Mintide Plus

Uses

Chromium is an ingredient found in a variety of supplements and vitamins.

Indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN), to maintain chromium serum levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms .

Glipizide is used for an adjunct to diet for the control of hyperglycaemia and its associated symptomatology in the treatment of non-insulin-dependent diabetes mellitus (NIDDM type II) when diet modification has not been proved effective on its own. In certain patients who are receiving insulin, the concurrent use of Glipizide would allow a reduction in the daily dose of insulin.

Use of Glipizide must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, short term administration may be required if diet control alone results in transient control of blood glucose level.

During maintenance, if satisfactory lowering of blood glucose is no longer achieved, use of Glipizide should be discontinued.

Metformin Hydrochloride, as monotherapy, is used for an adjunct to diet to lower blood glucose especially in overweight patients with non-insulin-dependent diabetes mellitus (NIDDM) or type 2 diabetes mellitus whose hyperglycemia cannot be satisfactorily managed on diet alone. Metformin Hydrochloride may be used concomitantly with a sulfonylurea when diet and metformin hydrochloride or sulfonylureas alone do not result in adequate glycemic control.

Mintide Plus is also used to associated treatment for these conditions: Mineral supplementationType 2 Diabetes MellitusPolycystic Ovaries Syndrome, Type 2 Diabetes Mellitus, Glycemic Control

How Mintide Plus works

Chromium is an essential nutrient involved in the metabolism of glucose, insulin and blood lipids. Its role in potentiating insulin signalling cascades has been implicated in several studies. Chromium upregulates insulin-stimulated insulin signal transduction via affecting effector molecules downstream of the insulin receptor (IR). IR-mediated signalling pathway involves phoshorylation of multiple intracellular domains and protein kinases, and downstream effector molecules . Upon activation by ligands, intracellular β-subunit of IR autophosphorylates and activates tyrosine kinase domain of the IR, followed by activation and phosphorylation of regulatory proteins and downstream signalling effectors including phosphatidylinositol 2-kinase (PI3K). PI3K activates further downstream reaction cascades to activate protein kinase B (Akt) to ultimately promote translocation of glucose transporter-4 (Glut4)-vesicles from the cytoplasm to the cell surface and regulate glucose uptake . Chromium enhances the kinase activity of insulin receptor β and increases the activity of downstream effectors, pI3-kinase and Akt.

Under insulin-resistant conditions, chromium also promotes GLUT-4 transporter translocation that is independent of activity of IR, IRS-1, PI3-kinase, or Akt; chromium mediates cholesterol efflux from the membranes via increasing fluidity of the membrane by decreasing the membrane cholesterol and upregulation of sterol regulatory element-binding protein . As a result, intracellular GLUT-4 transporters are stimulated to translocate from intracellular to the plasma membrane, leading to enhanced glucose uptake in muscle cells . Chromium attenuates the activity of PTP-1B in vitro, which is a negative regulator of insulin signaling. It also alleviates ER stress that is observed to be elevated the suppression of insulin signaling. ER stress is thought to activate c-Jun N-terminal kinase (JNK), which subsequently induces serine phosphorylation of IRS and aberration of insulin signalling . Transient upregulation of AMPK by chromium also leads to increased glucose uptake .

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder with increasing prevalence worldwide. Characterized by higher-than-normal levels of blood glucose, T2DM is a complex disorder that arises from the interaction between genetic, environmental and behavioral risk factors. Insulin is a peptide hormone that plays a critical role in regulating blood glucose levels. In response to high blood glucose levels, insulin promotes the uptake of glucose into the liver, muscle cells, and fat cells for storage. Although there are multiple events occurring that lead to the pathophysiology of T2DM, the disorder mainly involves insulin insensitivity as a result of insulin resistance, declining insulin production, and eventual failure of beta cells of pancreatic islets that normally produce insulin. Early management with lifestyle intervention, such as controlled diet and exercise, is critical in reducing the risk of long-term secondary complications, such as cardiovascular mortality.

