Brand Name: Micronase, Glynase PressTabs
Generic Name: Glyburide

Contents:

Description
Clinical Pharmacology
Indications and Usage
Contraindications
Special warning on increased risk of cardiovascular mortality
Precautions
Adverse Reactions
Overdosage
Dosage and Administration
How is Supplied

Micronase, glyburide, patient information (in plain English)

Description

Micronase Tablets contain glyburide, which is an oral blood-glucose-lowering drug of the sulfonylurea class. Glyburide is a white, crystalline compound, formulated as Micronase Tablets of 1.25, 2.5, and 5 mg strengths for oral administration. Inactive ingredients: colloidal silicon dioxide, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, sodium alginate, talc. In addition, the 2.5 mg contains aluminum oxide and FD&C Red No. 40 and the 5 mg contains aluminum oxide and FD&C Blue No. 1. The chemical name for glyburide is 1-[ [p-[2-(5-chloro-o-anisamido)-ethyl]phenyl]-sulfonyl]-3-cyclohexylurea and the molecular weight is 493.99. The structural formula is represented below.

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Clinical Pharmacology

Actions

Glyburide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. The combination of glyburide and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different but complementary mechanisms.

Some patients who are initially responsive to oral hypoglycemic drugs, including Micronase, may become unresponsive or poorly responsive over time. Alternatively, Micronase Tablets may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs.

In addition to its blood glucose lowering actions, glyburide produces a mild diuresis by enhancement of renal free water clearance. Disulfiram-like reactions have very rarely been reported in patients treated with Micronase Tablets.

Pharmacokinetics

Single dose studies with Micronase Tablets in normal subjects demonstrate significant absorption of glyburide within one hour, peak drug levels at about four hours, and low but detectable levels at twenty-four hours. Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve, increase in proportion to corresponding increases in dose. Multiple dose studies with Micronase in diabetic patients demonstrate drug level concentration-time curves similar to single dose studies, indicating no buildup of drug in tissue depots. The decrease of glyburide in the serum of normal healthy individuals is biphasic; the terminal half-life is about 10 hours. In single dose studies in fasting normal subjects, the degree and duration of blood glucose lowering is proportional to the dose administered and to the area under the drug level concentration-time curve. The blood glucose lowering effect persists for 24 hours following single morning doses in nonfasting diabetic patients. Under conditions of repeated administration in diabetic patients, however, there is no reliable correlation between blood drug levels and fasting blood glucose levels. A one year study of diabetic patients treated with Micronase showed no reliable correlation between administered dose and serum drug level.

The major metabolite of glyburide is the 4-transhydroxy derivative. A second metabolite, the 3-cishydroxy derivative, also occurs. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400th and 1/40th as active, respectively, as glyburide) in rabbits.

Glyburide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine.

Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding exhibited by glyburide is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as phenylbutazone, warfarin, and salicylates displace the ionic-binding sulfonylureas from serum proteins to a far greater extent than the non-ionic binding glyburide. It has not been shown that this difference in protein binding will result in fewer drug-drug interactions with Micronase Tablets in clinical use.

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Indications and Usage

Micronase is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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Contraindications

Micronase Tablets are contraindicated in patients with:

1. Known hypersensitivity or allergy to the drug.
2. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
3. Type I diabetes mellitus.

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Special warning on increased risk of cardiovascular mortality

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 ½ 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 Micronase 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.

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Precautions

General

Macrovascular Outcomes

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

Hypoglycemia

All sulfonylureas are capable of producing severe hypoglycemia. Proper patient selection and dosage and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insufficiency may cause elevated drug levels of glyburide and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose lowering drug is used. The risk of hypoglycemia may be increased with combination therapy.

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 loss of control may occur. At such times it may be necessary to discontinue Micronase and administer insulin.

The effectiveness of any hypoglycemic drug, including Micronase, in lowering blood glucose to a desired level decreases in many patients over a period of time which may be due to progression of the severity of diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when Micronase is first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.

Information for Patients

Patients should be informed of the potential risks and advantages of Micronase and of alternative modes of therapy. They also should be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood glucose.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure also should be explained.

Physician Counseling Information for Patients

In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible. Use of Micronase or other antidiabetic medications must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of Micronase or other antidiabetic medications. Maintenance or discontinuation of Micronase or other antidiabetic medications should be based on clinical judgment using regular clinical and laboratory evaluations.

Laboratory Tests

Therapeutic response to Micronase Tablets should be monitored by frequent urine glucose tests and periodic blood glucose tests. Measurement of glycosylated hemoglobin levels may be helpful in some patients.

Hemolytic Anemia

Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because GLYNASE PresTab belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In post marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

Drug Interactions

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving Micronase, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving Micronase, the patient should be observed closely for loss of control.

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides 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 Micronase, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving Micronase, the patient should be observed closely for hypoglycemia.

A possible interaction between glyburide and ciprofloxacin, a fluoroquinolone antibiotic, has been reported, resulting in a potentiation of the hypoglycemic action of glyburide. The mechanism for this interaction is not known.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical or vaginal preparations of miconazole is not known.

Metformin

In a single-dose interaction study in NIDDM subjects, decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain. Coadministration of glyburide and metformin did not result in any changes in either metformin pharmacokinetics or pharmacodynamics.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Studies in rats at doses up to 300 mg/kg/day for 18 months showed no carcinogenic effects. Glyburide is nonmutagenic when studied in the Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay. No drug related effects were noted in any of the criteria evaluated in the two year oncogenicity study of glyburide in mice.

Pregnancy

Teratogenic Effects

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at doses up to 500 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to glyburide. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to 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 who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If Micronase is used during pregnancy, it should be discontinued at least two weeks before the expected delivery date.

Nursing Mothers

Although it is not known whether glyburide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If the drug is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Elderly patients are particularly susceptible to the hypoglycemic action of glucose lowering drugs. Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS). The initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see DOSAGE AND ADMINISTRATION).

Elderly patients are prone to develop renal insufficiency, which may put them at risk of hypoglycemia. Dose selection should include assessment of renal function.

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Adverse Reactions

Hypoglycemia

See Precautions and Overdosage Sections.

Gastrointestinal Reactions

Cholestatic jaundice and hepatitis may occur rarely; Micronase Tablets should be discontinued if this occurs.

Liver function abnormalities, including isolated transaminase elevations, have been reported.

Gastrointestinal disturbances, eg, nausea, epigastric fullness, and heartburn are the most common reactions, having occurred in 1.8% of treated patients during clinical trials. They tend to be dose related and may disappear when dosage is reduced.

Dermatologic Reactions

Allergic skin reactions, eg, pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions occurred in 1.5% of treated patients during clinical trials. These may be transient and may disappear despite continued use of Micronase; if skin reactions persist, the drug should be discontinued.

Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.

Hematologic Reactions

Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see PRECAUTIONS), aplastic anemia, and pancytopenia have been reported with sulfonylureas.

Metabolic Reactions

Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas; however, hepatic porphyria has not been reported with Micronase and disulfiram-like reactions have been reported very rarely.

Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH.

Other Reactions

Changes in accommodation and/or blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels.

In addition to dermatologic reactions, allergic reactions such as angioedema, arthralgia, myalgia and vasculitis have been reported.

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Overdosage

Overdosage of sulfonylureas, including Micronase Tablets, can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate which will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery.

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Dosage and Administration

There is no fixed dosage regimen for the management of diabetes mellitus with Micronase Tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient's blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, ie, inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, ie, loss of adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy.

Short-term administration of Micronase may be sufficient during periods of transient loss of control in patients usually controlled well on diet.

Usual Starting Dose

The usual starting dose of Micronase Tablets is 2.5 to 5 mg daily, administered with breakfast or the first main meal. Those patients who may be more sensitive to hypoglycemic drugs should be started at 1.25 mg daily. (See PRECAUTIONS section for patients at increased risk.) Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary and drug regimen are more prone to exhibit unsatisfactory response to therapy.

Transfer From Other Hypoglycemic Therapy Patients Receiving Other Oral Antidiabetic Therapy

Transfer of patients from other oral antidiabetic regimens to Micronase should be done conservatively and the initial daily dose should be 2.5 to 5 mg. When transferring patients from oral hypoglycemic agents other than chlorpropamide to Micronase, no transition period and no initial or priming dose are necessary. When transferring patients from chlorpropamide, particular care should be exercised during the first two weeks because the prolonged retention of chlorpropamide in the body and subsequent overlapping drug effects may provoke hypoglycemia.

Patients Receiving Insulin

Some Type II diabetic patients being treated with insulin may respond satisfactorily to Micronase. If the insulin dose is less than 20 units daily, substitution of Micronase Tablets 2.5 to 5 mg as a single daily dose may be tried. If the insulin dose is between 20 and 40 units daily, the patient may be placed directly on Micronase Tablets 5 mg daily as a single dose. If the insulin dose is more than 40 units daily, a transition period is required for conversion to Micronase. In these patients, insulin dosage is decreased by 50% and Micronase Tablets 5 mg daily is started. Please refer to Titration to Maintenance Dose for further explanation.

Titration to Maintenance Dose

The usual maintenance dose is in the range of 1.25 to 20 mg daily, which may be given as a single dose or in divided doses (See Dosage Interval section). Dosage increases should be made in increments of no more than 2.5 mg at weekly intervals based upon the patient's blood glucose response.

No exact dosage relationship exists between Micronase and the other oral hypoglycemic agents. Although patients may be transferred from the maximum dose of other sulfonylureas, the maximum starting dose of 5 mg of Micronase Tablets should be observed. A maintenance dose of 5 mg of Micronase Tablets provides approximately the same degree of blood glucose control as 250 to 375 mg chlorpropamide, 250 to 375 mg tolazamide, 500 to 750 mg acetohexamide, or 1000 to 1500 mg tolbutamide.

When transferring patients receiving more than 40 units of insulin daily, they may be started on a daily dose of Micronase Tablets 5 mg concomitantly with a 50% reduction in insulin dose. Progressive withdrawal of insulin and increase of Micronase in increments of 1.25 to 2.5 mg every 2 to 10 days is then carried out. During this conversion period when both insulin and Micronase are being used, hypoglycemia may rarely occur. During insulin withdrawal, patients should test their urine for glucose and acetone at least three times daily and report results to their physician. The appearance of persistent acetonuria with glycosuria indicates that the patient is a Type I diabetic who requires insulin therapy.

Concomitant Glyburide and Metformin Therapy

Micronase Tablets should be added gradually to the dosing regimen of patients who have not responded to the maximum dose of metformin monotherapy after four weeks (see Usual Starting Dose and Titration to Maintenance Dose). Refer to metformin package insert.

With concomitant glyburide and metformin therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the optimal dose of each drug needed to achieve this goal. With concomitant glyburide and metformin therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken (see PRECAUTIONS section).

Maximum Dose

Daily doses of more than 20 mg are not recommended.

Dosage Interval

Once-a-day therapy is usually satisfactory. Some patients, particularly those receiving more than 10 mg daily, may have a more satisfactory response with twice-a-day dosage.

Specific Patient Populations

Micronase is not recommended for use in pregnancy or for use in pediatric patients.

In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions. (See PRECAUTIONS section.)

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How is Supplied

Micronase Tablets are supplied as follows:

Micronase Tablets 1.25 mg (White, Round, Scored, imprinted Micronase 1.25)

Bottles of 100 NDC 0009-0131-01

Micronase Tablets 2.5 mg (Dark Pink, Round, Scored, imprinted Micronase 2.5)

Bottles of 100 NDC 0009-0141-01

Bottles of 1000 NDC 0009-0141-03

Unit Dose Pkg of 100 NDC 0009-0141-02

Micronase Tablets 5 mg (Blue, Round, Scored imprinted Micronase 5)

Bottles of 30 NDC 0009-0171-11

Bottles of 60 NDC 0009-0171-12

Bottles of 100 NDC 0009-0171-05

Bottles of 500 NDC 0009-0171-06

Bottles of 1000 NDC 0009-0171-07

Unit Dose Pkg of 100 NDC 0009-0171-03

Rx only

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Dispensed in well closed containers with safety closures. Keep container tightly closed.

