Kontroger

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Kontroger uses


INDICATIONS AND USAGE

Kontroger (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.

CONTRAINDICATIONS

Kontroger is contraindicated in patients with:

1.Severe renal impairment (eGFR below 30 mL/min/1.73m2).

2.Known hypersensitivity to metformin hydrochloride or Kontroger.

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.

WARNINGS

Metformin Hydrochloride

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 Kontroger and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see PRECAUTIONS ).

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to 1 of 4 treatment groups (Diabetes 19 (Suppl. 2):747-830, 1970).

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 g per day) had a rate of cardiovascular mortality approximately 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 Kontroger 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

Kontroger

Lactic Acidosis

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 Kontroger. In Kontroger 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 Kontroger 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 Kontroger, 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 Kontroger 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 Kontroger. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

- In patients taking Kontroger whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.


Hypoglycemia

Kontroger 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 Kontroger 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.

Kontroger

Hemolytic anemia

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

Metformin Hydrochloride

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.

Macrovascular Outcomes

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

Addition of Thiazolidinediones to Kontroger Therapy

Hypoglycemia

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

Weight gain

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

Hepatic effects

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

Information for Patients

Kontroger

Patients should be informed of the potential risks and benefits of Kontroger 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 Kontroger 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 Kontroger, 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 Kontroger.

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 Kontroger prior to any surgical or radiological procedure, as temporary discontinuation of Kontroger may be required until renal function has been confirmed to be normal.

Drug Interactions

Kontroger

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 Kontroger, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Kontroger, 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.

Kontroger

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 Kontroger, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving Kontroger, the patient should be observed closely for loss of blood glucose control.

An increased risk of liver enzyme elevations was observed in patients receiving Kontroger concomitantly with bosentan. Therefore concomitant administration of Kontroger and bosentan is contraindicated.

A possible interaction between Kontroger and ciprofloxacin, a fluoroquinolone antibiotic, has been reported, resulting in a potentiation of the hypoglycemic action of Kontroger. 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 Kontroger resulted in reductions in Kontroger AUC and Cmax of 32% and 47%, respectively. The reductions in Kontroger AUC and Cmax were 20% and 15%, respectively, when administered 1 hour before, and not significantly changed when administered 4 hours before colesevelam.

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 (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 Kontroger may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

Alcohol

Alcohol is known to potentiate the effects of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving Kontroger.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Kontroger

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

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

Metformin Hydrochloride

Long-term carcinogenicity studies were performed with metformin alone in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 4 times the MRHD dose of 2000 mg of the metformin component of Kontroger 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 Kontroger based on body surface area comparisons.

Pregnancy

Teratogenic Effects: Pregnancy Category B

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

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

Kontroger

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

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 Kontroger 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 (4-10 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 Kontroger be used during pregnancy. However, if it is used, Kontroger should be discontinued at least 2 weeks before the expected delivery date.

Nursing Mothers

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

Pediatric Use

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

Kontroger

2.5 mg

tablets

Metformin

500 mg

tablets

Kontroger

1.25 mg/250 mg

tablets


Mean Final Dose


6.5 mg


1500 mg


3.1 mg/623 mg


Hemoglobin A1c


N=49


N=54


N=57


Baseline Mean (%)


7.70


7.99


7.85


Mean Change from Baseline


−0.96


−0.48


−0.80


Difference from Metformin


−0.32


Difference from Kontroger


+0.16

Geriatric Use

Of the 642 patients who received Kontroger in double-blind clinical studies, 23.8% were 65 and older while 2.8% were 75 and older. Of the 1302 patients who received Kontroger 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.

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ADVERSE REACTIONS

Kontroger

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


Adverse Event

Number (%) of Patients
Placebo

N=161

Kontroger

N=324

Metformin

N=312

Kontroger

N=642


Upper respiratory infection


22 (13.7)


57 (17.6)


51 (16.3)


111 (17.3)


Diarrhea


9 (5.6)


20 (6.2)


64 (20.5)


109 (17.0)


Headache


17 (10.6)


37 (11.4)


29 (9.3)


57 (8.9)


Nausea/vomiting


10 (6.2)


17 (5.2)


38 (12.2)


49 (7.6)


Abdominal pain


6 (3.7)


10 (3.1)


25 (8.0)


44 (6.9)


Dizziness


7 (4.3)


18 (5.6)


12 (3.8)


35 (5.5)


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

Hypoglycemia

In controlled clinical trials of Kontroger 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 Kontroger are summarized in Table 7. The frequency of hypoglycemic symptoms in patients treated with Kontroger 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 Kontroger 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 Kontroger experienced hypoglycemic symptoms. When rosiglitazone was added to Kontroger 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.

