DRUGS & SUPPLEMENTS

Dibizide-M

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Dibizide-M uses


INDICATIONS AND USAGE

Dibizide-M tablets USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

CONTRAINDICATIONS

Dibizide-M tablets are contraindicated in patients with:

  • Severe renal impairment (eGFR below 30 mL/min/1.73 m2) (see WARNINGS and PRECAUTIONS).
  • Known hypersensitivity to Dibizide-M or metformin hydrochloride.
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

WARNINGS

WARNING: LACTIC ACIDOSIS

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels, anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally > 5 mcg/mL.

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

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided.

If metformin-associated lactic acidosis is suspected, immediately discontinue Dibizide-M tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

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 grams per day) had a rate of cardiovascular mortality approximately 2½ 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 Dibizide-M 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

Dibizide-M Tablets

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

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

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue Dibizide-M tablets and report these symptoms to their healthcare provider.

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

  • Renal Impairment-The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patients renal function include (see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY):
    • Before initiating Dibizide-M tablets, obtain an estimated glomerular filtration rate (eGFR)
    • Dibizide-M tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2. Initiation of Dibizide-M tablets is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2 (see CONTRAINDICATIONS).
    • Obtain an eGFR at least annually in all patients taking Dibizide-M and metfomin hydrochloride tablets. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
    • In patients taking Dibizide-M tablets whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.
  • Drug interactions-The concomitant use of Dibizide-M tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients.
  • Age 65 or Greater-The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
  • Radiologic studies with contrast-Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop Dibizide-M tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism or heart failure, or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imagining procedure, and restart Dibizide-M tablets if renal function is stable.
  • Surgery and other procedures-Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. Dibizide-M tablets should be temporarily discontinued while patients have restricted food and fluid intake.
  • Hypoxic states-Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue Dibizide-M tablets.
  • Excessive 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 Dibizide-M tablets.
  • Hepatic impairment-Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of Dibizide-M tablets in patients with clinical or laboratory evidence of hepatic disease.
Hypoglycemia

Dibizide-M tablets are capable of producing hypoglycemia; 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 insufficiency may cause elevated drug levels of both Dibizide-M. Hepatic insufficiency may increase drug levels of Dibizide-M and 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 people who are taking beta-adrenergic blocking drugs.

Dibizide-M

Renal and hepatic disease

The metabolism and excretion of Dibizide-M may be slowed in patients with impaired renal and/or hepatic function. If hypoglycemia should occur in such patients, it may be prolonged and appropriate management should be instituted.

Hemolytic anemia

Treatment of patients with glucose-6-phosphate dehydrogenase deficiency with sulfonylurea agents can lead to hemolytic anemia. Because Dibizide-M tablets belong 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.

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.

Macrovascular Outcomes

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

Information for Patients

Dibizide-M Tablets

Patients should be informed of the potential risks and benefits of Dibizide-M tablets and alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions; a regular exercise program; and 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 Dibizide-M tablets immediately and 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 Dibizide-M tablets, 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 Dibizide-M tablets.

Laboratory Tests

Periodic fasting blood glucose (FBG) and 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.

Instruct patients to inform their doctor that they are taking Dibizide-M tablets prior to any surgical or radiological procedure, as temporary discontinuation of Dibizide-M tablets may be required until renal function has been confirmed to be normal (see PRECAUTIONS).

Drug Interactions

Dibizide-M Tablets

Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control. These drugs include 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 Dibizide-M tablets, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Dibizide-M tablets, 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.

Dibizide-M

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including non-steroidal anti-inflammatory agents, some azoles, 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 Dibizide-M tablets, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving Dibizide-M tablets, the patient should be observed closely for loss of blood glucose control. In vitro binding studies with human serum proteins indicate that Dibizide-M binds differently than tolbutamide and does not interact with salicylate or dicumarol. However, caution must be exercised in extrapolating these findings to the clinical situation and in the use of Dibizide-M tablets with these drugs.

