Actoplus Met XR

Name: Actoplus Met XR

What is the most important information I should know about Actoplus Met XR (metformin and pioglitazone)?

You should not use this medicine if you have severe or uncontrolled heart failure, kidney problems, active bladder cancer, metabolic acidosis, or diabetic ketoacidosis (call your doctor for treatment with insulin). Metformin and pioglitazone is not for treating type 1 diabetes.

Metformin and pioglitazone can cause or worsen congestive heart failure. Call your doctor at once if you have shortness of breath (even with mild exertion), swelling, or rapid weight gain.

If you need to have any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking metformin and pioglitazone.

Some people develop lactic acidosis while taking metformin. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or uneven heart rate, dizziness, or feeling very weak or tired.

Precautions While Using Actoplus Met XR

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly and to decide if you should continue to use it. Blood and urine tests may be needed to check for unwanted effects.

If you are rapidly gaining weight, having shortness of breath, chest pain or discomfort, extreme tiredness or weakness, irregular breathing, irregular heartbeat, or excessive swelling of the hands, wrist, ankles, or feet, check with your doctor immediately. These may be symptoms of heart problems or fluid retention (too much water in the body).

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

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

Check with your doctor right away if you have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, vomiting, or yellow eyes or skin. These could be symptoms of a serious liver problem.

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

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

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

This medicine can cause hypoglycemia (low blood sugar). Low blood sugar can also occur if you delay or miss a meal or snack, exercise more than usual, drink alcohol, or cannot eat because of nausea or vomiting or take certain medicines. Low blood sugar must be treated before it causes you to pass out (unconsciousness). People feel different symptoms with low blood sugar. It is important that you learn which symptoms you have in order to treat it quickly. Talk to your doctor about the best way to treat low blood sugar.

Hyperglycemia (high blood sugar) may occur if you do not take enough or skip a dose of your medicine, overeat or do not follow your meal plan, have a fever or infection, or do not exercise as much as usual. High blood sugar can be very serious and must be treated right away. It is important that you learn which symptoms you have in order to treat it quickly. Talk to your doctor about the best way to treat high blood sugar.

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

This medicine may cause some women who do not have regular monthly periods to ovulate. This can increase the chance of pregnancy. If you are a woman of childbearing potential, you should discuss birth control options with your doctor.

Limit how much alcohol you drink while using this medicine. Heavy alcohol use can increase your risk for lactic acidosis.

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.

Actoplus Met XR Dosage and Administration

Recommendations for All Patients

Actoplus Met XR should be taken with meals to reduce the gastrointestinal side effects associated with metformin.

If therapy with a combination tablet containing pioglitazone and extended-release metformin is considered appropriate the recommended starting dose is:

• 15 mg/1000 mg or 30 mg/1000 mg once daily and gradually titrated as needed, after assessing adequacy of therapeutic response and tolerability, • for patients with NYHA Class I or Class II congestive heart failure: 15 mg/1000 mg or 30 mg/1000 mg once daily and gradually titrated as needed, after assessing adequacy of therapeutic response and tolerability. • for patients inadequately controlled on metformin monotherapy: 15 mg/1000 mg twice daily or 30 mg/1000 mg once daily (depending on the dose of metformin already being taken) and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability, • for patients inadequately controlled on pioglitazone monotherapy: 15 mg/1000 mg twice daily or 30 mg/1000 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability. • for patients who are changing from combination therapy of pioglitazone plus metformin as separate tablets: Actoplus Met XR should be taken at doses that are as close as possible to the dose of pioglitazone and metformin already being taken.

Actoplus Met XR may be titrated up to a maximum daily dose of 45 mg/2000 mg of pioglitazone/extended-release metformin.

Metformin doses above 2000 mg may be better tolerated given three times a day.

Patients should be informed that Actoplus Met XR must be swallowed whole and not chewed, cut, or crushed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

After initiation of Actoplus Met XR or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)]. Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating Actoplus Met XR. Routine periodic monitoring of liver tests during treatment with Actoplus Met XR is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of Actoplus Met XR or who are found to have abnormal liver tests while taking Actoplus Met XR should be managed as described under Warnings and Precautions [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

Recommendations for Use in Renal Impairment

Assess renal function prior to initiation of Actoplus Met XR and periodically thereafter.

Actoplus Met XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2.

