Glimepiride/metformin hydrochloride/pioglitazone Overdose

How do you administer this medicine?
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Consists of glimepiride, metformin hydrochloride, pioglitazone

What happens if I overdose Glimepiride?

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include coma; confusion; fainting; fast heartbeat; lethargy; lightheadedness; seizures; severe dizziness or drowsiness; tremor; unusual sweating.

Proper storage of glimepiride:

Store glimepiride at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep glimepiride out of the reach of children and away from pets.

Overdose of Glimepiride in details

When a dose is taken in higher dose than the recommended doses, it is called Overdose. Overdose always needs a clinical supervision. Any medicine or drug when consumed in Overdose produces untoward side effects on one or various organs in the body. A medicine is excreted in the kidney or metabolized in the liver most of the times. This process goes without any hurdles when taken in normal dose, but when taken in an overdose, the body is not able to metabolize it or send it out properly which causes the effects of anoverdose.
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Overdose: Hypoglycemia, which may be mild to severe in some cases life-threatening, may occur as a result of overdose of Glimepiride tablet 3 mg. For symptoms of hypoglycemia, see Adverse Reactions.

Treatment: Management of glimepiride-induced hypoglycemia depends on the severity of the reaction: Life-threatening hypoglycemia is medical emergency and requires immediate hospitalization and treatment eg, detoxification (by eg, gastric lavage, activated charcoal) as well as observation until complete recovery is ensured.

Severe hypoglycemia with coma, seizures or neurologic impairment requires immediate hospitalization and treatment with glucagon (IM or SC) or concentrated glucose solution (IV) and observation until complete recovery is ensured.

Mild hypoglycemia is usually, but not always, readily controlled by administration of glucose eg, orally taken carbohydrates.

What should I avoid while taking Glimepiride?

If you also take colesevelam, avoid taking it within 4 hours after you take glimepiride.

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

Avoid exposure to sunlight or tanning beds. Glimepiride can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Glimepiride warnings

Warnings are a mix of Precautions. Contraindications and interactions and serious harmful effects associated with the medicine intake. A diabetic or Hypertensive patient need to be warned about few drug interactions. A known hypersensitivity patient needs to be careful about the reactions or anaphylactic shock. A pregnant woman or a breastfeeding woman should be warned of certain medications. A Hepatitis [liver disease] patient or a cardiac patient should avoid few drugs.
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Hypoglycemia

All sulfonylureas, including Glimepiride, can cause severe hypoglycemia. The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. These impairments may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death.

Patients must be educated to recognize and manage hypoglycemia. Use caution when initiating and increasing Glimepiride doses in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other anti-diabetic medications). Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of glucose-lowering medications. Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested.

Early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.

Hypersensitivity Reactions

There have been postmarketing reports of hypersensitivity reactions in patients treated with Glimepiride, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue Glimepiride, assess for other potential causes for the reaction, and institute alternative treatment for diabetes.

Hemolytic Anemia

Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because Glimepiride is a sulfonylurea, use caution in patients with G6PD deficiency and consider the use of a non-sulfonylurea alternative. There are also postmarketing reports of hemolytic anemia in patients receiving Glimepiride who did not have known G6PD deficiency.

Increased Risk of Cardiovascular Mortality with Sulfonylureas

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2–1/2 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of Glimepiride and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Glimepiride or any other anti-diabetic drug.

What should I discuss with my healthcare provider before taking Glimepiride?

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For glimepiride, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to glimepiride or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

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

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of glimepiride in the elderly. However, elderly patients are more likely to have low blood sugar and age-related kidney problems, which may require caution and an adjustment in the dose for patients receiving glimepiride.

Pregnancy

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.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking glimepiride, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using glimepiride with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Using glimepiride with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of glimepiride. Make sure you tell your doctor if you have any other medical problems, especially:

Glimepiride precautions

Certain people who are very sick or very old or who are sensitive show an exacerbation of side effect of the drug which can turn dangerous at times. So, it is very important to remember the precautions while taking the medicine. Pregnancy and Breastfeeding are also special categories wherein extra care or precaution is needed when taking a drug. Few patients may have a hypersensitivity reaction to few medications, and that can be life-threatening rarely. Penicillin hypersensitivity is one example. Diarrhea, rashes are few other symptoms which need a watch. A patient with other co-existing diseases like liver disease, heart disease, kidney disease should take special precautions.
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Hypoglycemia

All sulfonylureas, including Glimepiride, can cause severe hypoglycemia. The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. These impairments may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death.

