Actos

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Pioglitazone is usually taken once daily. You may take the medicine with or without food.

Your blood sugar will need to be checked often, and you may need other blood tests at your doctor's office.

Low blood sugar (hypoglycemia) can happen to everyone who has diabetes. Symptoms include headache, hunger, sweating, pale skin, irritability, dizziness, feeling shaky, or trouble concentrating.

Keep a source of sugar with you in case you have low blood sugar. Sugar sources include fruit juice, hard candy, crackers, raisins, and non-diet soda. Be sure your family and close friends know how to help you in an emergency. If you have severe hypoglycemia and cannot eat or drink, use a glucagon injection. Your doctor can prescribe a glucagon emergency injection kit and tell you how to use it.

Check your blood sugar carefully during times of stress, travel, illness, surgery or medical emergency, vigorous exercise, or if you drink alcohol or skip meals. These things can affect your glucose levels and your dose needs may also change. Do not change your medication dose or schedule without your doctor's advice.

Use pioglitazone regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Pioglitazone is only part of a treatment program that may also include diet, exercise, weight control, blood sugar testing, and special medical care. Follow your doctor's instructions very closely.

Store at room temperature away from moisture, heat, and light. Keep the bottle tightly closed when not in use.

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.

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).

Absorption

Bioavailability

Peak serum concentrations attained within 2 hours.1

Absolute bioavailability is 83%.81

Food

Food delays time to peak serum concentration to 3–4 hours but does not affect extent of absorption.1

Special Populations

In patients with hepatic impairment (Child-Pugh class B or C), peak pioglitazone concentration is decreased by 45%.1

In geriatric patients, AUC of pioglitazone is increased; not clinically relevant.1

In females, peak serum concentration and AUC are increased by 20–60%.1

Distribution

Extent

Distributed into milk in rats.1 Not known whether the drug distributes into human milk.1

Plasma Protein Binding

>99% (mainly albumin).1

Elimination

Metabolism

Extensively metabolized, principally by CYP2C8 and, to a lesser extent, by CYP3A4 and other isoenzymes (e.g., CYP1A1).1

Elimination Route

Excreted in urine (15–30%) and in feces, primarily as metabolites.1

Half-life

3–7 hours (for pioglitazone) or 16–24 hours (for pioglitazone and metabolites).1

Special Populations

In geriatric patients, terminal half-life is prolonged; not clinically relevant.1

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.

• Importance of reading medication guide provided by manufacturer before starting pioglitazone and each time prescription is refilled.1

• Importance of informing patients of potential risks and advantages of therapy and of alternative therapies.28

• Discuss potential for alterations in dosage requirements during periods of stress (e.g., fever, trauma, infection, surgery); importance of contacting a clinician promptly.1 27

• Importance of informing patients that pioglitazone must not be used in patients with severe heart failure (NYHA class III or IV).1 Importance of immediately informing clinician if potential manifestations of CHF (e.g., rapid weight gain, edema, unusual fatigue, trouble breathing, shortness of breath) occur.1 27 28

• Importance of informing patients that liver function tests will be performed prior to initiation of therapy and periodically thereafter.1 (See Hepatic Effects under Cautions.) Advise patients to inform clinician if potential manifestations of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine, yellowing of skin or whites of eyes) occur.1 27 28

• Increased risk of bladder cancer.1 27 28 Importance of patient not taking pioglitazone if receiving treatment for bladder cancer.1 27 28 Importance of patient reporting any sign of macroscopic hematuria or symptoms such as dysuria or urinary urgency that develop or increase during pioglitazone treatment.1 27 28

• Importance of taking exactly as prescribed.1 27 28 If a dose is missed on one day, take the next dose as prescribed unless otherwise instructed by clinician; do not double the dose to make up for the missed dose.1 27 28 Importance of changing dosage with caution and only under medical supervision.27 28 Importance of immediately contacting a clinician or going to the nearest hospital emergency department if accidental overdosage occurs.1