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. The effect of concomitant administration of fluconazole and Dibizide-M has been demonstrated in a placebo-controlled crossover study in normal volunteers. All subjects received Dibizide-M alone and following treatment with 100 mg of fluconazole as a single oral daily dose for 7 days, the mean percent increase in the Dibizide-M AUC after fluconazole administration was 56.9%.

In studies assessing the effect of colesevelam on the pharmacokinetics of Dibizide-M ER in healthy volunteers, reductions in Dibizide-M AUC0-∞ and Cmax of 12% and 13%, respectively, were observed when colesevelam was coadministered with Dibizide-M ER. When Dibizide-M ER was administered 4 hours prior to colesevelam, there was no significant change in Dibizide-M AUC0-∞ or Cmax, –4% and 0%, respectively. Therefore, Dibizide-M tablets should be administered at least 4 hours prior to colesevelam to ensure that colesevelam does not reduce the absorption of Dibizide-M.

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.

Drugs that reduce metformin clearance

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use. 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.

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

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 the sulfonylureas, which are extensively bound to serum proteins.

Other
Carbonic Anhydrase Inhibitors

Topiramate or other carbonic anhydrase inhibitors frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with Dibizide-M tablets may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

Alcohol

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving Dibizide-M tablets.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Dibizide-M

A 20-month study in rats and an 18-month study in mice at doses up to 75 times the maximum human dose revealed no evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both sexes at doses up to 75 times the human dose showed no effects on fertility.

Metformin Hydrochloride

Long-term carcinogenicity studies were performed with metformin alone in rats 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 (MRHD) dose of 2000 mg of the metformin component of Dibizide-M tablets 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 MRHD dose of the metformin component of Dibizide-M tablets based on body surface area comparisons.

Pregnancy

Teratogenic Effects: Pregnancy Category C

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, Dibizide-M tablets should not be used during pregnancy unless clearly needed.

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

Dibizide-M

Dibizide-M was found to be mildly fetotoxic in rat reproductive studies at all dose levels (5 to 50 mg/kg). This fetotoxicity has been similarly noted with other sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal and believed to be directly related to the pharmacologic (hypoglycemic) action of Dibizide-M. In studies in rats and rabbits, no teratogenic effects were found.

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 MRHD dose of 2000 mg of the metformin component of Dibizide-M tablets 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 Dibizide-M tablets be used during pregnancy. However, if they are used, Dibizide-M tablets should be discontinued at least 1 month before the expected delivery date (see Pregnancy, Teratogenic Effects: Pregnancy Category C).

Nursing Mothers

Although it is not known whether Dibizide-M 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 Dibizide-M tablets, taking into account the importance of the drug to the mother. If Dibizide-M tablets are discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

Safety and effectiveness of Dibizide-M tablets in pediatric patients have not been established.

Geriatric Use

Of the 345 patients who received Dibizide-M tablets, 2.5 mg/250 mg and 2.5 mg/500 mg in the initial therapy trial, 67 (19.4%) were aged 65 and older while 5 (1.4%) were aged 75 and older. Of the 87 patients who received Dibizide-M tablets in the second-line therapy trial, 17 (19.5%) were aged 65 and older while 1 (1.1%) was at least aged 75. No overall differences in effectiveness or safety were observed between these patients and younger patients in either the initial therapy trial or the second-line therapy trial, 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.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients (see also WARNINGS, PRECAUTIONS and DOSAGE AND ADMINISTRATION).

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ADVERSE REACTIONS

Dibizide-M Tablets

In a double-blind 24-week clinical trial involving Dibizide-M tablets as initial therapy, a total of 172 patients received Dibizide-M tablets, 2.5 mg/250 mg, 173 received Dibizide-M tablets, 2.5 mg/500 mg, 170 received Dibizide-M, and 177 received metformin. The most common clinical adverse events in these treatment groups are listed in Table 4.