Patients must be educated to recognize and manage hypoglycemia. Use caution when initiating and increasing Glimepiride doses in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other anti-diabetic medications). Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of glucose-lowering medications. Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested.

Early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.

Hypersensitivity Reactions

There have been postmarketing reports of hypersensitivity reactions in patients treated with Glimepiride, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson Syndrome. If a hypersensitivity reaction is suspected, promptly discontinue Glimepiride, assess for other potential causes for the reaction, and institute alternative treatment for diabetes.

Hemolytic Anemia

Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because Glimepiride is a sulfonylurea, use caution in patients with G6PD deficiency and consider the use of a non-sulfonylurea alternative. There are also postmarketing reports of hemolytic anemia in patients receiving Glimepiride who did not have known G6PD deficiency.

Increased Risk Of Cardiovasular Mortality With Sulfonylureas

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2–1/2 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of Glimepiride and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Glimepiride or any other anti-diabetic drug.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, And Impairment Of Fertility

Studies in rats at doses of up to 5000 parts per million (ppm) in complete feed (approximately 340 times the maximum recommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months resulted in an increase in benign pancreatic adenoma formation that was dose-related and was thought to be the result of chronic pancreatic stimulation. No adenoma formation in mice was observed at a dose of 320 ppm in complete feed, or 46–54 mg/kg body weight/day. This is about 35 times the maximum human recommended dose of 8 mg once daily based on surface area.

Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, and mouse micronucleus test).

There was no effect of glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg body weight (>1,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of Glimepiride in pregnant women. In animal studies there was no increase in congenital anomalies, but an increase in fetal deaths occurred in rats and rabbits at glimepiride doses 50 times (rats) and 0.1 times (rabbits) the maximum recommended human dose (based on body surface area). This fetotoxicity, observed only at doses inducing maternal hypoglycemia, is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride and has been similarly noted with other sulfonylureas. Glimepiride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because data suggest that abnormal blood glucose during pregnancy is associated with a higher incidence of congenital abnormalities, diabetes treatment during pregnancy should maintain blood glucose as close to normal as possible.

Nonteratogenic Effects

Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery.

Nursing Mothers

It is not known whether Glimepiride is excreted in human milk. During pre- and post-natal studies in rats, significant concentrations of glimepiride were present in breast milk and the serum of the pups. Offspring of rats exposed to high levels of glimepiride during pregnancy and lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. These skeletal deformations were determined to be the result of nursing from mothers exposed to glimepiride. Based on these animal data and the potential for hypoglycemia in a nursing infant, a decision should be made whether to discontinue nursing or discontinue Glimepiride, taking into account the importance of Glimepiride to the mother.

Pediatric Use

The pharmacokinetics, efficacy and safety of Glimepiride have been evaluated in pediatric patients with type 2 diabetes as described below. Glimepiride is not recommended in pediatric patients because of its adverse effects on body weight and hypoglycemia.

The pharmacokinetics of a 1 mg single dose of Glimepiride was evaluated in 30 patients with type 2 diabetes (male = 7; female = 23) between ages 10 and 17 years. The mean (± SD) AUC(0–last) (339±203 ng·hr/mL), Cmax (102±48 ng/mL) and t (%) Baseline (mean) 8.2 8.3 Change from baseline

(adjusted LS mean)Difference is Glimepiride – metformin with positive differences favoring metformin

The profile of adverse reactions in pediatric patients treated with Glimepiride was similar to that observed in adults.

Hypoglycemic events documented by blood glucose values <36 mg/dL were observed in 4% of pediatric patients treated with Glimepiride and in 1% of pediatric patients treated with metformin. One patient in each treatment group experienced a severe hypoglycemic episode (severity was determined by the investigator based on observed signs and symptoms).

Geriatric Use

In clinical trials of Glimepiride, 1053 of 3491 patients (30%) were >65 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

There were no significant differences in glimepiride pharmacokinetics between patients with type 2 diabetes ≤65 years (n=49) and those >65 years (n=42).

Glimepiride is substantially excreted by the kidney. Elderly patients are more likely to have renal impairment. In addition, hypoglycemia may be difficult to recognize in the elderly. Use caution when initiating Glimepiride and increasing the dose of Glimepiride in this patient population.

Renal Impairment

To minimize the risk of hypoglycemia, the recommended starting dose of Glimepiride is 1 mg daily for all patients with type 2 diabetes and renal impairment.