LAB-0109-4.0

last updated 02/2009

Micronase, glyburide, patient information (in plain English)

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse.

back to: Browse all Medications for Diabetes

Brand name: Diabinese
Generic name: Chlorpropamide

Diabinese, chlorpropamide, full prescribing information

Why is Diabinese prescribed?

Diabinese is an oral antidiabetic medication used to treat type 2 (non-insulin-dependent) diabetes. Diabetes occurs when the body fails to produce enough insulin or is unable to use it properly. Insulin is believed to work by helping sugar penetrate the cell wall so it can be used by the cell.

There are two forms of diabetes: type 1 insulin-dependent and type 2 non-insulin-dependent. Type 1 usually requires insulin injection for life, while type 2 diabetes can usually be treated by dietary changes and oral antidiabetic medications such as Diabinese. Apparently, Diabinese controls diabetes by stimulating the pancreas to secrete more insulin. Occasionally, type 2 diabetics must take insulin injections on a temporary basis, especially during stressful periods or times of illness.

Most important fact about Diabinese

Always remember that Diabinese is an aid to, not a substitute for, good diet and exercise. Failure to follow a sound diet and exercise plan can lead to serious complications, such as dangerously high or low blood sugar levels. Remember, too, that Diabinese is not an oral form of insulin, and cannot be used in place of insulin.

How should you take Diabinese?

Ordinarily, your doctor will ask you to take a single daily dose of Diabinese each morning with breakfast. However, if this upsets your stomach, he or she may ask you to take Diabinese in smaller doses throughout the day.

To prevent low blood sugar levels (hypoglycemia):

• You should understand the symptoms of hypoglycemia
• Know how exercise affects your blood sugar levels
• Maintain an adequate diet
• Keep a source of quick-acting sugar with you all the time
• If you miss a dose...
  Take it as soon as you remember. If it is almost time for the next dose, skip the one you missed and go back to your regular schedule. Do not take 2 doses at the same time.
• Storage instructions...
  Store at room temperature.

continue story below

What side effects may occur with Diabinese?

Side effects cannot be anticipated. If any develop or change in intensity, inform your doctor as soon as possible. Only your doctor can determine if it is safe for you to continue taking Diabinese.

Side effects from Diabinese are rare and seldom require discontinuation of the medication.

• More common side effects include:
  Diarrhea, hunger, itching, loss of appetite, nausea, stomach upset, vomiting

Diabinese, like all oral antidiabetics, can cause hypoglycemia (low blood sugar). The risk of hypoglycemia is increased by missed meals, alcohol, other medications, and excessive exercise. To avoid hypoglycemia, closely follow the dietary and exercise regimen suggested by your physician.

• Symptoms of mild hypoglycemia may include:
  Cold sweat, drowsiness, fast heartbeat, headache, nausea, nervousness
• Symptoms of more severe hypoglycemia may include:
  Coma, pale skin, seizures, shallow breathing

Contact your doctor immediately if these symptoms of severe low blood sugar occur.

Why should Diabinese not be prescribed?

You should not take Diabinese if you have ever had an allergic reaction to it.

Do not take Diabinese if you are suffering from diabetic ketoacidosis (a life-threatening medical emergency caused by insufficient insulin and marked by excessive thirst, nausea, fatigue, pain below the breastbone, and a fruity breath).

Special warnings about Diabinese

It's possible that drugs such as Diabinese may lead to more heart problems than diet treatment alone, or diet plus insulin. If you have a heart condition, you may want to discuss this with your doctor.

If you are taking Diabinese, you should check your blood and urine periodically for the presence of abnormal sugar levels.

Remember that it is important that you closely follow the diet and exercise regimen established by your doctor.

Even people with well-controlled diabetes may find that stress, illness, surgery, or fever results in a loss of control. If this happens, your doctor may recommend that Diabinese be discontinued temporarily and insulin used instead.

In addition, the effectiveness of any oral antidiabetic, including Diabinese, may decrease with time. This may occur because of either a diminished responsiveness to the medication or a worsening of the diabetes.

Possible food and drug interactions when taking Diabinese

When you take Diabinese with certain other drugs, the effects of either could be increased, decreased, or altered. It is important that you consult with your doctor before taking Diabinese with the following:

• Anabolic steroids
• Aspirin in large doses
• Barbiturates such as secobarbital
• Beta-blocking blood pressure medications such as atenolol and propranolol
• Calcium-blocking blood pressure medications such as diltiazem and nifedipine
• Chloramphenicol
• Warfarin
• Diuretics such as hydrochlorothiazide
• Epinephrine
• Estrogen medications
• Isoniazid
• Major tranquilizers such as chlorpromazine and thioridazine
• MAO inhibitor-type antidepressants such as phenelzine and tranylcypromine
• Nicotinic acid
• Nonsteroidal anti-inflammatory agents such as ibuprofen and naproxen
• Oral contraceptives
• Phenothiazines
• Phenylbutazone
• Phenytoin
• Probenecid
• Steroids such as prednisone
• Sulfa drugs such as sulfamethoxazole
• Thyroid medications such as levothyroxine

Avoid alcohol since excessive alcohol consumption can cause low blood sugar, breathlessness, and facial flushing.

Special information if you are pregnant or breastfeeding

The effects of Diabinese during pregnancy have not been adequately established. If you are pregnant or plan to become pregnant you should inform your doctor immediately. Since studies suggest the importance of maintaining normal blood sugar (glucose) levels during pregnancy, your physician may prescribe injected insulin.

To minimize the risk of low blood sugar (hypoglycemia) in newborn babies, Diabinese, if prescribed during pregnancy, should be discontinued at least 1 month before the expected delivery date.

Since Diabinese appears in breast milk, it is not recommended for nursing mothers. If diet alone does not control glucose levels, then insulin should be considered.

Recommended dosage for Diabinese

Dosage levels are determined by each individual's needs.

ADULTS

Usually, an initial daily dose of 250 milligrams is recommended for stable, middle-aged, non-insulin-dependent diabetics. After 5 to 7 days, your doctor may adjust this dosage in increments of 50 to 125 milligrams every 3 to 5 days to achieve the best benefit. People with mild diabetes may respond well to daily doses of 100 milligrams or less of Diabinese, while those with severe diabetes may require 500 milligrams daily. Maintenance doses above 750 milligrams are not recommended.

OLDER ADULTS

People who are old, malnourished, or debilitated and those with impaired kidney and liver function usually take an initial dose of 100 to 125 milligrams.

CHILDREN

Safety and effectiveness have not been established.

Overdosage

An overdose of Diabinese can cause low blood sugar (see "What side effects may occur?" for symptoms).

Eating sugar or a sugar-based product will often correct the condition. If you suspect an overdose, seek medical attention immediately.

last updated 02/2009

Diabinese, chlorpropamide, full prescribing information

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

back to: Browse all Medications for Diabetes

Brand Name: Glucovance
Generic name: Glyburide, Metformin

Glucovance, glyburide, metformin, full prescribing information 

What is Glucovance and why is Glucovance prescribed?

Glucovance is used in the treatment of type 2 (noninsulin dependent) diabetes. Diabetes develops when the body's ability to burn sugar declines and the unused sugar builds up in the bloodstream. Ordinarily, sugar is moved out of the blood and into the body's cells by the hormone insulin. A buildup occurs when the body either fails to make enough insulin or doesn't respond to it properly.

Glucovance is a combination of 2 drugs—glyburide and metformin—that attack high blood sugar levels in several ways. The glyburide component stimulates the pancreas to produce more insulin and helps the body use it properly. The metformin component also encourages proper insulin utilization, and in addition works to decrease sugar production and absorption.

Glucovance is prescribed when diet and exercise prove insufficient to keep blood sugar levels under control. Glucovance can also be combined with other diabetes drugs such as Avandia.

Most important fact about Glucovance

Very rarely, Glucovance has been known to cause a dangerous condition called lactic acidosis, a buildup of lactic acid in the blood. Lactic acidosis is a medical emergency that requires immediate treatment in the hospital. Notify your doctor without delay if you experience any of the following symptoms:

A slow or irregular heartbeat; a cold, dizzy, or light-headed feeling; a weak, tired, or uncomfortable feeling; stomach discomfort; trouble breathing; unusual muscle pain

How should you take Glucovance?

Glucovance is taken once or twice a day with meals.

• If you miss a dose...
  Take it as soon as you remember. If it is almost time for your next dose, skip the one you missed and go back to your regular schedule. Never take 2 doses at the same time.

• Storage instructions...
  Store at room temperature and protect from light.

continue story below

What side effects may occur?

Side effects cannot be anticipated. If any develop or change in intensity, inform your doctor as soon as possible. Only your doctor can determine if it is safe for you to continue taking Glucovance.

• Side effects may include:
  Cold sweats, diarrhea, dizziness, headache, hunger, nausea, shakiness, stomach pain, upper respiratory infections, vomiting

Why should Glucovance not be prescribed?

Glucovance is processed primarily by the kidneys, and can build up to excessive levels in the body if the kidneys aren't working properly. It should be avoided if you have kidney disease or your kidney function has been impaired by a condition such as shock, blood poisoning, or a heart attack. It should also be avoided if you need to take medicine for congestive heart failure, and you'll probably be unable to use it if you have liver disease.

If you need to have an x-ray procedure done, find out if it requires injection of a contrast agent. If so, Glucovance will have to be temporarily discontinued. (Check with your doctor for instructions; do not discontinue the drug on your own.)

If you have ever had an allergic reaction to metformin, glyburide, or diabetes medications similar to glyburide, you should not take Glucovance. It also should not be prescribed if you have acute or chronic metabolic acidosis.

Special warnings about Glucovance

Avoid excessive alcohol intake while taking Glucovance. Heavy drinking increases the danger of lactic acidosis and can also trigger an attack of low blood sugar (hypoglycemia).

Missed meals, malnutrition, general debility, liver or kidney problems, other medications, and over-exertion also increase the risk of hypoglycemia. Symptoms of a mild case include cold sweats, dizziness, shakiness, and hunger. Severe hypoglycemia can lead to seizures and coma. If you notice any of the warning signs, check with your doctor immediately.

Lactic acidosis also becomes more likely when you become dehydrated. If you experience severe vomiting, diarrhea, fever, or if your fluid intake is significantly reduced, tell your doctor.

Taking Glucovance with certain diabetes drugs, such as rosiglitazone, can increase the risk of hypoglycemia, weight gain, and liver problems. Your doctor will periodically test your liver function to guard against any problems.

Glucovance occasionally causes a mild deficiency of vitamin B12. Your doctor will check annually and may prescribe a supplement if necessary.

Some experts suspect that the glyburide component of Glucovance may lead to more heart problems than treatment with diet alone. In a long-term trial of a similar drug, researchers noted an increase in heart-related deaths (though the overall mortality rate remained unchanged). If you have a heart condition, you may want to discuss this potential risk with your doctor.