Adverse Event


Number of Patients


Dibizide-M

5 mg Tablets

N = 170


Metformin 500 mg Tablets

N = 177


Dibizide-M Tablets, 2.5 mg/250 mg

N = 172


Dibizide-M Tablets, 2.5 mg/500 mg

N = 173


Upper respiratory infection


12 (7.1)


15 (8.5)


17 (9.9)


14 (8.1)


Diarrhea


8 (4.7)


15 (8.5)


4 (2.3)


9 (5.2)


Dizziness


9 (5.3)


2 (1.1)


3 (1.7)


9 (5.2)


Hypertension


17 (10.0)


10 (5.6)


5 (2.9)


6 (3.5)


Nausea/vomiting


6 (3.5)


9 (5.1)


1 (0.6)


3 (1.7)


In a double-blind 18-week clinical trial involving Dibizide-M tablets as second-line therapy, a total of 87 patients received Dibizide-M tablets, 84 received Dibizide-M, and 75 received metformin. The most common clinical adverse events in this clinical trial are listed in Table 5.


Number (%) of Patients


Adverse Event


Dibizide-M

5 mg Tablets The dose of Dibizide-M was fixed at 30 mg daily; doses of metformin and Dibizide-M tablets were titrated.

N = 84


Metformin

500 mg Tablets

N = 75


Dibizide-M Tablets,

5 mg/500 mg

N = 87


Diarrhea


11 (13.1)


13 (17.3)


16 (18.4)


Headache


5 (6.0)


4 (5.3)


11 (12.6)


Upper respiratory infection


11 (13.1)


8 (10.7)


9 (10.3)


Musculoskeletal pain


6 (7.1)


5 (6.7)


7 (8.0)


Nausea/vomiting


5 (6.0)


6 (8.0)


7 (8.0)


Abdominal pain


7 (8.3)


5 (6.7)


5 (5.7)


UTI


4 (4.8)


6 (8.0)


1 (1.1)

Hypoglycemia

In a controlled initial therapy trial of Dibizide-M tablets, 2.5 mg/250 mg and 2.5 mg/500 mg the numbers of patients with hypoglycemia documented by symptoms (such as dizziness, shakiness, sweating, and hunger) and a fingerstick blood glucose measurement ≤ 50 mg/dL were 5 (2.9%) for Dibizide-M, 0 (0%) for metformin, 13 (7.6%) for Dibizide-M tablets, 2.5 mg/250 mg, and 16 (9.3%) for Dibizide-M tablets, 2.5 mg/500 mg. Among patients taking either Dibizide-M tablets, 2.5 mg/250 mg or Dibizide-M tablets, 2.5 mg/500 mg, 9 (2.6%) patients discontinued Dibizide-M tablets due to hypoglycemic symptoms and 1 required medical intervention due to hypoglycemia. In a controlled second-line therapy trial of Dibizide-M tablets, 5 mg/500 mg, the numbers of patients with hypoglycemia documented by symptoms and a fingerstick blood glucose measurement ≤ 50 mg/dL were 0 (0%) for Dibizide-M, 1 (1.3%) for metformin, and 11 (12.6%) for Dibizide-M tablets. One (1.1%) patient discontinued Dibizide-M tablet therapy due to hypoglycemic symptoms and none required medical intervention due to hypoglycemia (see PRECAUTIONS).

Gastrointestinal Reactions

Among the most common clinical adverse events in the initial therapy trial were diarrhea and nausea/vomiting; the incidences of these events were lower with both Dibizide-M tablets dosage strengths than with metformin therapy. There were 4 patients in the initial therapy trial who discontinued Dibizide-M tablet therapy due to gastrointestinal (GI) adverse events. Gastrointestinal symptoms of diarrhea, nausea/vomiting, and abdominal pain were comparable among Dibizide-M tablets, Dibizide-M and metformin in the second-line therapy trial. There were 4 (4.6%) patients in the second-line therapy trial who discontinued Dibizide-M tablet therapy due to GI adverse events.

