DRUGS & SUPPLEMENTS
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Gluforz (Glyburide and Metformin HCl) Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Gluforz is contraindicated in patients with:
1.Severe renal impairment (eGFR below 30 mL/min/1.73m2).
2.Known hypersensitivity to metformin hydrochloride or Gluforz.
3.Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
4.Concomitant administration of bosentan.
WARNING: LACTIC ACIDOSIS
Post-marketing 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 (see PRECAUTIONS ).
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 (see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and PRECAUTIONS).
If metformin-associated lactic acidosis is suspected, immediately discontinue Gluforz and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see PRECAUTIONS ).
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 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 Gluforz 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.
There have been post-marketing 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 Gluforz. In Gluforz 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 Gluforz 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 patient’s renal function include
(see DOSAGE AND ADMINISTRATION , CLINICAL PHARMACOLOGY).
- Before initiating Gluforz, obtain an estimated glomerular filtration rate (eGFR).
- GLUCOVANCE is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2.
- Initiation of Gluforz is not recommended in patients with eGFR between 30-45 mL/min/1.73 m2.
- Obtain an eGFR at least annually in all patient taking Gluforz. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
- In patients taking Gluforz whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.
Gluforz 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 Gluforz 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 people who are taking beta-adrenergic blocking drugs.
Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because Gluforz 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.
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.
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.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Gluforz or any other antidiabetic drug.
Patients receiving Gluforz in combination with a thiazolidinedione may be at risk for hypoglycemia.
Weight gain was seen with the addition of rosiglitazone to Gluforz, similar to that reported for thiazolidinedione therapy alone.
When a thiazolidinedione is used in combination with Gluforz, periodic monitoring of liver function tests should be performed in compliance with the labeled recommendations for the thiazolidinedione.
Patients should be informed of the potential risks and benefits of Gluforz 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 Gluforz 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 Gluforz, 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 Gluforz.
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 Gluforz prior to any surgical or radiological procedure, as temporary discontinuation of Gluforz may be required until renal function has been confirmed to be normal.
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 Gluforz, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Gluforz, 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.
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 Gluforz, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving Gluforz, the patient should be observed closely for loss of blood glucose control.
An increased risk of liver enzyme elevations was observed in patients receiving Gluforz concomitantly with bosentan. Therefore concomitant administration of Gluforz and bosentan is contraindicated.
A possible interaction between Gluforz and ciprofloxacin, a fluoroquinolone antibiotic, has been reported, resulting in a potentiation of the hypoglycemic action of Gluforz. 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.
Colesevelam: Concomitant administration of colesevelam and Gluforz resulted in reductions in Gluforz AUC and Cmax of 32% and 47%, respectively. The reductions in Gluforz AUC and Cmax were 20% and 15%, respectively, when administered 1 hour before, and not significantly changed when administered 4 hours before colesevelam.
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.
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 (e.g., organic cationic transport-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the accumulation of metformin and 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.
Carbonic Anhydrase Inhibitors
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with Gluforz may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.
Alcohol is known to potentiate the effects of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving Gluforz.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No animal studies have been conducted with the combined products in Gluforz. The following data are based on findings in studies performed with the individual products.
Studies in rats with Gluforz alone at doses up to 300 mg/kg/day (approximately 145 times the maximum recommended human daily [MRHD] dose of 20 mg for the Gluforz component of Gluforz based on body surface area comparisons) for 18 months revealed no carcinogenic effects. In a 2-year oncogenicity study of Gluforz in mice, there was no evidence of treatment-related tumors.
There was no evidence of mutagenic potential of Gluforz alone in the following in vitro tests: Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay.
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 MRHD dose of 2000 mg of the metformin component of Gluforz 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 Gluforz based on body surface area comparisons.
There are no adequate and well-controlled studies in pregnant women with Gluforz or its individual components. No animal studies have been conducted with the combined products in Gluforz. The following data are based on findings in studies performed with the individual products.
Reproduction studies were performed in rats and rabbits at doses up to 500 times the MRHD dose of 20 mg of the Gluforz component of Gluforz based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to Gluforz.
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 Gluforz based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Prolonged severe hypoglycemia (4-10 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 Gluforz be used during pregnancy. However, if it is used, Gluforz should be discontinued at least 2 weeks before the expected delivery date.
Although it is not known whether Gluforz 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 Gluforz, taking into account the importance of the drug to the mother. If Gluforz is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
The safety and efficacy of Gluforz were evaluated in an active-controlled, double-blind, 26-week randomized trial involving a total of 167 pediatric patients with type 2 diabetes. Gluforz was not shown statistically to be superior to either metformin or Gluforz with respect to reducing HbA1c from baseline (see Table 5). No unexpected safety findings were associated with Gluforz in this trial.
| Gluforz |
| Metformin |
| Gluforz |
1.25 mg/250 mg
Mean Final Dose
3.1 mg/623 mg
Baseline Mean (%)
Mean Change from Baseline
Difference from Metformin
Difference from Gluforz
Of the 642 patients who received Gluforz in double-blind clinical studies, 23.8% were 65 and older while 2.8% were 75 and older. Of the 1302 patients who received Gluforz 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.
