Avandamet

Uses

This is used for an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus who are not adequately controlled on Metformin alone. Management of type 2 diabetes mellitus should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient because they help improve insulin sensitivity. This is important not only in the primary treatment of type 2 diabetes but also in maintaining the efficacy of drug therapy.

Avandamet is also used to associated treatment for these conditions: Polycystic Ovaries Syndrome, Type 2 Diabetes Mellitus, Glycemic ControlType 2 Diabetes Mellitus

How Avandamet works

Metformin's mechanisms of action are unique from other classes of oral antihyperglycemic drugs. Metformin decreases blood glucose levels by decreasing hepatic glucose production (gluconeogenesis), decreasing the intestinal absorption of glucose, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization . It is well established that metformin inhibits mitochondrial complex I activity, and it has since been generally postulated that its potent antidiabetic effects occur through this mechanism . The above processes lead to a decrease in blood glucose, managing type II diabetes and exerting positive effects on glycemic control.

After ingestion, the organic cation transporter-1 (OCT1) is responsible for the uptake of metformin into hepatocytes (liver cells). As this drug is positively charged, it accumulates in cells and in the mitochondria because of the membrane potentials across the plasma membrane as well as the mitochondrial inner membrane. Metformin inhibits mitochondrial complex I, preventing the production of mitochondrial ATP leading to increased cytoplasmic ADP:ATP and AMP:ATP ratios . These changes activate AMP-activated protein kinase (AMPK), an enzyme that plays an important role in the regulation of glucose metabolism . Aside from this mechanism, AMPK can be activated by a lysosomal mechanism involving other activators. Following this process, increases in AMP:ATP ratio also inhibit fructose-1,6-bisphosphatase enzyme, resulting in the inhibition of gluconeogenesis, while also inhibiting adenylate cyclase and decreasing the production of cyclic adenosine monophosphate (cAMP) , a derivative of ATP used for cell signaling . Activated AMPK phosphorylates two isoforms of acetyl-CoA carboxylase enzyme, thereby inhibiting fat synthesis and leading to fat oxidation, reducing hepatic lipid stores and increasing liver sensitivity to insulin .

In the intestines, metformin increases anaerobic glucose metabolism in enterocytes (intestinal cells), leading to reduced net glucose uptake and increased delivery of lactate to the liver. Recent studies have also implicated the gut as a primary site of action of metformin and suggest that the liver may not be as important for metformin action in patients with type 2 diabetes. Some of the ways metformin may play a role on the intestines is by promoting the metabolism of glucose by increasing glucagon-like peptide I (GLP-1) as well as increasing gut utilization of glucose .

In addition to the above pathway, the mechanism of action of metformin may be explained by other ways, and its exact mechanism of action has been under extensive study in recent years .

Rosiglitazone acts as a highly selective and potent agonist at peroxisome proliferator activated receptors (PPAR) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-gamma receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, rosiglitazone enhances tissue sensitivity to insulin.

Dosage

Avandamet dosage

The selection of the dose of Rosiglitazone and Metformin combination should be based on the patient’s current doses of Rosiglitazone and/or Metformin. The safety and efficacy of Rosiglitazone and Metformin combination as initial therapy for patients with type 2 diabetes mellitus have not been established.

The following recommendations regarding the use of Rosiglitazone and Metformin combination in patients inadequately controlled on Rosiglitazone and Metformin monotherapies are based on clinical practice experience with Rosiglitazone and Metformin combination therapy.

• The dosage of antidiabetic therapy with Rosiglitazone and Metformin combination should be individualized on the basis of effectiveness and tolerability while not exceeding the maximum recommended daily dose of 8 mg/2,000 mg.
• Rosiglitazone and Metformin combination should be given in divided doses with meals, with gradual dose escalation. This reduces GI side effects (largely due to Metformin) and permits determination of the minimum effective dose for the individual patient.
• Sufficient time should be given to assess adequacy of therapeutic response. Fasting plasma glucose (FPG) should be used to determine the therapeutic response to Rosiglitazone and Metformin combination . After an increase in Metformin dosage, dose titration is recommended if patients are not adequately controlled after 1 to 2 weeks. After an increase in Rosiglitazone dosage, dose titration is recommended if patients are not adequately controlled after 8 to 12 weeks.

For patients inadequately controlled on Metformin monotherapy: The usual starting dose of Rosiglitazone and Metformin combination is 4 mg Rosiglitazone (total daily dose) plus the dose of Metformin already being taken.

For patients inadequately controlled on Rosiglitazone monotherapy: The usual starting dose of Rosiglitazone and Metformin combination is 1,000 mg Metformin (total daily dose) plus the dose of Rosiglitazone already being taken.

Side Effects

The incidence and types of adverse events reported in clinical trials of Rosiglitazone as monotherapy are upper respiratory tract infection, headache, back pain, hyperglycemia, fatigue, sinusitis, diarrhea, and hypoglycemia. Adverse reactions reported in greater than 5% of the Metformin patients, and that were more common in Metformin- than placebo-treated patients are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, headache.

Toxicity

Metformin (hydrochloride) toxicity data:

Oral LD50 (rat): 1 g/kg; Intraperitoneal LD50 (rat): 500 mg/kg; Subcutaneous LD50 (rat): 300 mg/kg; Oral LD50 (mouse): 1450 mg/kg; Intraperitoneal LD50 (mouse): 420 mg/kg; Subcutaneous LD50 (mouse): 225 mg/kg .

A note on lactic acidosis

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

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment .

A note on renal function

In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased .

