestive heart failure was reported in either group. There was one myocardial ischemic event and one sudden death in the group receiving Avandamet plus insulin (N = 161). [See Warnings and Precautions (5.2).]

The incidence of anemia was 2% for Avandamet in combination with insulin compared with 1% for insulin monotherapy.

Long-term Trial of Rosiglitazone as Monotherapy: A long-term, 4- to 6-year trial (ADOPT) compared the use of rosiglitazone (n = 1,456), glyburide (n = 1,441), and metformin (n = 1,454) as monotherapy in patients recently diagnosed with type 2 diabetes who were not previously treated with antidiabetic medication. Table 6 presents adverse reactions without regard to causality; rates are expressed per 100 patient-years (PY) exposure to account for the differences in exposure to trial medication across the 3 treatment groups.

In ADOPT, fractures were reported in a greater number of women treated with rosiglitazone (9.3%, 2.7/100 patient-years) compared with glyburide (3.5%, 1.3/100 patient-years) or metformin (5.1%, 1.5/100 patient-years). The majority of the fractures in the women who received rosiglitazone were reported in the upper arm, hand, and foot. [See Warnings and Precautions (5.8).] The observed incidence of fractures for male patients was similar among the 3 treatment groups.

Table 6. On-therapy Adverse Events [≥5 Events/100 Patient-years (PY)] in any Treatment Group Reported in a 4- to 6-Year Clinical Trial of Rosiglitazone as Monotherapy (ADOPT)

Preferred Term

Rosiglitazone

Glyburide

Metformin

N = 1,456

N = 1,441

N = 1,454

PY = 4,954

PY = 4,244

PY = 4,906

Nasopharyngitis

6.3

6.9

6.6

Back pain

5.1

4.9

5.3

Arthralgia

5.0

4.8

4.2

Hypertension

4.4

6.0

6.1

Upper respiratory tract infection

4.3

5.0

4.7

Hypoglycemia

2.9

13.0

3.4

Diarrhea

2.5

3.2

6.8

Long-term Trial of Rosiglitazone as Combination Therapy (RECORD): RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) was a multicenter, randomized, open-label, non-inferiority trial in subjects with type 2 diabetes inadequately controlled on maximum doses of metformin or sulfonylurea (glyburide, gliclazide, or glimepiride) to compare the time to reach the combined cardiovascular endpoint of cardiovascular death or cardiovascular hospitalization between patients randomized to the addition of rosiglitazone versus metformin or sulfonylurea. The trial included patients who have failed metformin or sulfonylurea monotherapy; those who failed metformin (n = 2,222) were randomized to receive either add-on rosiglitazone (n = 1,117) or add-on sulfonylurea (n = 1,105), and those who failed sulfonylurea (n = 2,225) were randomized to receive either add-on rosiglitazone (n = 1,103) or add-on metformin (n = 1,122). Patients were treated to target HbA1c ≤7% throughout the trial.

The mean age of patients in this trial was 58 years, 52% were male, and the mean duration of follow-up was 5.5 years. Rosiglitazone demonstrated non-inferiority to active control for the primary endpoint of cardiovascular hospitalization or cardiovascular death (HR 0.99, 95% CI: 0.85-1.16). There were no significant differences between groups for secondary endpoints with the exception of congestive heart failure (see Table 7). The incidence of congestive heart failure was significantly greater among patients randomized to rosiglitazone.

Table 7. Cardiovascular (CV) Outcomes for the RECORD Trial

Primary Endpoint

Rosiglitazone

N = 2,220

Active Control

N = 2,227

Hazard Ratio

95% CI

CV death or CV hospitalization

321

323

0.99

0.85-1.16

Secondary Endpoint

All-cause death

136

157

0.86

0.68-1.08

CV death

60

71

0.84

0.59-1.18

Myocardial infarction

64

56

1.14

0.80-1.63

Stroke

46

63

0.72

0.49-1.06

CV death, myocardial infarction, or stroke

154

165

0.93

0.74-1.15

Heart failure

61

29

2.10

1.35-3.27

There was an increased incidence of bone fracture for subjects randomized to rosiglitazone in addition to metformin or sulfonylurea compared with those randomized to metformin plus sulfonylurea (8.3% versus 5.3%) [see Warnings and Precautions (5.8)]. The majority of fractures were reported in the upper limbs and distal lower limbs. The risk of fracture appeared to be higher in females relative to control (11.5% versus 6.3%), than in males relative to control (5.3% versus 4.3%). Additional data are necessary to determine whether there is an increased risk of fracture in males after a longer period of follow-up.

Laboratory Abnormalities

Hematologic: Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone (mean decreases in individual trials as much as 1.0 gram/dL hemoglobin and as much as 3.3% hematocrit). The changes occurred primarily during the first 3 months following initiation of rosiglitazone therapy or following an increase in rosiglitazone dose. The time course and magnitude of decreases were similar in patients treated with a combination of rosiglitazone and other hypoglycemic agents or monotherapy with rosiglitazone. Pre-treatment levels of hemoglobin and hematocrit were lower in patients in metformin combination trials and may have contributed to the higher reporting rate of anemia. In a single trial in pediatric patients, decreases in hemoglobin and hematocrit (mean decreases of 0.29 g/dL and 0.95%, respectively) were reported with rosiglitazone. White blood cell counts also decreased slightly in adult patients treated with rosiglitazone. Decreases in hematologic parameters may be related to increased plasma volume observed with rosiglitazone treatment.