Possible food and drug interactions when taking Glucovance

If Glucovance is taken with certain other drugs, the effects of either drug could be increased, decreased, or altered. It is especially important to check with your doctor before combining Glucovance with the following:

• Airway-opening drugs such as Proventil and Ventolin
• Beta-blockers (heart and blood-pressure drugs such as atenolol and metoprolol)
• Birth control pills
• Calcium channel blockers (heart medications) such as nifedipine and verapamil
• Chloramphenicol
• Ciprofloxacin
• Estrogens
• Furosemide, hydrochlorothiazide and other diuretics
• Isoniazid
• Major tranquilizers such as chlorpromazine
• MAO inhibitors such as the antidepressants phenelzine and tranylcypromine
• Nonsteroidal anti-inflammatory drugs such as ibuprofen and naproxen
• Niacin
• Phenytoin
• Probenecid
• Steroids such as prednisone
• Sulfa drugs such as sulfamethoxazole
• Thyroid medications such as levothyroxine
• Warfarin

Special information if you are pregnant or breastfeeding

Glucovance is not recommended during pregnancy. To control blood sugar during this crucial period, most doctors prefer insulin instead of Glucovance. If you are pregnant or plan to become pregnant, inform your doctor immediately.

You'll also need to avoid Glucovance while breastfeeding. If blood sugar becomes a problem, your doctor can prescribe insulin.

Recommended dosage for Glucovance

ADULTS

Your doctor will start therapy at a low dose and increase it until your blood sugar levels are under control.

For patients not previously treated with diabetes medications

The recommended starting dose is 1.25 milligrams of glyburide with 250 milligrams of metformin once or twice daily with meals. The dosage can be increased every two weeks until blood sugar levels are controlled. The maximum recommended daily dosage of Glucovance for previously untreated patients is 10 milligrams of glyburide with 2,000 milligrams of metformin.

For patients previously treated with glyburide (or a similar drug) or metformin:

The recommended starting dose of Glucovance is either 2.5 or 5 milligrams of glyburide with 500 milligrams of metformin twice daily with meals. The maximum recommended daily dosage of Glucovance for previously treated patients is 20 milligrams of glyburide with 2,000 milligrams of metformin.

CHILDREN

Glucovance is not for use in children.

OLDER ADULTS

Since kidney function declines with age, it should be closely monitored in people taking Glucovance after age 65. Older patients are usually not prescribed the maximum recommended dose of Glucovance.

Overdosage

An overdose of Glucovance can cause an attack of hypoglycemia requiring immediate treatment. If you experience any of the symptoms listed in "Special warnings about Glucovance," see a doctor immediately.

An excessive dose of Glucovance can also trigger lactic acidosis. If you begin to notice the warning signs listed in "Most important fact about Glucovance," seek emergency treatment.

last updated 02/2009

Glucovance, glyburide, metformin, full prescribing information

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

back to: Browse all Medications for Diabetes

Brand Name: Diabinese
Generic Name: Chlorpropamide

Contents:

Description
Clinical Pharmacology
Indications and Usage
Contraindications
Warnings
Precautions
Drug Interactions
Adverse Reactions
Overdosage
Dosage and Administration
How is Supplied

Diabinese (Chlorpropamide) Patient Information (in plain English)

Description

Diabinese® (chlorpropamide), is an oral blood-glucose-lowering drug of the sulfonylurea class. Chlorpropamide is 1-[(p-Chlorophenyl)sulfonyl]-3-propylurea, C10H13ClN2O3S, and has the structural formula:

Chlorpropamide is a white crystalline powder, that has a slight odor. It is practically insoluble in water at pH 7.3 (solubility at pH 6 is 2.2 mg/mL). It is soluble in alcohol and moderately soluble in chloroform. The molecular weight of chlorpropamide is 276.74. Diabinese is available as 100 mg and 250 mg tablets.

Inert ingredients are: alginic acid; Blue 1 Lake; hydroxypropyl cellulose; magnesium stearate; precipitated calcium carbonate; sodium lauryl sulfate; starch.

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Clinical Pharmacology

Diabinese appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which Diabinese lowers blood glucose during long-term administration has not been clearly established. Extra-pancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. While chlorpropamide is a sulfonamide derivative, it is devoid of antibacterial activity.

Diabinese may also prove effective in controlling certain patients who have experienced primary or secondary failure to other sulfonylurea agents.

A method developed which permits easy measurement of the drug in blood is available on request.

Chlorpropamide does not interfere with the usual tests to detect albumin in the urine.

Diabinese is absorbed rapidly from the gastrointestinal tract. Within one hour after a single oral dose, it is readily detectable in the blood, and the level reaches a maximum within two to four hours. It undergoes metabolism in humans and it is excreted in the urine as unchanged drug and as hydroxylated or hydrolyzed metabolites. The biological half-life of chlorpropamide averages about 36 hours. Within 96 hours, 80-90% of a single oral dose is excreted in the urine. However, long-term administration of therapeutic doses does not result in undue accumulation in the blood, since absorption and excretion rates become stabilized in about 5 to 7 days after the initiation of therapy.

Diabinese exerts a hypoglycemic effect in healthy subjects within one hour, becoming maximal at 3 to 6 hours and persisting for at least 24 hours. The potency of chlorpropamide is approximately six times that of tolbutamide. Some experimental results suggest that its increased duration of action may be the result of slower excretion and absence of significant deactivation.

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Indications and Usage

Diabinese is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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Contraindications

Diabinese is contraindicated in patients with:

1. Known hypersensitivity to any component of this medicine.
2. Type 1 diabetes mellitus, diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

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Warnings

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY

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 (Diabetes, 19 [supp. 2]:747-830, 1970).

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 ½ 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 over-all 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 Diabinese 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.

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Precautions

General

Macrovascular Outcomes

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

Hypoglycemia

All sulfonylurea drugs including chlorpropamide are capable of producing severe hypoglycemia, which may result in coma, and may require hospitalization. Patients experiencing hypoglycemia should be managed with appropriate glucose therapy and be monitored for a minimum of 24 to 48 hours (see Overdosage section). Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Regular, timely carbohydrate intake is important to avoid hypoglycemic events occurring when a meal is delayed or insufficient food is eaten or carbohydrate intake is unbalanced. Renal or hepatic insufficiency may affect the disposition of Diabinese and may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used.

Because of the long half-life of chlorpropamide, patients who become hypoglycemic during therapy require careful supervision of the dose and frequent feedings for at least 3 to 5 days. Hospitalization and intravenous glucose may be necessary.

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 loss of control may occur. At such times, it may be necessary to discontinue Diabinese and administer insulin.

The effectiveness of any oral hypoglycemic drug, including Diabinese, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.

Geriatric Use

The safety and effectiveness of Diabinese in patients aged 65 and over has not been properly evaluated in clinical studies. Adverse event reporting suggests that elderly patients may be more prone to developing hypoglycemia and/or hyponatremia when using Diabinese. Although the underlying mechanisms are unknown, abnormal renal function, drug interaction and poor nutrition appear to contribute to these events.

Information for Patients

Patients should be informed of the potential risks and advantages of Diabinese and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure should also be explained.

Patients should be instructed to contact their physician promptly if they experience symptoms of hypoglycemia or other adverse reactions.

Physician Counseling Information for Patients

In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible. Use of Diabinese or other antidiabetic medications must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of Diabinese or other antidiabetic medications. Maintenance or discontinuation of Diabinese or other antidiabetic medications should be based on clinical judgment using regular clinical and laboratory evaluations.

Laboratory Tests

Blood glucose should be monitored periodically. Measurement of glycosylated hemoglobin should be performed and goals assessed by the current standard of care.

Hemolytic Anemia

Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because Diabinese belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In post marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

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Drug Interactions

The following products can lead to hypoglycemia

The hypoglycemic action of sulfonylurea may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving Diabinese, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving Diabinese, the patient should be observed closely for loss of control.

Miconazole

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with intravenous, topical, or vaginal preparations of miconazole is not known.

Alcohol

In some patients, a disulfiram-like reaction may be produced by the ingestion of alcohol. Moderate to large amounts of alcohol may increase the risk of hypoglycemia (ref.1), (ref. 2).

The following products can lead to hyperglycemia

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides 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 Diabinese, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving Diabinese, the patient should be observed closely for hypoglycemia.

Since animal studies suggest that the action of barbiturates may be prolonged by therapy with chlorpropamide, barbiturates should be employed with caution.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with Diabinese have not been conducted to evaluate carcinogenic or mutagenic potential.

Rats treated with continuous Diabinese therapy for 6 to 12 months showed varying degrees of suppression of spermatogenesis at a dose level of 250 mg/kg (five times the human dose based on body surface area). The extent of suppression seemed to follow that of growth retardation associated with chronic administration of high-dose Diabinese in rats. The human dose of chlorpropamide is 500 mg/day (300 mg/M2). Six- and 12-month toxicity work in the dog and rat, respectively, indicates the 150 mg/kg is well tolerated. Therefore, the safety margins based upon body-surface-area comparisons are three times human exposure in the rat and 10 times human exposure in the dog.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Animal reproductive studies have not been conducted with Diabinese. It is also not known whether Diabinese can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Diabinese should be given to a pregnant woman only if the potential benefits justify the potential risk to the patient and fetus.

Because data suggest that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Nonteratogenic Effects

Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If Diabinese is used during pregnancy, it should be discontinued at least one month before the expected delivery date and other therapies instituted to maintain blood glucose levels as close to normal as possible.

Nursing Mothers

An analysis of a composite of two samples of human breast milk, each taken five hours after ingestion of 500 mg of chlorpropamide by a patient, revealed a concentration of 5 mcg/mL. For reference, the normal peak blood level of chlorpropamide after a single 250 mg dose is 30 mcg/mL. Therefore, it is not recommended that a woman breast feed while taking this medication.

Use in Children

Safety and effectiveness in children have not been established.

Ability to Drive and Use Machines

The effect of Diabinese on the ability to drive or operate machinery has not been studied. However, there is no evidence to suggest that Diabinese may affect these abilities. Patients should be aware of the symptoms of hypoglycemia and take caution while driving and operating machinery.

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Adverse Reactions

Body as a Whole

Disulfiram-like reactions have rarely been reported with Diabinese (see DRUG INTERACTIONS).

Central and Peripheral Nervous System

Dizziness and headache.

Hypoglycemia

See PRECAUTIONS and OVERDOSAGE sections.

Gastrointestinal

Gastrointestinal disturbances are the most common reactions; nausea has been reported in less than 5% of patients, and diarrhea, vomiting, anorexia, and hunger in less than 2%. Other gastrointestinal disturbances have occurred in less than 1% of patients including proctocolitis. They tend to be dose-related and may disappear when dosage is reduced.

Liver/Biliary

Cholestatic jaundice may occur rarely; Diabinese should be discontinued if this occurs. Hepatic porphyria and disulfiram-like reactions have been reported with Diabinese.

Skin/Appendages

Pruritus has been reported in less than 3% of patients. Other allergic skin reactions, e.g., urticaria and maculopapular eruptions have been reported in approximately 1% or less of patients. These may be transient and may disappear despite continued use of Diabinese; if skin reactions persist the drug should be discontinued.

As with other sulfonylureas, porphyria cutanea tarda and photosensitivity reactions have been reported.

Skin eruptions rarely progressing to erythema multiforme and exfoliative dermatitis have also been reported.

Hematologic Reactions

Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see PRECAUTIONS), aplastic anemia, pancytopenia, and eosinophilia have been reported with sulfonylureas.

Metabolic/Nutritional Reactions

Hypoglycemia (see PRECAUTIONS and OVERDOSAGE sections). Hepatic porphyria and disulfiram-like reactions have been reported with Diabinese. See DRUG INTERACTIONS section.

Endocrine Reactions

On rare occasions, chlorpropamide has caused a reaction identical to the syndrome of inappropriate antidiuretic hormone (ADH) secretion. The features of this syndrome result from excessive water retention and include hyponatremia, low serum osmolality, and high urine osmolality. This reaction has also been reported for other sulfonylureas.

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Overdosage

Overdosage of sulfonylureas including Diabinese can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery.

