Possible side effects
Stop taking metformin and rosiglitazone and seek emergency medical attention if you experience an allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives).
Notify your doctor immediately if you develop nausea, vomiting, abdominal pain, unusual fatigue, loss of appetite, yellow skin or eyes, or dark urine. These symptoms may be early signs of liver problems.
Notify your doctor immediately if you experience an unusually rapid increase in weight or edema (water retention), shortness of breath, or chest pain during treatment with metformin rosiglitazone. These may be early symptoms of heart problems.
A small number of people who have taken metformin (with and without rosiglitazone), have developed a serious condition called lactic acidosis that has been fatal in up to 50% of cases. Lactic acidosis has occurred most often in people whose kidneys were not working properly. Liver problems may also increase the risk of developing lactic acidosis. Stop taking metformin and rosiglitazone and call your doctor immediately if you experience a feeling of general discomfort or sickness; weakness; sore or aching muscles; trouble breathing, unusual drowsiness, dizziness or lightheadedness; unusual or unexplained stomach upset (after the initial stomach upset that may occur at the start of therapy with metformin and rosiglitazone); or the sudden development of a slow or irregular heartbeat. These may be signs of lactic acidosis.
Metformin and rosiglitazone does not usually cause hypoglycemia (low blood sugar). Nevertheless, hypoglycemia may occur, as a result of skipped meals, excessive exercise, or alcohol consumption. Know the signs and symptoms of low blood sugar, which include hunger, headache, drowsiness, weakness, dizziness, a fast heartbeat, sweating, tremor, and nausea. Carry a non-dietetic candy or glucose tablets to treat episodes of low blood sugar.
Other, less serious side effects may be more likely to occur. Continue to take metformin and rosiglitazone and talk to your doctor if you experience
- nausea, vomiting, abdominal pain, or diarrhea at the start of therapy;
- abdominal bloating or increased gas production;
- decreased appetite or changes in taste (metallic taste in the mouth);
- cold-like symptoms (may indicate an upper respiratory tract infection);
- weight gain;
- fatigue; or
- headache.
Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.
What other drugs will affect Avandamet?
You may be more likely to have hyperglycemia (high blood sugar) if you are taking Avandamet with other drugs that raise blood sugar. Drugs that can raise blood sugar include:
- isoniazid;
- diuretics (water pills);
- steroids (prednisone and others);
- phenothiazines (Compazine and others);
- thyroid medicine (Synthroid and others);
- birth control pills and other hormones;
- seizure medicines (Dilantin and others); and
- diet pills or medicines to treat asthma, colds or allergies.
You may be more likely to have hypoglycemia (low blood sugar) if you are taking Avandamet with other drugs that lower blood sugar. Drugs that can lower blood sugar include:
- some nonsteroidal anti-inflammatory drugs (NSAIDs);
- aspirin or other salicylates (including Pepto-Bismol);
- sulfa drugs (Bactrim and others);
- a monoamine oxidase inhibitor (MAOI);
- beta-blockers (Tenormin and others); or
- probenecid (Benemid).
Some medications may interact with Avandamet. Tell your doctor if you are using any of the following drugs:
- gemfibrozil (Gemcor);
- rifampin (Rifater, Rifadin, Rimactane);
- nifedipine (Adalat, Procardia);
- cimetidine (Tagamet) or ranitidine (Zantac);
- amiloride (Midamor) or triamterene (Dyrenium);
- digoxin (Lanoxin);
- morphine (MS Contin, Kadian, Oramorph);
- procainamide (Procan, Pronestyl, Procanbid);
- quinidine (Cardioquin, Quinidex, Quinaglute);
- trimethoprim (Proloprim, Primsol, Bactrim, Cotrim, Septra); or
- vancomycin (Vancocin, Lyphocin).
If you are using any of these drugs, you may not be able to take Avandamet, or you may require a dosage adjustment or special monitoring.
There may be other drugs not listed that can affect Avandamet. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.
What should I avoid while taking Avandamet?