Initiation of Actoplus Met XR in patients with an eGFR between 30 – 45 mL/min/1.73 m2 is not recommended.

In patients taking Actoplus Met XR whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy.

Discontinue Actoplus Met XR if the patient's eGFR later falls below 30 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.12)].

Concomitant Use with Strong CYP2C8 Inhibitors

Coadministration of pioglitazone (one of the ingredients in Actoplus Met XR) and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure by approximately 3-fold. Therefore, the maximum recommended dose of Actoplus Met XR is 15 mg/1000 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue Actoplus Met XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart Actoplus Met XR if renal function is stable [see Warnings and Precautions (5.2)].

Adverse Reactions

The following serious adverse reactions are discussed elsewhere in the labeling:

• Congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)] • Lactic acidosis [see Boxed Warning and Warnings and Precautions (5.2)] • Edema [see Warnings and Precautions (5.3)] • Fractures [see Warnings and Precautions (5.7)]

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.

Pioglitazone

Over 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with pioglitazone from the PROactive clinical trial. In these trials, over 6000 patients have been treated with pioglitazone for 6 months or longer, over 4500 patients have been treated with pioglitazone for one year or longer, and over 3000 patients have been treated with pioglitazone for at least two years.

In six pooled 16- to 26-week placebo-controlled monotherapy and 16- to 24-week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with pioglitazone and 5.8% for patients treated with comparator. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with pioglitazone than with placebo (3.0%).

In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with pioglitazone and 7.7% for patients treated with placebo. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with pioglitazone and 0.6% of patients treated with placebo.

Common Adverse Events: 16- to 26-Week Monotherapy Trials

A summary of the incidence and type of common adverse events reported in three pooled 16- to 26-week placebo-controlled monotherapy trials of pioglitazone is provided in Table 1. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo. None of these adverse events were related to the pioglitazone dose.

 
Table 1. Three Pooled 16- to 26-Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Events Reported at an Incidence >5% and More Commonly in Patients Treated with Pioglitazone than in Patients Treated with Placebo

% of Patients

Placebo
N=259

Pioglitazone
N=606

Upper Respiratory Tract Infection

8.5

13.2

Headache

6.9

9.1

Sinusitis

4.6

6.3

Myalgia

2.7

5.4

Pharyngitis

0.8

5.1

Common Adverse Events: 16- to 24-Week Add-on Combination Therapy Trials

A summary of the overall incidence and types of common adverse events reported in trials of pioglitazone add-on to metformin is provided in Table 2. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of pioglitazone.

 
Table 2. 16- to 24-Week Clinical Trials of Pioglitazone Add-on to Metformin

16-Week Placebo-Controlled Trial
Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with Pioglitazone + Metformin than in Patients Treated with Placebo + Metformin

% of Patients

Placebo
+ Metformin
N=160

Pioglitazone 30 mg
+ Metformin
N=168

Edema

2.5

6.0

Headache

1.9

6.0

24-Week Non-Controlled Double-Blind Trial Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with Pioglitazone 45 mg + Metformin than in Patients Treated with Pioglitazone 30 mg + Metformin

% of Patients

Pioglitazone 30 mg
+ Metformin
N=411

Pioglitazone 45 mg
+ Metformin
N=416

Upper Respiratory Tract Infection

12.4

13.5

Edema

5.8

13.9

Headache

5.4

5.8

Weight Increased

2.9

6.7

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of "edema."

Common Adverse Events: PROactive Trial

A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 3. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo.

  Table 3. PROactive Trial: Incidence and Types of Adverse Events Reported in >5% of Patients Treated with Pioglitazone and More Commonly than Placebo

% of Patients

Placebo

N=2633

Pioglitazone

N=2605

Hypoglycemia

18.8

27.3

Edema

15.3

26.7

Cardiac Failure

6.1

8.1

Pain in Extremity

5.7

6.4

Back Pain

5.1

5.5

Chest Pain

5.0

5.1

Mean duration of patient follow-up was 34.5 months.

Congestive Heart Failure

A summary of the incidence of adverse events related to congestive heart failure is provided in Table 4 for the 16- to 24-week add-on to metformin trials. None of the events were fatal.