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Dosage and Administration

There is no fixed dosage regimen for the management of type 2 diabetes with Diabinese or any other hypoglycemic agent. The patient's blood glucose must be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy.

Short-term administration of Diabinese may be sufficient during periods of transient loss of control in patients usually controlled well on diet.

The total daily dosage is generally taken at a single time each morning with breakfast. Occasionally cases of gastrointestinal intolerance may be relieved by dividing the daily dosage. A LOADING OR PRIMING DOSE IS NOT NECESSARY AND SHOULD NOT BE USED.

Initial Therapy

1. The mild to moderately severe, middle-aged, stable type 2 diabetes patient should be started on 250 mg daily. In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS section). Older patients should be started on smaller amounts of Diabinese, in the range of 100 to 125 mg daily.
2. No transition period is necessary when transferring patients from other oral hypoglycemic agents to Diabinese. The other agent may be discontinued abruptly and chlorpropamide started at once. In prescribing chlorpropamide, due consideration must be given to its greater potency.

Many mild to moderately severe, middle-aged, stable type 2 diabetes patients receiving insulin can be placed directly on the oral drug and their insulin abruptly discontinued. For patients requiring more than 40 units of insulin daily, therapy with Diabinese may be initiated with a 50 per cent reduction in insulin for the first few days, with subsequent further reductions dependent upon the response.

During the initial period of therapy with chlorpropamide, hypoglycemic reactions may occasionally occur, particularly during the transition from insulin to the oral drug. Hypoglycemia within 24 hours after withdrawal of the intermediate or long-acting types of insulin will usually prove to be the result of insulin carry-over and not primarily due to the effect of chlorpropamide.

During the insulin withdrawal period, the patient should self-monitor glucose levels at least three times daily. If they are abnormal, the physician should be notified immediately. In some cases, it may be advisable to consider hospitalization during the transition period.

Five to seven days after the initial therapy, the blood level of chlorpropamide reaches a plateau. Dosage may subsequently be adjusted upward or downward by increments of not more than 50 to l25 mg at intervals of three to five days to obtain optimal control. More frequent adjustments are usually undesirable.

Maintenance Therapy

Most moderately severe, middle-aged, stable type 2 diabetes patients are controlled by approximately 250 mg daily. Many investigators have found that some milder diabetics do well on daily doses of 100 mg or less. Many of the more severe diabetics may require 500 mg daily for adequate control. PATIENTS WHO DO NOT RESPOND COMPLETELY TO 500 MG DAILY WILL USUALLY NOT RESPOND TO HIGHER DOSES. MAINTENANCE DOSES ABOVE 750 mg DAILY SHOULD BE AVOIDED.

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How is Supplied

RECOMMENDED STORAGE: Store below 86°F (30°C).

Rx only

last updated 02/2009

Diabinese (Chlorpropamide) Patient Information (in plain English)

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse.

back to: Browse all Medications for Diabetes

Brand Name: Apidra
Generic Name: Insulin Glulisine

Apidra (insulin glulisine) is a man-made product almost identical to human insulin. It is used to treat diabetes mellitus. Usage, dosage, side effects.

Contents:

Indications and Usage
Dosage and Administration
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Overdosage
Description
Clinical Pharmacology
Nonclinical Toxicology
Clinical Studies
How Supplied

Apidra, insulin glusine, patient information (in plain English)

Indications

Apidra is a rapid acting human insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus.

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Dosage and Administration

Dosage considerations

APIDRA is a recombinant insulin analog that is equipotent to human insulin (i.e. one unit of APIDRA has the same glucose-lowering effect as one unit of regular human insulin) when given intravenously. When given subcutaneously, APIDRA has a more rapid onset of action and a shorter duration of action than regular human insulin.

The dosage of APIDRA must be individualized. Blood glucose monitoring is essential in all patients receiving insulin therapy.

The total daily insulin requirement may vary and is usually between 0.5 to 1 Unit/kg/day. Insulin requirements may be altered during stress, major illness, or with changes in exercise, meal patterns, or coadministered drugs.

Subcutaneous administration

APIDRA should be given within 15 minutes before a meal or within 20 minutes after starting a meal.

APIDRA given by subcutaneous injection should generally be used in regimens with an intermediate or long-acting insulin.

APIDRA should be administered by subcutaneous injection in the abdominal wall, thigh, or upper arm. Injection sites should be rotated within the same region (abdomen, thigh or upper arm) from one injection to the next to reduce the risk of lipodystrophy [See ADVERSE REACTIONS].

Continuous subcutaneous infusion (insulin pump)

APIDRA may be administered by continuous subcutaneous infusion in the abdominal wall. Do not use diluted or mixed insulins in external insulin pumps. Infusion sites should be rotated within the same region to reduce the risk of lipodystrophy [See ADVERSE REACTIONS]. The initial programming of the external insulin infusion pump should be based on the total daily insulin dose of the previous regimen.

The following insulin pumps† have been used in APIDRA clinical trials conducted by sanofi-aventis, the manufacturer of APIDRA:

• Disetronic® H-Tron® plus V100 and D-Tron® with Disetronic catheters (Rapid™, Rapid C™, Rapid D™, and Tender™)
• MiniMed® Models 506, 507, 507c and 508 with MiniMed catheters (Sof-set Ultimate QR™, and Quick-set™).

Before using a different insulin pump with APIDRA, read the pump label to make sure the pump has been evaluated with APIDRA.

Physicians and patients should carefully evaluate information on pump use in the APIDRA prescribing information, Patient Information Leaflet, and the pump manufacturer's manual. APIDRA-specific information should be followed for in-use time, frequency of changing infusion sets, or other details specific to APIDRA usage, because APIDRA-specific information may differ from general pump manual instructions.

Based on in vitro studies which have shown loss of the preservative, metacresol and insulin degradation, APIDRA in the reservoir should be changed at least every 48 hours. APIDRA in clinical use should not be exposed to temperatures greater than 98.6° F (37° C). [See WARNINGS AND PRECAUTIONS and HOW SUPPLIED/Storage and Handling].

Intravenous administration

APIDRA can be administered intravenously under medical supervision for glycemic control with close monitoring of blood glucose and serum potassium to avoid hypoglycemia and hypokalemia. For intravenous use, APIDRA should be used at concentrations of 0.05 Units/mL to 1 Unit/mL insulin glulisine in infusion systems using polyvinyl chloride (PVC) bags. APIDRA has been shown to be stable only in normal saline solution (0.9% sodium chloride). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer insulin mixtures intravenously.

Dosage Forms and Strengths

Apidra 100 units per mL (U-100) is available as:

• 10 mL vials
• 3 mL cartridges for use in the OptiClik® Insulin Delivery Device
• 3 mL SoloStar prefilled pen

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Contraindications

Apidra is contraindicated:

• during episodes of hypoglycemia
• in patients who are hypersensitive to Apidra or to any of its excipients

When used in patients with known hypersensitivity to Apidra or its excipients, patients may develop localized or generalized hypersensitivity reactions [See Adverse Reactions].

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Warnings and Precautions

Dosage adjustment and monitoring

Glucose monitoring is essential for patients receiving insulin therapy. Changes to an insulin regimen should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in insulin dose. Concomitant oral antidiabetic treatment may need to be adjusted.

As with all insulin preparations, the time course of action for Apidra may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the site of injection, local blood supply, or local temperature. Patients who change their level of physical activity or meal plan may require adjustment of insulin dosages.

Hypoglycemia

Hypoglycemia is the most common adverse reaction of insulin therapy, including Apidra. The risk of hypoglycemia increases with tighter glycemic control. Patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with Apidra.

The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also alter the risk of hypoglycemia [See Drug Interactions].

As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.

Rapid changes in serum glucose levels may induce symptoms similar to hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic nerve disease, use of medications such as beta-blockers [See Drug Interactions], or intensified diabetes control. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient's awareness of hypoglycemia.

Intravenously administered insulin has a more rapid onset of action than subcutaneously administered insulin, requiring closer monitoring for hypoglycemia.

Hypersensitivity and allergic reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Apidra [See Adverse reactions].

Hypokalemia

All insulin products, including Apidra, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations). Monitor glucose and potassium frequently when Apidra is administered intravenously.

Renal or hepatic impairment

Frequent glucose monitoring and insulin dose reduction may be required in patients with renal or hepatic impairment [See Clinical Pharmacology].

Mixing of insulins

Apidra for subcutaneous injection should not be mixed with insulin preparations other than NPH insulin. If Apidra is mixed with NPH insulin, Apidra should be drawn into the syringe first. Injection should occur immediately after mixing.

Do not mix Apidra with other insulins for intravenous administration or for use in a continuous subcutaneous infusion pump.

Apidra for intravenous administration should not be diluted with solutions other than 0.9% sodium chloride (normal saline). The efficacy and safety of mixing Apidra with diluents or other insulins for use in external subcutaneous infusion pumps have not been established.

Subcutaneous insulin infusion pumps

When used in an external insulin pump for subcutaneous infusion, Apidra should not be diluted or mixed with any other insulin. Apidra in the reservoir should be changed at least every 48 hours. Apidra should not be exposed to temperatures greater than 98.6°F (37°C).

Malfunction of the insulin pump or infusion set or insulin degradation can rapidly lead to hyperglycemia and ketosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim subcutaneous injections with Apidra may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure. [See Dosage and Administration, How Supplied/Storage and Handling].

Intravenous administration

When Apidra is administered intravenously, glucose and potassium levels must be closely monitored to avoid potentially fatal hypoglycemia and hypokalemia.

Do not mix Apidra with other insulins for intravenous administration. Apidra may be diluted only in normal saline solution.

Drug interactions

Some medications may alter insulin requirements and the risk for hypoglycemia or hyperglycemia [See Drug Interactions].

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Adverse Reactions

The following adverse reactions are discussed elsewhere:

• Hypoglycemia [See Warnings and Precautions]
• Hypokalemia [See Warnings and Precautions]

Clinical trial experience

Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.

The frequencies of adverse drug reactions during Apidra clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.

Table 1: Treatment -emergent adverse events in pooled studies of adults with type 1 diabetes (adverse events with frequency ≥ 5%)

Table 2: Treatment -emergent adverse events in pooled studies of adults with type 2 diabetes (adverse events with frequency ≥ 5%)

• Pediatrics

Table 3 summarizes the adverse reactions occurring with frequency higher than 5% in a clinical study in children and adolescents with type 1 diabetes treated with APIDRA (n=277) or insulin lispro (n=295).

Table 3: Treatment -emergent adverse events in children and adolescents with type 1 diabetes (adverse reactions with frequency ≥5%)

• Severe symptomatic hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including Apidra [See Warnings and Precautions]. The rates and incidence of severe symptomatic hypoglycemia, defined as hypoglycemia requiring intervention from a third party, were comparable for all treatment regimens (see Table 4). In the phase 3 clinical trial, children and adolescents with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to adults with type 1 diabetes. (see Table 4) [See Clinical Studies].

Table 4: Severe Symptomatic Hypoglycemia*

• Insulin initiation and intensification of glucose control

Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.

• Lipodystrophy

Long-term use of insulin, including Apidra, can cause lipodystrophy at the site of repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy. [See Dosage and Administration].

• Weight gain

Weight gain can occur with insulin therapy, including Apidra, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.

• Peripheral Edema

Insulin, including Apidra, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

• Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII)

In a 12-week randomized study in patients with type 1 diabetes (n=59), the rates of catheter occlusions and infusion site reactions were similar for Apidra and insulin aspart treated patients (Table 5).

Table 5: Catheter Occlusions and Infusion Site Reactions.

• Allergic Reactions

Local Allergy

As with any insulin therapy, patients taking Apidra may experience redness, swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks, but in some occasions may require discontinuation of Apidra. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique.

Systemic Allergy

Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including Apidra. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.

