Pioglitazone and metformin

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.

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

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

Swallow the medicine whole. Do not crush, break, or chew it.

Part of the extended-release tablet may pass into your stool (bowel movement). This is normal and nothing to worry about.

Dosing

The dose of pioglitazone and metformin 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 pioglitazone and metformin. 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 type 2 diabetes:
  • For oral dosage form (extended-release tablets):
    • Adults—At first, 1 tablet once or two times a day with food. Your doctor may adjust your dose as needed and tolerated. However, the dose is usually not more than 45 milligrams (mg) of pioglitazone and 2000 mg of metformin per day.
    • Children—Use and dose must be determined by your doctor.
  • For oral dosage form (tablets):
    • Adults—At first, 1 tablet once or two times a day with food. Your doctor may adjust your dose as needed and tolerated. However, the dose is usually not more than 45 milligrams (mg) of pioglitazone and 2550 mg of metformin per day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of pioglitazone and metformin, 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Do not keep outdated medicine or medicine no longer needed.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.

It is very important that your doctor check your progress at regular visits to make sure that pioglitazone and metformin 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 pioglitazone and metformin. Your doctor may advise you to stop taking pioglitazone and metformin 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 pioglitazone and metformin. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

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

pioglitazone and metformin 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.

pioglitazone and metformin 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.

pioglitazone and metformin 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 pioglitazone and metformin. 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.

(pye oh GLI ta zone & met FOR min)

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, oral: 15/500: Pioglitazone 15 mg and metformin hydrochloride 500 mg; 15/850: Pioglitazone 15 mg and metformin hydrochloride 850 mg

Actoplus Met:

15/500: Pioglitazone 15 mg and metformin hydrochloride 500 mg

15/850: Pioglitazone 15 mg and metformin hydrochloride 850 mg

Tablet, variable release, oral:

Actoplus Met XR:

15/1000: Pioglitazone 15 mg [immediate release] and metformin hydrochloride 1000 mg [extended release]

30/1000: Pioglitazone 30 mg [immediate release] and metformin hydrochloride 1000 mg [extended release]

• Antidiabetic Agent, Biguanide
• Antidiabetic Agent, Thiazolidinedione

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture and humidity

Percentages of adverse effects as reported with the combination product. Also see individual agents.

>10%:

Cardiovascular: Lower extremity edema (3% to 11%)

Respiratory: Upper respiratory tract infection (12% to 16%)

1% to 10%:

Central nervous system: Headache (2% to 6%), dizziness (5%)

Endocrine & metabolic: Weight gain (3% to 7%)

Gastrointestinal: Diarrhea (5% to 6%), nausea (4% to 6%)

Genitourinary: Urinary tract infection (5% to 6%)

Hematologic & oncologic: Anemia (≤2%)

Respiratory: Sinusitis (4% to 5%)

<1% (Limited to important or life-threatening): Bladder carcinoma (FDA Safety Alert, Dec. 19, 2016)

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 with pioglitazone; 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.

• 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. 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. In addition, metformin should be discontinued in patients who develop hypoxic states (eg, cardiovascular collapse [shock], acute heart failure, acute myocardial infarction, other conditions with hypoxemia) due to risk of lactic acidosis.

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

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

• Hypoglycemia: Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when ethanol is ingested, or when more than one glucose-lowering drug is used. It is also more likely in elderly patients, debilitated or malnourished patients, and in patients with adrenal or pituitary insufficiency.

• Lactic acidosis: [US Boxed Warning]: Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset is often subtle, accompanied by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, abdominal pain); elevated blood lactate levels (>5 mmol/L); anion gap acidosis (without evidence of ketonuria or ketonemia); increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Risk factors for lactic acidosis include patients with renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65 years, having a radiologic study with contrast, surgery and other procedures, hypoxic states (eg, acute heart failure), excessive alcohol intake, and hepatic impairment. Discontinue immediately if lactic acidosis is suspected; prompt hemodialysis is recommended. Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue use in patients with conditions associated with dehydration, hypoperfusion, sepsis, or hypoxemia. Temporarily discontinue therapy in patients with restricted food and fluid intake. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.

• 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.

• Vitamin B12 concentrations: Long-term metformin use is associated with vitamin B12 deficiency; monitor vitamin B12 serum concentrations periodically with long-term therapy. Monitoring of B12 serum concentrations should be considered in all patients receiving metformin and in particular those with peripheral neuropathy or anemia (ADA 2017c).

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

Disease-related concerns:

• Hepatic impairment: Avoid use of metformin in patients with hepatic impairment or with clinical or laboratory evidence of hepatic disease due to potential for lactic acidosis. Due to the possible risk of drug-induced liver injury with pioglitazone, 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.

• Renal impairment: Metformin is substantially excreted by the kidney; use is contraindicated in patients with eGFR <30 mL/minute/1.73 m2. Monitor renal function prior to initiation; obtain an eGFR at least annually in all patients and may assess more frequently in patients at increased risk of developing renal impairment (eg, elderly). Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin associated lactic acidosis occurred more in patients with significant renal impairment; withhold metformin in patients with dehydration and/or prerenal azotemia.

• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

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.

Special populations:

• Elderly: Use with caution; risk of metformin associated lactic acidosis increases with age.

Dosage form specific issues:

• Extended release tablet: Insoluble tablet shell may remain intact and be visible in the stool.

Other warnings/precautions:

• Appropriate use: Not for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus (insulin-dependent, IDDM).

• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism and increase risk of lactic acidosis.

• Iodinated contrast: The manufacturer recommends temporary discontinuation of metformin at the time of or before iodinated contrast imaging procedures in patients with an eGFR 30 to 60 mL/minute/1.73 m2; or with a history of hepatic disease, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after imaging procedure; restart if renal function is stable. Alternatively, the American College of Radiology (ACR) guidelines recommend that metformin may be used prior to or following administration of iodinated contrast media in patients with no evidence of acute kidney injury (AKI) and with an eGFR ≥30 mL/minute/1.73 m2; ACR guidelines recommend temporary discontinuation of metformin in patients with known AKI or severe chronic kidney disease ([stage IV or V [ie, eGFR <30 mL/minute/1.73 m2]) or who are undergoing arterial catheter studies (ACR 2015).

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

• Surgical procedures: Metformin should be withheld 24 hours before surgery (all other oral hypoglycemic agents should be withheld the morning of surgery or procedure) (ADA 2017d).