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.
In double-blind clinical trials involving Gluforz as initial therapy or as second-line therapy, a total of 642 patients received Gluforz, 312 received metformin therapy, 324 received Gluforz therapy, and 161 received placebo. The percent of patients reporting events and types of adverse events reported in clinical trials of Gluforz as initial therapy and second-line therapy are listed in Table 6.
|Number (%) of Patients|
| Placebo |
| Gluforz |
| Metformin |
| Gluforz |
Upper respiratory infection
In a controlled clinical trial of rosiglitazone versus placebo in patients treated with Gluforz (n=365), 181 patients received Gluforz with rosiglitazone and 184 received Gluforz 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 Gluforz tablets.
In controlled clinical trials of Gluforz 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 Gluforz are summarized in Table 7. The frequency of hypoglycemic symptoms in patients treated with Gluforz 1.25 mg/250 mg was highest in patients with a baseline HbA1c <7%, lower in those with a baseline HbA1c of between 7% and 8%, and was comparable to placebo and metformin in those with a baseline HbA1c >8%. For patients with a baseline HbA1c between 8% and 11% treated with Gluforz 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 Gluforz experienced hypoglycemic symptoms. When rosiglitazone was added to Gluforz 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.
The incidence of gastrointestinal (GI) side effects (diarrhea, nausea/vomiting, and abdominal pain) in the initial therapy trial are summarized in Table 7. Across all Gluforz trials, GI symptoms were the most common adverse events with Gluforz and were more frequent at higher dose levels. In controlled trials, <2% of patients discontinued Gluforz therapy due to GI adverse events.
|Variable|| Placebo |
| Gluforz |
| Metformin |
| Gluforz |
1.25 mg/250 mg
| Gluforz |
2.5 mg/500 mg
Mean Final Dose
2.78 mg/557 mg
4.1 mg/824 mg
Number (%) of patients
with symptoms of
Number (%) of patients
Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.
Cholestatic jaundice and hepatitis may occur rarely which may progress to liver failure; the drug should be discontinued if this occurs. Liver function abnormalities, including isolated transaminase elevations, have been reported.
Allergic skin reactions, eg, pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.5% of glyburide-treated patients. These may be transient and may disappear despite continued use; if skin reactions persist, the drug should be discontinued.
Postmarketing Adverse Reactions
The following adverse reactions have been identified during post-approval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Allergic: Angioedema, arthralgia, myalgia, and vasculitis have been reported.
Dermatologic: Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.
Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, which occasionally may present as purpura, hemolytic anemia, aplastic anemia, and pancytopenia, have been reported with sulfonylureas.
Metabolic: Hepatic porphyria reactions have been reported with sulfonylureas; however, these have not been reported with Gluforz. Disulfiram-like reactions have been reported very rarely with Gluforz. Cases of hyponatremia have been reported with Gluforz 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.
Other Reactions: Changes in accommodation and/or blurred vision have been reported with Gluforz and other sulfonylureas. These are thought to be related to fluctuation in glucose levels.
Overdosage of sulfonylureas, including Gluforz 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 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.
Overdose of metformin hydrochloride has occurred, including ingestion of amounts >50 g. 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. 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 of Gluforz 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. Gluforz 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 Gluforz 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 Gluforz therapy in patients taking concomitant Gluforz (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.
Recommended starting dose: 1.25 mg Gluforz and 250 mg metformin hydrochloride once or twice daily with meals. Gluforz 1.25 mg/250 mg tablets are no longer available, however Gluforz 1.25 mg and metformin hydrochloride 250mg tablets are available as individual components or a combination tablet.
For patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone, the recommended starting dose is 1.25 mg Gluforz and 250 mg metformin hydrochloride 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 1.25 mg Gluforz and 250 mg metformin hydrochloride twice daily with the morning and evening meals may be used. Dosage increases should be made in increments of 1.25 mg glyburide and 250 mg metformin hydrochloride per day every 2 weeks up to the minimum effective dose necessary to achieve adequate control of blood glucose. In clinical trials of Gluforz as initial therapy, there was no experience with total daily doses >10 mg/2000 mg per day. Gluforz 5 mg/500 mg should not be used as initial therapy due to an increased risk of hypoglycemia.
Recommended starting dose: 2.5 mg/500 mg or 5 mg/500 mg twice daily with meals.
For patients not adequately controlled on either Gluforz or metformin alone, the recommended starting dose of Gluforz 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 Gluforz should not exceed the daily doses of Gluforz 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 Gluforz (or another sulfonylurea) plus metformin, if switched to Gluforz, the starting dose should not exceed the daily dose of Gluforz (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 Gluforz should be titrated as described above to achieve adequate control of blood glucose.
For patients not adequately controlled on Gluforz, a thiazolidinedione can be added to Gluforz therapy. When a thiazolidinedione is added to Gluforz therapy, the current dose of Gluforz 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 Gluforz plus a thiazolidinedione may increase the potential for hypoglycemia at any time of day. In patients who develop hypoglycemia when receiving Gluforz and a thiazolidinedione, consideration should be given to reducing the dose of the Gluforz component of Gluforz. As clinically warranted, adjustment of the dosages of the other components of the antidiabetic regimen should also be considered.