 
Table 4. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) Patients Treated with Pioglitazone or Placebo Added on to Metformin

Number (%) of Patients

Placebo-Controlled Trial
(16 weeks)

Non-Controlled
Double Blind Trial
(24 weeks)

Placebo
+ Metformin
N=160

Pioglitazone
30 mg
+ Metformin
N=168

Pioglitazone
30 mg
+ Metformin
N=411

Pioglitazone
45 mg
+ Metformin
N=416

At least one congestive heart failure event

0

1 (0.6%)

0

1 (0.2%)

Hospitalized

0

1 (0.6%)

0

1 (0.2%)



Table 5. Treatment–Emergent Adverse Events of Congestive Heart Failure (CHF)

Patients Treated with Pioglitazone or Placebo Added on to a Sulfonylurea

Number (%) of Patients

Placebo-Controlled Trial
(16 weeks)

Non-Controlled Double Blind
Trial
(24 weeks)

Placebo
+ Sulfonylurea
N=187

Pioglitazone
15 mg
+ Sulfonylurea
N=184

Pioglitazone
30 mg
+ Sulfonylurea
N=189

Pioglitazone
30 mg
+ Sulfonylurea
N=351

Pioglitazone
45 mg
+ Sulfonylurea
N=351

At least one congestive
heart failure event

2 (1.1%)

0

0

1 (0.3%)

6 (1.7%)

Hospitalized

2 (1.1%)

0

0

0

2 (0.6%)

Patients Treated with Pioglitazone or Placebo Added on to Insulin

Number (%) of Patients

Placebo-Controlled Trial
(16 weeks)

Non-Controlled Double Blind
Trial
(24 weeks)

Placebo
+ Insulin
N=187

Pioglitazone
15 mg
+ Insulin
N=191

Pioglitazone
30 mg
+ Insulin
N=188

Pioglitazone
30 mg
+ Insulin
N=345

Pioglitazone
45 mg
+ Insulin
N=345

At least one congestive
heart failure event

0

2 (1.0%)

2 (1.1%)

3 (0.9%)

5 (1.4%)

Hospitalized

0

2 (1.0%)

1 (0.5%)

1 (0.3%)

3 (0.9%)

Patients Treated with Pioglitazone or Placebo Added on to Metformin

Number (%) of Patients

Placebo-Controlled Trial
(16 weeks)

Non-Controlled Double Blind
Trial
(24 weeks)

Placebo
+ Metformin
N=160

Pioglitazone
30 mg
+ Metformin
N=168

Pioglitazone
30 mg
+ Metformin
N=411

Pioglitazone
45 mg
+ Metformin
N=416

At least one congestive
heart failure event

0

1 (0.6%)

0

1 (0.2%)

Hospitalized

0

1 (0.6%)

0

1 (0.2%)

 
Table 6. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in Patients with NYHA Class II or III Congestive Heart Failure Treated with Pioglitazone or Glyburide

Number (%) of Subjects

Pioglitazone
N=262

Glyburide
N=256

Death due to cardiovascular causes (adjudicated)

5 (1.9%)

6 (2.3%)

Overnight hospitalization for worsening CHF (adjudicated)

26 (9.9%)

12 (4.7%)

Emergency room visit for CHF (adjudicated)

4 (1.5%)

3 (1.2%)

Patients experiencing CHF progression during study

35 (13.4%)

21 (8.2%)

Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 7.

  Table 7. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in PROactive Trial

Number (%) of Patients

Placebo
N=2633

Pioglitazone
N=2605

  At least one hospitalized congestive heart failure event

108 (4.1%)

149 (5.7%)

  Fatal

22 (0.8%)

25 (1%)

  Hospitalized, non-fatal

86 (3.3%)

124 (4.7%)

Cardiovascular Safety

In the PROactive trial, 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins and fibrates). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years, and mean HbA1c of 8.1%. Mean duration of follow-up was 34.5 months.

The primary objective of this trial was to examine the effect of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, non-fatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg. A total of 514 (19.7%) patients treated with pioglitazone and 572 (21.7%) patients treated with placebo experienced at least one event from the primary composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p=0.10).

Although there was no statistically significant difference between pioglitazone and placebo for the 3-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with pioglitazone. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 8.