A multiple-dose titration study was conducted in 16 patients with type 2 diabetes and renal impairment using doses ranging from 1 mg to 8 mg daily for 3 months. Baseline creatinine clearance ranged from 10–60 mL/min. The pharmacokinetics of Glimepiride were evaluated in the multiple-dose titration study and the results were consistent with those observed in patients enrolled in a single-dose study. In both studies, the relative total clearance of Glimepiride increased when kidney function was impaired. Both studies also demonstrated that the elimination of the two major metabolites was reduced in patients with renal impairment.

What happens if I miss a dose of Glimepiride?

When you miss a dose, you should take it as soon as you remember, but you should take care that it should be well spaced from the next dose. You should not take an extra dose at the time of the second dose as it will become a double dose. The double dose can give unwanted side effects, so be careful. In chronic conditions or when you have a serious health issue, if you miss a dose, you should inform your health care provider and ask his suggestion.

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.

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

What happens if I overdose Metformin hydrochloride?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

An overdose of metformin may cause lactic acidosis. Get emergency medical help if you have any of these symptoms of lactic acidosis: weakness, increasing sleepiness, slow heart rate, cold feeling, muscle pain, shortness of breath, stomach pain, feeling light-headed, and fainting.

Overdose of Metformin hydrochloride in details

When a dose is taken in higher dose than the recommended doses, it is called Overdose. Overdose always needs a clinical supervision. Any medicine or drug when consumed in Overdose produces untoward side effects on one or various organs in the body. A medicine is excreted in the kidney or metabolized in the liver most of the times. This process goes without any hurdles when taken in normal dose, but when taken in an overdose, the body is not able to metabolize it or send it out properly which causes the effects of anoverdose.
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Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no casual association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected

What should I avoid while taking Metformin hydrochloride?

Avoid drinking alcohol. It lowers blood sugar and may increase your risk of lactic acidosis while taking metformin.

Metformin hydrochloride warnings

Warnings are a mix of Precautions. Contraindications and interactions and serious harmful effects associated with the medicine intake. A diabetic or Hypertensive patient need to be warned about few drug interactions. A known hypersensitivity patient needs to be careful about the reactions or anaphylactic shock. A pregnant woman or a breastfeeding woman should be warned of certain medications. A Hepatitis [liver disease] patient or a cardiac patient should avoid few drugs.

Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of metformin hydrochloride extended-release tablets. In metformin hydrochloride extended-release tablets treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue metformin hydrochloride extended-release tablets and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include :

Vitamin B12 Deficiency

In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2 to 3 year intervals in patients on metformin hydrochloride extended-release tablets and manage any abnormalities.

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Metformin hydrochloride extended-release tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with metformin hydrochloride extended-release tablets.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride extended-release tablets.

What should I discuss with my healthcare provider before taking Metformin hydrochloride?

Some people develop a life-threatening condition called lactic acidosis while taking metformin. You may be more likely to develop lactic acidosis if you have liver or kidney disease, congestive heart failure, a severe infection, if you are dehydrated, or if you drink large amounts of alcohol. Talk with your doctor about your individual risk.

You should not use this medication if you are allergic to metformin, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

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

To make sure you can safely take metformin, tell your doctor if you have any of these other conditions:

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether metformin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using metformin.

Metformin should not be given to a child younger than 10 years old. Extended-release metformin (Glucophage XR) should not be given to a child younger than 17 years old.

Metformin hydrochloride precautions

Certain people who are very sick or very old or who are sensitive show an exacerbation of side effect of the drug which can turn dangerous at times. So, it is very important to remember the precautions while taking the medicine. Pregnancy and Breastfeeding are also special categories wherein extra care or precaution is needed when taking a drug. Few patients may have a hypersensitivity reaction to few medications, and that can be life-threatening rarely. Penicillin hypersensitivity is one example. Diarrhea, rashes are few other symptoms which need a watch. A patient with other co-existing diseases like liver disease, heart disease, kidney disease should take special precautions.

Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of metformin hydrochloride extended-release tablets. In metformin hydrochloride extended-release tablets treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue metformin hydrochloride extended-release tablets and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include :

Vitamin B12 Deficiency

In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2 to 3 year intervals in patients on metformin hydrochloride extended-release tablets and manage any abnormalities.

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Metformin hydrochloride extended-release tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with metformin hydrochloride extended-release tablets.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride extended-release tablets.

What happens if I miss a dose of Metformin hydrochloride?

When you miss a dose, you should take it as soon as you remember, but you should take care that it should be well spaced from the next dose. You should not take an extra dose at the time of the second dose as it will become a double dose. The double dose can give unwanted side effects, so be careful. In chronic conditions or when you have a serious health issue, if you miss a dose, you should inform your health care provider and ask his suggestion.

Take the missed dose as soon as you remember (be sure to take the medicine with food). 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.