When colesevelam is coadministered with Gluforz, maximum plasma concentration and total exposure to Gluforz is reduced. Therefore, Gluforz should be administered at least 4 hours prior to colesevelam.
Assess renal function prior to initiation of Gluforz and periodically thereafter.
Gluforz is contraindicated in patients with an estimated glomerular filtration rate below 30 mL/minute/1.73 m2.
Initiation of Gluforz in patients with an eGFR between 30 – 45 mL/minute/1.73 m2 is not recommended.
In patients taking Gluforz whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy.
Discontinue Gluforz if the patient’s eGFR later falls below 30 mL/minute/1.73 m2
Discontinue Gluforz 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 Gluforz if renal function is stable.
Gluforz is not recommended for use during pregnancy. The initial and maintenance dosing of Gluforz 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.
Gluforz 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.
Gluforz 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.
|Gluforz||NDC 0087-xxxx-xx for unit of use|
Metformin hydrochloride (mg)
Bottle of 100
Store at temperatures up to 25°C (77°F).
Dispense in light-resistant containers.
Gluforz® 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 LLC.
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
Rev April 2017
PATIENT INFORMATION ABOUT
Gluforz® (Glyburide and Metformin HCl) Tablets
WARNING: A small number of people who have taken metformin hydrochloride have developed a serious condition called lactic acidosis. Properly functioning kidneys are needed to help prevent lactic acidosis. Most people with kidney problems should not take Gluforz.
Q1. Why do I need to take Gluforz?
Your doctor has prescribed Gluforz 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 Gluforz you should first try to control your diabetes by exercise and weight loss. Even if you are taking Gluforz, you should still exercise and follow the diet recommended for your diabetes.
Q5. Does Gluforz work differently from other glucose-control medications?
Yes, it does. Gluforz combines 2 glucose-lowering drugs, Gluforz and metformin. These 2 drugs work together to improve the different metabolic defects found in type 2 diabetes. Gluforz 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 Gluforz your doctor may prescribe injectable insulin or take other measures to control your diabetes.
Q7. Can Gluforz cause side effects?
Gluforz, 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 Gluforz (see Q9-Q13).
Q8. What are the most common side effects of Gluforz?
The most common side effects of Gluforz 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 Gluforz with meals can help reduce these side effects.
Less frequently, 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 Gluforz can cause?
People who have a condition known as glucose-6-phosphate dehydrogenase (G6PD) deficiency and who take Gluforz 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 Gluforz.
Gluforz rarely causes serious side effects. The most serious side effect that Gluforz can cause is called lactic acidosis.
Q10. What is lactic acidosis and can it happen to me?
Metformin, one of the medicines in Gluforz 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.
Q11. Are there other risk factors for lactic acidosis?
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 Gluforz if you.
|-have severe kidney problems, or your kidneys are affected by certain x-ray tests that use injectable dye|
|-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 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 Gluforz for a while if you have any of these things.
Q12. What are the symptoms of lactic acidosis?
Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis:
Q13. What does my doctor need to know to decrease my risk of lactic acidosis?
Before you take Gluforz, tell your doctor if you:
Q14. Can I take Gluforz with other medications?
Remind your doctor that you are taking Gluforz when any new drug is prescribed or a change is made in how you take a drug already prescribed. Gluforz may interfere with the way some drugs work and some drugs may interfere with the action of Gluforz.
Do not take Gluforz if you are taking bosentan used for pulmonary arterial hypertension (PAH), which is high blood pressure in the vessels of the lungs.
Q15. What if I become pregnant while taking Gluforz?
Tell your doctor if you plan to become pregnant or have become pregnant. As with other oral glucose-control medications, you should not take Gluforz 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 Gluforz if you are nursing a child.
Q16. How do I take Gluforz?
Your doctor will tell you how many Gluforz 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 Gluforz and your dosage will be increased gradually until your blood sugar is controlled.
Q17. Where can I get more information about Gluforz?
This leaflet is a summary of the most important information about Gluforz. If you have any questions or problems, you should talk to your doctor or other healthcare provider about type 2 diabetes as well as Gluforz and its side effects. There is also a leaflet (package insert) written for health professionals that your pharmacist can let you read.
Gluforz® is a registered trademark of Merck Santé S.A.S., an associate of Merck KGaA of Darmstadt, Germany. Licensed to Bristol-Myers Squibb Company.
Other brands listed are the trademarks of their respective owners.
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
Rev April 2017
(Glyburide and Metformin HCl) Tablets
2.5 mg/500 mg
Image Gluforz 2.5 mg-lbl
(Glyburide and Metformin HCl) Tablets
5 mg/500 mg
Image Gluforz 5- 500mg-lbl
Depending on the reaction of the Gluforz after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Gluforz 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 Gluforz 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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The information was verified by Dr. Rachana Salvi, MD Pharmacology