Table 8. PROactive: Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint

Cardiovascular Events

Placebo
N=2633

Pioglitazone
N=2605

First Events
n (%)

Total Events
n

First Events
n (%)

Total Events
n

Any event

572 (21.7)

900

514 (19.7)

803

  All-cause mortality

122 (4.6)

186

110 (4.2)

177

  Non-fatal myocardial infarction (MI)

118 (4.5)

157

105 (4.0)

131

  Stroke

96 (3.6)

119

76 (2.9)

92

  Acute coronary syndrome

63 (2.4)

78

42 (1.6)

65

  Cardiac intervention (CABG/PCI)

101 (3.8)

240

101 (3.9)

195

  Major leg amputation

15 (0.6)

28

9 (0.3)

28

  Leg revascularization

57 (2.2)

92

71 (2.7)

115

CABG = coronary artery bypass grafting; PCI = percutaneous intervention

Weight Gain

Dose-related weight gain occurs when pioglitazone is used alone or in combination with other anti-diabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Tables 9 and 10 summarize the changes in body weight with pioglitazone and placebo in the 16- to 26-week randomized, double-blind monotherapy and 16- to 24-week combination add-on therapy trials and in the PROactive trial.


Table 9. Weight Changes (kg) from Baseline during Randomized, Double-Blind Clinical Trials

Control
Group
(Placebo)

Pioglitazone
15 mg

Pioglitazone
30 mg

Pioglitazone
45 mg

Median
(25th/75th
percentile)

Median
(25th/75th
percentile)

Median
(25th/75th
percentile)

Median
(25th/75th
percentile)

Monotherapy (16 to 26 weeks)

-1.4 (-2.7, 0.0)
N=256

0.9 (-0.5, 3.4)
N=79

1.0 (-0.9, 3.4)
N=188

  2.6 (0.2, 5.4)
N=79

Combination
Therapy
(16 to 24 weeks)

Sulfonylurea

-0.5 (-1.8, 0.7)
N=187

2.0 (0.2, 3.2)
N=183

3.1 (1.1, 5.4)
N=528

  4.1 (1.8, 7.3)
N=333

Metformin

-1.4 (-3.2, 0.3)
N=160

N/A

0.9 (-1.3, 3.2)
N=567

  1.8 (-0.9, 5.0)
N=407

Insulin

0.2 (-1.4, 1.4)
N=182

2.3 (0.5, 4.3)
N=190

3.3 (0.9, 6.3)
N=522

  4.1 (1.4, 6.8)
N=338
  Table 10. Median Change in Body Weight in Patients Treated with Pioglitazone Versus Patients Treated with Placebo During the Double-Blind Treatment Period in the PROactive Trial

Placebo

Pioglitazone

Median
(25th, 75th
percentile)

Median
(25th, 75th
percentile)

Change from Baseline to Final Visit (kg)

-0.5 (-3.3, 2.0)
N=2581

+3.6 (0.0, 7.5)
N=2560

Note: Median exposure for both Pioglitazone and Placebo was 2.7 years.

Edema

Edema induced from taking pioglitazone is reversible when pioglitazone is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure. A summary of the frequency and types of edema adverse events occurring in clinical investigations of pioglitazone is provided in Table 11.


Table 11. Adverse Events of Edema in Patients Treated with Pioglitazone

Number (%) of Patients

Placebo

Pioglitazone
15 mg

Pioglitazone
30 mg

Pioglitazone
45 mg

  Monotherapy (16 to 26 weeks)

3 (1.2%)
N=259

2 (2.5%)
N=81

13 (4.7%)
N=275

11 (6.5%)
N=169

Combined
Therapy
(16 to 24 weeks)

Sulfonylurea

4 (2.1%)
N=187

3 (1.6%)
N=184

61 (11.3%)
N=540

81 (23.1%)
N=351

Metformin

4 (2.5%)
N=160

N/A

34 (5.9%)
N=579

58 (13.9%)
N=416

Insulin

13 (7.0%)
N=187

24 (12.6%)
N=191

109 (20.5%)
N=533

90 (26.1%)
N=345

  Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of "edema."
  Table 12. Adverse Events of Edema in Patients in the PROactive Trial

Number (%) of Patients

Placebo
N=2633

Pioglitazone
N=2605

419 (15.9%)

712 (27.3%)

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of "edema."

Hepatic Effects

There has been no evidence of pioglitazone-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date. One randomized, double-blind, 3-year trial comparing pioglitazone to glyburide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than three times the upper limit of the reference range, measured every 8 weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with pioglitazone and 9/1046 (0.9%) patients treated with glyburide developed ALT values >three times the upper limit of the reference range. None of the patients treated with pioglitazone in the pioglitazone controlled clinical trial database to date have had a serum ALT >three times the upper limit of the reference range and a corresponding total bilirubin >two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.