What happens if I overdose Pioglitazone?

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of pioglitazone:

Store pioglitazone between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep pioglitazone out of the reach of children and away from pets.

Overdose of Pioglitazone in details

When a dose is taken in higher dose than the recommended doses, it is called Overdose. Overdose always needs a clinical supervision. Any medicine or drug when consumed in Overdose produces untoward side effects on one or various organs in the body. A medicine is excreted in the kidney or metabolized in the liver most of the times. This process goes without any hurdles when taken in normal dose, but when taken in an overdose, the body is not able to metabolize it or send it out properly which causes the effects of anoverdose.

There is limited data on pioglitazone overdosage in humans. Pioglitazone doses of up to 180 mg/day for 7 days have been taken without any clinical symptom. Hypoglycemia may occur in combination with sulfonylureas or insulin.

Initiate appropriate supportive treatment dictated by the patient's clinical signs and symptoms if overdose occurs.

What should I avoid while taking Pioglitazone?

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

Pioglitazone warnings

Warnings are a mix of Precautions. Contraindications and interactions and serious harmful effects associated with the medicine intake. A diabetic or Hypertensive patient need to be warned about few drug interactions. A known hypersensitivity patient needs to be careful about the reactions or anaphylactic shock. A pregnant woman or a breastfeeding woman should be warned of certain medications. A Hepatitis [liver disease] patient or a cardiac patient should avoid few drugs.

Congestive Heart Failure

Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when Pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of Pioglitazone must be considered.

Hypoglycemia

Patients receiving Pioglitazone in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia.

Hepatic Effects

There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking Pioglitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the Pioglitazone controlled clinical trial database to date.

Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating Pioglitazone therapy. In patients with abnormal liver tests, Pioglitazone should be initiated with caution.

Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than 3 times the upper limit of the reference range), Pioglitazone treatment should be interrupted and investigation done to establish the probable cause. Pioglitazone should not be restarted in these patients without another explanation for the liver test abnormalities.

Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury, and should not be restarted on Pioglitazone. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with Pioglitazone can be used with caution.

Urinary Bladder Tumors

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. In two 3-year trials in which Pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking Pioglitazone compared to 5/3679 (0.14%) in patients not taking Pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on Pioglitazone and two (0.05%) cases on placebo.

A five-year interim report of an ongoing 10-year observational cohort study found a non-significant increase in the risk for bladder cancer in subjects ever exposed to Pioglitazone, compared to subjects never exposed to Pioglitazone (HR 1.2 [95% CI 0.9 –1.5]). Compared to never exposure, a duration of Pioglitazone therapy longer than 12 months was associated with an increase in risk (HR 1.4 [95% CI 0.9 –2.1]), which reached statistical significance after more than 24 months of Pioglitazone use (HR 1.4 [95% CI 1.03 –2.0]). Interim results from this study suggested that taking Pioglitazone longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of three cases in 10,000 (from approximately seven in 10,000 [without Pioglitazone] to approximately 10 in 10,000 [with Pioglitazone]).

There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, Pioglitazone should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with Pioglitazone should be considered in patients with a prior history of bladder cancer.

Edema

In controlled clinical trials, edema was reported more frequently in patients treated with Pioglitazone than in placebo-treated patients and is dose-related. In postmarketing experience, reports of new onset or worsening edema have been received.

Pioglitazone should be used with caution in patients with edema. Because thiazolidinediones, including Pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Pioglitazone should be used with caution in patients at risk for congestive heart failure. Patients treated with Pioglitazone should be monitored for signs and symptoms of congestive heart failure.

Fractures

In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to Pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for Pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the incidence of fracture was observed in men treated with Pioglitazone (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with Pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care.

Macular Edema

Macular edema has been reported in postmarketing experience in diabetic patients who were taking Pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.

Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione.

Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings.

Ovulation

Therapy with Pioglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking Pioglitazone. This effect has not been investigated in clinical trials, so the frequency of this occurrence is not known. Adequate contraception in all premenopausal women treated with Pioglitazone is recommended.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Pioglitazone or any other antidiabetic drug.

What should I discuss with my healthcare provider before taking Pioglitazone?

You should not use Pioglitazone if you are allergic to pioglitazone, or if you have severe or uncontrolled heart failure, or bladder cancer. Do not use this medicine if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

To make sure Pioglitazone is safe for you, tell your doctor if you have:

Taking this medicine may increase your risk of serious heart problems. However, not treating your diabetes can damage your heart and other organs. Talk to your doctor about the risks and benefits of treating your diabetes with Pioglitazone.