Metformin should be avoided in those with severely compromised renal function (creatinine clearance < 30 ml/min), acute/decompensated heart failure, severe liver disease and for 48 hours after the use of iodinated contrast dyes due to the risk of lactic acidosis . Lower doses should be used in the elderly and those with decreased renal function. Metformin decreases fasting plasma glucose, postprandial blood glucose and glycosolated hemoglobin (HbA1c) levels, which are reflective of the last 8-10 weeks of glucose control. Metformin may also have a positive effect on lipid levels.

A note on hypoglycemia

When used alone, metformin does not cause hypoglycemia, however, it may potentiate the hypoglycemic effects of sulfonylureas and insulin when they are used together .

Use in pregnancy

Available data from post-marketing studies have not indicated a clear association of metformin with major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was ingested during pregnancy. Despite this, the abovementioned studies cannot definitively establish the absence of any metformin-associated risk due to methodological limitations, including small sample size and inconsistent study groups .

Use in nursing

A limited number of published studies indicate that metformin is present in human milk. There is insufficient information to confirm the effects of metformin on the nursing infant and no available data on the effects of metformin on the production of milk. The developmental and health benefits of breastfeeding should be considered as well as the mother’s clinical need for metformin and any possible adverse effects on the nursing child .

Side effects include fluid retention, congestive heart failure (CHF), liver disease

Precaution

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 combination of Rosiglitazone and Metformin and temporarily administer insulin. Combination of Rosiglitazone and Metformin may be reinstituted after the acute episode is resolved. Combination of Rosiglitazone and Metformin should be used with caution in patients with edema.

Interaction

If an inhibitor or an inducer of CYP2C8 (such as gemfibrozil or rifampin) is started or stopped during treatment with Rosiglitazone, changes in diabetes treatment may be needed based upon clinical response.

Although drug interactions with cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of combination of Rosiglitazone and Metformin and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

When drugs that produce hyperglycemia which may lead to loss of glycemic control are administered to a patient receiving combination of Rosiglitazone and Metformin, the patient should be closely observed to maintain adequate glycemic control.

Volume of Distribution

The apparent volume of distribution (V/F) of metformin after one oral dose of metformin 850 mg averaged at 654 ± 358 L .

• 17.6 L [oral volume of distribution Vss/F]
• 13.5 L [population mean, pediatric patients]
  

Elimination Route

Regular tablet absorption

The absolute bioavailability of a metformin 500 mg tablet administered in the fasting state is about 50%-60%. Single-dose clinical studies using oral doses of metformin 500 to 1500 mg and 850 to 2550 mg show that there is a lack of dose proportionality with an increase in metformin dose, attributed to decreased absorption rather than changes in elimination .

At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are achieved within 24-48 hours and are normally measured at Label.

Extended-release tablet absorption

After a single oral dose of metformin extended-release, Cmax is reached with a median value of 7 hours and a range of between 4 and 8 hours. Peak plasma levels are measured to be about 20% lower compared to the same dose of regular metformin, however, the extent of absorption of both forms (as measured by area under the curve - AUC), are similar .

Effect of food

Food reduces the absorption of metformin, as demonstrated by about a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute increase in time to peak plasma concentration (Tmax) after ingestion of an 850 mg tablet of metformin taken with food, compared to the same dose administered during fasting .

Though the extent of metformin absorption (measured by the area under the curve - AUC) from the metformin extended-release tablet is increased by about 50% when given with food, no effect of food on Cmax and Tmax of metformin is observed. High and low-fat meals exert similar effects on the pharmacokinetics of extended-release metformin .

The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in C_max and a delay in T_max (1.75 hours). These changes are not likely to be clinically significant; therefore, rosiglitazone may be administered with or without food. Maximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range.

Half Life

Approximately 6.2 hours in the plasma and in the blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution .

3-4 hours (single oral dose, independent of dose)

Clearance

Renal clearance is about 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours .

• Oral clearance (CL) = 3.03 ± 0.87 L/hr [1 mg Fasting]
• Oral CL = 2.89 ± 0.71 L/hr [2 mg Fasting]
• Oral CL = 2.85 ± 0.69 L/hr [8 mg Fasting]
• Oral CL = 2.97 ± 0.81 L/hr [8 mg Fed]
• 3.15 L/hr [Population mean, Pediatric patients]

Elimination Route

This drug is substantially excreted by the kidney .

Renal clearance of metformin is about 3.5 times higher than creatinine clearance, which shows that renal tubular secretion is the major route of metformin elimination. After oral administration, about 90% of absorbed metformin is eliminated by the kidneys within the first 24 hours post-ingestion .

Following oral or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively.

Pregnancy & Breastfeeding use

Pregnancy Category C. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible. Combination of Rosiglitazone and Metformin should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant women with combination of Rosiglitazone and Metformin or its individual components.

It is not known whether Rosiglitazone and/or Metformin are excreted in human milk. Because many drugs are excreted in human milk, a combination of Rosiglitazone and Metformin should not be administered to a nursing woman.

Contraindication

Combination of Rosiglitazone and Metformin tablets arecontraindicated in patients with:

• Renal disease or renal dysfunction which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
• Congestive heart failure requiring pharmacologic treatment.
• Known hypersensitivity to Rosiglitazone maleate or Metformin hydrochloride.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

Combination of Rosiglitazone and Metformin 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.

Special Warning

Pediatric Use: Safety and effectiveness of combination of Rosiglitazone and Metformin in pdiatric patients have not been established.

Geriatric Use: Because aging is associated with reduced renal function, combination of Rosi litazone and Metformin should be used with caution as age increases. 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 combination of Rosiglitazone and Metformin.

Acute Overdose

Hypoglycemia has not been seen with metformin doses up to 85g, although lactic acidosis has occurred in such circumstances. High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is hemodialysis.

Storage Condition

Store in a cool dry place protected from light. Keep out of reach of children.

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