Hypoglycemia

In the pioglitazone clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing.

In the 16-week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with pioglitazone 30 mg and 0.5% with placebo. In the 16-week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with pioglitazone 15 mg, 15.4% with pioglitazone 30 mg, and 4.8% with placebo.

The incidence of reported hypoglycemia was higher with pioglitazone 45 mg compared to pioglitazone 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% vs. 13.4%) and in the 24-week add-on to insulin trial (47.8% vs. 43.5%).

Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving pioglitazone 30 mg (0.9%) in the 24-week add-on to insulin trial. An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient's usual activities) that did not require hospitalization. These patients were receiving pioglitazone 45 mg in combination with sulfonylurea (n=2) or pioglitazone 30 mg or 45 mg in combination with insulin (n=12).

Urinary Bladder Tumors

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology (13.1)]. During the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR =1.00; 95% CI: 0.59-1.72) [see Warnings and Precautions (5.6)].

Metformin hydrochloride

In a double-blind clinical study of metformin in patients with type 2 diabetes, a total of 141 patients received metformin therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin patients, and that were more common in metformin than patients treated with placebo, are listed in Table 13. In this trial, diarrhea led to discontinuation of study medication in 6% of patients treated with metformin.

* Reactions that were more common in metformin than patients treated with placebo.
  Table 13. Most Common Adverse Reactions (>5.0%) in a Placebo-Controlled Clinical Study of Metformin Monotherapy*

Adverse Reaction

Metformin Monotherapy
(n=141)

Placebo
(n=145)

% of Patients

Diarrhea

53.2

11.7

Nausea/Vomiting

25.5

8.3

Flatulence

12.1

5.5

Asthenia

9.2

5.5

Indigestion

7.1

4.1

Abdominal Discomfort

6.4

4.8

Headache

5.7

4.8

Laboratory Abnormalities

Hematologic Effects

Pioglitazone may cause decreases in hemoglobin and hematocrit. In placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone compared with a mean change in hemoglobin of -1% to +1% in patients treated with placebo. These changes primarily occurred within the first four to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with pioglitazone therapy and are not likely to be associated with any clinically significant hematologic effects.

Vitamin B12 concentrations

Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on Actoplus Met XR and any apparent abnormalities should be appropriately investigated and managed [see Warnings and Precautions (5.9)].

Creatine Phosphokinase

During protocol-specified measurement of serum creatine phosphokinase (CPK) in pioglitazone clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in 9 (0.2%) patients treated with pioglitazone (values of 2150 to 11400 IU/L) and in no patients treated with comparator. Six of these nine patients continued to receive pioglitazone, two patients were noted to have the CPK elevation on the last day of dosing, and one patient discontinued pioglitazone due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown.

Postmarketing Experience

Pioglitazone

The following adverse reactions have been identified during post-approval use of pioglitazone. 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.

• New onset or worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions (5.8)]. • Fatal and non-fatal hepatic failure [see Warnings and Precautions (5.5)].

Postmarketing reports of congestive heart failure have been reported in patients treated with pioglitazone, both with and without previously known heart disease and both with and without concomitant insulin administration.

In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)].

Drug Interactions

Strong CYP2C8 Inhibitors

An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t½) of pioglitazone. Therefore, the maximum recommended dose of pioglitazone is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

CYP2C8 Inducers

An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for pioglitazone [see Clinical Pharmacology (12.3)].

Carbonic Anhydrase Inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with Actoplus Met XR may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

Drugs that Reduce Metformin Clearance

Drugs that are eliminated by renal tubular secretion (e.g., cationic drugs such as cimetidine) have the potential for interaction with metformin by competing for common renal tubular transport systems, and may increase the accumulation of metformin and the risk for lactic acidosis [see Clinical Pharmacology (12.3)]. Consider more frequent monitoring of these patients.

Alcohol

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving Actoplus Met XR.

Insulin Secretagogues or Insulin

If hypoglycemia occurs in a patient coadministered Actoplus Met XR and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient coadministered Actoplus Met XR and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.

Drugs Affecting Glycemic Control

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 blockers, and isoniazid. When such drugs are administered to a patient receiving Actoplus Met XR, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Actoplus Met XR, the patient should be observed closely for hypoglycemia.