Dibizide-M

Gastrointestinal Reactions

Cholestatic and hepatocellular forms of liver injury accompanied by jaundice have been reported rarely in association with Dibizide-M; Dibizide-M tablets should be discontinued if this occurs.

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OVERDOSAGE

Dibizide-M

Overdosage of sulfonylureas, including Dibizide-M, 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 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. Clearance of Dibizide-M from plasma would be prolonged in persons with liver disease. Because of the extensive protein binding of Dibizide-M, dialysis is unlikely to be of benefit.

Metformin Hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts > 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.

DOSAGE AND ADMINISTRATION

General Considerations

Dosage of Dibizide-M tablets must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 20 mg glipizide/2000 mg metformin. Dibizide-M tablets 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, reduce GI side effects (largely due to metformin), and 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 Dibizide-M tablets 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, 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 Dibizide-M tablet therapy in patients taking concomitant Dibizide-M (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.

When colesevelam is coadministered with Dibizide-M ER, maximum plasma concentration and total exposure to Dibizide-M is reduced. Therefore, Dibizide-M tablets should be administered at least 4 hours prior to colesevelam.

Dibizide-M Tablets in Patients with Inadequate Glycemic Control on Diet and Exercise Alone

For patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone, the recommended starting dose of Dibizide-M tablets is 2.5 mg/250 mg once a day with a meal. For patients whose FPG is 280 mg/dL to 320 mg/dL a starting dose of Dibizide-M tablets, 2.5 mg/500 mg twice daily should be considered. The efficacy of Dibizide-M tablets in patients whose FPG exceeds 320 mg/dL has not been established. Dosage increases to achieve adequate glycemic control should be made in increments of 1 tablet per day every 2 weeks up to maximum of 10 mg/1000 mg or 10 mg/2000 mg Dibizide-M tablets per day given in divided doses. In clinical trials of Dibizide-M tablets as initial therapy, there was no experience with total daily doses > 10 mg/2000 mg per day.

Dibizide-M Tablets in Patients with Inadequate Glycemic Control on a Sulfonylurea and/or Metformin

For patients not adequately controlled on either Dibizide-M or metformin alone, the recommended starting dose of Dibizide-M tablets 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 Dibizide-M tablets should not exceed the daily doses of Dibizide-M 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.

Patients previously treated with combination therapy of Dibizide-M (or another sulfonylurea) plus metformin may be switched to Dibizide-M tablets, 2.5 mg/500 mg or 5 mg/500 mg; the starting dose should not exceed the daily dose of Dibizide-M (or equivalent dose of another sulfonylurea) and metformin already being taken. The decision to switch to the nearest equivalent dose or to titrate should be based on clinical judgment. Patients should be monitored closely for signs and symptoms of hypoglycemia following such a switch and the dose of Dibizide-M tablets should be titrated as described above to achieve adequate control of blood glucose.

Recommendations for Use in Renal Impairment

Assess renal function prior to initiation of Dibizide-M tablets and periodically thereafter.

Dibizide-M tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2.

Initiation of Dibizide-M tablets in patients with an eGFR between 30 and 45 mL/minute/1.73 m2 is not recommended.

In patients taking Dibizide-M tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy.

Discontinue Dibizide-M tablets if the patient’s eGFR later falls below 30 mL/minute/1.73 m2. (See WARNINGS.)

Discontinuation for Iodinated Contrast Imaging Procedure

Discontinue Dibizide-M tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart Dibizide-M tablets if renal function is stable.

Specific Patient Populations

Dibizide-M tablets are not recommended for use during pregnancy or for use in pediatric patients. The initial and maintenance dosing of Dibizide-M tablets 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 Dibizide-M tablets 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 and PRECAUTIONS.)

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HOW SUPPLIED

Dibizide-M tablets USP are available as follows:

2.5 mg/250 mg are pink, film-coated, modified capsule-shaped tablets, debossed with “93” on one side and “7455” on the other in bottles of 100 (NDC 0093-7455-01).