In controlled clinical trials up to 12 months duration, potential systemic allergic reactions were reported in 79 of 1833 patients (4.3%) who received Apidra and 58 of 1524 patients (3.8%) who received the comparator short-acting insulins. During these trials treatment with Apidra was permanently discontinued in 1 of 1833 patients due to a potential systemic allergic reaction.

Localized reactions and generalized myalgias have been reported with the use of metacresol, which is an excipient of Apidra.

Antibody Production

In a study in patients with type 1 diabetes (n=333), the concentrations of insulin antibodies that react with both human insulin and insulin glulisine (cross-reactive insulin antibodies) remained near baseline during the first 6 months of the study in the patients treated with Apidra. A decrease in antibody concentration was observed during the following 6 months of the study. In a study in patients with type 2 diabetes (n=411), a similar increase in cross-reactive insulin antibody concentration was observed in the patients treated with Apidra and in the patients treated with human insulin during the first 9 months of the study. Thereafter the concentration of antibodies decreased in the Apidra patients and remained stable in the human insulin patients. There was no correlation between cross-reactive insulin antibody concentration and changes in HbA1c, insulin doses, or incidence of hypoglycemia. The clinical significance of these antibodies is not known.

Apidra did not elicit a significant antibody response in a study of children and adolescents with type 1 diabetes.

Postmarketing experience

The following adverse reactions have been identified during post-approval use of Apidra.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure.

Medication errors have been reported in which other insulins, particularly long-acting insulins, have been accidentally administered instead of Apidra.

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Drug Interactions

A number of drugs affect glucose metabolism and may necessitate insulin dose adjustment and particularly close monitoring.

Drugs that may increase the blood glucose-lowering effect of insulins including Apidra, and therefore increase the risk of hypoglycemia, include oral antidiabetic products, pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, propoxyphene, pentoxifylline, salicylates, somatostatin analogs, and sulfonamide antibiotics.

Drugs that may reduce the blood-glucose-lowering effect of Apidra include corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), protease inhibitors, and atypical antipsychotics.

Beta-blockers, clonidine, lithium salts, and alcohol may either increase or decrease the blood-glucose-lowering effect of insulin.

Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.

The signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs such as beta-blockers, clonidine, guanethidine, and reserpine.

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Use in Specific Populations

Pregnancy

Pregnancy Category C: Reproduction and teratology studies have been performed with insulin glulisine in rats and rabbits using regular human insulin as a comparator. Insulin glulisine was given to female rats throughout pregnancy at subcutaneous doses up to 10 Units/kg once daily (dose resulting in an exposure 2 times the average human dose, based on body surface area comparison) and did not have any remarkable toxic effects on embryo-fetal development.

Insulin glulisine was given to female rabbits throughout pregnancy at subcutaneous doses up to 1.5 Units/kg/day (dose resulting in an exposure 0.5 times the average human dose, based on body surface area comparison). Adverse effects on embryo-fetal development were only seen at maternal toxic dose levels inducing hypoglycemia. Increased incidence of post-implantation losses and skeletal defects were observed at a dose level of 1.5 Units/kg once daily (dose resulting in an exposure 0.5 times the average human dose, based on body surface area comparison) that also caused mortality in dams. A slight increased incidence of post-implantation losses was seen at the next lower dose level of 0.5 Units/kg once daily (dose resulting in an exposure 0.2 times the average human dose, based on body surface area comparison) which was also associated with severe hypoglycemia but there were no defects at that dose. No effects were observed in rabbits at a dose of 0.25 Units/kg once daily (dose resulting in an exposure 0.1 times the average human dose, based on body surface area comparison). The effects of insulin glulisine did not differ from those observed with subcutaneous regular human insulin at the same doses and were attributed to secondary effects of maternal hypoglycemia.

There are no well-controlled clinical studies of the use of Apidra in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is essential for patients with diabetes or a history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients.

Nursing mothers

It is unknown whether insulin glulisine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Apidra is administered to a nursing woman. Use of Apidra is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses.

Pediatric use

The safety and effectiveness of subcutaneous injections of Apidra have been established in pediatric patients (age 4 to 17 years) with type 1 diabetes [See Clinical Studies]. Apidra has not been studied in pediatric patients with type 1 diabetes younger than 4 years of age and in pediatric patients with type 2 diabetes.

As in adults, the dosage of Apidra must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose.

Geriatric use

In clinical trials (n=2408), Apidra was administered to 147 patients ≥65 years of age and 27 patients ≥75 years of age. The majority of this small subset of elderly patients had type 2 diabetes. The change in HbA1c values and hypoglycemia frequencies did not differ by age. Nevertheless, caution should be exercised when Apidra is administered to geriatric patients.

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Overdosage

Excess insulin may cause hypoglycemia and, particularly when given intravenously, hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

Description

Apidra® (insulin glulisine [rDNA origin] injection) is a rapid-acting human insulin analog used to lower blood glucose. Insulin glulisine is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Insulin glulisine differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid. Chemically, insulin glulisine is 3B-lysine-29B-glutamic acid-human insulin, has the empirical formula C258H384N64O78S6 and a molecular weight of 5823 and has the following structural formula:

Apidra is a sterile, aqueous, clear, and colorless solution. Each milliliter of Apidra contains 100 units (3.49 mg) insulin glulisine, 3.15 mg metacresol, 6 mg tromethamine, 5 mg sodium chloride, 0.01 mg polysorbate 20, and water for injection. Apidra has a pH of approximately 7.3. The pH is adjusted by addition of aqueous solutions of hydrochloric acid and/or sodium hydroxide.

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Clinical Pharmacology

Mechanism of action

Regulation of glucose metabolism is the primary activity of insulins and insulin analogs, including insulin glulisine. Insulins lower blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.

The glucose lowering activities of Apidra and of regular human insulin are equipotent when administered by the intravenous route. After subcutaneous administration, the effect of Apidra is more rapid in onset and of shorter duration compared to regular human insulin. [See Pharmacodynamics].

Pharmacodynamics

Studies in healthy volunteers and patients with diabetes demonstrated that Apidra has a more rapid onset of action and a shorter duration of activity than regular human insulin when given subcutaneously.

In a study in patients with type 1 diabetes (n= 20), the glucose-lowering profiles of Apidra and regular human insulin were assessed at various times in relation to a standard meal at a dose of 0.15 Units/kg. (Figure 1.)

The maximum blood glucose excursion (ΔGLUmax; baseline subtracted glucose concentration) for Apidra injected 2 minutes before a meal was 65 mg/dL compared to 64 mg/dL for regular human insulin injected 30 minutes before a meal (see Figure 1A), and 84 mg/dL for regular human insulin injected 2 minutes before a meal (see Figure 1B). The maximum blood glucose excursion for Apidra injected 15 minutes after the start of a meal was 85 mg/dL compared to 84 mg/dL for regular human insulin injected 2 minutes before a meal (see Figure 1C).

Figure 1. Serial mean blood glucose collected up to 6 hours following a single dose of Apidra and regular human insulin. Apidra given 2 minutes (Apidra - pre) before the start of a meal compared to regular human insulin given 30 minutes (Regular - 30 min) before start of the meal (Figure 1A) and compared to regular human insulin (Regular - pre) given 2 minutes before a meal (Figure 1B). Apidra given 15 minutes (Apidra - post) after start of a meal compared to regular human insulin (Regular - pre) given 2 minutes before a meal (Figure 1C). On the x-axis zero (0) is the start of a 15-minute meal.

In a randomized, open-label, two-way crossover study, 16 healthy male subjects received an intravenous infusion of Apidra or regular human insulin with saline diluent at a rate of 0.8 milliUnits/kg/min for two hours. Infusion of the same dose of Apidra or regular human insulin produced equivalent glucose disposal at steady state.

Pharmacokinetics

Absorption and bioavailability

Pharmacokinetic profiles in healthy volunteers and patients with diabetes (type 1 or type 2) demonstrated that absorption of insulin glulisine was faster than that of regular human insulin.

In a study in patients with type 1 diabetes (n=20) after subcutaneous administration of 0.15 Units/kg, the median time to maximum concentration (Tmax) was 60 minutes (range 40 to 120 minutes) and the peak concentration (Cmax) was 83 microUnits/mL (range 40 to 131 microUnits/mL) for insulin glulisine compared to a median Tmax of 120 minutes (range 60 to 239 minutes) and a Cmax of 50 microUnits/mL (range 35 to 71 microUnits/mL) for regular human insulin. (Figure 2)

Figure 2. Pharmacokinetic profiles of insulin glulisine and regular human insulin in patients with type 1 diabetes after a dose of 0.15 Units/kg.

Insulin glulisine and regular human insulin were administered subcutaneously at a dose of 0.2 Units/kg in an euglycemic clamp study in patients with type 2 diabetes (n=24) and a body mass index (BMI) between 20 and 36 kg/m2. The median time to maximum concentration (Tmax) was 100 minutes (range 40 to 120 minutes) and the median peak concentration (Cmax) was 84 microUnits/mL (range 53 to 165 microUnits/mL) for insulin glulisine compared to a median Tmax of 240 minutes (range 80 to 360 minutes) and a median Cmax of 41 microUnits/mL (range 33 to 61 microUnits/mL) for regular human insulin. (Figure 3.)

Figure 3. Pharmacokinetic profiles of insulin glulisine and regular human insulin in patients with type 2 diabetes after a subcutaneous dose of 0.2 Units/kg.

When Apidra was injected subcutaneously into different areas of the body, the time-concentration profiles were similar. The absolute bioavailability of insulin glulisine after subcutaneous administration is approximately 70%, regardless of injection area (abdomen 73%, deltoid 71%, thigh 68%).

In a clinical study in healthy volunteers (n=32) the total insulin glulisine bioavailability was similar after subcutaneous injection of insulin glulisine and NPH insulin (premixed in the syringe) and following separate simultaneous subcutaneous injections. There was 27% attenuation of the maximum concentration (Cmax) of Apidra after premixing; however, the time to maximum concentration (Tmax) was not affected. No data are available on mixing Apidra with insulin preparations other than NPH insulin. [See Clinical Studies].

Distribution and elimination

The distribution and elimination of insulin glulisine and regular human insulin after intravenous administration are similar with volumes of distribution of 13 and 21 L and half-lives of 13 and 17 minutes, respectively. After subcutaneous administration, insulin glulisine is eliminated more rapidly than regular human insulin with an apparent half-life of 42 minutes compared to 86 minutes.

Clinical pharmacology in specific populations

Pediatric patients

The pharmacokinetic and pharmacodynamic properties of Apidra and regular human insulin were assessed in a study conducted in children 7 to 11 years old (n=10) and adolescents 12 to 16 years old (n=10) with type 1 diabetes. The relative differences in pharmacokinetics and pharmacodynamics between Apidra and regular human insulin in these patients with type 1 diabetes were similar to those in healthy adult subjects and adults with type 1 diabetes.

Race

A study in 24 healthy Caucasians and Japanese subjects compared the pharmacokinetics and pharmacodynamics after subcutaneous injection of insulin glulisine, insulin lispro, and regular human insulin. With subcutaneous injection of insulin glulisine, Japanese subjects had a greater initial exposure (33%) for the ratio of AUC(0-1h) to AUC(0-clamp end) than Caucasians (21%) although the total exposures were similar. There were similar findings with insulin lispro and regular human insulin.

Obesity

Insulin glulisine and regular human insulin were administered subcutaneously at a dose of 0.3 Units/kg in a euglycemic clamp study in obese, non-diabetic subjects (n=18) with a body mass index (BMI) between 30 and 40 kg/m2. The median time to maximum concentration (Tmax) was 85 minutes (range 49 to 150 minutes) and the median peak concentration (Cmax) was 192 microUnits/mL (range 98 to 380 microUnits/mL) for insulin glulisine compared to a median Tmax of 150 minutes (range 90 to 240 minutes) and a median Cmax of 86 microUnits/mL (range 43 to 175 microUnits/mL) for regular human insulin.