Glipizide, like other sulfonylurea drugs, is an insulin secretagogue, which works by stimulating the insulin release from the pancreatic beta cells thereby increasing the plasma concentrations of insulin. Thus, the main therapeutic action of the drug depends on the functional beta cells in the pancreatic islets. Sulfonylureas bind to the sulfonylurea receptor expressed on the pancreatic beta-cell plasma membrane, leading to the closure of the ATP-sensitive potassium channel and reduced potassium conductance. This results in depolarization of the pancreatic beta cell and opening of the voltage-sensitive calcium channels, promoting calcium ion influx. Increased intracellular concentrations of calcium ions in beta cells stimulates the secretion, or exocytosis, of insulin granules from the cells. Apart from this main mechanism of action, the blood-glucose-lowering effect of glipizide involves increased peripheral glucose utilization via stimulating hepatic gluconeogenesis and by increasing the number and sensitivity of insulin receptors.

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 .

Dosage

Mintide Plus dosage

Like any other oral hypoglycaemic agent, dosage of Glipizide is not fixed and may be adjusted through periodic monitoring of blood glucose level. Short term administration of Glipizide may be sufficient during periods of transient loss of control of blood glucose in patients, usually controlled well on diet.

In general, Glipizide should be given approximately 30 minutes before a meal to achieve the maximum reduction in postprandial hyperglycaemia.

• Initial dose: The recommended starting dose is 5 mg, given before breakfast. Geriatric patients or those with liver disease may be started on 2.5 mg.
• Dosage adjustments: Dosage adjustment may be done at intervals of several days by an increment of 2.5-5 mg, as determined by blood glucose response. If response to a single dose is not satisfactory, dividing that dose might prove effective. The maximum recommended once daily dose is 15 mg. Doses above 15 mg should ordinarily be divided and given before meals of adequate calorie content. The maximum recommended total daily dose is 40 mg.
• Maintenance: Some patients may be effectively controlled on a once daily regimen, while others show better response with divided dosing. Total daily dose above 30 mg have been safely given on bid basis to long term patients. Patients can usually be stabilized on a dosage ranging from 2.5 to 30 mg daily.

In elderly, debilitated or malnourished patients, and patients with impaired renal or hepatic function:

The initial and maintenance dosing should be conservative to avoid hypoglycaemic reactions.

Patients receiving insulin: Many stable non-insulin-dependent diabetic patients receiving Insulin may be safely placed on Glipizide if the physician decides to do so.

Patients receiving other oral hypoglycaemic agents: As with other sulphonylurea, no transition period is necessary while transferring patients to Glipizide. Patients should be observed carefully for any possible hypoglycaemic effect due to overlapping of drug effects.

Adult-

Metformin 500 mg tablet: Initial dosage is 500 mg tablet 2-3 times daily with or after meals, gradually increased if necessary to 2 to 3 gm daily.

Metformin 850 mg tablet: Initial dosage is 850 mg tablet once or twice daily with or after meals, gradually increased if necessary to 2 to 3 gm daily.

Metformin extended release orlong acting tablet: The usual starting dose of Metformin extended release tabletis 500 mg once daily with the evening meal. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal. If glycemic control is not achieved on Metformin extended release tablet 2000 mg once daily, a trial of Metformin extended release tablet 1000 mg twice daily should be considered. The maximum recommended dose of metformin is 3 gm daily.

Transfer from other antidiabetic therapy: When transferring patients from standard oral hypoglycemic agents other than Chlorpropamide to Metformin HCl, no transition period generally is necessary. When transferring patients fromChlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of Chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.

Children and adolescents-

Monotherapy and combination with insulin

• Metformin tablets can be used in children from 10 years of age and adolescents.
• The usual starting dose is one tablet of 500 mg or 850 mg once daily, given during meals or after meals.

After 10 to 15 days the should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin is 2 g daily, taken as 2 or 3 divided doses.

Elderly-

Due to the potential for decreased renal function in elderly subjects, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary.

Side Effects

The most potential adverse reaction is hypoglycemia (1% to 3.4%). Other side effects reported were asthenia, headache, dizziness, nervousness, tremor, diarrhea, flatulence.