Gastrointestinal Reactions

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 Kontroger trials, GI symptoms were the most common adverse events with Kontroger and were more frequent at higher dose levels. In controlled trials, <2% of patients discontinued Kontroger therapy due to GI adverse events.

Variable Placebo

N=161

Kontroger

Tablets

N=160

Metformin

Tablets

N=159

Kontroger

1.25 mg/250 mg

Tablets

N=158

Kontroger

2.5 mg/500 mg

Tablets

N=162


Mean Final Dose


0 mg


5.3 mg


1317 mg


2.78 mg/557 mg


4.1 mg/824 mg


Number (%) of patients

with symptoms of

hypoglycemia


5 (3.1)


34 (21.3)


5 (3.1)


18 (11.4)


61 (37.7)


Number (%) of patients

with gastrointestinal

adverse events


39 (24.2)


38 (23.8)


69 (43.3)


50 (31.6)


62 (38.3)


Metformin Hydrochloride

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

Kontroger

Gastrointestinal Reactions

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.

Dermatologic Reactions

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 Kontroger. Disulfiram-like reactions have been reported very rarely with Kontroger. Cases of hyponatremia have been reported with Kontroger 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 Kontroger and other sulfonylureas. These are thought to be related to fluctuation in glucose levels.

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OVERDOSAGE

Kontroger

Overdosage of sulfonylureas, including Kontroger 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.

Metformin Hydrochloride

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 AND ADMINISTRATION

General Considerations

Dosage of Kontroger 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. Kontroger 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 Kontroger 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 Kontroger therapy in patients taking concomitant Kontroger (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.

In Patients with Inadequate Glycemic Control on Diet and Exercise

Recommended starting dose: 1.25 mg Kontroger and 250 mg metformin hydrochloride once or twice daily with meals. Kontroger 1.25 mg/250 mg tablets are no longer available, however Kontroger 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 Kontroger 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 Kontroger 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 Kontroger as initial therapy, there was no experience with total daily doses >10 mg/2000 mg per day. Kontroger 5 mg/500 mg should not be used as initial therapy due to an increased risk of hypoglycemia.

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

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

For patients not adequately controlled on either Kontroger or metformin alone, the recommended starting dose of Kontroger 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 Kontroger should not exceed the daily doses of Kontroger 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 Kontroger (or another sulfonylurea) plus metformin, if switched to Kontroger, the starting dose should not exceed the daily dose of Kontroger (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 Kontroger should be titrated as described above to achieve adequate control of blood glucose.

Addition of Thiazolidinediones to Kontroger Therapy

For patients not adequately controlled on Kontroger, a thiazolidinedione can be added to Kontroger therapy. When a thiazolidinedione is added to Kontroger therapy, the current dose of Kontroger 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 Kontroger plus a thiazolidinedione may increase the potential for hypoglycemia at any time of day. In patients who develop hypoglycemia when receiving Kontroger and a thiazolidinedione, consideration should be given to reducing the dose of the Kontroger component of Kontroger. As clinically warranted, adjustment of the dosages of the other components of the antidiabetic regimen should also be considered.

Patients Receiving Colesevelam

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

Recommendations for Use in Renal Impairment

Assess renal function prior to initiation of Kontroger and periodically thereafter.

Kontroger is contraindicated in patients with an estimated glomerular filtration rate below 30 mL/minute/1.73 m2.

Initiation of Kontroger in patients with an eGFR between 30 – 45 mL/minute/1.73 m2 is not recommended.

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

Discontinue Kontroger if the patient’s eGFR later falls below 30 mL/minute/1.73 m2

.

Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue Kontroger 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 Kontroger if renal function is stable.

Specific Patient Populations

Kontroger is not recommended for use during pregnancy. The initial and maintenance dosing of Kontroger 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.