Overdosage

Pioglitazone

During controlled clinical trials, one case of overdose with pioglitazone was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.

In the event of overdosage, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

Metformin hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.2)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated metformin from patients in whom metformin overdosage is suspected.

Actoplus Met XR Precautions

Serious side effects have been reported with Actoplus Met XR including the following:

  • Congestive heart failure. Tell your healthcare provider right away if you have some or all of the following symptoms of congestive heart failure.
    • large weight gain in a short period of time
    • shortness of breath
    • swelling of the arms, hands, feet, ankles, or lower legs
    • swelling or pain in the stomach
    • waking up short of breath during the night
    • needing to sleep with extra pillows under your head in order to breathe easier while lying down
    • frequent dry cough or wheezing
    • difficulty thinking clearly or confusion
    • fast or racing heart beat
    • not able to walk or exercise as well
    • increased tiredness
  • Lactic acidosis. Tell your healthcare provider right away if you have some or all of the following symptoms of congestive heart failure.
    • Extreme tiredness
    • Weakness or discomfort
    • Unusual or unexpected stomach pain
    • Decreased appetite
    • Deep and rapid breathing or shortness of breath
    • Dizziness
    • Lightheadedness
    • Fast or slow heart beat
    • Flushing of the skin
    • Muscle pain
    • Feeling cold
  • Hypoglycemia (low blood sugar). Tell your healthcare provider right away if you have some or all of the following symptoms of hypoglycemia.
    • Lightheadedness
    • Dizziness
    • Shakiness
    • Hunger
    • Blurred vision
  • Liver problems. Tell your healthcare provider right away if you have some or all of the following symptoms of liver problems.
    • Nausea
    • Vomiting
    • Loss of appetite
    • Pain in the upper right part of the abdomen
    • Flu-like symptoms
    • Dark urine
    • Yellowing of the skin or eyes
    • Unusual bleeding or bruising
    • Lack of energy
  • Ovulation. Pioglitazone, like other thiazolidinediones, may stimulate ovulation in premenopausal women and increase the chance of pregnancy.

Do not take Actoplus Met XR if you:

  • are allergic to Actoplus Met XR or to any of its ingredients
  • have NYHA Class III or IV heart failure
  • have kidney problems
  • have metabolic acidosis

Actoplus Met XR and Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed.

No studies of the combination of ingredients in Actoplus Met XR have been evaluated in nursing women. The individual components have been detected in human breast milk. Because of the possibility for adverse reactions in nursing infants from Actoplus Met XR, a choice should be made whether to stop nursing or to stop use of this medication. The importance of the drug to the mother should be considered. 

For Healthcare Professionals

Applies to metformin / pioglitazone: oral tablet, oral tablet extended release

Cardiovascular

Metformin-pioglitazone:
Common (1% to 10%): Edema

Pioglitazone:
Very common (10% or more): Edema (26.7%)
Common (1% to 10%): Cardiac failure, chest pain[Ref]

Thiazolidinediones, including pioglitazone can cause dose-related fluid retention which can cause or exacerbate congestive heart failure in some patients. Combination with insulin and use in patients with NYHA Class I and II congestive heart failure may increase risk.[Ref]

Gastrointestinal

Metformin-pioglitazone:
Very common (10% or more): Abdominal pain, diarrhea, loss of appetite, nausea, vomiting
Uncommon (0.1% to 1%): Flatulence

Metformin:
Very common (10% or more): Abdominal pain, diarrhea, loss of appetite, nausea, vomiting[Ref]

Gastrointestinal events occur most frequently during initiation of therapy and resolve spontaneously in most cases.[Ref]

Hematologic

Metformin-pioglitazone
Common (1% to 10%): Anemia
Very rare (less than 0.01%): Vitamin B12 absorption decreased, lactic acidosis

Metformin:
Very rare (less than 0.01%): Vitamin B12 absorption decreased, lactic acidosis[Ref]

Metabolic

Metformin-pioglitazone:
Common (1% to 10%): Weight increased

Pioglitazone:
Very common (10% or more): Hypoglycemia (27.3%)
Common (1% to 10%): Weight gain[Ref]

Mean weight increase in patients receiving pioglitazone monotherapy for 1 year was 2 to 3 kg. In combination with metformin, mean weight increase over 1 year was 1.5 kg. The mechanism of weight gain is unclear, but probably involves a combination of fluid retention and fat accumulation.[Ref]