Some conditions may increase the risk of developing lactic acidosis while taking metformin and rosiglitazone. Tell your doctor that you are taking metformin and rosiglitazone if you become ill; if you have a heart attack; have a stroke; develop congestive heart failure; experience diarrhea, vomiting, fever, or dehydration from any cause; decrease the amount of food or liquid in your normal diet, or develop other health conditions. You may need to stop treatment with metformin and rosiglitazone for a short amount of time until you are feeling better.
Avoid excessive alcohol intake while taking metformin and rosiglitazone. Together, alcohol and metformin and rosiglitazone may increase the risk of lactic acidosis and hypoglycemia.
Follow diet, medication, and exercise routines very closely. Changing any of these things can affect blood sugar levels.
Tell your doctor or other health care provider that you are taking this medication if you need to have surgery or x-ray procedures that require injection of contrast agents. Treatment with metformin and rosiglitazone may need to be stopped for a short period of time.
Contraindications
Initiation of Avandamet in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.
Avandamet is contraindicated in patients with renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ?1.5 mg/dL [males], ?1.4 mg/dL [females], or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.
Avandamet is contraindicated in patients with known hypersensitivity to rosiglitazone maleate or metformin hydrochloride.
Avandamet is contraindicated in patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
Avandamet should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.
Warnings
Use Avandamet with caution if you have a problem with fluid retention or swelling. The drug has been known to cause this problem, which in turn can lead to heart failure. Also use caution if you’re at risk for heart failure. Call the doctor immediately if you develop symptoms of heart failure such as a sudden weight change, fatigue, shortness of breath, or swelling of the ankles or legs.
Before you start therapy with Avandamet, and at least once a year thereafter, your doctor will do a complete assessment of your kidney function. If you develop kidney problems while on Avandamet, your doctor will discontinue Avandamet. If you are an older person, you will need to have your kidney function monitored more frequently, and your doctor may want to start you at a lower dosage.
Poor liver function could increase the risk of lactic acidosis. Therefore, your doctor will check to make sure your liver function is normal before prescribing Avandamet, then recheck it every 2 months for the first 12 months and periodically thereafter. Warning signs of liver damage include nausea, vomiting, abdominal pain, fatigue, loss of appetite, dark urine, and yellowing of the skin or whites of the eyes. If you develop any of these symptoms, tell your doctor immediately. You may need to discontinue treatment with Avandamet. You should not take Avandamet for 2 days before and after having an X-ray procedure (such as an angiogram) that uses an injectable dye. Also, if you are going to have surgery, except minor surgery, you should stop taking Avandamet. Once you have resumed normal food and fluid intake, your doctor will tell you when you can start drug therapy again.
Avoid drinking too much alcohol while taking Avandamet. Heavy drinking increases the danger of lactic acidosis and can also trigger an attack of low blood sugar.
Avandamet occasionally causes a mild deficiency of vitamin B12. Your doctor will check for this with yearly blood tests and may prescribe a supplement if necessary.
While taking Avandamet, you should check your blood or urine periodically for abnormal sugar levels. If you notice sudden changes after you’ve been stabilized for a while, tell your doctor immediately. It could be a sign you’re developing lactic acidosis or ketoacidosis.
Avandamet does not usually cause hypoglycemia (low blood sugar). However, it remains a possibility, especially in older, weak, and undernourished people and those with kidney, liver, adrenal, or pituitary gland problems. The risk of low blood sugar increases when Avandamet is combined with other diabetes medications. The risk is also boosted by missed meals, alcohol, and excessive exercise. To avoid low blood sugar, you should closely follow the diet and exercise plan suggested by your doctor.
If your blood sugar becomes unstable due to the stress of a fever, injury, infection, or surgery, your doctor may temporarily take you off Avandamet and ask you to take insulin instead.
You should stop taking Avandamet if you become seriously dehydrated, since this increases the likelihood of developing lactic acidosis. Tell your doctor if you lose a significant amount of fluid due to vomiting, diarrhea, fever, or some other condition.
Avandamet could trigger ovulation in premenopausal women who have stopped ovulating. It is important for all women who do not wish to get pregnant to use adequate birth control while taking Avandamet.
Precautions
Metformin hydrochloride
Monitoring of renal function
Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function.
Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Avandamet. In patients with advanced age, Avandamet should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ?80 years of age, renal function should be monitored regularly and, generally, Avandamet should not be titrated to the maximum dose of the metformin component, i.e., 2,000 mg.
Before initiation of therapy with Avandamet and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and Avandamet discontinued if evidence of renal impairment is present.
Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion, should be used with caution.
Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography [CT] scans with contrast materials): Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, Avandamet should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
Hypoxic states
Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients receiving Avandamet, the drug should be promptly discontinued.
Surgical procedures
Use of Avandamet should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal.
Alcohol intake
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Avandamet.
Impaired hepatic function
Since impaired hepatic function has been associated with some cases of lactic acidosis, Avandamet should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 levels
In controlled clinical trials of metformin hydrochloride of 29 weeks� duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Avandamet and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful.
Change in clinical status of previously controlled diabetic
A patient with type 2 diabetes previously well-controlled on Avandamet who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Avandamet must be stopped immediately and other appropriate corrective measures initiated.
Hypoglycemia
Hypoglycemia does not occur in patients receiving metformin hydrochloride alone under usual circumstances of use but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with hypoglycemic agents (such as sulfonylureas or insulin) or ethanol. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking?-adrenergic blocking drugs.
Loss of control of blood glucose
When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Avandamet and temporarily administer insulin. Avandamet may be reinstituted after the acute episode is resolved.
Rosiglitazone maleate
General
Due to its mechanism of action, rosiglitazone is active only in the presence of endogenous insulin. Therefore, Avandamet should not be used in patients with type 1 diabetes.
Hypoglycemia
Patients receiving rosiglitazone in combination with other hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.
Edema
Avandamet should be used with caution in patients with edema. In a clinical study in healthy volunteers who received rosiglitazone 8 mg once daily for 8 weeks, there was a statistically significant increase in median plasma volume compared to placebo. Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Avandamet should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure.
In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with rosiglitazone maleate, and may be dose related. Patients with ongoing edema are more likely to have adverse events associated with edema if started on combination therapy with insulin and rosiglitazone.
Macular Edema
Macular edema has been reported in postmarketing experience in some diabetic patients who were taking rosiglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been 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 their thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient�s underlying medications or other physical findings.
Fractures
In a 4- to 6-year comparative study (ADOPT) of glycemic control with monotherapy in drug-naive patients recently diagnosed with type 2 diabetes mellitus, an increased incidence of bone fracture was noted in female patients taking rosiglitazone. Over the 4- to 6-year period, the incidence of bone fracture in females was 9.3% (60/645) for rosiglitazone versus 3.5% (21/605) for glyburide and 5.1% (30/590) for metformin. This increased incidence was noted after the first year of treatment and persisted during the course of the study. The majority of the fractures in the women who received rosiglitazone occurred in the upper arm, hand, and foot. These sites of fracture are different from those usually associated with postmenopausal osteoporosis (e.g., hip or spine). No increase in fracture rates was observed in men treated with rosiglitazone. The risk of fracture should be considered in the care of patients, especially female patients, treated with rosiglitazone, and attention given to assessing and maintaining bone health according to current standards of care.
Weight Gain
Dose-related weight gain was seen with rosiglitazone alone and rosiglitazone together with other hypoglycemic agents. No overall change in median weight was observed with Avandamet in drug-naive patients. The mechanism of weight gain with rosiglitazone is unclear but probably involves a combination of fluid retention and fat accumulation.
Hematologic
Across all controlled clinical studies in adults, decreases in hemoglobin and hematocrit (mean decreases in individual studies of approximately ?1.0 gram/dL and?3.3%, respectively) were observed for rosiglitazone maleate alone and in combination with other hypoglycemic agents. The changes occurred primarily during the first 3 months following initiation of rosiglitazone therapy or following an increase in rosiglitazone dose. The decrease in hemoglobin was seen more frequently in combination rosiglitazone and metformin therapy than in rosiglitazone therapy alone. Vitamin B12 deficiency may contribute to the observed reductions in hemoglobin. White blood cell counts also decreased slightly in adult patients treated with rosiglitazone. Small decreases in hemoglobin and hematocrit have also been reported in pediatric patients treated with rosiglitazone. The observed changes may be related to the increased plasma volume observed with treatment with rosiglitazone and may be dose related.