The more rapid onset of action and shorter duration of activity of Apidra and insulin lispro compared to regular human insulin were maintained in an obese non-diabetic population (n= 18). (Figure 4.)

Figure 4. Glucose infusion rates (GIR) in a euglycemic clamp study after subcutaneous injection of 0.3 Units/kg of Apidra, insulin lispro or regular human insulin in an obese population.

Renal impairment

Studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. In a study performed in 24 non-diabetic subjects with normal renal function (ClCr >80 mL/min), moderate renal impairment (30-50 mL/min) and severe renal impairment (Warnings and Precautions].

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of Apidra has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. [See Warnings and Precautions].

Gender

The effect of gender on the pharmacokinetics and pharmacodynamics of Apidra has not been studied.

Pregnancy

The effect of pregnancy on the pharmacokinetics and pharmacodynamics of Apidra has not been studied.

Smoking

The effect of smoking on the pharmacokinetics and pharmacodynamics of Apidra has not been studied.

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Nonclinical Toxicology

Carcinogenesis, mutagenesis, impairment of fertility

Standard 2-year carcinogenicity studies in animals have not been performed. In Sprague Dawley rats, a 12-month repeat dose toxicity study was conducted with insulin glulisine at subcutaneous doses of 2.5, 5, 20 or 50 Units/kg twice daily (dose resulting in an exposure 1, 2, 8, and 20 times the average human dose, based on body surface area comparison).

There was a non-dose dependent higher incidence of mammary gland tumors in female rats administered insulin glulisine compared to untreated controls. The incidence of mammary tumors for insulin glulisine and regular human insulin was similar. The relevance of these findings to humans is not known. Insulin glulisine was not mutagenic in the following tests: Ames test, in vitro mammalian chromosome aberration test in V79 Chinese hamster cells, and in vivo mammalian erythrocyte micronucleus test in rats.

In fertility studies in male and female rats at subcutaneous doses up to 10 Units/kg once daily (dose resulting in an exposure 2 times the average human dose, based on body surface area comparison), no clear adverse effects on male and female fertility, or general reproductive performance of animals were observed.

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Clinical Studies

The safety and efficacy of Apidra was studied in adult patients with type 1 and type 2 diabetes (n =1833) and in children and adolescent patients (4 to 17 years) with type 1 diabetes (n=572). The primary efficacy parameter in these trials was glycemic control, assessed using glycated hemoglobin (GHb reported as HbA1c equivalent).

Type 1 Diabetes-Adults

A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in patients with type 1 diabetes to assess the safety and efficacy of Apidra (n= 339) compared to insulin lispro (n= 333) when administered subcutaneously within 15 minutes before a meal. Insulin glargine was administered once daily in the evening as the basal insulin. There was a 4-week run-in period with insulin lispro and insulin glargine prior to randomization. Most patients were Caucasian (97%). Fifty eight percent of the patients were men. The mean age was 39 years (range 18 to 74 years). Glycemic control, the number of daily short-acting insulin injections and the total daily doses of Apidra and insulin lispro were similar in the two treatment groups (Table 6).

Table 6: Type 1 Diabetes Mellitus - Adult

Type 2 Diabetes-Adults

A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in insulin-treated patients with type 2 diabetes to assess the safety and efficacy of Apidra (n= 435) given within 15 minutes before a meal compared to regular human insulin (n=441) administered 30 to 45 minutes prior to a meal. NPH human insulin was given twice a day as the basal insulin. All patients participated in a 4-week run-in period with regular human insulin and NPH human insulin. Eighty-five percent of patients were Caucasian and 11% were Black. The mean age was 58 years (range 26 to 84 years). The average body mass index (BMI) was 34.6 kg/m2. At randomization, 58% of the patients were taking an oral antidiabetic agent. These patients were instructed to continue use of their oral antidiabetic agent at the same dose throughout the trial. The majority of patients (79%) mixed their short-acting insulin with NPH human insulin immediately prior to injection. The reductions from baseline in GHb were similar between the 2 treatment groups (see Table 7). No differences between Apidra and regular human insulin groups were seen in the number of daily short-acting insulin injections or basal or short-acting insulin doses. (See Table 7.)

Table 7: Type 2 Diabetes Mellitus-Adult

Type 1 Diabetes-Adults: Pre- and post-meal administration

A 12-week, randomized, open-label, active-controlled, non-inferiority study was conducted in patients with type 1 diabetes to assess the safety and efficacy of Apidra administered at different times with respect to a meal. Apidra was administered subcutaneously either within 15 minutes before a meal (n=286) or immediately after a meal (n=296) and regular human insulin (n= 278) was administered subcutaneously 30 to 45 minutes prior to a meal. Insulin glargine was administered once daily at bedtime as the basal insulin. There was a 4-week run-in period with regular human insulin and insulin glargine followed by randomization. Most patients were Caucasian (94%). The mean age was 40 years (range 18 to 73 years). Glycemic control (see Table 8) was comparable for the 3 treatment regimens. No changes from baseline between the treatments were seen in the total daily number of short-acting insulin injections. (See Table 8.)

Table 8: Pre- and Post-Meal Administration in Type 1 Diabetes Mellitus-Adult

Type 1 Diabetes-Pediatric patients

A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in children and adolescents older than 4 years of age with type 1 diabetes mellitus to assess the safety and efficacy of Apidra (n= 277) compared to insulin lispro (n= 295) when administered subcutaneously within 15 minutes before a meal. Patients also received insulin glargine (administered once daily in the evening) or NPH insulin (administered once in the morning and once in the evening). There was a 4-week run-in period with insulin lispro and insulin glargine or NPH prior to randomization. Most patients were Caucasian (91%). Fifty percent of the patients were male. The mean age was 12.5 years (range 4 to 17 years). Mean BMI was 20.6 kg/m2. Glycemic control (see Table 9) was comparable for the two treatment regimens.

Table 9: Results from a 26-week study in pediatric patients with type 1 diabetes mellitus

Type 1 Diabetes-Adults: Continuous subcutaneous insulin infusion

A 12-week randomized, active control study (Apidra versus insulin aspart) conducted in adults with type 1 diabetes (Apidra n= 29, insulin aspart n=30) evaluated the use of Apidra in an external continuous subcutaneous insulin pump. All patients were Caucasian. The mean age was 46 years (range 21 to 73 years). The mean GHb increased from baseline to endpoint in both treatment groups (from 6.8% to 7.0% for Apidra; from 7.1% to 7.2% for insulin aspart).

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How Supplied/Storage and Handling

How supplied

Pen needles are not included in the packs.

BD Ultra-Fine™ pen needles1 to be used in conjunction with OptiClik are sold separately and are manufactured by Becton Dickinson and Company.

Solostar is compatible with all pen needles from Becton Dickinson and Company, Ypsomed and Owen Mumford.

Storage

Do not use after the expiration date (see carton and container).

Unopened Vial/Cartridge System/SoloStar

Unopened Apidra vials, cartridge systems and SoloStar should be stored in a refrigerator, 36°F-46°F (2°C-8°C). Protect from light. Apidra should not be stored in the freezer and it should not be allowed to freeze. Discard if it has been frozen.

Unopened vials/cartridge systems/SoloStar not stored in a refrigerator must be used within 28 days.

Open (In-Use) Vial:

Opened vials, whether or not refrigerated, must be used within 28 days. If refrigeration is not possible, the open vial in use can be kept unrefrigerated for up to 28 days away from direct heat and light, as long as the temperature is not greater than 77°F (25°C).

Open (In-Use) Cartridge System:

The opened (in-use) cartridge system inserted in OptiClik® should NOT be refrigerated but should be kept below 77°F (25°C) away from direct heat and light. The opened (in-use) cartridge system must be discarded after 28 days. Do not store OptiClik®, with or without cartridge system, in a refrigerator at any time.

Open (In-Use) SoloStar prefilled pen:

The opened (in-use) SoloStar should NOT be refrigerated but should be kept below 77°F (25°C) away from direct heat and light. The opened (in-use) SoloStar kept at room temperature must be discarded after 28 days.

Infusion sets:

Infusion sets (reservoirs, tubing, and catheters) and the Apidra in the reservoir should be discarded after 48 hours of use or after exposure to temperatures that exceed 98.6°F (37°C).

Intravenous use:

Infusion bags prepared as indicated under DOSAGE AND ADMINISTRATION are stable at room temperature for 48 hours.

Preparation and handling

After dilution for intravenous use, the solution should be inspected visually for particulate matter and discoloration prior to administration. Do not use the solution if it has become cloudy or contains particles; use only if it is clear and colorless. Apidra is not compatible with Dextrose solution and Ringers solution and, therefore, cannot be used with these solution fluids. The use of Apidra with other solutions has not been studied and is, therefore, not recommended.

Cartridge system: If OptiClik® (the Insulin Delivery Device for Apidra) malfunctions, Apidra may be drawn from the cartridge system into a U-100 syringe and injected.

Apidra, insulin glusine, patient information (in plain English)

last updated: 02/2009

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse.

back to: Browse all Medications for Diabetes

Brand Name: Glucovance
Generic Name: (glyburide and metformin HCl)

Contents:

Description
Clinical Pharmacology
Indications and Usage
Contraindications
Warnings
Precautions
Adverse Reactions
Overdosage
Dosage and Administration
How Supplied

Glucovance patient information (in plain English)

Description

Glucovance® (Glyburide and Metformin HCl) Tablets contains 2 oral antihyperglycemic drugs used in the management of type 2 diabetes, glyburide and metformin hydrochloride.

Glyburide is an oral antihyperglycemic drug of the sulfonylurea class. The chemical name for glyburide is 1-[[p-[2-(5-chloro-o-anisamido)ethyl]phenyl]sulfonyl]-3-cyclo-hexylurea. Glyburide is a white to off-white crystalline compound with a molecular formula of C23H28ClN3O5S and a molecular weight of 494.01. The glyburide used in Glucovance has a particle size distribution of 25% undersize value not more than 6 µm, 50% undersize value not more than 7 to 10 µm, and 75% undersize value not more than 21 µm. The structural formula is represented below.

Metformin hydrochloride is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide monohydrochloride) is not chemically or pharmacologically related to sulfonylureas, thiazolidinediones, or α-glucosidase inhibitors. It is a white to off-white crystalline compound with a molecular formula of C4H12ClN5 (monohydrochloride) and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown:

Glucovance is available for oral administration in tablets containing 1.25 mg glyburide with 250 mg metformin hydrochloride, 2.5 mg glyburide with 500 mg metformin hydrochloride, and 5 mg glyburide with 500 mg metformin hydrochloride. In addition, each tablet contains the following inactive ingredients: microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate. The tablets are film coated, which provides color differentiation.

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Clinical Pharmacology

Mechanism of Action

Glucovance combines glyburide and metformin hydrochloride, 2 antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes.

Glyburide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in patients with type 2 diabetes, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

Metformin hydrochloride is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Pharmacokinetics

Absorption and Bioavailability

Glucovance

In bioavailability studies of Glucovance 2.5 mg/500 mg and 5 mg/500 mg, the mean area under the plasma concentration versus time curve (AUC) for the glyburide component was 18% and 7%, respectively, greater than that of the Micronase® brand of glyburide coadministered with metformin. The glyburide component of Glucovance, therefore, is not bioequivalent to Micronase®. The metformin component of Glucovance is bioequivalent to metformin coadministered with glyburide.