HOW SUPPLIED

Kontroger® Tablets

Kontroger 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.

Kontroger 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.

Kontroger NDC 0087-xxxx-xx for unit of use

Kontroger (mg)


Metformin hydrochloride (mg)


Bottle of 100


2.5


500


6073-11


5


500


6074-11

STORAGE

Store at temperatures up to 25°C (77°F).

Dispense in light-resistant containers.

Kontroger® 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.

Distributed by:

Bristol-Myers Squibb Company

Princeton, NJ 08543 USA

[print code]

Rev April 2017

PATIENT INFORMATION ABOUT

Kontroger® (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 Kontroger.

Q1. Why do I need to take Kontroger?

Your doctor has prescribed Kontroger 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 Kontroger you should first try to control your diabetes by exercise and weight loss. Even if you are taking Kontroger, you should still exercise and follow the diet recommended for your diabetes.

Q5. Does Kontroger work differently from other glucose-control medications?

Yes, it does. Kontroger combines 2 glucose-lowering drugs, Kontroger and metformin. These 2 drugs work together to improve the different metabolic defects found in type 2 diabetes. Kontroger 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 Kontroger your doctor may prescribe injectable insulin or take other measures to control your diabetes.

Q7. Can Kontroger cause side effects?

Kontroger, 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 Kontroger (see Q9-Q13).

Q8. What are the most common side effects of Kontroger?

The most common side effects of Kontroger 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 Kontroger 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 Kontroger can cause?

People who have a condition known as glucose-6-phosphate dehydrogenase (G6PD) deficiency and who take Kontroger 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 Kontroger.

Kontroger rarely causes serious side effects. The most serious side effect that Kontroger can cause is called lactic acidosis.

Q10. What is lactic acidosis and can it happen to me?

Metformin, one of the medicines in Kontroger 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 Kontroger 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 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 Kontroger 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 Kontroger, tell your doctor if you:


Q14. Can I take Kontroger with other medications?

Remind your doctor that you are taking Kontroger when any new drug is prescribed or a change is made in how you take a drug already prescribed. Kontroger may interfere with the way some drugs work and some drugs may interfere with the action of Kontroger.

Do not take Kontroger 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 Kontroger?

Tell your doctor if you plan to become pregnant or have become pregnant. As with other oral glucose-control medications, you should not take Kontroger 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 Kontroger if you are nursing a child.

Q16. How do I take Kontroger?

Your doctor will tell you how many Kontroger 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 Kontroger and your dosage will be increased gradually until your blood sugar is controlled.

Q17. Where can I get more information about Kontroger?

This leaflet is a summary of the most important information about Kontroger. If you have any questions or problems, you should talk to your doctor or other healthcare provider about type 2 diabetes as well as Kontroger and its side effects. There is also a leaflet (package insert) written for health professionals that your pharmacist can let you read.

Kontroger® 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.

Distributed by:

Bristol-Myers Squibb Company

Princeton, NJ 08543 USA

[print code]

Rev April 2017

100 Tablets

NDC 0087-6073-11

Kontroger®

(Glyburide and Metformin HCl) Tablets

2.5 mg/500 mg

Rx only

Bristol-Myers Squibb

Image Kontroger 2.5 mg-lbl

100 Tablets

NDC 0087-6074-11

Kontroger®

(Glyburide and Metformin HCl) Tablets

5 mg/500 mg

Rx only

Bristol-Myers Squibb

Image Kontroger 5- 500mg-lbl

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Kontroger pharmaceutical active ingredients containing related brand and generic drugs:

Active 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.


Kontroger available forms, composition, doses:

Form 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.


Kontroger destination | category:

Destination 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.


Kontroger Anatomical Therapeutic Chemical codes:

A 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.


Kontroger pharmaceutical companies:

Pharmaceutical 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."GLYBURIDE TABLET [LAKE ERIE MEDICAL DBA QUALITY CARE PRODUCTS LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."METFORMIN HYDROCHLORIDE (METFORMIN HYDROCHLORIDE ) TABLET, FILM COATED [BRYANT RANCH PREPACK]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "metformin". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Kontroger?

Depending on the reaction of the Kontroger after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Kontroger 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 Kontroger 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 Kontroger, 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 Kontroger 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. Rachana Salvi, MD Pharmacology

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