Actos

Name: Actos

Pioglitazone Interactions

Tell your doctor about all prescription, non-prescription, illegal, recreational, herbal, nutritional, or dietary drugs you're taking, especially:

  • Atorvastatin (Lipitor)
  • Gemfibrozil (Lopid)
  • Contraceptives, such as birth-control pills, patches, rings, implants, and injections
  • Diabetes medications
  • Insulin
  • Ketoconazole (Nizoral)
  • Midazolam (Versed)
  • Nifedipine (Procardia)
  • Rifampin (Rifadin, Rifater, Rimactance, in Rifamate)

Pioglitazone and Alcohol

Alcohol can cause your blood-sugar levels to decrease.

Ask your doctor if it's safe for you to consume alcoholic beverages while taking pioglitazone.

Is Actos (pioglitazone) available as a generic drug?

Yes

Do I need a prescription for Actos (pioglitazone)?

Yes

Drug interactions

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Other medications can affect the removal of pioglitazone from your body, which may affect how pioglitazone works. Examples include gemfibrozil, rifamycins including rifampin, among others.Beta-blocker medications (such as metoprolol, propranolol, glaucoma eye drops such as timolol) may prevent the fast/pounding heartbeat you would usually feel when your blood sugar level falls too low (hypoglycemia). Other symptoms of low blood sugar, such as dizziness, hunger, or sweating, are unaffected by these drugs.Many drugs can affect your blood sugar levels, making it more difficult to control your blood sugar. Before you start, stop, or change any medication, talk with your doctor or pharmacist about how the medication may affect your blood sugar. Check your blood sugar levels regularly as directed by your doctor. Tell your doctor about the results and of any symptoms of high or low blood sugar. (See also Side Effects section.) Your doctor may need to adjust your anti-diabetic medication, exercise program, or diet.

Pioglitazone side effects

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using pioglitazone and call your doctor at once if you have symptoms of liver damage: nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

Call your doctor at once if you have:

  • shortness of breath (even with mild exertion), swelling, rapid weight gain;

  • pink or red urine, painful or difficult urination, new or worsening urge to urinate;

  • changes in your vision; or

  • sudden unusual pain in your hand, arm, or foot.

Common side effects may include:

  • headache;

  • muscle pain; or

  • cold symptoms such as stuffy nose, sinus pain, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Uses for Actos

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Diabetes Mellitus

Used alone or in combination with a sulfonylurea, metformin, or insulin as an adjunct to diet and exercise to improve glycemic control in patients with type 2 (noninsulin-dependent) diabetes mellitus (NIDDM).1 2 14 27 28 Should be added to, not substituted for, other antidiabetic agents in patients whose NIDDM is not adequately controlled by these agents.13

May be added to glyburide/metformin fixed combination therapy if hyperglycemia is not adequately controlled with the fixed combination.14 May be used in combination with repaglinide if hyperglycemia is not adequately controlled with diet, exercise, and monotherapy with another oral antidiabetic agent.17

Not effective as sole therapy for type 1 diabetes mellitus or diabetic ketoacidosis.1

Actos Dosage and Administration

Administration

Oral Administration

Administer pioglitazone once daily without regard to meals.1

Administer fixed combination of pioglitazone and immediate-release metformin hydrochloride (ActoPlus Met) once or twice daily with meals to reduce the GI effects of metformin component.27

Administer fixed combination of pioglitazone and extended-release metformin hydrochloride (ActoPlus Met XR) once daily with the evening meal to reduce GI effects of metformin component.27

Administer fixed combination of pioglitazone and glimepiride (Duetact) once daily with the first main meal.28

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as pioglitazone hydrochloride; dosage expressed in terms of pioglitazone.1

Initiation or discontinuance of a CYP2C8 inducer during pioglitazone therapy may necessitate changes in antidiabetic therapy.1 (See Interactions.)

If a potent CYP2C8 inhibitor is used concomitantly, reduction of the maximum daily pioglitazone dosage is recommended.1 (See Interactions.)