Following administration of a single Glucovance 5 mg/500 mg tablet with either a 20% glucose solution or a 20% glucose solution with food, there was no effect of food on the Cmax and a relatively small effect of food on the AUC of the glyburide component. The Tmax for the glyburide component was shortened from 7.5 hours to 2.75 hours with food compared to the same tablet strength administered fasting with a 20% glucose solution. The clinical significance of an earlier Tmax for glyburide after food is not known. The effect of food on the pharmacokinetics of the metformin component was indeterminate.

Glyburide

Single-dose studies with Micronase® tablets in normal subjects demonstrate significant absorption of glyburide within 1 hour, peak drug levels at about 4 hours, and low but detectable levels at 24 hours. Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve, increase in proportion to corresponding increases in dose. Bioequivalence has not been established between Glucovance and single ingredient glyburide products.

Metformin Hydrochloride

The absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin tablets of 500 mg and 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower peak concentration and a 25% lower AUC in plasma and a 35-minute prolongation of time to peak plasma concentration following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution

Glyburide

Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding exhibited by glyburide is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as phenylbutazone, warfarin, and salicylates displace the ionic-binding sulfonylureas from serum proteins to a far greater extent than the non-ionic binding glyburide. It has not been shown that this difference in protein binding results in fewer drug-drug interactions with glyburide tablets in clinical use.

Metformin Hydrochloride

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg averaged 654 ±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally

Metabolism and Elimination

Glyburide

The decrease of glyburide in the serum of normal healthy individuals is biphasic; the terminal half-life is about 10 hours. The major metabolite of glyburide is the 4-trans-hydroxy derivative. A second metabolite, the 3-cis-hydroxy derivative, also occurs. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400 and 1/40 as active, respectively, as glyburide) in rabbits. Glyburide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine.

Metformin Hydrochloride

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (see Table 1) is approximately 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, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Special Populations

Patients With Type 2 Diabetes

Multiple-dose studies with glyburide in patients with type 2 diabetes demonstrate drug level concentration-time curves similar to single-dose studies, indicating no buildup of drug in tissue depots.

In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses.

Hepatic Insufficiency

No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for either glyburide or metformin.

Renal Insufficiency

No information is available on the pharmacokinetics of glyburide in patients with renal insufficiency.

In patients with decreased renal function (based on creatinine clearance), theplasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1; also, see WARNINGS).

Geriatrics

There is no information on the pharmacokinetics of glyburide in elderly patients.

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1). Metformin treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.

Table 1: Select Mean ( ±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin

Pediatrics

After administration of a single oral GLUCOPHAGE® (metformin hydrochloride) 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.

After administration of a single oral Glucovance tablet with food, dose-normalized geometric mean glyburide Cmax and AUC in pediatric patients with type 2 diabetes (11 to 16 years of age, n=28, mean body weight of 97 kg) differed less than 6% from historical values in healthy adults.

Gender

There is no information on the effect of gender on the pharmacokinetics of glyburide.

Metformin pharmacokinetic parameters did not differ significantly in subjects with or without type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

Race

No information is available on race differences in the pharmacokinetics of glyburide.

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Clinical Studies

Patients with Inadequate Glycemic Control on Diet and Exercise Alone

In a 20-week, double-blind, multicenter U.S. clinical trial, a total of 806 drug-naive patients with type 2 diabetes, whose hyperglycemia was not adequately controlled with diet and exercise alone (baseline fasting plasma glucose [FPG]

Table 2: Placebo- and Active-Controlled Trial of Glucovance in Patients with Inadequate Glycemic Control on Diet and Exercise Alone: Summary of Trial Data at 20 Weeks

Treatment with Glucovance resulted in significantly greater reduction in HbA1c and postprandial plasma glucose (PPG) compared to glyburide, metformin, or placebo. Also, Glucovance therapy resulted in greater reduction in FPG compared to glyburide, metformin, or placebo, but the differences from glyburide and metformin did not reach statistical significance.

Changes in the lipid profile associated with Glucovance treatment were similar to those seen with glyburide, metformin, and placebo.

The double-blind, placebo-controlled trial described above restricted enrollment to patients with HbA1c <11% or FPG

Patients with Inadequate Glycemic Control on Sulfonylurea Alone

In a 16-week, double-blind, active-controlled U.S. clinical trial, a total of 639 patients with type 2 diabetes not adequately controlled (mean baseline HbA1c 9.5%, mean baseline FPG 213 mg/dL) while being treated with at least one-half the maximum dose of a sulfonylurea (e.g., glyburide 10 mg, glipizide 20 mg) were randomized to receive glyburide (fixed dose, 20 mg), metformin (500 mg), Glucovance 2.5 mg/500 mg, or Glucovance 5 mg/500 mg. The doses of metformin and Glucovance were titrated to a maximum of 4 tablets daily as needed to achieve FPG

Table 3: Glucovance in Patients with Inadequate Glycemic Control on Sulfonylurea Alone: Summary of Trial Data at 16 Weeks

After 16 weeks, there was no significant change in the mean HbA1c in patients randomized to glyburide or to metformin therapy. Treatment with Glucovance at doses up to 20 mg/2000 mg per day resulted in significant lowering of HbA1c, FPG, and PPG from baseline compared to glyburide or metformin alone.

Addition of Thiazolidinediones to Glucovance Therapy

In a 24-week, double-blind, multicenter U.S. clinical trial, patients with type 2 diabetes not adequately controlled on current oral antihyperglycemic therapy (either monotherapy or combination therapy) were first switched to open label Glucovance 2.5 mg/500 mg tablets and titrated to a maximum daily dose of 10 mg/2000 mg. A total of 365 patients inadequately controlled (HbA1c >7.0% and ≤10%) after 10 to 12 weeks of a daily Glucovance dose of at least 7.5 mg/1500 mg were randomized to receive add-on therapy with rosiglitazone 4 mg or placebo once daily. After 8 weeks, the rosiglitazone dose was increased to a maximum of 8 mg daily as needed to reach a target mean daily glucose of 126 mg/dL or HbA1c <7%. Trial data at 24 weeks or at the last prior visit are summarized in Table 4.

Table 4: Effects of Adding Rosiglitazone or Placebo in Patients Treated with Glucovance in a 24-Week Trial

For patients who did not achieve adequate glycemic control on Glucovance, the addition of rosiglitazone, compared to placebo, resulted in significant lowering of HbA1c and FPG.

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Indications and Usage

Glucovance is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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Contraindications

Glucovance (Glyburide and Metformin HCl) Tablets is contraindicated in patients with:

1. 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 (see WARNINGS and PRECAUTIONS).
2. Known hypersensitivity to metformin hydrochloride or glyburide.
3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

Glucovance 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. (See also PRECAUTIONS.)

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Warnings

Metformin Hydrochloride

Lactic acidosis:

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Glucovance; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 µg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Glucovance treatment should not be initiated in patients≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, Glucovance should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, Glucovance should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking Glucovance, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, Glucovance should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS).

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). Glucovance should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of Glucovance, gastrointestinal symptoms, which are common during initiation of therapy with metformin, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking Glucovance do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. (See also PRECAUTIONS.)

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking Glucovance, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS.)

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY

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 1 of 4 treatment groups (Diabetes 19 (Suppl. 2):747-830, 1970).

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 g per day) had a rate of cardiovascular mortality approximately 2 ½ 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 benefits of glyburide and of alternative modes of therapy.

Although only 1 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 hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

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Precautions

General

Macrovascular Outcomes

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

Glucovance

Hypoglycemia

Glucovance is capable of producing hypoglycemia or hypoglycemic symptoms, therefore, proper patient selection, dosing, and instructions are important to avoid potential hypoglycemic episodes. The risk of hypoglycemia is increased when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents or ethanol. Renal or hepatic insufficiency may cause elevated drug levels of both glyburide and metformin hydrochloride and the hepatic insufficiency may also diminish gluconeogenic capacity, both of which increase the risk of hypoglycemic reactions. 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 beta-adrenergic blocking drugs.

Glyburide

Hemolytic anemia

Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because Glucovance belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In postmarketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

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 Glucovance. In patients with advanced age, Glucovance 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, Glucovance should not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION). Before initiation of Glucovance therapy 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 Glucovance 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 (see PRECAUTIONS: Drug Interactions), 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 intravascular 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 (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, Glucovance 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 reevaluated 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 on Glucovance therapy, the drug should be promptly discontinued.

Surgical procedures

Glucovance therapy 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 Glucovance. Due to its effect on the gluconeogenic capacity of the liver, alcohol may also increase the risk of hypoglycemia.

Impaired hepatic function

Since impaired hepatic function has been associated with some cases of lactic acidosis, Glucovance should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Vitamin B12 levels

In controlled clinical trials with metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12, 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 metformin and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests).

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 patients with previously controlled type 2 diabetes

A patient with type 2 diabetes previously well controlled on metformin 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, Glucovance must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS).

Addition of Thiazolidinediones to Glucovance Therapy

Hypoglycemia

Patients receiving Glucovance in combination with a thiazolidinedione may be at risk for hypoglycemia.

Weight gain

Weight gain was seen with the addition of rosiglitazone to Glucovance, similar to that reported for thiazolidinedione therapy alone.

Hepatic effects

When a thiazolidinedione is used in combination with Glucovance, periodic monitoring of liver function tests should be performed in compliance with the labeled recommendations for the thiazolidinedione.

Information for Patients

Glucovance

Patients should be informed of the potential risks and benefits of Glucovance and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.

The risks of lactic acidosis associated with metformin therapy, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue Glucovance immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of Glucovance, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members.

Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving Glucovance.

Laboratory Tests

Periodic fasting blood glucose and glycosylated hemoglobin (HbA1c) measurements should be performed to monitor therapeutic response.

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, vitamin B12 deficiency should be excluded.

Drug Interactions

Glucovance

Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control. These drugs include the thiazides 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 Glucovance, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Glucovance, the patient should be observed closely for hypoglycemia. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid as compared to sulfonylureas, which are extensively bound to serum proteins.

Glyburide

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving Glucovance, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving Glucovance, the patient should be observed closely for loss of blood glucose control.

A possible interaction between glyburide and ciprofloxacin, a fluoroquinolone antibiotic, has been reported, resulting in a potentiation of the hypoglycemic action of glyburide. The mechanism for this interaction is not known.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known.

Metformin Hydrochloride

Furosemide

A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically.

Nifedipine

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Cationic drugs

Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Glucovance and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Other

In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been conducted with the combined products in Glucovance. The following data are based on findings in studies performed with the individual products.

Glyburide

Studies in rats with glyburide alone at doses up to 300 mg/kg/day (approximately 145 times the maximum recommended human daily dose of 20 mg for the glyburide component of Glucovance based on body surface area comparisons) for 18 months revealed no carcinogenic effects. In a 2-year oncogenicity study of glyburide in mice, there was no evidence of treatment-related tumors.

There was no evidence of mutagenic potential of glyburide alone in the following in vitro tests: Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay.

Metformin Hydrochloride

Long-term carcinogenicity studies were performed with metformin alone 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 1500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2000 mg of the metformin component of Glucovance based on body surface area comparisons. No evidence of carcinogenicity with metformin alone was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin alone in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day of metformin alone.

There was no evidence of a mutagenic potential of metformin alone 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 alone when administered 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 Glucovance based on body surface area comparisons.

Pregnancy

Teratogenic Effects: Pregnancy Category B

Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose as close to normal as possible. Because animal reproduction studies are not always predictive of human response, Glucovance should not be used during pregnancy unless clearly needed. (See below.)

There are no adequate and well-controlled studies in pregnant women with Glucovance or its individual components. No animal studies have been conducted with the combined products in Glucovance. The following data are based on findings in studies performed with the individual products.

Glyburide

Reproduction studies were performed in rats and rabbits at doses up to 500 times the maximum recommended human daily dose of 20 mg of the glyburide component of Glucovance based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to glyburide.