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 a 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.

Lipids: Changes in serum lipids have been observed following treatment with rosiglitazone in adults [see Clinical Pharmacology (12.2)].

Serum Transaminase Levels: In pre-approval clinical trials in 4,598 patients treated with rosiglitazone encompassing approximately 3,600 patient-years of exposure, and in a long-term 4- to 6-year trial in 1,456 patients treated with rosiglitazone (4,954 patient-years exposure), there was no evidence of drug-induced hepatotoxicity.

In pre-approval controlled trials, 0.2% of patients treated with rosiglitazone had reversible elevations in ALT >3X the upper limit of normal compared with 0.2% on placebo and 0.5% on active comparators. The ALT elevations in patients treated with rosiglitazone were reversible. Hyperbilirubinemia was found in 0.3% of patients treated with rosiglitazone compared with 0.9% treated with placebo and 1% in patients treated with active comparators. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure. [See Warnings and Precautions (5.6).]

In the 4- to 6-year ADOPT trial, patients treated with rosiglitazone (4,954 patient-years exposure), glyburide (4,244 patient-years exposure), or metformin (4,906 patient-years exposure) as monotherapy, had the same rate of ALT increase to >3X upper limit of normal (0.3 per 100 patient-years exposure).

In the RECORD trial, patients randomized to rosiglitazone in addition to metformin or sulfonylurea (10,849 patient-years exposure) and to metformin plus sulfonylurea (10,209 patient-years exposure) had a rate of ALT increase to ≥3X upper limit of normal of approximately 0.2 and 0.3 per 100 patient-years exposure, respectively.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of Avandamet or its individual components. Because these events are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or to always establish a causal relationship to drug exposure.

In patients receiving thiazolidinedione therapy, serious adverse events with or without a fatal outcome, potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions) have been reported [see Boxed Warning, Warnings and Precautions (5.2)].

There are postmarketing reports with rosiglitazone of hepatitis, hepatic enzyme elevations to 3 or more times the upper limit of normal, and hepatic failure with and without fatal outcome, although causality has not been established.

There are postmarketing reports with rosiglitazone of rash, pruritus, urticaria, angioedema, anaphylactic reaction, Stevens-Johnson syndrome [see Contraindications (4)], and new onset or worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions (5.7)].

(See also GLUCOPHAGE® prescribing information.)

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What other drugs will affect Avandamet?

Many other medicines can affect your blood sugar, and some medicines can increase or decrease the effects of Avandamet. Some drugs can also cause you to have fewer symptoms of hypoglycemia, making it harder to tell when your blood sugar is low. Tell your doctor about all your current medicines and any you start or stop using, especially:

  • insulin or other oral diabetes medications;

  • heart or blood pressure medicine; or

  • cholesterol-lowering medicine.

This list is not complete. Other drugs may interact with metformin and rosiglitazone, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

For the Consumer

Applies to metformin / rosiglitazone: oral tablet

Along with its needed effects, metformin / rosiglitazone 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 while taking metformin / rosiglitazone:

More common
  • Pale skin
  • troubled breathing with exertion
  • unusual bleeding or bruising
  • unusual tiredness or weakness
Less common
  • Anxiety
  • blurred vision
  • chest pain or discomfort
  • chills
  • cold sweats
  • coma
  • confusion
  • cool, pale skin
  • depression
  • dilated neck veins
  • dizziness
  • extreme fatigue
  • fast heartbeat
  • headache
  • increased hunger
  • irregular breathing
  • irregular heartbeat
  • nausea
  • nightmares
  • seizures
  • shakiness
  • slurred speech
  • swelling of the face, fingers, feet, or lower legs
  • weight gain
Rare
  • Abdominal or stomach discomfort
  • decreased appetite
  • diarrhea
  • fast, shallow breathing
  • general feeling of discomfort
  • muscle pain or cramping
  • sleepiness
Incidence not known
  • Change in vision
  • dark urine
  • decreased urine output
  • hives or welts, itching, or skin rash
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • pain or discomfort in the arms, jaw, back, or neck
  • redness of the skin
  • stomach pain
  • sweating
  • vomiting

Some side effects of metformin / rosiglitazone 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, fever, sneezing, or sore throat
  • difficulty with breathing
  • ear congestion
  • loss of voice
  • pain or tenderness around the eyes and cheekbones
  • stuffy or runny nose
Less common
  • Back pain
  • cold or flu-like symptoms
  • difficulty with moving
  • pain in the joints

Metformin / rosiglitazone Breastfeeding Warnings

A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown (rosiglitazone); Yes (metformin) Excreted into animal milk: Yes (rosiglitazone); Yes (metformin) Comments: The effects in the nursing infant are unknown.

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