Adults

Diabetes Mellitus Monotherapy Oral

Initially, 15 or 30 mg once daily.1 If response inadequate, increase dosage gradually up to maximum of 45 mg daily.1

Allow sufficient time (8–12 weeks) to evaluate adequacy of response as determined by HbA1c unless glycemic control based on fasting plasma glucose deteriorates.27

Pioglitazone/Immediate-release Metformin Hydrochloride Fixed-combination Therapy (ActoPlus Met) Oral

Base initial dosage of fixed combination on patient's current dosage of pioglitazone and/or immediate-release metformin hydrochloride and on usual initial dosages of these drugs.27

Initially, 15 mg of pioglitazone and 500 or 850 mg of immediate-release metformin hydrochloride once or twice daily.27

Gradually titrate dosage based on adequacy of therapeutic response.27 Allow sufficient time (8–12 weeks) to evaluate adequacy of response as determined by HbA1c unless glycemic control based on fasting plasma glucose deteriorates.27

Pioglitazone/Extended-release Metformin Hydrochloride Fixed-combination Therapy (ActoPlus Met XR) Oral

Base initial dosage of fixed combination on patient's current dosage of pioglitazone and/or extended-release metformin hydrochloride and on usual initial dosages of these drugs.27

Initially, 15 or 30 mg of pioglitazone and 1 g of extended-release metformin hydrochloride once daily.1

Gradually titrate dosage based on adequacy of therapeutic response.27 Allow sufficient time (8–12 weeks) to evaluate adequacy of response as determined by HbA1c unless glycemic control based on fasting plasma glucose deteriorates.27

Pioglitazone/Glimepiride Fixed-combination Therapy (Duetact) Oral

Base initial dosage of fixed combination on patient's current dosage of pioglitazone and/or sulfonylurea (e.g., glimepiride).28

Patients currently receiving glimepiride monotherapy: Initially, 30 mg of pioglitazone and 2 or 4 mg of glimepiride once daily.28

Patients currently receiving pioglitazone monotherapy: Initially, 30 mg of pioglitazone and 2 mg of glimepiride once daily.28

Patients switching from combined therapy with separate pioglitazone and glimepiride preparations: Usual initial dosage of the fixed combination is the same as the patient's existing dosage of the individual drugs.28 When switching to the fixed combination, carefully monitor patients with inadequate glycemic control on pioglitazone 15 mg daily in combination with glimepiride.28

Patients switching from monotherapy with a sulfonylurea other than glimepiride (e.g., glyburide, glipizide, chlorpropamide, tolbutamide, acetohexamide) or from combined therapy with pioglitazone plus a sulfonylurea other than glimepiride: Initially, 30 mg of pioglitazone and 2 mg of glimepiride once daily; no exact dosage relationship exists between glimepiride and other sulfonylureas.28

Gradually titrate dosage based on adequacy of therapeutic response.28 Allow sufficient time (8–12 weeks) to evaluate adequacy of response as determined by HbA1c unless glycemic control based on fasting plasma glucose deteriorates.28

Prescribing Limits

Adults

Maximum 45 mg daily (as monotherapy or in combination with a sulfonylurea, metformin, or insulin).1 27 28

Special Populations

Hepatic Impairment

Monotherapy

No dosage adjustment necessary.1

Pioglitazone/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

Do not initiate in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).27

Pioglitazone/Glimepiride Fixed-combination Therapy

Initially, glimepiride 1 mg daily as monotherapy, followed by conservative initial and maintenance dosages of the fixed combination; individuals with hepatic impairment may be particularly sensitive to the hypoglycemic effects of glimepiride.28

Do not initiate in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).28

Renal Impairment

Monotherapy

No dosage adjustment necessary.1

Pioglitazone/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

Do not use in patients with renal impairment.27

Pioglitazone/Glimepiride Fixed-combination Therapy

Initially, glimepiride 1 mg daily as monotherapy, followed by conservative initial and maintenance dosages of the fixed combination; individuals with renal impairment may be particularly sensitive to the hypoglycemic effects of glimepiride.28

Geriatric Patients

Monotherapy

No dosage adjustment necessary.1

Pioglitazone/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

Conservative initial and maintenance dosages recommended; geriatric individuals are particularly sensitive to hypoglycemic effects.27 Generally, do not titrate to maximum recommended dosage.27