Metformin may cause gastro-intestinal adverse effects like diarrhoea, anorexia, nausea & vomiting. Lactic acidosis and malabsorption of vitamin B12 may be occurred. Patients may experience a metallic taste and there may be weight loss, which in some diabetics could be an advantage.

Toxicity

Oral LD50 for Cr (VI) is 135 - 175 mg/kg in mouse and 46 - 113 mg/kg in rat . Oral LD50 for Cr (III) in rat is >2000 mg/kg . LD50 of chromium (III) oxide in rats is reported to be > 5g/kg . Other LD50 values reported for rats include: 3.5 g/kg (CI 3.19-3.79 g/kg) for chromium sulphate; 11.3 g/kg for chromium (III) acetate; 3.3 g/kg for chromium nitrate; and 1.5 g/kg for chromium nitrate nonahydrate .

Acute overdose of chromium is rare and seriously detrimental effects of hexavalent chromium are primarily the result of chronic low-level exposure . In case of overdose with minimal toxicity following acute ingestion, treatment should be symptomatic and supportive . There is no known antidote for chromium toxicity.

Hexavalent chromium is a Class A carcinogen by the inhalation route of exposure and Class D by the oral route . The oral lethal dose in humans has been estimated to be 1-3 g of Cr (VI); oral toxicity most likely involves gastrointestinal bleeding rather than systemic toxicity . Chronic exposure may cause damage to the following organs: kidneys, lungs, liver, upper respiratory tract . Soluble chromium VI compounds are human carcinogens. Hexavalent chromium compounds were mutagenic in bacteria assays and caused chromosome aberrations in mammalian cells. There have been associations of increased frequencies of chromosome aberrations in lymphocytes from chromate production workers . In human cells in vitro, Cr (VI) caused chromosomal aberrations, sister chromatid exchanges and oxidative DNA damage .

In rats, the oral LD₅₀ is reported to be greater than 4000 mg/kg and the intraperitoneal LD₅₀ is 1200 mg/kg. The lowest published toxic dose (TDLo) via oral route in child was 379 μg/kg.

Symptoms of overdose in sulfonylureas, including glipizide, may be related to severe hypoglycemia and may include coma, seizure, or other neurological impairment. These are symptoms of severe hypoglycemia and require immediate treatment with glucagon or intravenous glucose and close monitoring for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated with oral glucose.

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 .

Precaution

Hypoglycaemia: All sulphonylurea drugs are capable of producing severe hypoglycaemia. Proper patient selection, dosage and instructions are important to avoid hypoglycaemic episodes. Renal or hepatic insufficiency may cause elevated blood levels of Glipizide and the latter may also diminis gluconeogenic capacity, both of which increase the risk of serious hypoglycaemic reactions. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycaemic actions of glucose lowering drugs. Patients should be instructed to take their meals regularly and not to exercise excessively without additional calorie intake.

Renal and hepatic disease: The metabolism and excretion of Glipizide may be slowed in patients with impaired renal and/or hepatic function. These patients may suffer from prolonged hypoglycaemia and appropriate measures should be instituted.

Loss of control on blood glucose: When a patient stabilized on any antidiabetic regimen is exposed to stress such as fever, trauma, infection or surgery, a loss of control on blood glucose may occur. At that time it may be necessary to discontinue Glipizide and administer Insulin.

The effectiveness of any oral hypoglycaemic drug including Glipizide, in lowering blood glucose to a desired level, decreases in many patients over a period of time, which may be due to secondary failure, i.e., progression of the severity of the diabetes or diminished responsiveness to the drug.

Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, metformin should be discontinued and the patient should be hospitalized immediately.

Renal function: As metformin is excreted by the kidney, serum creatinine levels should be determined before initiating treatment and regularly thereafter: at least annually in patients with normal renal function, at least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly subjects. Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with an NSAID.

Administration of iodinated contrast agent: As the intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure, metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.

Surgery: Metformin hydrochloride should be discontinued 48 hours before elective surgery with general anesthesia and should not be usually resumed earlier than 48 hours afterwards.