• Importance of advising patient not to chew, cut, or crush the combination preparation containing pioglitazone and extended-release metformin hydrochloride (ActoPlus Met XR); must swallow this dosage form whole.27 Advise patients that biologically inert components of the extended-release combination tablet may occasionally be eliminated in feces as a soft mass that may resemble original tablet.27

• Risk of hypoglycemia in patients receiving concomitant insulin or other antidiabetic therapy.1 Provide instructions regarding management of hypoglycemia, including recognition of symptoms, predisposing conditions, and treatment.1

• Risk of pregnancy in premenopausal anovulatory women.1 27 28 Advise patients to utilize effective contraception during therapy.1 27 28

• Importance of adhering to diet and exercise regimen.1 Importance of regular monitoring (preferably self-monitoring) of blood glucose and of HbA1c.1 27

• Risk of fractures (e.g., hand, upper arm, foot) in women.1 50

• Importance of regular eye examinations.1 Importance of reporting changes in vision.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 27

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 27 28

• Importance of informing patients of other important precautionary information.1 27 (See Cautions.)

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about this medicine (Actos), please talk with the doctor, pharmacist, or other health care provider.
• 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.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine (Actos). It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine (Actos).

Review Date: October 4, 2017

During controlled clinical trials, one case of overdose with Actos 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder of male rats. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m2). Urinary calculi with subsequent irritation and hyperplasia were postulated as the mechanism for bladder tumors observed in male rats. A two-year mechanistic study in male rats utilizing dietary acidification to reduce calculi formation was completed in 2009. Dietary acidification decreased but did not abolish the hyperplastic changes in the bladder. The presence of calculi exacerbated the hyperplastic response to pioglitazone but was not considered the primary cause of the hyperplastic changes.

The relevance to humans of the bladder findings in the male rat cannot be excluded.

A two-year carcinogenicity study was also conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m2). No drug-induced tumors were observed in any organ.

Pioglitazone hydrochloride was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.

No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone hydrochloride daily prior to and throughout mating and gestation (approximately nine times the maximum recommended human oral dose based on mg/m2).

Animal Toxicology and/or Pharmacology

Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone hydrochloride (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m2). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m2). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately four times the maximum recommended human oral dose based on mg/m2), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m2).

Actos is available in 15 mg, 30 mg, and 45 mg tablets as follows:

15 mg tablet: White to off-white, round, convex, nonscored tablet with "Actos" on one side, and "15" on the other, available in:

NDC 64764-151-04 Bottles of 30
NDC 64764-151-05 Bottles of 90
NDC 64764-151-06 Bottles of 500

30 mg tablet: White to off-white, round, flat, nonscored tablet with "Actos" on one side, and "30" on the other, available in:

NDC 64764-301-14 Bottles of 30
NDC 64764-301-15 Bottles of 90
NDC 64764-301-16 Bottles of 500

45 mg tablet: White to off-white, round, flat, nonscored tablet with "Actos" on one side, and "45" on the other, available in:

NDC 64764-451-24 Bottles of 30
NDC 64764-451-25 Bottles of 90
NDC 64764-451-26 Bottles of 500

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from light, moisture and humidity.

Monotherapy And Combination Therapy

ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings [see Clinical Studies].

Important Limitations Of Use

ACTOS exerts its antihyperglycemic effect only in the presence of endogenous insulin. ACTOS should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.

Use caution in patients with liver disease [see WARNINGS AND PRECAUTIONS].

Actos may cause serious side effects. See “Drug Precautions” section.

The most common side effects of Actos include:

• cold-like symptoms (respiratory tract infection)
• headache
• sinus infection
• muscle pain
• sore throat

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the side effects of Actos. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• Store Actos at 20° to 25°C (68° to 77°F). Keep Actos tablets in the original container and protect from light.
• Keep the Actos bottle tightly closed and protect from getting wet (away from moisture and humidity).
• Keep Actos and all medicines out of the reach of children.