Ovulation
Therapy with rosiglitazone, 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 Avandamet Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical studies so the frequency of this occurrence is not known.
Although hormonal imbalance has been seen in preclinical studies, the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with Avandamet should be reviewed.
Hepatic Effects
Another drug of the thiazolidinedione class, troglitazone, was associated with idiosyncratic hepatotoxicity, and very rare cases of liver failure, liver transplants, and death were reported during clinical use. In pre-approval controlled clinical trials in patients with type 2 diabetes, troglitazone was more frequently associated with clinically significant elevations in liver enzymes (ALT >3X upper limit of normal) compared to placebo. Very rare cases of reversible jaundice were also reported
. In pre-approval clinical studies in 4,598 patients treated with rosiglitazone maleate, encompassing approximately 3,600 patient years of exposure, there was no signal of drug-induced hepatotoxicity or elevation of ALT levels. In the pre-approval controlled trials, 0.2% of patients treated with rosiglitazone had elevations in ALT >3X the upper limit of normal compared to 0.2% on placebo and 0.5% on active comparators. The ALT elevations in patients treated with rosiglitazone were reversible and were not clearly causally related to therapy with rosiglitazone.
In postmarketing experience with rosiglitazone maleate, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Rosiglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and rare cases of liver failure, liver transplants, and death during clinical use. Pending the availability of the results of additional large, long-term controlled clinical trials and additional postmarketing safety data, it is recommended that patients treated with Avandamet undergo periodic monitoring of liver enzymes.
Liver enzymes should be checked prior to the initiation of therapy with Avandamet in all patients and periodically thereafter per the clinical judgement of the healthcare professional. Therapy with Avandamet should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5X upper limit of normal). Patients with mildly elevated liver enzymes (ALT levels ?2.5X upper limit of normal) at baseline or during therapy with Avandamet should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with Avandamet in patients with mild liver enzyme elevations should proceed with caution and include close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to >3X the upper limit of normal in patients on therapy with Avandamet, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with Avandamet should be discontinued.
If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, and/or dark urine, liver enzymes should be checked. If jaundice is observed, drug therapy should be discontinued.
In addition, if the presence of hepatic disease or hepatic dysfunction of sufficient magnitude to predispose to lactic acidosis is confirmed, therapy with Avandamet should be discontinued.
There are no data available from clinical trials to evaluate the safety of Avandamet in patients who experienced liver abnormalities, hepatic dysfunction, or jaundice while on troglitazone. Avandamet should not be used in patients who experienced jaundice while taking troglitazone.
Information For Patients
Carcinogenesis/ Mutagenesis/ Impairment of Fertility
No animal studies have been conducted with the combined products in Avandamet. The following data are based on findings in studies performed with rosiglitazone or metformin individually.
Rosiglitazone maleate
A 2-year carcinogenicity study was conducted in Charles River CD-1 mice at doses of 0.4, 1.5, and 6 mg/kg/day in the diet (highest dose equivalent to approximately 12 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of Avandamet). Sprague-Dawley rats were dosed for 2 years by oral gavage at doses of 0.05, 0.3, and 2 mg/kg/day (highest dose equivalent to approximately 10 and 20 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of Avandamet for male and female rats, respectively).
Rosiglitazone was not carcinogenic in the mouse. There was an increase in incidence of adipose hyperplasia in the mouse at doses ?1.5 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of Avandamet). In rats, there was a significant increase in the incidence of benign adipose tissue tumors (lipomas) at doses ?0.3 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of Avandamet). These proliferative changes in both species are considered due to the persistent pharmacological overstimulation of adipose tissue.
Rosiglitazone was not mutagenic or clastogenic in the in vitro bacterial assays for gene mutation, the in vitro chromosome aberration test in human lymphocytes, the in vivo mouse micronucleus test, and the in vivo/in vitro rat UDS assay. There was a small (about 2-fold) increase in mutation in the in vitro mouse lymphoma assay in the presence of metabolic activation.