Children and adolescents: The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin is initiated. No effect of metformin on growth and puberty has been detected during controlled clinical studies of one-year duration but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-treated children, especially pre-pubescent children, is recommended.

Children aged between 10 and 12 years: Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although metformin efficacy and safety in children below 12 did not differ from efficacy and safety in older children, particular caution is recommended when prescribing to children aged between 10 and 12 years.

Other precautions: All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet. The usual laboratory tests for diabetes monitoring should be performed regularly. Metformin alone never causes hypoglycemia, although caution is advised when it is used in combination with insulin or sulphonylureas.

Interaction

The hypoglycaemic action of sulphonylurea may be potentiated by certain drugs including non-steroidal anti inflammatory agents and other drugs that are highly protein bound e.g., Salicylates, Sulphonamides, Chloramphenicol, Probenecid, Coumarins, Monoamine Oxidase Inhibitors, and β adrenergic blocking agents. When such drugs are administered to a patient receiving Glipizide, the patients should be observed closely for hypoglycaemia. When such drugs are withdrawn from a patient receiving Glipizide, the patient should be observed closely for loss of control on blood glucose.

Certain drugs tend to produce hyperglycaemia and may lead to loss of control on blood glucose. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, oestrogens, oral contraceptives, Phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs and Isoniazid. When such drugs are administered to or withdrawn from a patient receiving Glipizide, the patient should be closely observed for loss of control on blood glucose. Diabetic control may be altered also in patients treated with cyclophosphamide.

Concomitant use not recommended-

Alcohol: Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of: fasting or malnutrition, hepatic insufficiency. Avoid consumption of alcohol and alcohol-containing medications.

Iodinated contrast agents: Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis. Metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.

Combinations requiring precautions for use-

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include thiazide and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Metformin HCl, the patient should be closely observed to maintain adequate glycemic control. Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.

Nifedipine appears to enhance the absorption of Metformin. Metformin has minimal effects on nifedipine. ACE-inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.

Volume of Distribution

Absorbed chromium is distributed to all tissues of the body and its distribution in the body depends on the species, age, and chemical form . Circulating Cr (III) following oral or parenteral administration of different compounds can be taken up by tissues and accumulates in the liver, kidney, spleen, soft tissue, and bone .

The mean volume of distribution was approximately 10 L following administration of single intravenous doses in patients with type 2 diabetes mellitus. In mice and rat studies, the presence of the drug and its metabolites was none to minimal in the fetus of pregnant female animals. Other sulfonylurea drugs were shown to cross the placenta and enter breast milk thus the potential risk of glipizide in fetus or infants cannot be excluded.

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

Elimination Route

Chromium compounds are both absorbed by the lung and the gastrointestinal tract. Oral absorption of chromium compounds in humans can range between 0.5% and 10%, with the hexavalent (VI) chromium more easily absorbed than the trivalent (III) form . Absorption of chromium from the intestinal tract is low, ranging from less than 0.4% to 2.5% of the amount consumed . Vitamin C and the vitamin B niacin is reported to enhance chromium absorption .

Most hexavalent Cr (VI) undergoes partial intragastric reduction to Cr (III) upon absorption, which is an action mainly mediated by sulfhydryl groups of amino acids . Cr (VI) readily penetrates cell membranes and chromium can be found in both erythrocytes and plasma after gastrointestinal absorption of Cr (IV). In comparison, the presence of chromium is limited to the plasma as Cr (III) displays poor cell membrane penetration . Once transported through the cell membrane, Cr (VI) is rapidly reduced to Cr (III), which subsequently binds to macromolecules or conjugate with proteins. Cr (III) may be bound to transferrin or other plasma proteins, or as complexes, such as glucose tolerance factor (GTF).

Gastrointestinal absorption of glipizide is uniform, rapid, and essentially complete. The absolute bioavailability of glipizide in patients with type 2 diabetes receiving a single oral dose was 100%. The maximum plasma concentrations are expected to be reached within 6 to 12 hours following initial dosing. The steady-state plasma concentrations of glipizide from extended-release oral formulations are maintained over the 24-hour dosing interval. In healthy volunteers, the absorption of glipizide was delayed by the presence of food but the total absorption was unaffected.