Pioglitazone/Glimepiride Fixed-combination Therapy

Initially, glimepiride 1 mg daily as monotherapy, followed by conservative initial and maintenance dosages of the fixed combination; geriatric individuals may be particularly sensitive to the hypoglycemic effects of glimepiride.28

Patients with CHF

NYHA class III or IV heart failure: Use contraindicated.1 27 28

Monotherapy

NYHA class I or II heart failure: Initially, 15 mg once daily.1 Increase dosage gradually, if needed, up to maximum of 45 mg daily based on HbA1c concentrations.1 Monitor carefully for weight gain, edema, or other manifestations of CHF exacerbation following initiation and dosage increase.1

Pioglitazone/Glimepiride Fixed-combination Therapy

Systolic dysfunction: Initially, pioglitazone 15 mg once daily as monotherapy; safely titrate dosage to 30 mg once daily as monotherapy before initiating the fixed combination of glimepiride 2 mg and pioglitazone 30 mg.28 If subsequent dosage adjustment is necessary with the fixed-combination preparation, monitor closely for weight gain, edema, or other manifestations of CHF exacerbation.28

Debilitated or Malnourished Patients

Pioglitazone/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

Generally, do not titrate to maximum recommended dosage; these individuals are particularly susceptible to hypoglycemic effects.27

Pioglitazone/Glimepiride Fixed-combination Therapy

Initially, glimepiride 1 mg daily as monotherapy, followed by conservative initial and maintenance dosages of the fixed combination; these individuals are particularly susceptible to hypoglycemic effects.28

Patients with Adrenal or Pituitary Insufficiency

Pioglitazone/Glimepiride Fixed-combination Therapy

Initially, glimepiride 1 mg daily as monotherapy, followed by conservative initial and maintenance dosages of the fixed combination; these individuals are particularly susceptible to hypoglycemic effects.28

Actions

  • Structurally and pharmacologically related to rosiglitazone and troglitazone (no longer commercially available in the US);1 8 9 1 12 unrelated to other antidiabetic agents (e.g., sulfonylureas, biguanides, α-glucosidase inhibitors).1 12

  • A peroxisome proliferator-activated receptorγ (PPARγ) agonist; increases transcription of insulin-responsive genes.1

  • Increases insulin sensitivity in target tissues and decreases hepatic gluconeogenesis.1 Ameliorates insulin resistance associated with type 2 diabetes mellitus without increasing insulin secretion from pancreatic β cells.1 Does not lower glucose concentrations below euglycemia.1

  • Ineffective in absence of insulin.1

Proper Use of Actos

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. Exercise regularly and test for sugar in your blood or urine as directed.

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

The tablets may be taken with or without food.

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:
      • Adults—At first, 15 or 30 milligrams (mg) once a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 45 mg once a day.
      • 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.

Precautions While Using Actos

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.

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.

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 a serious heart problem.

If you have abdominal or stomach pain, dark urine, a loss of appetite, nausea or vomiting, unusual tiredness or weakness, or yellow eyes or skin, check with your doctor right away. These may be symptoms of a serious liver problem.

Check with your doctor right away if blurred vision, decreased vision, or any other change in vision occurs while you are taking 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). However, low blood sugar can occur if you delay or miss a meal or snack, exercise more than usual, drink alcohol, 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 of 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.

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.

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.
  • Bone pain.
  • Feeling very tired or weak.
  • Change in eyesight.
  • Pain when passing urine or blood in urine.
  • Passing urine more often.
  • 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.
  • Very bad and sometimes deadly liver problems have happened with this medicine (Actos). Call your doctor right away if you have 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.

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)] • Edema [see Warnings and Precautions (5.5)] • Fractures [see Warnings and Precautions (5.6)]

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.

Over 8500 patients with type 2 diabetes have been treated with Actos in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with Actos in the PROactive clinical trial. In these trials, over 6000 patients have been treated with Actos for six months or longer, over 4500 patients have been treated with Actos for one year or longer, and over 3000 patients have been treated with Actos 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 Actos and 5.8% for comparator-treated patients. 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 Actos than with placebo (3.0%).

In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with Actos and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with Actos 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 Actos 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 Actos than in patients who received placebo. None of these adverse events were related to Actos dose.