• Diabetes and Eye Problems
• Diabetes and Kidney Disease
• Diabetes Insipidus
• Diabetes Prescription Insulin Medications
• Diabetes Prevention (Type 2)
• Diabetes Treatment (Type 1 and Type 2 Medications and Diet)
• Diabetes: Caring for Your Diabetes at Special Times
• Diabetic Neuropathy
• Oral Diabetes Prescription Medications
• Tips for Managing Type 1 and 2 Diabetes at Home

Actos (pioglitazone) is an oral diabetes medicine that helps control blood sugar levels.

Actos is for people with type 2 diabetes.

Actos is not for treating type 1 diabetes.

Tell your doctor if you use insulin. Taking Actos while you are using insulin may increase your risk of serious heart problems.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• gemfibrozil;

• rifampin; or

• other oral diabetes medications, such as acetohexamide, chlorpropamide, glimepiride, glipizide, tolbutamide.

This list is not complete and many other medicines may increase or decrease the effects of pioglitazone on lowering your blood sugar. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Applies to pioglitazone: oral tablet

Along with its needed effects, pioglitazone (the active ingredient contained in Actos) 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 pioglitazone:

• Chest pain
• decreased urine output
• dilated neck veins
• extreme fatigue
• irregular breathing
• irregular heartbeat
• problems with teeth
• swelling of the face, fingers, feet, or lower legs
• tightness in the chest
• trouble breathing
• weight gain

• Pain or swelling in the arms or legs without an injury
• pale skin
• swelling
• trouble with breathing when active
• unusual bleeding or bruising
• unusual tiredness or weakness

• Dark urine
• loss of appetite
• nausea or vomiting
• stomach pain
• unexplained, rapid weight gain
• yellow eyes or skin

Some side effects of pioglitazone 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:

• Blurred vision or other changes in vision
• cough
• dry mouth
• flushed, dry skin
• fruit-like breath odor
• headache
• increased hunger
• increased thirst
• increased urination
• loss of consciousness
• muscle pain or soreness
• problems with your teeth
• runny or stuffy nose
• sore throat
• stomachache
• sweating
• unexplained weight loss

Applies to pioglitazone: oral tablet

Cardiovascular

Very common (greater than 10%): Edema
Common (1% to 10%): Congestive heart failure (including nonfatal and fatal cases), cardiac failure, chest pain[Ref]

In the PROactive trial, a study in 5238 patients with type 2 diabetes and a history of macrovascular disease who were force-uptitrated to pioglitazone 45 mg once a day or given placebo in addition to standard of care, edema occurred in 27.3% of patients treated with pioglitazone (n=2605) compared with 15.9% of placebo (n=2633) patients. Treatment-emergent adverse events leading to at least 1 hospitalized congestive heart failure event occurred in 5.7% of patients receiving pioglitazone and 4.1% of patients receiving placebo.

The primary objective of the 3-year PROactive trial was to examine the effect of pioglitazone on mortality and macrovascular morbidity in high-risk patients. No statistically significant difference between pioglitazone and placebo/standard care were observed for time to the first occurrence of their first event (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 patients receiving pioglitazone experienced at least 1 event compared with 572 patients receiving placebo/standard care.

Pioglitazone is associated with edema (peripheral, generalized, and pitting edema and fluid retention) when used alone or when used in combination therapy. In pioglitazone monotherapy trials, edema occurred in 2.5% (n=81), 4.7% (n=275), and 6.5% (n=169) of patients receiving 15 mg, 30 mg, and 45 mg of pioglitazone daily for 16 to 26 weeks. Pioglitazone in combination with a sulfonylurea for 16 to 24 weeks resulted in edema in 1.6% (n=184), 11.3% (n=540), and 23.1% (n=351) of patients receiving 15 mg, 30 mg, and 45 mg of pioglitazone daily, respectively. In a study in patients with NYHA class II or III heart failure the percentage of patients experiencing CHF progression during the study was 13.4% and 8.2% in patients receiving pioglitazone (n=262) and glyburide (n=256), respectively.