Respiratory

Metformin-pioglitazone
Common (1% to 10%): Upper respiratory infection
Uncommon (0.1% to 1%): Sinusitis

Pioglitazone:
Common (1% to 10%): Upper respiratory infection, pharyngitis
Uncommon (0.1% to 1%): Sinusitis[Ref]

Nervous system

Metformin-pioglitazone:
Common (1% to 10%): Hypoesthesia, headache, taste disturbance
Uncommon (0.1% to 1%): Insomnia

Metformin:
Common (1% to 10%): Taste disturbance

Pioglitazone:
Common (1% to 10%): Hypoesthesia, headache[Ref]

Ocular

Visual disturbances have been reported early in treatment and may be related to changes in blood glucose due to temporary alteration in the turgidity and refractive index of the lens. Macular edema has been reported postmarketing in patients taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, although some were diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at time of diagnosis. Some patients improved with drug discontinuation.[Ref]

Metformin-pioglitazone:
Common (1% to 10%): Visual disturbances
Postmarketing reports: Macular edema

Pioglitazone:
Common (1% to 10%): Visual disturbances
Frequency not reported: Macular edema[Ref]

Dermatologic

Metformin-pioglitazone:
Very rare (less than 0.01%): Erythema, pruritus, urticaria

Metformin:
Very rare (less than 0.01%): Erythema, pruritus, urticaria[Ref]

Endocrine

Common (1% to 10%): Erectile dysfunction[Ref]

General

The most commonly reported adverse events included upper respiratory tract infection, edema, diarrhea, headache, and weight gain.[Ref]

Hepatic

There have been postmarketing reports of hepatic failure, including fatalities, in patients taking pioglitazone. The reports contain insufficient information to establish causality.[Ref]

Metformin-pioglitazone:
Frequency not reported: Hepatitis, alanine aminotransferase increased, abnormal liver function tests

Metformin:
Frequency not reported: Hepatitis, abnormal liver function tests

Pioglitazone:
Frequency not reported: Alanine aminotransferase increased
Postmarketing reports: Hepatic failure[Ref]

Musculoskeletal

In pooled analysis of bone fractures in 8100 patients receiving pioglitazone and 7400 receiving comparator treatment; a higher rate of fractures was observed in women receiving pioglitazone (2.6% versus 1.7%). Some epidemiologic studies have suggested a similarly increased risk of fracture in men.[Ref]

Metformin-pioglitazone:
Common (1% to 10%): Bone fracture, arthralgia

Pioglitazone:
Common (1% to 10%): Bone fracture, myalgia, extremity pain, back pain
Uncommon (0.1% to 1%): Serum creatine phosphokinase elevations[Ref]

Oncologic

The US FDA has released results of its review of pioglitazone and bladder cancer and concluded that the data suggests use of this drug may be linked to an increase risk of bladder cancer. A 10-year prospective cohort study in diabetic patients performed by the manufacturer (n=158,918 never users; n=34,181 ever users) identified 1075 newly diagnosed cases of bladder cancer in never users and 186 cases in ever users. The fully adjusted hazard ratio (HR) showed pioglitazone use was not associated with an increased risk (HR 1.06 (95% confidence interval 0.89 to 1.26). And while a modest trend towards higher risk with increasing duration was observed, this trend was not statistically significant. Compared to the interim 5-year results, the 10-year results found weaker associations that were not statistically significant. However, there are studies that have shown a statistically significant association between exposure to this drug and bladder cancer and an association between cumulative dose or cumulative duration of exposure and bladder cancer. Overall, this drug may be associated with an increase in the risk of urinary bladder tumors, however there is insufficient data to determine whether this drug is a tumor promoter for urinary bladder tumors.[Ref]

Metformin-pioglitazone
Uncommon (0.1% to 1%): Bladder cancer

Pioglitazone:
Uncommon (0.1% to 1%): Bladder cancer[Ref]

Renal

Common (1% to 10%): Hematuria[Ref]

Hypersensitivity

Metformin-pioglitazone:
Postmarketing reports: Hypersensitivity and allergic reactions (anaphylaxis, angioedema, and urticaria)

Pioglitazone:
Postmarketing reports: Hypersensitivity and allergic reactions (anaphylaxis, angioedema, and urticaria)[Ref]

Some side effects of ActoPlus Met XR may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

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