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 .

Half Life

The elimination half-life of hexavalent chromium is 15 to 41 hours .

The mean terminal elimination half-life of glipizide ranged from 2 to 5 hours after single or multiple doses in patients with type 2 diabetes mellitus.

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 .

Clearance

Excretion of chromium is via the kidneys ranges from 3 to 50 μg/day . The 24-hour urinary excretion rates for normal human subjects are reported to be 0.22 μg/day .

The mean total body clearance of glipizide was approximately 3 L/hr following administration of single intravenous doses in patients with type 2 diabetes mellitus.

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 .

Elimination Route

Absorbed chromium is excreted mainly in the urine, accounting for 80% of total excretion of chromium; small amounts are lost in hair, perspiration and bile . Chromium is excreted primarily in the urine by glomerular filtration or bound to a low molecular-weight organic transporter .

Glipizide is mainly eliminated by hepatic biotransformation, where less than 10% of the initial dose of the drug can be detected in the urine and feces as unchanged glipizide. About 80% of the metabolites of glipizide is excreted in the urine while 10% is excreted in the feces.

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 .

Pregnancy & Breastfeeding use

Pregnancy: Glipizide should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Prolonged severe hypoglycaemia (4-10 days) has been reported in neonates born to mothers who were receiving sulphonylurea (e.g., Glipizide) at the time of delivery. So, if Glipizide is used during pregnancy, it should be discontinued at least one month before the expected delivery date.

Lactation: Although it is not known whether Glipizide is excreted in human milk, some sulphonylurea drugs are known to be so. Breast feeding is not therefore recommended while taking this medication.

Pregnancy Category B. Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or fetal development, parturition or postnatal development. There are no adequate and well-controlled studies in pregnant women. Can be used in pregnancy for both preexisting and gestational diabetes. Women with gestational diabetes should discontinue treatment after giving birth.

Lactation: Metformin is excreted into milk in lactating rats. Similar data is not available in humans and a decision should be made whether to discontinue nursing or to discontinue metformin, taking into account the importance of the drug to the mother. May be used during breast-feeding in women with pre existing diabetes.

Contraindication

Glipizide is contraindicated in the following conditions :

• Patients who are hypersensitive to Glipizide or any component of the product
• Juvenile onset diabetes
• Severe or unstable ‘brittle’ diabetes
• Diabetes complicated by ketosis and acidosis, major surgery, severe sepsis or severe trauma
• Severe renal, hepatic or thyroid impairment, co-existent renal and hepatic disease

• Hypersensitivity to metformin hydrochloride or to any of the excipients of the medication.
• Diabetic ketoacidosis, diabetic pre-coma
• Renal failure or renal dysfunction (creatinine clearance < 60 mL/min)
• Acute conditions with the potential to alter renal function such as: dehydration, severe infection, shock, intravascular
• administration of iodinated contrast agents.
• Acute or chronic disease which may cause tissue hypoxia such as: cardiac or respiratory failure, recent myocardial
• infarction, shock
• Hepatic insufficiency, acute alcohol intoxication, alcoholism
• Lactation

Special Warning

Pediatric Use: Safety and effectiveness in children have not been established.

Geriatric Use: There were no overall differences in effectiveness or safety between younger and older patients.

Renal Impairment: Severe: Contraindicated.

Hepatic Impairment: Severe: Contraindicated.

Renal Impairment: Metformin is contraindicated in patients with an eGFR < 30 mL/minute/1.73 m2 . Starting metformin in patients with an eGFR between 30-45 mL/minute/1.73 m2 is not recommended. In patients taking metformin whose eGFR later falls below 45 mL/minute/1.73 m2 , assess the benefits and risks of continuing treatment. Discontinue metformin if the patient’s eGFR later falls below 30 mL/minute/1.73 m2 .

Acute Overdose

There is no well-documented experience with Glipizide tablets overdosage in humans.

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

The tablets should be protected from moisture and humidity and stored at room temperature (below 30&deg; C).

Keep out of the reach of children. Do not store above 25°C. Keep in the original package in a cool & dry place in order to protect from light and moisture.

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