2.5 mg/500 mg are white, film-coated, modified capsule-shaped tablets, debossed with “93” on one side and “7456” on the other in bottles of 100 (NDC 0093-7456-01).

5 mg/500 mg are pink, film-coated, modified capsule-shaped tablets, debossed with “93” on one side and “7457” on the other in bottles of 100 (NDC 0093-7457-01).

STORAGE

Store at 20° to 25°C (68° to 77°F).

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Manufactured In Israel By:

Teva Pharmaceutical Ind. Ltd.

Jerusalem, 9777402, Israel

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. L 1/2017

PATIENT INFORMATION ABOUT

Dibizide-M (GLIP-i-zide) and Metformin Hydrochloride (met-FOR-min hye-dro-KLOR-ide) Tablets USP

Rx only


WARNING: A small number of people who have taken metformin hydrochloride have developed a serious condition called lactic acidosis. Tell your doctor if you have severe kidney problems.


Q1. Why do I need to take Dibizide-M tablets?

Your doctor has prescribed Dibizide-M tablets to treat your type 2 diabetes. This is also known as non-insulin-dependent diabetes mellitus.

Q2. What is type 2 diabetes?

People with diabetes are not able to make enough insulin and/or respond normally to the insulin their body does make. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems, including kidney damage, amputations, and blindness. Diabetes is also closely linked to heart disease. The main goal of treating diabetes is to lower your blood sugar to a normal level.

Q3. Why is it important to control type 2 diabetes?

The main goal of treating diabetes is to lower your blood sugar to a normal level. Studies have shown that good control of blood sugar may prevent or delay complications, such as heart disease, kidney disease, or blindness.

Q4. How is type 2 diabetes usually controlled?

High blood sugar can be lowered by diet and exercise, a number of oral medications, and insulin injections. Before taking Dibizide-M tablets you should first try to control your diabetes by exercise and weight loss. Even if you are taking Dibizide-M tablets, you should still exercise and follow the diet recommended for your diabetes.

Q5. Does Dibizide-M tablets work differently from other glucose-control medications?

Yes, they do. Dibizide-M tablets combine 2 glucose-lowering drugs, Dibizide-M and metformin. These 2 drugs work together to improve the different metabolic defects found in type 2 diabetes. Dibizide-M lowers blood sugar primarily by causing more of the body’s own insulin to be released, and metformin lowers blood sugar, in part, by helping your body use your own insulin more effectively. Together, they are efficient in helping you to achieve better glucose control.

Q6. What happens if my blood sugar is still too high?

When blood sugar cannot be lowered enough by Dibizide-M tablets, your doctor may prescribe injectable insulin or take other measures to control your diabetes.

Q7. Can Dibizide-M tablets cause side effects?

Dibizide-M tablets, like all blood sugar-lowering medications, can cause side effects in some patients. Most of these side effects are minor. However, there are also serious, but rare, side effects related to Dibizide-M tablets (see Question Nos. 9 to 13).

Q8. What are the most common side effects of Dibizide-M tablets?

The most common side effects of Dibizide-M tablets are normally minor ones such as diarrhea, nausea, and upset stomach. If these side effects occur, they usually occur during the first few weeks of therapy. Taking your Dibizide-M tablets with meals can help reduce these side effects.

Symptoms of hypoglycemia (low blood sugar), such as lightheadedness, dizziness, shakiness, or hunger may occur. The risk of hypoglycemic symptoms increases when meals are skipped, too much alcohol is consumed, or heavy exercise occurs without enough food. Following the advice of your doctor can help you to avoid these symptoms.

Q9. Are there any serious side effects that Dibizide-M tablets can cause?

People who have a condition known as glucose-6-phosphate dehydrogenase (G6PD) deficiency and who take Dibizide-M tablets may develop hemolytic anemia (fast breakdown of red blood cells). G6PD deficiency usually runs in families. Tell your doctor if you or any members of your family have been diagnosed with G6PD deficiency before you start taking Dibizide-M tablets.