Metformin Hydrochloride

Metformin alone was not teratogenic in rats or 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 2000 mg of the metformin component of Glucovance based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Nonteratogenic Effects

Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. It is not recommended that Glucovance be used during pregnancy. However, if it is used, Glucovance should be discontinued at least 2 weeks before the expected delivery date. (See Pregnancy: Teratogenic Effects: Pregnancy Category B.)

Nursing Mothers

Although it is not known whether glyburide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue Glucovance, taking into account the importance of the drug to the mother. If Glucovance is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

The safety and efficacy of Glucovance were evaluated in an active-controlled, double-blind, 26-week randomized trial involving a total of 167 pediatric patients (ranging from 9 to 16 years of age) with type 2 diabetes. Glucovance was not shown statistically to be superior to either metformin or glyburide with respect to reducing HbA1c from baseline (see Table 5). No unexpected safety findings were associated with Glucovance in this trial.

Table 5: HbA1c (Percent) Change From Baseline at 26 Weeks: Pediatric Study

Geriatric Use

Of the 642 patients who received Glucovance in double-blind clinical studies, 23.8% were 65 and older while 2.8% were 75 and older. Of the 1302 patients who received Glucovance in open-label clinical studies, 20.7% were 65 and older while 2.5% were 75 and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Metformin hydrochloride 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, Glucovance should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Pharmacokinetics). Because aging is associated with reduced renal function, Glucovance 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 Glucovance (see also WARNINGS and DOSAGE AND ADMINISTRATION).

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Adverse Reactions

Glucovance

In double-blind clinical trials involving Glucovance as initial therapy or as second-line therapy, a total of 642 patients received Glucovance, 312 received metformin therapy, 324 received glyburide therapy, and 161 received placebo. The percent of patients reporting events and types of adverse events reported in clinical trials of Glucovance (all strengths) as initial therapy and second-line therapy are listed in Table 6.

Table 6: Most Common Clinical Adverse Events (>5%) in Double-Blind Clinical Studies of Glucovance Used as Initial or Second-Line Therapy

In a controlled clinical trial of rosiglitazone versus placebo in patients treated with Glucovance (n=365), 181 patients received Glucovance with rosiglitazone and 184 received Glucovance with placebo.

Edema was reported in 7.7% (14/181) of patients treated with rosiglitazone compared to 2.2% (4/184) of patients treated with placebo. A mean weight gain of 3 kg was observed in rosiglitazone-treated patients.

Disulfiram-like reactions have very rarely been reported in patients treated with glyburide tablets.

Hypoglycemia

In controlled clinical trials of Glucovance there were no hypoglycemic episodes requiring medical intervention and/or pharmacologic therapy; all events were managed by the patients. The incidence of reported symptoms of hypoglycemia (such as dizziness, shakiness, sweating, and hunger), in the initial therapy trial of Glucovance are summarized in Table 7. The frequency of hypoglycemic symptoms in patients treated with Glucovance 1.25 mg/250 mg was highest in patients with a baseline HbA1c 8%. For patients with a baseline HbA1c between 8% and 11% treated with Glucovance 2.5 mg/500 mg as initial therapy, the frequency of hypoglycemic symptoms was 30% to 35%. As second-line therapy in patients inadequately controlled on sulfonylurea alone, approximately 6.8% of all patients treated with Glucovance experienced hypoglycemic symptoms. When rosiglitazone was added to Glucovance therapy, 22% of patients reported 1 or more fingerstick glucose measurements ≤50 mg/dL compared to 3.3% of placebo-treated patients. All hypoglycemic events were managed by the patients and only 1 patient discontinued for hypoglycemia. (See PRECAUTIONS: General: Addition of Thiazolidinediones to Glucovance Therapy.)

Gastrointestinal Reactions

The incidence of GI side effects (diarrhea, nausea/vomiting, and abdominal pain) in the initial therapy trial are summarized in Table 7. Across all Glucovance trials, GI symptoms were the most common adverse events with Glucovance and were more frequent at higher dose levels. In controlled trials, <2% of patients discontinued Glucovance therapy due to GI adverse events.

Table 7: Treatment Emergent Symptoms of Hypoglycemia or Gastrointestinal Adverse Events in a Placebo- and Active-Controlled Trial of Glucovance as Initial Therapy

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Overdosage

Glyburide

Overdosage of sulfonylureas, including glyburide tablets, can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery.

Metformin Hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS). 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.

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Dosage and Administration

General Considerations

Dosage of Glucovance must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 20 mg glyburide/2000 mg metformin. Glucovance should be given with meals and should be initiated at a low dose, with gradual dose escalation as described below, in order to avoid hypoglycemia (largely due to glyburide), to reduce GI side effects (largely due to metformin), and to permit determination of the minimum effective dose for adequate control of blood glucose for the individual patient.

With initial treatment and during dose titration, appropriate blood glucose monitoring should be used to determine the therapeutic response to Glucovance and to identify the minimum effective dose for the patient. Thereafter, HbA1c should be measured at intervals of approximately 3 months to assess the effectiveness of therapy. The therapeutic goal in all patients with type 2 diabetes is to decrease FPG, PPG, and HbA1c to normal or as near normal as possible. Ideally, the response to therapy should be evaluated using HbA1c (glycosylated hemoglobin), which is a better indicator of long-term glycemic control than FPG alone.

No studies have been performed specifically examining the safety and efficacy of switching to Glucovance therapy in patients taking concomitant glyburide (or other sulfonylurea) plus metformin. Changes in glycemic control may occur in such patients, with either hyperglycemia or hypoglycemia possible. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring.

Glucovance in Patients with Inadequate Glycemic Control on Diet and Exercise

Recommended starting dose: 1.25 mg/250 mg once or twice daily with meals.

For patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone, the recommended starting dose of Glucovance is 1.25 mg/250 mg once a day with a meal. As initial therapy in patients with baseline HbA1c >9% or an FPG >200 mg/dL, a starting dose of Glucovance 1.25 mg/250 mg twice daily with the morning and evening meals may be used. Dosage increases should be made in increments of 1.25 mg/250 mg per day every 2 weeks up to the minimum effective dose necessary to achieve adequate control of blood glucose. In clinical trials of Glucovance as initial therapy, there was no experience with total daily doses greater than 10 mg/2000 mg per day. Glucovance 5 mg/500 mg should not be used as initial therapy due to an increased risk of hypoglycemia.

Glucovance Use in Patients with Inadequate Glycemic Control on a Sulfonylurea and/or Metformin

Recommended starting dose: 2.5 mg/500 mg or 5 mg/500 mg twice daily with meals.

For patients not adequately controlled on either glyburide (or another sulfonylurea) or metformin alone, the recommended starting dose of Glucovance is 2.5 mg/500 mg or 5 mg/500 mg twice daily with the morning and evening meals. In order to avoid hypoglycemia, the starting dose of Glucovance should not exceed the daily doses of glyburide or metformin already being taken. The daily dose should be titrated in increments of no more than 5 mg/500 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 20 mg/2000 mg per day.

For patients previously treated with combination therapy of glyburide (or another sulfonylurea) plus metformin, if switched to Glucovance, the starting dose should not exceed the daily dose of glyburide (or equivalent dose of another sulfonylurea) and metformin already being taken. Patients should be monitored closely for signs and symptoms of hypoglycemia following such a switch and the dose of Glucovance should be titrated as described above to achieve adequate control of blood glucose.

Addition of Thiazolidinediones to Glucovance Therapy

For patients not adequately controlled on Glucovance, a thiazolidinedione can be added to Glucovance therapy. When a thiazolidinedione is added to Glucovance therapy, the current dose of Glucovance can be continued and the thiazolidinedione initiated at its recommended starting dose. For patients needing additional glycemic control, the dose of the thiazolidinedione can be increased based on its recommended titration schedule. The increased glycemic control attainable with Glucovance plus a thiazolidinedione may increase the potential for hypoglycemia at any time of day. In patients who develop hypoglycemia when receiving Glucovance and a thiazolidinedione, consideration should be given to reducing the dose of the glyburide component of Glucovance. As clinically warranted, adjustment of the dosages of the other components of the antidiabetic regimen should also be considered.

Specific Patient Populations

Glucovance is not recommended for use during pregnancy. The initial and maintenance dosing of Glucovance should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment requires a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of Glucovance to avoid the risk of hypoglycemia. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly. (See WARNINGS.)

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How Supplied

Glucovance® (Glyburide and Metformin HCl) Tablets

Glucovance 1.25 mg/250 mg tablet is a pale yellow, capsule-shaped, bevel-edged, biconvex, film-coated tablet with "BMS" debossed on one side and "6072" debossed on the opposite side.

Glucovance 2.5 mg/500 mg tablet is a pale orange, capsule-shaped, bevel-edged, biconvex, film-coated tablet with "BMS" debossed on one side and "6073" debossed on the opposite side.

Glucovance 5 mg/500 mg tablet is a yellow, capsule-shaped, bevel-edged, biconvex, film-coated tablet with "BMS" debossed on one side and "6074" debossed on the opposite side.

STORAGE

Store at temperatures up to 25°C (77°F). [See USP Controlled Room Temperature.]

Dispense in light-resistant containers.

Glucovance® is a registered trademark of Merck Santé S.A.S., an associate of Merck KGaA of Darmstadt, Germany. Licensed to Bristol-Myers Squibb Company.

GLUCOPHAGE® is a registered trademark of Merck Santé S.A.S., an associate of Merck KGaA of Darmstadt, Germany. Licensed to Bristol-Myers Squibb Company.

Micronase® is a registered trademark of Pharmacia & Upjohn Company.

Distributed by:

Bristol-Myers Squibb Company
Princeton, NJ 08543 USA

last updated 02/2009

Glucovance patient information (in plain English)

Detailed Info on Signs, Symptoms, Causes, Treatments of Diabetes

The information in this monograph is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects. This information is generalized and is not intended as specific medical advice. If you have questions about the medicines you are taking or would like more information, check with your doctor, pharmacist, or nurse.

back to: Browse all Medications for Diabetes

Today me and Chris got in a big fight. I didn't go to work. He held my on the couch so I couldn't move and hurt my wrist really bad. And when I tried to get him off he made a fist and said what you gonna do now. Christofer and Johnathen were right there crying and screaming. I did hit him back when I finally got up and it got pretty bad cause he wouldn't let me leave the house or call anyone and wouldn't let christofer go leave to get help. Eventually I think he realized he was in the wrong and he left. And he won't let me call the police but says if I call them he wouldn't go to jail cause he didn't do anything. I think he has absolutely lost it. I want out of this relationship so bad and he just won't leave. I'm running out of options and don't know what to do. Everytime there's a fight it just keeps getting worse. :*(

So this is day one of my blog. I wish I would have found this site earlier so I would have been able to remember dates and everything for when I need them. But I guess this is a better time to start then never.

HealthyPlace.com, the largest consumer mental health site, re-launches with important new features for the more than 30 million people who suffer from anxiety, depression and bipolar disorder

February 23, 2009, San Antonio, Texas—HealthyPlace.com, which provides the most extensive depression and anxiety information on the internet, unveils several important new features for those who suffer from mood disorder-related illnesses.

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With breaking headlines on new mental health research studies, information on the side effects of today's major prescription medications, and discussions on a wide variety of topics ranging from ADHD children, stress and pregnancy, links between alcoholism and depression and much more, HealthyPlace.com knows that as with any health issue, information is power. It is their mission to inform anyone with concerns or who may already be suffering from mental health issues, that they are not alone, and that information and support is available. With an active support network, online psychological tests that are instantly scored, mental health books and videos, the site offers a full support system for those with mental health concerns, as well as support for friends and family members.

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