Table 1. Three Pooled 16- to 26-Week Placebo-Controlled Clinical Trials of Actos Monotherapy: Adverse Events Reported at an Incidence >5% and More Commonly in Patients Treated with Actos than in Patients Treated with Placebo
% of Patients
Placebo
N=259
Actos
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 Actos add-on to sulfonylurea 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 Actos.

Table 2. 16- to 24-Week Clinical Trials of Actos Add-on to Sulfonylurea

16-Week Placebo-Controlled Trial
Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with Actos 30 mg + Sulfonylurea than in Patients Treated with Placebo + Sulfonylurea

% of Patients

Placebo
+ Sulfonylurea
N=187

Actos 15 mg
+ Sulfonylurea
N=184

Actos 30 mg
+ Sulfonylurea
N=189

Edema

2.1

1.6

12.7

Headache

3.7

4.3

5.3

Flatulence

0.5

2.7

6.3

Weight Increased

0

2.7

5.3

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

% of Patients

Actos 30 mg
+ Sulfonylurea
N=351

Actos 45 mg
+ Sulfonylurea
N=351

Hypoglycemia

13.4

15.7

Edema

10.5

23.1

Upper Respiratory Tract Infection

12.3

14.8

Weight Increased

9.1

13.4

Urinary Tract Infection

5.7

6.8

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

A summary of the overall incidence and types of common adverse events reported in trials of Actos add-on to metformin is provided in Table 3. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of Actos.

Table 3. 16- to 24-Week Clinical Trials of Actos Add-on to Metformin

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

% of Patients

Placebo
+ Metformin
N=160

Actos 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 Actos 45 mg + Metformin than in Patients Treated with Actos 30 mg + Metformin

% of Patients

Actos 30 mg
+ Metformin
N=411

Actos 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."

Table 4 summarizes the incidence and types of common adverse events reported in trials of Actos add-on to insulin. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of Actos.

Table 4. 16- to 24-Week Clinical Trials of Actos Add-on to Insulin

16-Week Placebo-Controlled Trial
Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with Actos 30 mg + Insulin than in Patients Treated with Placebo + Insulin

% of Patients

Placebo
+ Insulin
N=187

Actos 15 mg
+ Insulin
N=191

Actos 30 mg
+ Insulin
N=188

Hypoglycemia

4.8

7.9

15.4

Edema

7.0

12.6

17.6

Upper Respiratory Tract Infection

9.6

8.4

14.9

Headache

3.2

3.1

6.9

Weight Increased

0.5

5.2

6.4

Back Pain

4.3

2.1

5.3

Dizziness

3.7

2.6

5.3

Flatulence

1.6

3.7

5.3

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

% of Patients

Actos 30 mg
+ Insulin
N=345

Actos 45 mg
+ Insulin
N=345

Hypoglycemia

43.5

47.8

Edema

22.0

26.1

Weight Increased

7.2

13.9

Urinary Tract Infection

4.9

8.7

Diarrhea

5.5

5.8

Back Pain

3.8

6.4

Blood Creatine Phosphokinase Increased

4.6

5.5

Sinusitis

4.6

5.5

Hypertension

4.1

5.5

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

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

Table 5. PROactive Trial: Incidence and Types of Adverse Events Reported in >5% of Patients Treated with Actos and More Commonly than Placebo
% of Patients
Placebo
N=2633
Actos
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 6 for the 16- to 24-week add-on to sulfonylurea trials, for the 16- to 24-week add-on to insulin trials, and for the 16- to 24-week add-on to metformin trials. None of the events were fatal.

Table 6. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF)

Patients Treated with Actos 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

Actos 15 mg
+ Sulfonylurea
N=184

Actos 30 mg
+ Sulfonylurea
N=189

Actos 30 mg
+ Sulfonylurea
N=351

Actos 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 Actos 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

Actos 15 mg
+ Insulin
N=191

Actos 30 mg
+ Insulin
N=188

Actos 30 mg
+ Insulin
N=345

Actos 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 Actos 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

Actos 30 mg
+ Metformin
N=168

Actos 30 mg
+ Metformin
N=411

Actos 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%)

Patients with type 2 diabetes and NYHA class II or early class III congestive heart failure were randomized to receive 24 weeks of double-blind treatment with either Actos at daily doses of 30 mg to 45 mg (n=262) or glyburide at daily doses of 10 mg to 15 mg (n=256). A summary of the incidence of adverse events related to congestive heart failure reported in this study is provided in Table 7.