Pioglitazone may increase your risk of developing bladder cancer. Talk with your doctor about your specific risk.

Women may be more likely than men to have bone fractures in the upper arm, hand, or foot while taking Pioglitazone. Talk with your doctor if you are concerned about this possibility.

FDA pregnancy category C. It is not known whether Pioglitazone will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

Some women using Pioglitazone have started having menstrual periods, even after not having a period for a long time due to a medical condition. You may be able to get pregnant if your periods restart. Talk with your doctor about the need for birth control.

It is not known whether pioglitazone passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Do not give this medicine to anyone under 18 years old without medical advice. Pioglitazone should not be given to a child.

Pioglitazone precautions

Certain people who are very sick or very old or who are sensitive show an exacerbation of side effect of the drug which can turn dangerous at times. So, it is very important to remember the precautions while taking the medicine. Pregnancy and Breastfeeding are also special categories wherein extra care or precaution is needed when taking a drug. Few patients may have a hypersensitivity reaction to few medications, and that can be life-threatening rarely. Penicillin hypersensitivity is one example. Diarrhea, rashes are few other symptoms which need a watch. A patient with other co-existing diseases like liver disease, heart disease, kidney disease should take special precautions.

Congestive Heart Failure

Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when Pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of Pioglitazone must be considered.

Hypoglycemia

Patients receiving Pioglitazone in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia.

Hepatic Effects

There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking Pioglitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the Pioglitazone controlled clinical trial database to date.

Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating Pioglitazone therapy. In patients with abnormal liver tests, Pioglitazone should be initiated with caution.

Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than 3 times the upper limit of the reference range), Pioglitazone treatment should be interrupted and investigation done to establish the probable cause. Pioglitazone should not be restarted in these patients without another explanation for the liver test abnormalities.

Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury, and should not be restarted on Pioglitazone. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with Pioglitazone can be used with caution.

Urinary Bladder Tumors

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study. In two 3-year trials in which Pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking Pioglitazone compared to 5/3679 (0.14%) in patients not taking Pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on Pioglitazone and two (0.05%) cases on placebo.

A five-year interim report of an ongoing 10-year observational cohort study found a non-significant increase in the risk for bladder cancer in subjects ever exposed to Pioglitazone, compared to subjects never exposed to Pioglitazone (HR 1.2 [95% CI 0.9 –1.5]). Compared to never exposure, a duration of Pioglitazone therapy longer than 12 months was associated with an increase in risk (HR 1.4 [95% CI 0.9 –2.1]), which reached statistical significance after more than 24 months of Pioglitazone use (HR 1.4 [95% CI 1.03 –2.0]). Interim results from this study suggested that taking Pioglitazone longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of three cases in 10,000 (from approximately seven in 10,000 [without Pioglitazone] to approximately 10 in 10,000 [with Pioglitazone]).

There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, Pioglitazone should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with Pioglitazone should be considered in patients with a prior history of bladder cancer.

Edema

In controlled clinical trials, edema was reported more frequently in patients treated with Pioglitazone than in placebo-treated patients and is dose-related. In postmarketing experience, reports of new onset or worsening edema have been received.

Pioglitazone should be used with caution in patients with edema. Because thiazolidinediones, including Pioglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Pioglitazone should be used with caution in patients at risk for congestive heart failure. Patients treated with Pioglitazone should be monitored for signs and symptoms of congestive heart failure.

Fractures

In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to Pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for Pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the incidence of fracture was observed in men treated with Pioglitazone (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with Pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care.

Macular Edema

Macular edema has been reported in postmarketing experience in diabetic patients who were taking Pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.

Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione.

Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings.

Ovulation

Therapy with Pioglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking Pioglitazone. This effect has not been investigated in clinical trials, so the frequency of this occurrence is not known. Adequate contraception in all premenopausal women treated with Pioglitazone is recommended.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Pioglitazone or any other antidiabetic drug.

What happens if I miss a dose of Pioglitazone?

When you miss a dose, you should take it as soon as you remember, but you should take care that it should be well spaced from the next dose. You should not take an extra dose at the time of the second dose as it will become a double dose. The double dose can give unwanted side effects, so be careful. In chronic conditions or when you have a serious health issue, if you miss a dose, you should inform your health care provider and ask his suggestion.

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.



References

  1. DailyMed. "GLIMEPIRIDE; PIOGLITAZONE HYDROCHLORIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
  2. DrugBank. "Pioglitazone". http://www.drugbank.ca/drugs/DB01132 (accessed September 17, 2018).
  3. DrugBank. "metformin". http://www.drugbank.ca/drugs/DB00331 (accessed September 17, 2018).

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