Postmarketing reports of congestive heart failure have been received in patients treated with pioglitazone. Reports have been received from patients both with and without a history of a known history of heart disease and both with and without concomitant insulin use.[Ref]

Hypersensitivity

Frequency not reported: Hypersensitivity and allergic reactions[Ref]

Metabolic

Very common (10% or more): Hypoglycemia (up to 27.3%), increased weight (up to 26.2%)[Ref]

General

The most commonly reported side effects were hypoglycemia, increased weight, edema, and upper respiratory tract infection.[Ref]

Hematologic

Frequency not reported: Small reduction in mean hemoglobin and hematocrit[Ref]

Ocular

Common (1% to 10%): Visual disturbance, abnormal vision
Frequency not reported: Macular edema[Ref]

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]

Hepatic

Postmarketing reports of fatal and nonfatal hepatic failure have been received in patients treated with this drug; these reports have been insufficient to establish causality. During clinical trials, there was no evidence of drug-induced hepatotoxicity.[Ref]

Uncommon (0.1% to 1%): Increased alanine aminotransferase
Frequency not reported: Decreased mean values of bilirubin, AST, alkaline phosphatase, and GGT
Postmarketing reports: Fatal and nonfatal hepatic failure, hepatocellular dysfunction[Ref]

Other

Common (1% to 10%): Fatigue, accidental injury, peripheral edema, asthenia, malaise[Ref]

Gastrointestinal

Common (1% to 10%): Tooth disorder, tooth abscess, gastroenteritis, diarrhea, upper abdominal pain[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection[Ref]

Musculoskeletal

Common (1% to 10%): Fractures, myalgia, pain in extremity, back pain, cramped legs, arthralgia[Ref]

In the prospective pioglitazone clinical trial in macrovascular events (PROactive), the incidence of bone fractures in female patients with this drug was 5.1% (44/870) compared to 2.5% (23/905) for placebo treated patients. The majority of fractures were nonvertebral including lower limb and distal upper limb. The incidence in men was 1.7% and no different than placebo (2.1%).[Ref]

Nervous system

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

Psychiatric

Uncommon (0.1% to 1%): Insomnia[Ref]

Respiratory

Very common (10% or more): Upper respiratory tract infection (up to 13.2%)
Common (1% to 10%): Sinusitis, pharyngitis, bronchitis, influenza[Ref]

Oncologic

The US FDA has released results of its review of pioglitazone (the active ingredient contained in Actos) 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]

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

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

This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. AU TGA pregnancy category: B3 US FDA pregnancy category: Not Assigned Comments: Premenopausal anovulatory women may be at risk for pregnancy; these women should be informed of pregnancy risk.

Animal studies using pioglitazone at 10 to 40 times the maximum recommended human dose have shown increased rates of postimplantation loss, delayed development, reduced fetal weights, and delayed parturition. There are no adequate and well-controlled studies in pregnant women. Abnormal blood glucose concentrations during pregnancy are associated with a higher incidence of congenital anomalies, increased neonatal morbidity, and mortality. Most experts recommend insulin use during pregnancy to maintain blood glucose concentrations as close to normal as possible. AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Summary of Use during Lactation

Because no information is available on the use of pioglitazone during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. Monitoring of the breastfed infant's blood glucose is advisable during maternal therapy with hypoglycemic agents.[1][2]

Drug Levels

Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Acarbose, Chlorpropamide, Glyburide, Insulin, Metformin, Tolbutamide

References

1. Everett JA. Use of oral antidiabetic agents during breastfeeding. J Hum Lact. 1997;13:319-21. PMID: 9429368

2. Berlin CM, Briggs GG. Drugs and chemicals in human milk. Semin Fetal Neonatal Med. 2005;10:149-59. PMID: 15701580