Table 7. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in Patients with NYHA Class II or III Congestive Heart Failure Treated with Actos or Glyburide
Number (%) of Subjects
Actos
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 8.

Table 8. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in PROactive Trial
Number (%) of Patients
Placebo
N=2633
Actos
N=2605

At least one hospitalized congestive heart failure event

108 (4.1%)

149 (5.7%)

Fatal

22 (0.8%)

25 (1.0%)

Hospitalized, nonfatal

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 Actos (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 Actos 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, nonfatal 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 Actos and 572 (21.7%) placebo-treated patients 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 Actos and placebo for the three-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with Actos. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 9.

Table 9. PROactive: Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint
Cardiovascular Events Placebo
N=2633
Actos
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

    Nonfatal 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 Actos is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Tables 10 and 11 summarize the changes in body weight with Actos 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 10. Weight Changes (kg) from Baseline During Randomized, Double-Blind Clinical Trials
Control Group
(Placebo)
Actos
15 mg
Actos
30 mg
Actos
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 11. Median Change in Body Weight in Patients Treated with Actos Versus Patients Treated with Placebo During the Double-Blind Treatment Period in the PROactive Trial

Placebo

Actos

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 Actos and Placebo was 2.7 years.

Edema

Edema induced from taking Actos is reversible when Actos 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 Actos is provided in Table 12.

Table 12. Adverse Events of Edema in Patients Treated with Actos
Number (%) of Patients
Placebo Actos
15 mg
Actos
30 mg
Actos
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 13. Adverse Events of Edema in Patients in the PROactive Trial
Number (%) of Patients
Placebo
N=2633
Actos
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 induced hepatotoxicity with Actos in the Actos controlled clinical trial database to date. One randomized, double-blind 3-year trial comparing Actos 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 eight weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with Actos and 9/1046 (0.9%) patients treated with glyburide developed ALT values greater than three times the upper limit of the reference range. None of the patients treated with Actos in the Actos controlled clinical trial database to date have had a serum ALT greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.

Hypoglycemia

In the Actos 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 Actos 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 Actos 15 mg, 15.4% with Actos 30 mg, and 4.8% with placebo.

The incidence of reported hypoglycemia was higher with Actos 45 mg compared to Actos 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 Actos 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 Actos 45 mg in combination with sulfonylurea (n=2) or Actos 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 Actos 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 Actos 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 Actos. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to Actos or placebo (HR =1.00; 95% CI: 0.59-1.72) [see Warnings and Precautions (5.4)].

Laboratory Abnormalities

Hematologic Effects

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

Creatine Phosphokinase

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

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Actos. 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 (5.7)]. • Fatal and nonfatal hepatic failure [see Warnings and Precautions (5.3)].

Postmarketing reports of congestive heart failure have been reported in patients treated with Actos, 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 (t1/2) of pioglitazone. Therefore, the maximum recommended dose of Actos 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 Actos, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for Actos [see Clinical Pharmacology (12.3)].

Actos Drug Class

Actos is part of the drug class:

  • Thiazolidinediones

Actos and Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known if Actos passes into your milk and if it can harm your baby. You should not take Actos if you breastfeed your baby. Talk to your doctor about the best way to control your blood glucose levels while breastfeeding.

Pediatric

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

Pregnancy

Information about this pioglitazone-oral-route
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.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. You may have signs of low blood sugar, such as extreme weakness, blurred vision, sweating, trouble speaking, tremors, stomach pain, confusion, and seizure (convulsions).

Actos side effects

Get emergency medical help if you have signs of an allergic reaction to Actos: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using Actos and call your doctor at once if you have symptoms of liver damage: nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

Call your doctor at once if you have:

  • shortness of breath (even with mild exertion), swelling, rapid weight gain;

  • pink or red urine, painful or difficult urination, new or worsening urge to urinate;

  • changes in your vision; or

  • sudden unusual pain in your hand, arm, or foot.

Common Actos side effects may include:

  • headache;

  • muscle pain; or

  • cold symptoms such as stuffy nose, sinus pain, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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