Rosiglitazone had no effects on mating or fertility of male rats given up to 40 mg/kg/day (approximately 116 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of Avandamet). Rosiglitazone altered estrous cyclicity (2 mg/kg/day) and reduced fertility (40 mg/kg/day) of female rats in association with lower plasma levels of progesterone and estradiol (approximately 20 and 200 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of Avandamet, respectively). No such effects were noted at 0.2 mg/kg/day (approximately 3 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of Avandamet). In juvenile rats dosed from 27 days of age through to sexual maturity (at up to 40 mg/kg/day), there was no effect on male reproductive performance, or on estrous cyclicity, mating performance or pregnancy incidence in females (approximately 68 times human AUC at the maximum recommended daily dose of rosiglitazone). In monkeys, rosiglitazone (0.6 and 4.6 mg/kg/day; approximately 3 and 15 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of Avandamet, respectively) diminished the follicular phase rise in serum estradiol with consequential reduction in the luteinizing hormone surge, lower luteal phase progesterone levels, and amenorrhea. The mechanism for these effects appears to be direct inhibition of ovarian steroidogenesis.
Metformin hydrochloride
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2,000 mg of the metformin component of Avandamet based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.
There was no evidence of mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin when administrated at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose of the metformin component of Avandamet based on body surface area comparisons.
Pregnancy
Pregnancy Category C.
All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Careful monitoring of glucose control is essential in such patients. Most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible. Avandamet should not be used during pregnancy.
Human Data: There are no adequate and well-controlled studies in pregnant women with Avandamet or its individual components.
Rosiglitazone maleate: Rosiglitazone has been reported to cross the human placenta and be detectable in fetal tissue. The clinical significance of these findings is unknown.
Animal Studies: No animal studies have been conducted with the combined products in Avandamet. The following data are based on findings in studies performed with rosiglitazone or metformin individually.
Rosiglitazone maleate
There was no effect on implantation or the embryo with rosiglitazone treatment during early pregnancy in rats, but treatment during mid-late gestation was associated with fetal death and growth retardation in both rats and rabbits. Teratogenicity was not observed at doses up to 3 mg/kg in rats and 100 mg/kg in rabbits (approximately 20 and 75 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of Avandamet, respectively). Rosiglitazone caused placental pathology in rats (3 mg/kg/day). Treatment of rats during gestation through lactation reduced litter size, neonatal viability, and postnatal growth, with growth retardation reversible after puberty. For effects on the placenta, embryo/fetus, and offspring, the no-effect dose was 0.2 mg/kg/day in rats and 15 mg/kg/day in rabbits. These no-effect levels are approximately 4 times human AUC at the maximum recommended human daily dose of the rosiglitazone component of Avandamet. Rosiglitazone reduced the number of uterine implantations and live offspring when juvenile female rats were treated at 40 mg/kg/day from 27 days of age through to sexual maturity (approximately 68 times human AUC at the maximum recommended daily dose). The no-effect level was 2 mg/kg/day (approximately 4 times human AUC at the maximum recommended daily dose). There was no effect on pre- or post-natal survival or growth.
Metformin hydrochloride
Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Nursing Mothers
No studies have been conducted with the combined components of Avandamet. In studies performed with the individual components, both rosiglitazone-related material and metformin were detectable in milk from lactating rats. It is not known whether rosiglitazone and/or metformin is excreted in human milk. Because many drugs are excreted in human milk, Avandamet should not be administered to a nursing woman. If Avandamet is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Pediatric Use
Safety and effectiveness of Avandamet in pediatric patients have not been established. Avandamet and rosiglitazone are not indicated for use in pediatric patients.
Geriatric Use
Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Avandamet should only be used in patients with normal renal function. Because reduced renal function is associated with increasing age, Avandamet should be used with caution in elderly patients. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of Avandamet.
Most important information about Avandamet
More information about AVANDAMET (Rosiglitazone/Metformin):
FDA Approves Avandamet as Initial Therapy for Type 2 Diabetes
Too Many Meds: Try Combinations
New Avandamet dosage strengths approved for treatment of type 2 diabetes
To buy AVANDAMET (Rosiglitazone/Metformin) click HERE: My Family Drugstore