Dibizide-M tablets rarely cause serious side effects. Metformin, one of the medicines in Dibizide-M tablets, can cause a rare but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital.

Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis:

  • you feel cold in your hands or feet
  • you feel dizzy or lightheaded
  • you have a slow or irregular heartbeat
  • you feel very weak or tired
  • you have unusual (not normal) muscle pain
  • you have trouble breathing
  • you feel sleepy or drowsy
  • you have stomach pains, nausea or vomiting

Most people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with Dibizide-M and metformin tablets if you:

  • have severe kidney problems
  • your kidneys are affected by certain x-ray tests that use injectable dye. Tell your doctor if you are going to get an injection or dye or contrast agents for an x-ray procedure.
  • have liver problems
  • drink alcohol very often, or drink a lot of alcohol in short-term “binge” drinking
  • get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids
  • have surgery
  • have a heart attack, severe infection, or stroke

The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems in the list above. Your doctor may decide to stop your Dibizide-M tablets for a while if you have any of these things.

Dibizide-M tablets can have other serious side effects. See “What are the possible side effects of Dibizide-M tablets?

Q10. Can I take Dibizide-M tablets with other medications?

Remind your doctor that you are taking Dibizide-M tablets when any new drug is prescribed or a change is made in how you take a drug already prescribed.

Dibizide-M tablets may interfere with the way some drugs work and some drugs may interfere with the action of Dibizide-M tablets.

Q11. What if I become pregnant while taking Dibizide-M tablets?

Tell your doctor if you plan to become pregnant or have become pregnant. As with other oral glucose-control medications, you should not take Dibizide-M tablets during pregnancy.

Usually your doctor will prescribe insulin while you are pregnant. As with all medications, you and your doctor should discuss the use of Dibizide-M tablets if you are nursing a child.

Q12. How do I take Dibizide-M tablets?

Your doctor will tell you how many Dibizide-M tablets to take and how often.

This should also be printed on the label of your prescription. You will probably be started on a low dose of Dibizide-M tablets and your dosage will be increased gradually until your blood sugar is controlled.

Q13. Where can I get more information about Dibizide-M tablets?

This leaflet is a summary of the most important information about Dibizide-M tablets.

If you have any questions or problems, you should talk to your doctor or other healthcare provider about type 2 diabetes as well as Dibizide-M tablets and its side effects. There is also a leaflet (package insert) written for health professionals that your pharmacist can let you read.

All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA, Inc.

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 9777402, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. E 4/2016

NDC 0093-7455-01

Dibizide-M

and Metformin

Hydrochloride

Tablets USP

2.5 mg/250 mg

PHARMACIST: PLEASE DISPENSE WITH

ATTACHED PATIENT INFORMATION LEAFLET

Rx only

100 TABLETS

TEVA

NDC 0093-7456-01

Dibizide-M

and Metformin

Hydrochloride

Tablets USP

2.5 mg/500 mg

PHARMACIST: PLEASE DISPENSE WITH

ATTACHED PATIENT INFORMATION LEAFLET

Rx only

100 TABLETS

TEVA

NDC 0093-7457-01

Dibizide-M

and Metformin

Hydrochloride

Tablets USP

5 mg/500 mg

PHARMACIST: PLEASE DISPENSE WITH

ATTACHED PATIENT INFORMATION LEAFLET

Rx only

100 TABLETS

TEVA

Dibizide-M pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Dibizide-M available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Dibizide-M destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Dibizide-M Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Dibizide-M pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."METFORMIN HYDROCHLORIDE (METFORMIN HYDROCHLORIDE ) TABLET, FILM COATED [BRYANT RANCH PREPACK]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."GLUCOTROL (GLIPIZIDE) TABLET [ROERIG]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."GLIPIZIDE; METFORMIN HYDROCHLORIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Dibizide-M?

Depending on the reaction of the Dibizide-M after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Dibizide-M not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Dibizide-M addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sDrugs.com conducted a study on Dibizide-M, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Dibizide-M consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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