Pioglitazone

• Actos and similar drugs can cause or women congestive heart failure in some patients.
• Patients should be monitored for signs and symptoms of heart failure (for example, excessive, rapid weight gain, dyspnea, and/or edema) at the beginning of treatment and after dose increases.
• Actos is not recommended for patients with symptomatic heart failure and patients with established New York Heart Association (NYHA) Class III or IV heart failure should not use Actos.

The most common side effects of Actos alone or in combination with sulfonylureas, metformin, or insulin are:

• Upper respiratory tract infection
• Headache
• Sinusitis
• Muscle aches
• Tooth disorders
• Hypoglycemia (low blood sugar)
• Sore throat

Possible serious side effects of Actos include:

• Anemia
• Liver injury
• Edema
• Fractures
• Bladder cancer
• Diabetic macular edema

Dose related fluid accumulation (edema) can occur especially when combined with insulin. Fluid accumulation can worsen or lead to heart failure. Actos should not be used in patients with heart disease classified by the New York Heart Association (NYHA) as Class III and IV heart failure or symptomatic heart failure.

Fluid accumulation also may lead to macular edema, resulting in reduced vision. Actos also can reduce red blood cells.

There have been post-marketing reports of liver failure while taking Actos.

Actos has been associated with liver injury. Periodic monitoring of liver-related side effects and liver tests should be conducted in patients taking Actos.

Symptoms of liver injury are:

• Nausea
• Vomiting
• Abdominal pain
• Fatigue
• Anorexia (loss of appetite)
• Dark urine

Actos should be stopped if patients have symptoms of liver injury and liver function test results that are greater than three times the normal level. Liver blood tests are obtained before starting treatment. Monitoring liver tests during treatment is not recommended for patients without liver disease.

Actos may cause ovulation in women who have stopped ovulating if they are premenopausal and insulin resistant. This may lead to pregnancy. For women (but not men) taking Actos, there is an increased risk of bone fractures of the distal bones of the arm and leg. Patients taking Actos should maintain proper bone health.

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of pioglitazone there are no specific foods that you must exclude from your diet when receiving this medication.

• Take pioglitazone tablets exactly as your doctor tells you to take it.
• Your doctor may change your dose of pioglitazone. Do not change your pioglitazone dose unless your doctor tells you to.
• Pioglitazone may be prescribed alone or with other diabetes medicines. This will depend on how well your blood sugar is controlled.
• Take pioglitazone one time each day, with or without food.
• If you miss a dose of pioglitazone, take your next dose as prescribed unless your doctor tells you differently. Do not take two doses at one time the next day.
• If you take too much pioglitazone, call your doctor or go to the nearest hospital emergency room right away.
• If your body is under stress such as from a fever, infection, accident or surgery the dose of your diabetes medicines may need to be changed. Call your doctor right away.
• Stay on your diet and exercise programs and test your blood sugar regularly while taking pioglitazone.
• Your doctor should do certain blood tests before you start and while you take pioglitazone.
• Your doctor should also do hemoglobin A1C testing to check how well your blood sugar is controlled with pioglitazone.
• Your doctor should check your eyes regularly while you take pioglitazone.
• It may take 2 to 3 months to see the full effect of pioglitazone on your blood sugar level.

If you take too much pioglitazone, call your doctor or go to the nearest hospital emergency room right away.

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

Avoid drinking alcohol. It lowers blood sugar and may interfere with your diabetes treatment.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• To gain the most benefit, do not miss doses.
• Keep taking pioglitazone as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

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 pioglitazone. 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.

• Pioglitazone HCl

Delayed; Peak effect: Glucose control: Several weeks

Time to Peak

~2 hours; delayed with food

Half-Life Elimination

Parent drug: 3 to 7 hours; M-III and M-IV metabolites: 16 to 24 hours

Protein Binding

Pioglitazone >99% and active metabolites >98%; primarily to albumin

Concerns related to adverse effects:

• Bladder cancer: Clinical trial data is inconsistent regarding the risk of bladder cancer in patients exposed to pioglitazone. Given the uncertainty of the findings, the manufacturer recommends to avoid use in patients with active bladder cancer and consider risks vs. benefits prior to initiating therapy in patients with a history of bladder cancer.

• Edema: Dose-related edema, including new-onset or exacerbation of existing edema, has been reported; use with caution in patients with edema. Monitor for signs/symptoms of heart failure.

• Fractures: An increased incidence of bone fractures in females treated with pioglitazone has been observed; majority of fractures occurred in the lower limb and distal upper limb. Consider risk of fracture prior to initiation and during use. According to the American Diabetes Association guidelines, thiazolidinediones should be avoided in patients with fracture risk factors (ADA 2016a).

• Heart failure/cardiac effects: [US Boxed Warning]: Thiazolidinediones, including pioglitazone, may cause or exacerbate heart failure; closely monitor for signs and symptoms of heart failure (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases; if heart failure develops, treat accordingly and consider dose reduction or discontinuation of pioglitazone. Not recommended for use in any patient with symptomatic heart failure. Initiation of therapy is contraindicated in patients with NYHA class III or IV heart failure; if used in patients with NYHA class I or II (systolic) heart failure, initiate at lowest dosage and monitor closely.

• Hematologic effects: May decrease hemoglobin/hematocrit; effects may be related to increased plasma volume.

• Hepatic effects: Hepatic failure, including fatalities, has been reported. Monitor for signs/symptoms of liver injury closely during therapy; discontinuation of therapy may be necessary.

• Hypoglycemia: The risk of hypoglycemia is increased when pioglitazone is combined with insulin or other diabetic medications; dosage adjustment of concomitant hypoglycemic agents may be necessary.

• Macular edema: Has been reported with thiazolidinedione use, including pioglitazone; some patients with macular edema presented with blurred vision or decreased visual acuity, and most had peripheral edema at time of diagnosis. Patients should be seen by an ophthalmologist if any visual symptoms arise during therapy and all diabetic patients should have regular eye exams.

• Weight gain: Dose-related weight gain observed with use; mechanism unknown but likely associated with fluid retention and fat accumulation.

Disease-related concerns:

• Diabetes, type 1: Mechanism requires the presence of insulin; therefore, use in type 1 diabetes (insulin dependent, IDDM) or diabetic ketoacidosis is not recommended.

• Hepatic impairment: Due to the possible risk of drug-induced liver injury, serum liver function tests (ALT, AST, alkaline phosphatase, and total bilirubin) should be obtained prior to initiation in all patients. In patients with abnormal hepatic tests, therapy should be initiated with caution. During therapy, if signs/symptoms of liver injury (eg, fatigue, anorexia, jaundice, dark urine, right upper abdominal discomfort) arise, interrupt pioglitazone therapy, obtain liver tests immediately and evaluate alternative etiologies. If an alternative etiology is not identified and serum ALT is >3 times ULN, do not resume therapy. Patients with serum ALT >3 times ULN and serum total bilirubin >2 times ULN are at risk for severe drug-induced liver injury.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.